CDK inhibitors and their use as medicines

Abstract

The present disclosure is directed to compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I), and methods of use and preparation thereof. TIFF2023554643000243.tif35128

Description

[Technical Field]

[0001] The present disclosure is directed to CDK inhibitors and methods of use thereof. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are a family of conserved serine / threonine kinases that play important roles in cell cycle and gene transcription regulation (Malumbres 2014). Among the cell cycle CDK subfamily, CDK4 and CDK6 are master regulators that control cell entry from the first gap phase (G1) to the DNA synthesis phase (S). During this process, cyclin D protein levels increase, forming a complex with CDK4 / 6 and activating their kinase activity. The activated CDK4 / 6 complex phosphorylates retinoblastoma protein 1 (RB1) and other RB1-like proteins, reducing their binding affinity and releasing RB1-containing transcriptional repressor complexes from E2F transcription factors, leading to the activation of E2F-regulated cell cycle genes and cell cycle progression (Lapenna and Giordano 2009; Asghar, Witkiewicz et al. 2015).

[0003] Given that CDK4 / 6 plays a central role in cell cycle regulation and its dysfunction is a hallmark of cancer (Hanahan and Weinberg 2011), dysregulation of the CDK4 / 6 pathway, such as (epi)genetic inactivation of the endogenous CDK4 / 6 inhibitor p16INK4A and amplification / overexpression of CDK4 / 6 and cyclin D proteins, has been frequently observed in cancer (Lapenna and Giordano 2009; Malumbres and Barbacid 2009; Asghar, Witkiewicz et al. 2015; O'Leary, Finn et al. 2016). CDK4 / 6 have been intensively investigated as potential therapeutic targets for cancer treatment, and the recent approval of CDK4 / 6 selective inhibitors, namely palbociclib (US Food & Drug Administration, 2017), ribociclib (US Food & Drug Administration, 2017), and abemaciclib (US Food & Drug Administration, 2018), for the treatment of hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer in combination with endocrine therapy further validates this paper.

[0004] Central nervous system (CNS) diseases, such as glioblastoma (GBM) and brain metastases, are challenging malignancies with urgent unmet medical needs. GBM is the most common and aggressive primary brain tumor in adults, with an overall 5-year survival rate of less than 6% (Ostrom, Gittleman et al. 2016). Large-scale genomic studies have revealed that the cyclin D-CDK4 / 6-RB1 pathway alternates in the majority of gliomas and represents one of the most disrupted pathways (Cancer Genome Atlas Research 2008, Brennan, Verhaak et al. 2013), suggesting that CDK4 / 6 may be a good target for GBM. Meanwhile, brain metastases, which may arise from an estimated 20% of all cancer patients, still lack effective treatments (Achrol, Rennert et al. 2019). Interestingly, genomic studies have also identified the CDK pathway as one of the three most altered and actionable genetic changes in brain metastases (Brastianos, Carter et al. 2015; Valiente, Ahluwalia et al. 2018). However, despite positive preclinical data supporting targeting CDK4 / 6 to treat GBM (Yin, Li et al. 2018; Bronner, Merrick et al. 2019) and early signs of brain penetration of abemaciclib in patients (Patnaik, Rosen et al. 2016; Sahebjam, Rhun et al. 2016), clinical development of CDK4 / 6 inhibitors in the clinic for GBM or brain metastases is still in its infancy or has been unsuccessful (Anders, Rhun et al. 2019; Nguyen, Searle et al. 2019; Sahebjam, Le Rhun et al. 2016), likely due to their inability to penetrate the blood-brain barrier (BBB) ​​(de Gooijer, Zhang et al. 2015; Parrish, Pokorny et al. 2015; Raub, Wishart et al. 2015). al. 2019).

[0005] Additional small molecule CDK4 / 6 inhibitors are needed. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides a compound of formula I:

[0007] [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3- to 8-membered cycloalkyl or heterocycloalkyl ring; Ring B is a 6-membered aryl or a 5-6 membered heteroaryl, and Ring B is optionally substituted with 1, 2, or 3 R4 substituents; Z is O, S, NR b , NOR b , or N-CN, V is CL1R1 or N; n is 1, 2, or 3; m is 1 or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, each L1 is independently a bond, O, —C(O), S, NR, C2-C6 alkylyne, or C1-C6 alkylene; R is H or C1-C6 alkyl; Each R1 is independently H, D, halogen, -OH, -CN, -NO2, -C1-C6 alkyl, C 1~6 Alkoxide, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b, -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), or -S(O)R b and each R2 is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, or CN; Each R3 is independently H, D, halogen, —OH, —CN, —NO2, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, C 0~ Calk-aryl, C 0~ C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR a , -SR b , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , or -B(OR d )(OR c ) and each R4 is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, or CN; Each R a are independently H, D, and -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NRb)NR b R c , -C(=NORb )NR b R c , -C(=NCN)NR b R c , -P(OR c )2, -P(O)OR c OR b , -S(O)2R b , -S(O)NR c R d , SiRb3, -C1~C 10 Alkyl, -C2~C 10 Alkenyl, -C2-C 10 Alkynyl, C 0~ C1alk-aryl, cycloalkyl, cycloalkenyl, C 0~ Calk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0~ C1alk-aryl, cycloalkyl, cycloalkenyl, C 0~ Calk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R c or R d are independently H, D, -C1~C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, aryl, C1alk-aryl, heteroaryl, cycloalkyl, cycloalkenyl, C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; or R c and R d together with the atom to which they are both attached form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocycloalkenyl group; R5 is H, D, ORb, C 1~4 alkyl, C 1~4 The alkyl may be substituted with at least one of halogen, —OH, —CN, or amine, or may be cycloalkyl; R6 is independently H, D, halogen, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), or -S(O)R b is.

[0008] Stereoisomers of the compounds of Formula I, as well as pharmaceutical salts and solvates thereof, are also contemplated, described and encompassed herein. Methods of using the compounds of Formula I, as well as pharmaceutical compositions comprising the compounds of Formula I, are described. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure may be more fully understood by reference to the following specification, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0010] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. "C0 alkyl" refers to a covalent bond.

[0011] Furthermore, the compounds of the invention are intended to be stable. As used herein, "stable" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably amenable to formulation into an efficacious therapeutic agent.

[0012] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0013] The term "alkyl" when used alone or as part of a substituent group refers to a group containing 1 to 12 carbon atoms ("C1-C 12"), preferably refers to a straight or branched chain hydrocarbon group having from 1 to 6 carbon atoms ("C1-C6"). Examples of alkyl groups include methyl (Me, C1 alkyl), ethyl (Et, C2 alkyl), n-propyl (C3 alkyl), isopropyl (C3 alkyl), butyl (C4 alkyl), isobutyl (C4 alkyl), sec-butyl (C4 alkyl), tert-butyl (C4 alkyl), pentyl (C5 alkyl), isopentyl (C5 alkyl), tert-pentyl (C5 alkyl), hexyl (C6 alkyl), isohexyl (C6 alkyl), and the like. Alkyl groups of the present disclosure can be unsubstituted or substituted. In those embodiments in which the alkyl group is substituted, the alkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Further substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl).

[0014] The term "alkoxide" refers to the conjugate base of an alcohol, which contains an organic group bonded to a negatively charged oxygen atom.

[0015] The term "halo" or halogen refers to chloro, fluoro, bromo, or iodo.

[0016] The term "haloalkyl" refers to any alkyl radical having one or more hydrogen atoms replaced by halogen atoms.

[0017] The term "cycloalkyl" when used alone or as part of a substituent group means a group containing 3 to 10 carbon atoms ("C3-C 10"), preferably 3 to 6 carbon atoms ("C3-C6"). Cycloalkyl groups of the present disclosure include monocyclic groups and polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic cycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one polycyclic cycloalkyl group, the cyclic groups share two common atoms. Examples of cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2-methylcyclopentyl (C4), adamantanyl (C6), and the like. 10 ), spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, and the like. The cycloalkyl groups of the present disclosure can be unsubstituted or substituted. In those embodiments in which the cycloalkyl group is substituted, the cycloalkyl group can be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy. Additional substituents include -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl), -OC(O)NH(C-C alkyl), -OC(O)N(C-C alkyl), -S(O)NH(C-C alkyl), and -S(O)N(C-C alkyl).

[0018] The term "cycloalkenyl" refers to alkyl groups containing 3 to 10 carbon atoms ("C 3~ C 10 "), preferably 3 to 6 carbon atoms ("C 3~ C6") and containing at least one carbon-carbon double bond. For example, cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, and the like.

[0019] The term "heterocycloalkyl," when used alone or as part of a substituent, refers to any 3- to 10-membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Heterocycloalkyl groups of the present disclosure include monocyclic groups and polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one polycyclic heterocycloalkyl group, the cyclic groups share two common atoms. The term -C3-C6 heterocycloalkyl refers to a heterocycloalkyl group having 3 to 6 carbon ring atoms. -C3-C6 heterocycloalkyl 10The term heterocycloalkyl refers to a heterocycloalkyl group having from 3 to 10 ring atoms. The heterocycloalkyl group can be attached at any heteroatom or carbon atom of the ring that results in a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl, diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2]pentanyl, oxazaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl, dioxaspiro[3.3]heptanyl, etc. The heterocycloalkyl groups of the present disclosure can be unsubstituted or substituted. In those embodiments in which the heterocycloalkyl group is substituted, the heterocycloalkyl group can be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, and C-C haloalkoxy. Additional substituents include -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl), -OC(O)NH(C-C alkyl), -OC(O)N(C-C alkyl), -S(O)NH(C-C alkyl), and -S(O)N(C-C alkyl).

[0020] The term "heterocycloalkenyl," when used alone or as part of a substituent, refers to any 3- to 10-membered monocyclic or bicyclic partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Heterocycloalkenyl groups of the present disclosure include monocyclic groups and polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocycloalkynyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one polycyclic heterocycloalkenyl group, the cyclic groups share two common atoms. The term -C3-C6 heterocycloalkenyl refers to a heterocycloalkenyl group having 3 to 6 carbon atoms. -C3-C6 10 The term heterocycloalkenyl refers to a heterocycloalkenyl group having 3 to 10 ring atoms. A heterocycloalkenyl group can be attached at any heteroatom or carbon atom of the ring that results in a stable structure. The heterocycloalkenyl groups of the present disclosure can be unsubstituted or substituted. In those embodiments in which a heterocycloalkenyl group is substituted, the heterocycloalkenyl group can be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Further substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl).

[0021] The term "heteroaryl," when used alone or as part of a substituent, refers to a monocyclic or bicyclic aromatic ring structure containing carbon atoms and up to five heteroatoms selected from nitrogen, oxygen, and sulfur. The heteroaryl ring can contain a total of 5, 6, 7, 8, 9, or 10 ring atoms. -C5-C 10The term heteroaryl refers to a heteroaryl group containing 5 to 10 ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like. The heteroaryl groups of the present disclosure can be unsubstituted or substituted. In those embodiments in which a heteroaryl group is substituted, the heteroaryl group can be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Further substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl).

[0022] The term "aryl," when used alone or as part of a substituent, refers to a monocyclic or bicyclic aromatic carbocyclic ring structure. The aryl ring can contain a total of 6, 7, 8, 9, or 10 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like. The aryl groups of the present disclosure can be unsubstituted or substituted. In those embodiments in which the aryl group is substituted, the aryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Further substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl).

[0023] The term "alkenyl" refers to a C alkyl group containing at least one carbon-carbon double bond. 2~ C 12 In some embodiments, an alkenyl group is optionally substituted. In some embodiments, an alkenyl group is C 2~ It is a C6 alkenyl.

[0024] The term "alkynyl" refers to a C alkyl group containing at least one carbon-carbon triple bond. 2~ C 12 In some embodiments, an alkenyl group is optionally substituted. In some embodiments, an alkynyl group is C 2~ It is a C6 alkynyl.

[0025] The term "alkyline" refers to a straight or branched chain C 2~ C 12 In some embodiments, the alkylene group is a C 2~ It is a C6 alkylene.

[0026] The term "alkylene" refers to a divalent saturated C alkyl group that is considered to be derived from an alkene by opening a double bond or from an alkane by removing two hydrogen atoms from different carbon atoms. 2~ C 12 In some embodiments, the alkylene group is C 2~ It is a C6 alkylene group.

[0027] When ranges of carbon atoms are used herein, e.g., C1 to C6, all ranges as well as individual numbers of carbon atoms are included, e.g., "C 1~3 " is C 1~3 , C 1~2 , C 2~3 , C1, C2, and C3. 1~6The term "alk" refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms, and includes, for example, -CH-, -CH(CH)-, -CH(CH)-CH-, and -C(CH)-. The term "-Calk-" refers to a bond.

[0028] The term "C0-C6alk," when used alone or as part of a substituent group, refers to an aliphatic linker having 0, 1, 2, 3, 4, 5, or 6 carbon atoms. For example, the term "-C1alk-" refers to -CH2-. The term "-C0alk-" refers to a bond.

[0029] As used herein, each of -C1-C6 alkyl, -C1-C 10 Alkyl, -C2~C6 alkenyl, -C2~C 10 Alkenyl, -C2-C6 alkynyl, -C2-C 10 The alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Further substituents include -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl), -OC(O)NH(C1-C6 alkyl), -OC(O)N(C1-C6 alkyl), -S(O)2NH(C1-C6 alkyl), and -S(O)2N(C1-C6 alkyl).

[0030] As used herein, "alkoxy" refers to an -O-alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0031] As used herein, "hydroxylalkyl" refers to an alkyl group substituted with OH.

[0032] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, e.g., enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0033] The compounds of the present invention may also include tautomeric forms. All tautomeric forms are included.

[0034] In some embodiments, the compounds of the present invention may exist as rotamers. In some embodiments, the compounds of the present invention exist as a mixture of rotamers in any proportion. In other embodiments, the compounds of the present invention exist as a specific rotamer substantially free of other rotamers.

[0035] Compounds of the invention may also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0036] In some embodiments, the compounds of the present invention and salts thereof are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation can include, for example, a composition enriched for the compound of the present invention. Substantial isolation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present invention or a salt thereof. Methods for isolating compounds and salts thereof are routine in the art.

[0037] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0038] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem complications, commensurate with a reasonable benefit / risk ratio.

[0039] A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically acceptable, and otherwise biologically suitable for administration to a subject, such as an inert substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0040] "Solvate" refers to a physical association of a compound of Formula I with one or more solvent molecules.

[0041] A "subject" includes a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0042] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., preventing or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0043] "Compounds of the disclosure" and equivalent expressions are meant to encompass compounds of Formula I as described herein, as well as subgenera thereof, and where the context allows, the expressions also include stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of the compounds of Formula I, as well as pharmaceutically acceptable salts.

[0044] As used herein, the term "isotopic variant" refers to a compound that contains a proportion of an isotope that is greater than the natural abundance at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can be radiolabeled, i.e., contain one or more radioactive isotopes, or can contain, for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15( 15 In compounds where such isotopic substitutions are made, the following atoms, if present, are labeled with non-radioactive isotopes, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 2 H / D or any carbon 13 C or any nitrogen 15 It is understood that the presence and location of such atoms may vary, such as may be N, and that determination of such atoms is within the skill of the art.

[0045] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers," e.g., diastereomers, enantiomers, and atropisomers. Compounds of the present disclosure may have one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers at each asymmetric center, or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures thereof, racemic or otherwise. When a chiral center is present in a structure but no specific stereochemistry is indicated for that center, both enantiomers, individually or as mixtures of enantiomers, are encompassed by the structure. Where more than one chiral center is present in a structure, but no specific stereochemistry is indicated for that center, all enantiomers and diastereomers, individually or as mixtures, are encompassed by the structure. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art.

[0046] The present disclosure provides a compound of formula I:

[0047] [ka] or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, wherein ring A is a 3- to 8-membered cycloalkyl or heterocycloalkyl ring; Ring B is a 6-membered aryl or a 5- to 6-membered heteroaryl, and Ring B is optionally substituted with 1, 2, or 3 R4 substituents; Z is O, S, NR b , NOR b , or N-CN, V is CL1R1 or N, where n is 1, 2, or 3; m is 1 or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, 6, each L1 is independently a bond, O, —C(O), S, NR, C2-C6 alkyline, or C1-C6 alkylene; and R is H or C1-C6 alkyl; Each R1 is independently H, D, halogen, -OH, -CN, -NO2, -C1-C6 alkyl, C 1~6 Alkoxide, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d, —S(O)Rb, —S(O)NRcRd, —S(O)(═NRb)Rb, —SF5, —P(O)RbRb, —P(O)(ORb)(ORb), —B(ORc)(ORd), or —S(O)Rb; each R2 is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, or CN; Each R3 is independently H, D, halogen, —OH, —CN, —NO2, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, C 0~ Calk-aryl, C 0~ C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR a , -SR b , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , or -B(OR d )(OR c ) and each R4 is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, or CN; Each R a are independently H, D, and -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b )NR b R c , -C(=NOR b )NR b R c , -C(=NCN)NR b R c , -P(OR c )2, -P(O)OR c OR b , -S(O)2R b , -S(O)NR c Rd , SiRb3, -C1~C 10 Alkyl, -C2~C 10 Alkenyl, -C2-C 10 Alkynyl, C 0~ C1alk-aryl, cycloalkyl, cycloalkenyl, C 0~ Calk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0~ C1alk-aryl, cycloalkyl, cycloalkenyl, C 0~ Calk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R c or R d are independently H, D, -C1~C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, aryl, C1alk-aryl, heteroaryl, cycloalkyl, cycloalkenyl, C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; or R c and R d together with the atom to which they are both attached form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocycloalkenyl group; R5 is H, D, ORb, C 1~4 alkyl, C 1~4 The alkyl may be substituted with at least one of halogen, —OH, —CN, or amine, or may be cycloalkyl; R6 is independently H, D, halogen, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c Rd , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), or -S(O)R b is.

[0048] In some embodiments, ring A in formula (I) is a 3-8 membered cycloalkyl or heterocycloalkyl ring.

[0049] In some embodiments, ring A in formula (I) is a 3- to 8-membered cycloalkyl ring. In some embodiments, ring A is a 3-membered cycloalkyl ring. In other embodiments, ring A is a 4-membered cycloalkyl ring. In still other embodiments, ring A is a 5-membered cycloalkyl ring. In still other embodiments, ring A is a 6-membered cycloalkyl ring. In still other embodiments, ring A is a 7-membered cycloalkyl ring. In still other embodiments, ring A is an 8-membered cycloalkyl ring.

[0050] In some embodiments, ring A in Formula (I) is a 3- to 8-membered heterocycloalkyl ring. In some embodiments, ring A in Formula (I) is a 3- to 8-membered heterocycloalkyl ring. In some embodiments, ring A is a 3-membered heterocycloalkyl ring. In other embodiments, ring A is a 4-membered heterocycloalkyl ring. In still other embodiments, ring A is a 5-membered heterocycloalkyl ring. In still other embodiments, ring A is a 6-membered heterocycloalkyl ring. In still other embodiments, ring A is a 7-membered heterocycloalkyl ring. In still other embodiments, ring A is an 8-membered heterocycloalkyl ring.

[0051] In some embodiments, ring A in Formula (I) is cyclopropane, oxirane, or aziridine. In some embodiments, ring A in Formula (I) is cyclobutane, oxetane, or azetidine. In some embodiments, ring A in Formula (I) is cyclopentane, tetrahydrofuran, or pyrrolidine.

[0052] In some embodiments, ring B is a 6-membered aryl or a 5- to 6-membered heteroaryl, and ring B is optionally substituted with 1, 2, or 3 R4 substituents. In some embodiments, ring B in Formula (I) is a phenyl ring. In some embodiments, ring B in Formula (I) is a 5- to 6-membered heteroaryl ring. In some embodiments, ring B in Formula (I) is substituted with 1 R4 substituent. In some embodiments, ring B in Formula (I) is substituted with 2 R4 substituents. In some embodiments, ring B in Formula (I) is substituted with 3 R4 substituents.

[0053] In some embodiments, R4 in Formula I is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, and -CN. In some embodiments, R4 in Formula I is H. In some embodiments, R4 in Formula I is D. In some embodiments, R4 in Formula I is halogen. In some embodiments, R4 in Formula I is -C1-C8 alkoxide. In other embodiments, R4 in Formula I is -C1-C8 alkyl. In other embodiments, R4 in Formula I is methyl. In other embodiments, R4 is haloalkyl. In other embodiments, R4 in Formula I is -CN.

[0054] In some embodiments, Z in formula (I) is O, S, NR b , NOR b or N-CN. In some embodiments, Z is O. In some embodiments, Z is S. In some embodiments, Z is NR b In some embodiments, Z is NOR b In some embodiments, Z is N-CN.

[0055] In some embodiments, ring B in Formula (I) is a 5- to 6-membered heteroaryl ring. In some embodiments, ring B is a 5-membered heteroaryl ring. In some embodiments, ring B is a 6-membered heteroaryl ring. In other embodiments, ring B is a thiophene group.

[0056] In some embodiments, V in Formula (I) is N or CL1R1. In some embodiments, V is N. In other embodiments, V is CL1R1. In other embodiments, V is CH.

[0057] In some embodiments, n in Formula (I) is 1, 2, or 3. In some embodiments, n is 1. In other embodiments, n is 2. In yet other embodiments, n is 3.

[0058] In some embodiments, m in Formula (I) is 1 or 2. In some embodiments, m is 1. In other embodiments, m is 2.

[0059] In some embodiments, p in Formula (I) is 0, 1, or 2. In some embodiments, p is 0. In other embodiments, p is 1. In some embodiments, p is 2.

[0060] In some embodiments, q in Formula (I) is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In other embodiments, q is 3. In other embodiments, q is 4. In other embodiments, q is 5. In other embodiments, q is 6.

[0061] In some embodiments, each L in formula I 1 are independently a bond, O, —C(O), S, NR, C2-C6 alkyline, or C1-C6 alkylene, and R is H or C1-C6 alkyl.

[0062] In some embodiments, L 1 is a bond. In some embodiments, L 1 is O. In some embodiments, L 1 is —C(O). In some embodiments, L 1 is S. In some embodiments, L 1 is NR. In some embodiments, L 1 is C1-C6 alkylene. 1 is methylene. In some embodiments, L 1 is a C2-C6 alkylene.

[0063] In some embodiments, R is H. In some embodiments, R is C1-C6 alkyl. In some embodiments, R is methyl.

[0064] In some embodiments, each R in Formula I is independently H, D, halogen, —OH, —CN, —NO, —C-C alkyl, C 1~6 Alkoxide, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), or -S(O)R b In some embodiments, R1 is H. In some embodiments, R1 is D. In some embodiments, R1 is halogen. In some embodiments, R1 is -OH. In some embodiments, R1 is -CN. In some embodiments, R1 is NO2. In some embodiments, R1 is -C1-C6 alkyl. In some embodiments, R1 is C 1~6In some embodiments, R1 is an alkoxide. In some embodiments, R1 is -C2-C6 alkenyl. In some embodiments, R1 is -C2-C6 alkynyl. In some embodiments, R1 is aryl. In some embodiments, R1 is heteroaryl. In some embodiments, R1 is cycloalkyl. In some embodiments, R1 is cycloalkenyl. In some embodiments, R1 is heterocycloalkenyl. In some embodiments, R1 is -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), -S(O)R b And so on.

[0065] In other embodiments, R1 is heterocycloalkyl. In other embodiments, R1 is 6-membered heterocycloalkyl. In some embodiments, R1 is piperazine. In still other embodiments, R1 is 7-membered heterocycloalkyl. In still other embodiments, R1 is a spiro-fused group. In still other embodiments, R1 is diazaspiroheptane.

[0066] In still other embodiments, at least one R is a group of formula Y: During the ceremony,

[0067] [ka]

[0068] [ka] is the attachment point to L1, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R 10 is H, D, or C 1~6 is alkyl, R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, R 12 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, and t is 0, 1, 2, 3, 4, 5, or 6; Each g and h is independently 0, 1, 2, or 3.

[0069] In some embodiments, W of formula Y is CR 11 In other embodiments, W of formula Y is N.

[0070] In some embodiments, U of formula Y is C(R 11 In another embodiment, U of formula Y is NR 10 In still other embodiments, U of formula Y is O.

[0071] In some embodiments, R of formula Y 11 is H. In some embodiments, R of formula Y 11 is D. In some embodiments, R of formula Y 11 In some embodiments, R of formula Y is fluoro. 11 is C 1~6In another embodiment, R of formula Y is alkyl. 11 is methyl or ethyl. In some embodiments, R of formula Y 11 is C 1~6 It is an alkoxide.

[0072] In some embodiments, R of formula Y 10 is H. In some embodiments, R of formula Y 10 is D. In some embodiments, R of formula Y 10 is C 1~6 In another embodiment, R of formula Y is alkyl. 10 is methyl or ethyl.

[0073] In some embodiments, U in formula Y is C(R 11 )2, then each R 11 is H. In some embodiments, U of formula Y is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of formula Y is C(R 11 )2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U of formula Y is C(R 11 )2, then each R 10 is halogen. In some embodiments, U in formula Y is C(R 11 )2, then one R 11 is a halogen and one R 11 is hydrogen. In other embodiments, U in formula Y is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U in formula Y is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0074] In some embodiments, U of formula Y is NCH. In other embodiments, U of formula Y is NCH.

[0075] In some embodiments, g in formula Y is 0, 1, 2, or 3. In some embodiments, g in formula Y is 0. In some embodiments, g in formula Y is 1. In other embodiments, g in formula Y is 2. In other embodiments, g in formula Y is 3.

[0076] In some embodiments, h in formula Y is 0, 1, 2, or 3. In some embodiments, h in formula Y is 0. In some embodiments, h in formula Y is 1. In other embodiments, h in formula Y is 2. In other embodiments, h in formula Y is 3.

[0077] In some embodiments, R of formula Y 12 H, D, Fluor, C 1~6 Alkyl or C 1~6 In some embodiments, R of formula Y is an alkoxide. 12 is H. In some embodiments, R of formula Y 12 is D. In some embodiments, R of formula Y 12 In some embodiments, R of formula Y is fluoro. 12 is C 1~6 In another embodiment, R of formula Y is alkyl. 12 is methyl or ethyl. In some embodiments, R of formula Y 12 is C 1~6 It is an alkoxide.

[0078] In some embodiments, t in formula Y is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, t in formula Y is 0. In some embodiments, t in formula Y is 1. In other embodiments, t in formula Y is In other embodiments, t in formula Y is 2. In other embodiments, t in formula Y is 3. In some embodiments, t in formula Y is 4. In other embodiments, t in formula Y is 5. In other embodiments, t in formula Y is 6.

[0079] In some embodiments, at least one R is a group selected from:

[0080] [ka] In the formula, R 10 is H or C 1~6 It is alkyl.

[0081] In some embodiments, at least one R is

[0082] [ka] where R 10 is H or C 1~6 It is alkyl.

[0083] In some embodiments, at least one R is

[0084] [ka] where R 10 is H or C 1~6 It is alkyl.

[0085] In some embodiments, at least one R is

[0086] [ka] where R 10 is H or C 1~6 It is alkyl.

[0087] In some embodiments, at least one R is

[0088] [ka] where R 10 is H or C 1~6 It is alkyl.

[0089] In some embodiments, at least one R is

[0090] [ka] where R 10 is H or C 1~6 It is alkyl.

[0091] In some embodiments, at least one R is

[0092] [ka] where R 10 is H or C 1~6 It is alkyl.

[0093] In some embodiments, at least one R is

[0094] [ka] where R 10 is H or C 1~6 It is alkyl.

[0095] In some embodiments, at least one R is

[0096] [ka] where R 10 is H or C 1~6 It is alkyl.

[0097] In some embodiments, at least one R is

[0098] [ka] where R 10 is H or C 1~6 It is alkyl.

[0099] In some embodiments, at least one R is

[0100] [ka] where R 10 is H or C 1~6 It is alkyl.

[0101] In some embodiments, at least one R is

[0102] [ka] where R 10 is H or C 1~6 It is alkyl.

[0103] In some embodiments, at least one R is

[0104] [ka] where R 10 is H or C 1~6 It is alkyl.

[0105] In some embodiments, at least one R is

[0106] [ka] where R 10 is H or C 1~6 It is alkyl.

[0107] In some embodiments, at least one R is

[0108] [ka] where R 10 is H or C 1~6 It is alkyl.

[0109] In other embodiments, at least one R1 is piperazine. In other embodiments, at least one R1 is piperdine.

[0110] In some embodiments, at least one R is a group of formula Z:

[0111] [ka] During the ceremony,

[0112] [ka] is the attachment point to L1, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R 10 is H or C 1~6 is alkyl, R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 is an alkoxide, R 12 H, D, Fluor, C 1~6 Alkyl or C 1~6 is an alkoxide, t is 0, 1, 2, 3, 4, 5, or 6; Each g, h, j, and k is independently 0, 1, 2, or 3.

[0113] In some embodiments, W of formula Z is CR 11In other embodiments, W of formula Z is N.

[0114] In some embodiments, U of formula Z is C(R 11 In other embodiments, U of formula Z is NR 10 In yet other embodiments, U of formula Z is O.

[0115] In some embodiments, R of formula Z 11 is H. In some embodiments, R of formula Z 11 In some embodiments, R of formula Z is fluoro. 11 is C 1~6 In another embodiment, R of formula Z is alkyl. 11 is methyl or ethyl. In some embodiments, R of formula Z 11 is C 1~6 It is an alkoxide.

[0116] In some embodiments, R of formula Z 10 is H. In some embodiments, R of formula Z 10 is C 1~6 In another embodiment, R of formula Z is alkyl. 10 is methyl or ethyl.

[0117] In some embodiments, U of formula Z is C(R 11 )2, then each R 11 is H. In some embodiments, U of formula Z is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of formula Z is C(R 11 )2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U of formula Z is C(R 11 )2, then each R 10 is halogen. In some embodiments, U of formula Z is C(R 11 )2, then one R11 is a halogen and one R 11 is hydrogen. In other embodiments, U of formula Z is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U of formula Z is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0118] In some embodiments, U of formula Z is NCH. In other embodiments, U of formula Z is NCH.

[0119] In some embodiments, g in formula Z is 0, 1, 2, or 3. In some embodiments, g in formula Z is 0. In some embodiments, g in formula Z is 1. In other embodiments, g in formula Y is 2. In other embodiments, g in formula Z is 3.

[0120] In some embodiments, h in Formula Z is 0, 1, 2, or 3. In some embodiments, h in Formula XIII is 0. In some embodiments, h in Formula Z is 1. In other embodiments, h in Formula Z is 2. In other embodiments, h in Formula Z is 3.

[0121] In some embodiments, j in formula Z is 0, 1, 2, or 3. In some embodiments, j in formula Z is 0. In some embodiments, j in formula Z is 1. In other embodiments, j in formula Z is 2. In other embodiments, j in formula Z is 3.

[0122] In some embodiments, k in formula Z is 0, 1, 2, or 3. In some embodiments, k in formula Z is 0. In some embodiments, k in formula Z is 1. In other embodiments, k in formula Z is 2. In other embodiments, k in formula Z is 3.

[0123] In some embodiments, R of formula Z 12 H, D, Fluor, C 1~6 Alkyl or C 1~6 In some embodiments, R of formula Z is an alkoxide. 12 is H. In some embodiments, R of formula Z 12 is D. In some embodiments, R of formula Z 12 In some embodiments, R of formula Z is fluoro. 12 is C 1~6 In another embodiment, R of formula Z is alkyl. 12 is methyl or ethyl. In some embodiments, R of formula Z 12 is C 1~6 It is an alkoxide.

[0124] In some embodiments, t in formula Z is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, t in formula Z is 0. In some embodiments, t in formula Z is 1. In other embodiments, t in formula Z is 2. In other embodiments, t in formula Z is 3. In some embodiments, t in formula Z is 4. In other embodiments, t in formula Z is 5. In other embodiments, t in formula Z is 6.

[0125] In other embodiments, at least one R is a group selected from:

[0126] [ka] In the formula, R 10 is H or C 1~6 It is alkyl.

[0127] In other embodiments, at least one R is

[0128] [ka] where R 10 is H or C 1~6 It is alkyl.

[0129] In other embodiments, at least one R is

[0130] [ka] where R 10 is H or C 1~6 It is alkyl.

[0131] In other embodiments, at least one R is

[0132] [ka] where R 10 is H or C 1~6 It is alkyl.

[0133] In other embodiments, at least one R is

[0134] [ka] where R 10 is H or C 1~6 It is alkyl.

[0135] In other embodiments, at least one R is

[0136] [ka] where R 10 is H or C 1~6 It is alkyl.

[0137] In other embodiments, at least one R is

[0138] [ka] where R 10 is H or C 1~6 It is alkyl.

[0139] In other embodiments, at least one R is

[0140] [ka] where R 10 is H or C 1~6 It is alkyl.

[0141] In some embodiments, each R2 in Formula I is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, or -CN. In some embodiments, R2 is H. In some embodiments, R2 is D. In other embodiments, R2 is halogen. In other embodiments, R2 is fluoro. In still other embodiments, R2 is C1-C8 alkoxide. In still other embodiments, R2 is C1-C8 alkyl. In still other embodiments, R2 is haloalkyl. In still other embodiments, R2 is -CN.

[0142] In some embodiments, each R in Formula I is independently H, D, halogen, —OH, —CN, —NO, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, C 0~ Calk-aryl, C 0~ C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR a , -SR b , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c Rd , or -B(OR d )(OR c )

[0143] In some embodiments of the present disclosure, at least one R3 moiety is directly bonded to the remainder of the compound of Formula (I) through a carbon atom. In particularly preferred aspects of these embodiments, each R3 bonded through a carbon atom is independently selected from H, D, halogen, —OH, —CN, —NO2, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, C 0~ Calk-aryl, C 0~ C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR a , -SR b , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , or -B(OR d )(OR c )

[0144] In some embodiments, R3 is H. In some embodiments, R3 is D. In some embodiments, R3 is halogen. In some embodiments, R3 is -OH. In some embodiments, R3 is -CN. In some embodiments, R3 is NO2. In some embodiments, R3 is -C1-C6 alkyl. In some embodiments, R3 is -C2-C6 alkenyl. In some embodiments, R3 is -C2-C6 alkynyl. In other embodiments, R3 is C0-C1alk-aryl. In other embodiments, R3 is C0-C1alk-heteroaryl. In other embodiments, R3 is cycloalkyl. In other embodiments, R3 is C 3~10In other embodiments, R3 is cycloalkyl. In other embodiments, R3 is cycloalkenyl. In other embodiments, R3 is heterocycloalkyl. In other embodiments, R3 is heterocycloalkenyl. In still other embodiments, R3 is -OR a , -SR b , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , or -B(OR d )(OR c In some embodiments, at least one R3 is hydroxyalkyl. In other embodiments, R3 is C1-C6 alkyl, e.g., isopropyl. In other embodiments, R3 is oxo. In other embodiments, R3 is oxo attached to a nitrogen atom. In some embodiments, R3 is OR a is.

[0145] In some embodiments, each Ra in formula I is independently H, D, —C(O)R b , -C(O)OR c , -C(O)NRcRd, -C(=NRb)NRbRc, -C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORc)2, -P(O)ORcORb, -S(O)2Rb, -S(O)2NRcRd, SiRb3, -C1~C 10 Alkyl, -C2~C 10 Alkenyl, -C2-C 10 Alkynyl, C 0~ C1alk-aryl, cycloalkyl, cycloalkenyl, C 0~ It is a C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0146] In some embodiments, R a is H. In some embodiments, R ais D. In some embodiments, R a is -C(O)R b In some embodiments, R a is -C(O)OR c In some embodiments, R a is —C(O)NRcRd. In some embodiments, R a is -C(=NR b )NR b R c In some embodiments, Ra is C(=NOR b )NR b R c In some embodiments, R a is -C(=NCN)NR b R c is.

[0147] In other embodiments, R a is P(OR c )2, -P(O)OR c OR b , -S(O)2R b , -S(O)NR c R d , SiR b 3, etc. In still other embodiments, R a is -C1~C 10 Alkyl, -C2~C 10 Alkenyl, -C2-C 10 Alkynyl, C 0~ C1alk-aryl, cycloalkyl, cycloalkenyl, C 0~ and C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0148] In some embodiments, each R in Formula I b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0~ C1alk-aryl, cycloalkyl, cycloalkenyl, C 0~In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is C-heteroaryl, heterocycloalkyl, or heterocycloalkenyl. In some embodiments, R is H. In some embodiments, R is D. b is -C1-C6 alkyl. In some embodiments, R b is -C2-C6 alkenyl. In some embodiments, R b is -C2-C6 alkynyl. In another embodiment, R b is C0-C1alk-aryl. In another embodiment, R b is cycloalkyl. In other embodiments, R b is cycloalkenyl. In other embodiments, R b is C0-C1alk-heteroaryl. In another embodiment, R b is heterocycloalkyl. In other embodiments, R b is heterocycloalkenyl.

[0149] In some embodiments, each R in Formula I c or R d is independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, C1alk-aryl, cycloalkyl, cycloalkenyl, C1alk-heteroaryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. c or R d is H. In some embodiments, R c or R d is D. In some embodiments, R c or R d is -C1~C 10 In some embodiments, R c or R d is -C2-C6 alkenyl. In some embodiments, R c or R d is -C2-C6 alkynyl. In another embodiment, Rc or R d is —OC1-C6 alkyl. In another embodiment, R c or R d is -O-cycloalkyl. In other embodiments, R c or R d is aryl. In other embodiments, R c or R d is Calk-aryl. In other embodiments, R c or R d is cycloalkyl. In other embodiments, R c or R d is cycloalkenyl. In other embodiments, R c or R d is Calk-heteroaryl. In other embodiments, R c or R d is heteroaryl. In other embodiments, R c or R d is heterocycloalkyl. In other embodiments, R c or R d is heterocycloalkenyl.

[0150] In yet other embodiments, R c and R d together with the atoms to which they are both attached form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocycloalkenyl group. c and R d forms a monocyclic heterocycloalkyl. In yet other embodiments, R c and R d forms a polycyclic heterocycloalkyl. In yet other embodiments, R c and R d form a monocyclic heterocycloalkenyl group. c and R d forms a polycyclic heterocycloalkenyl group.

[0151] In some embodiments, each R in formula I is independently H, D, -ORb, C 1~4 alkyl, C 1~4 The alkyl may be substituted with at least one of halogen, -OH, -CN, or amine, or may be cycloalkyl. In some embodiments, R5 is H. In some embodiments, R5 is D. In some embodiments, R5 is -ORb. In some embodiments, R5 is -C1-4 alkyl. In other embodiments, the C1-4 alkyl group of R5 is substituted with at least one halogen. In other embodiments, the C1-4 alkyl group of R5 is substituted with at least one -OH. In other embodiments, the C1-4 alkyl group of R5 is substituted with at least one -CN. In other embodiments, the C1-4 alkyl group of R5 is substituted with at least one amine. In other embodiments, R5 is cycloalkyl.

[0152] In some embodiments, each R in Formula I is independently H, D, halogen, —OH, —CN, —NO, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(ORc )(OR d ), or -S(O)R b is.

[0153] In some embodiments, R6 is H. In some embodiments, R6 is D. In some embodiments, R6 is halogen. In some embodiments, R6 is -OH. In some embodiments, R6 is -CN. In some embodiments, R6 is NO2. In some embodiments, R6 is -C1-C6 alkyl. In some embodiments, R6 is -C2-C6 alkenyl. In some embodiments, R6 is -C2-C6 alkynyl. In other embodiments, R6 is aryl. In other embodiments, R6 is heteroaryl. In other embodiments, R6 is cycloalkyl. In other embodiments, R6 is cycloalkenyl. In other embodiments, R6 is heterocycloalkyl. In other embodiments, R6 is heterocycloalkenyl. In other embodiments, R6 is -OR. a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R b , -C(O)OR b , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR c )(OR d ), or -S(O)R b And so on.

[0154] In some embodiments, the compound of Formula (I) is a pharmaceutically acceptable salt. In some embodiments, the compound of Formula (I) is a solvate. In some embodiments, the compound of Formula (I) is an N-oxide of the compound of Formula (I).

[0155] In some embodiments, the compound of Formula (I) is a compound of Formula II, Formula IIa, and Formula IIb:

[0156] [ka] or a pharmaceutically acceptable salt thereof, wherein each (L1R1) n , (R2) m , R3, R4, R5, (R6) q , Z, V, ring A, and p are defined as for formula (I).

[0157] In some embodiments, the compound of formula (I) is a compound of formula III:

[0158] [ka] or a pharmaceutically acceptable salt thereof, wherein each (L1R1) n , (R2) m , R3, R4, R5, (R6) q , V, ring A, and p are defined as for formula (I).

[0159] In some embodiments, the compound of formula (I) is a compound of formula IV:

[0160] [ka] or a pharmaceutically acceptable salt thereof, wherein each (L1R1) n , R3, R4, R5, (R6) q , V, ring A, and p are defined as for formula (I).

[0161] In some embodiments, the compound of formula (I) is a compound of formula V:

[0162] [ka] or a pharmaceutically acceptable salt thereof, wherein E is a bond, —O—, —S—, C(R a )2, -C(=O)NR a - or NR a wherein each (L1R1) n , R3, R4, R5, (R6) q , V, and p are defined as for formula (I).

[0163] In some embodiments, E in formula V is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in formula V is a bond. In some embodiments, E in formula V is —O—. In some embodiments, E in formula V is —S—. In some embodiments, E in formula V is C(R a )2. In some embodiments, E in formula V is —C(═O)NR—. In some embodiments, E in formula V is NR a is.

[0164] In some embodiments, the compound of formula (I) is a compound of formula VI:

[0165] [ka] or a pharmaceutically acceptable salt thereof, wherein E is a bond, —O—, —S—, C(R a )2, -C(=O)NR a - or NR a wherein each (L1R1) n , R3, R4, R5, (R6) q , V, and p are defined as for formula (I).

[0166] In some embodiments, E in Formula VI is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in formula VI is a bond. In some embodiments, E in formula VI is -O-. In some embodiments, E in Formula VI is -S-. In some embodiments, E in Formula VI is -C(R a )2. In some embodiments, E in formula VI is —C(═O)NR—. In some embodiments, E in formula VI is NRa.

[0167] In some embodiments, the compound of formula (I) is a compound of formula VII:

[0168] [ka] or a pharmaceutically acceptable salt thereof, wherein E is a bond, —O—, —S—, C(R a )2, -C(=O)NR a - or NR a wherein each (L1R1) n , R3, R4, R5, (R6) q , V, and p are defined as for formula (I).

[0169] In some embodiments, E in Formula VII is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in Formula VII is a bond. In some embodiments, E in Formula VII is -O-. In some embodiments, E in Formula VII is -S-. In some embodiments, E in Formula VII is C(R a )2. In some embodiments, E in Formula VII is —C(═O)NR—. In some embodiments, E in Formula VII is NR a is.

[0170] In some embodiments, the compound of Formula (I) is a compound of Formula VIII:

[0171] [ka] or a pharmaceutically acceptable salt thereof, wherein E is a bond, —O—, —S—, C(R a )2, -C(=O)NR a - or NR a wherein each (L1R1) n , R3, R4, R5, (R6) q , V, and p are defined as for formula (I).

[0172] In some embodiments, E in Formula VIII is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in Formula VIII is a bond. In some embodiments, E in Formula VIII is -O-. In some embodiments, E in Formula VIII is -S-. In some embodiments, E in Formula VIII is C(R a )2. In some embodiments, E in Formula VIII is —C(═O)NR—. In some embodiments, E in Formula VIII is NR a is.

[0173] In some embodiments, the compound of formula (I) is a compound of formula IX:

[0174] [ka] or a pharmaceutically acceptable salt thereof, wherein E is a bond, —O—, —S—, C(R a )2, -C(=O)NR a - or NR a and each (L1R1) n , R3, R4, R5, (R6) q , V, and p are defined as for formula (I).

[0175] In some embodiments, E in formula IX is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in formula IX is a bond. In some embodiments, E in formula IX is -O-. In some embodiments, E in formula IX is -S-. In some embodiments, E in formula IX is -C(R a )2. In some embodiments, E in formula IX is —C(═O)NR—. In some embodiments, E in formula IX is NR a is.

[0176] In some embodiments, the compound of formula (I) is a compound of formula X:

[0177] [ka] or a pharmaceutically acceptable salt thereof, wherein E is a bond, —O—, —S—, C(Ra)2, —C(═O)NRa—, or NRa, and each (L1R1) n , R3, R4, R5, (R6) q , V, and p are defined as for formula (I).

[0178] In some embodiments, E in formula X is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in formula X is a bond. In some embodiments, E in formula X is -O-. In some embodiments, E in formula X is -S-. In some embodiments, E in formula X is C(R a )2. In some embodiments, E in formula X is —C(═O)NR—. In some embodiments, E in formula X is NR a is.

[0179] In some embodiments, the compound of formula (I) is a compound of formula XI:

[0180] [ka] or a pharmaceutically acceptable salt thereof, wherein E is a bond, —O—, —S—, C(R a )2, -C(=O) NRa- , or NR a and each (L1R1) n , R3, R4, R5, (R6) q , V, and p are defined as for formula (I).

[0181] In some embodiments, E in formula XI is a bond, —O—, —S—, —C(Ra) 2 , —C(═O)NR—, or NR a In some embodiments, E in formula XI is a bond. In some embodiments, E in formula XI is -O-. In some embodiments, E in formula XI is -S-. In some embodiments, E in formula XI is -C(R a )2. In some embodiments, E in formula XI is —C(═O)NR—. In some embodiments, E in formula XI is NR a is.

[0182] In some embodiments, the compound of formula (I) is a compound of formula XII:

[0183] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a and (R6) q is defined in relation to formula (I), L1 is a bond, -CH2-, or C=O, and V is CR 11 or N, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R 10 H, D, C 1~6 alkyl, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, and R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; Each g and h is independently 0, 1, 2, or 3.

[0184] In some embodiments, E in Formula XII is a bond, —O—, —S—, —C(Ra) 2 , —C(═O)NR—, or NR a In some embodiments, E in Formula XII is a bond. In some embodiments, E in Formula XII is -O-. In some embodiments, E in Formula XII is -S-. In some embodiments, E in Formula XII is C(R a )2 。 In some embodiments, E in formula XII is -C(=O)NR-. In some embodiments, E in formula XII is NR a is.

[0185] In some embodiments, L1 in formula XII is a bond. In some embodiments, L1 in formula XII is -CH2-. In some embodiments, L1 in formula XII is C=O.

[0186] In some embodiments, V in formula XII is CR 11 In other embodiments, V in formula XII is N.

[0187] In some embodiments, W in formula XII is CR 11In other embodiments, W in formula XII is N.

[0188] In some embodiments, U in formula XII is C(R 11 In other embodiments, U in formula XII is NR 10 In still other embodiments, U in formula XII is O.

[0189] In some embodiments, R4 of Formula XII is H. In some embodiments, R4 of Formula XII is D. In some embodiments, R4 of Formula XII is methyl. In some embodiments, R4 of Formula XII is haloalkyl.

[0190] In some embodiments, R5 of Formula XII is H. In some embodiments, R5 of Formula XII is D. In some embodiments, R5 of Formula XII is methyl. In some embodiments, R5 of Formula XII is haloalkyl.

[0191] In some embodiments, R of Formula XII 11 is H. In some embodiments, R of formula XII 11 is D. In some embodiments, R of formula XII 11 In some embodiments, R of Formula XII is fluoro. 11 is C 1~6 In another embodiment, R of formula XII is alkyl. 11 is methyl or ethyl. In some embodiments, R of Formula XII 11 is C 1~6 It is an alkoxide.

[0192] In some embodiments, R of Formula XII 10 is H. In some embodiments, R of formula XII 10 is D. In some embodiments, R of formula XXIV 10 is C 1~6In another embodiment, R of formula XII is alkyl. 10 is methyl or ethyl. In some embodiments, R of Formula XII 10 is haloalkyl.

[0193] In some embodiments, U in Formula XII is C(R 11 )2, then each R 11 is H. In some embodiments, U in formula XII is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of Formula XII is C(R 11 )2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U in formula XII is C(R 11 )2, then each R 10 is halogen. In some embodiments, U in Formula XII is C(R 11 )2, then one R 11 is a halogen and one R 11 is hydrogen. In other embodiments, U in formula XII is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U in formula XII is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0194] In some embodiments, U of formula XII is NCH. In other embodiments, U of formula XII is NCH.

[0195] In some embodiments, g in Formula XII is 0, 1, 2, or 3. In some embodiments, g in Formula XII is 0. In some embodiments, g in Formula XII is 1. In other embodiments, g in Formula XII is 2. In other embodiments, g in Formula XII is 3.

[0196] In some embodiments, h in Formula XII is 0, 1, 2, or 3. In some embodiments, h in Formula XII is 0. In some embodiments, h in Formula XII is 1. In other embodiments, h in Formula XII is 2. In other embodiments, h in Formula XII is 3.

[0197] In some embodiments, the compound of Formula (I) is a compound of Formula XIII:

[0198] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a and (R6) q is defined in relation to formula (I), L1 is a bond, -CH2-, or C=O, and V is CR 11 or N, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; R 10 H, D, C 1~6 alkyl, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, and each g, h, j, and k is independently 0, 1, 2, or 3.

[0199] In some embodiments, E in Formula XIII is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR aIn some embodiments, E in Formula XIII is a bond. In some embodiments, E in Formula XIII is -O-. In some embodiments, E in Formula XIII is -S-. In some embodiments, E in Formula XIII is C(R a )2. In some embodiments, E in Formula XIII is —C(═O)NR—. In some embodiments, E in Formula XIII is NR a is.

[0200] In some embodiments, L1 in formula XIII is a bond. In some embodiments, L1 in formula XIII is -CH2-. In some embodiments, L1 in formula XIII is C=O.

[0201] In some embodiments, V in Formula XIII is CR 11 In other embodiments, V in formula XIII is N.

[0202] In some embodiments, W in formula XIII is CR 11 In other embodiments, W in formula XIII is N.

[0203] In some embodiments, U in formula XIII is C(R 11 In other embodiments, U in formula XIII is NR 10 In still other embodiments, U in formula XIII is O.

[0204] In some embodiments, R of Formula XIII 11 is H. In some embodiments, R of Formula XIII 11 is D. In some embodiments, R of formula XIII 11 In some embodiments, R of Formula XIII is fluoro. 11 is C 1~6 In another embodiment, R of formula XIII is alkyl. 11is methyl or ethyl. In some embodiments, R of Formula XIII 11 is C 1~6 It is an alkoxide.

[0205] In some embodiments, R of Formula XIII 10 is H. In some embodiments, R of Formula XIII 10 is D. In some embodiments, R of formula XIII 10 is C 1~6 In another embodiment, R of formula XIII is alkyl. 10 is methyl or ethyl. In some embodiments, R of Formula XIII 10 is haloalkyl.

[0206] In some embodiments, U in Formula XIII is C(R 11 )2, then each R 11 is H. In some embodiments, U in formula XIII is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of Formula XIII is C(R 11 )2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U in formula XIII is C(R 11 )2, then each R 10 is halogen. In some embodiments, U in Formula XIII is C(R 11 )2, then one R 11 is a halogen and one R 11 is hydrogen. In other embodiments, U in formula XIII is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U in formula XIII is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0207] In some embodiments, U in formula XIII is NCH. In other embodiments, U in formula XIII is NCH.

[0208] In some embodiments, R4 of Formula XIII is H. In some embodiments, R4 of Formula XIII is D. In some embodiments, R4 of Formula XIII is methyl. In some embodiments, R4 of Formula XIII is haloalkyl.

[0209] In some embodiments, R5 of Formula XIII is H. In some embodiments, R5 of Formula XIII is D. In some embodiments, R5 of Formula XIII is methyl. In some embodiments, R5 of Formula XIII is haloalkyl.

[0210] In some embodiments, g in Formula XIII is 0, 1, 2, or 3. In some embodiments, g in Formula XIII is 0. In some embodiments, g in Formula XIII is 1. In other embodiments, g in Formula XIII is 2. In other embodiments, g in Formula XIII is 3.

[0211] In some embodiments, h in Formula XIII is 0, 1, 2, or 3. In some embodiments, h in Formula XIII is 0. In some embodiments, h in Formula XIII is 1. In other embodiments, h in Formula XIII is 2. In other embodiments, h in Formula XIII is 3.

[0212] In some embodiments, j in Formula XIII is 0, 1, 2, or 3. In some embodiments, j in Formula XIII is 0. In some embodiments, j in Formula XIII is 1. In other embodiments, j in Formula XIII is 2. In other embodiments, j in Formula XIII is 3.

[0213] In some embodiments, k in Formula XIII is 0, 1, 2, or 3. In some embodiments, k in Formula XIII is 0. In some embodiments, k in Formula XIII is 1. In other embodiments, k in Formula XIII is 2. In other embodiments, k in Formula XIII is 3.

[0214] In some embodiments, the compound of formula (I) is a compound of formula XIV:

[0215] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a and (R6) q is defined in relation to formula (I), L1 is a bond, -CH2-, or C=O, and V is CR 11 or N, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R 10 H, D, C 1~6 alkyl, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, and R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; Each g and h is independently 0, 1, 2, or 3.

[0216] In some embodiments, E in Formula XIV is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR aIn some embodiments, E in Formula XIV is a bond. In some embodiments, E in Formula XIV is -O-. In some embodiments, E in Formula XIV is -S-. In some embodiments, E in Formula XIV is C(R a )2. In some embodiments, E in Formula XIV is —C(═O)NR—. In some embodiments, E in Formula XIV is NR a is.

[0217] In some embodiments, L1 in formula XIV is a bond. In some embodiments, L1 in formula XIV is -CH2-. In some embodiments, L1 in formula XIV is C=O.

[0218] In some embodiments, V in formula XIV is CR 11 In other embodiments, V in formula XIV is N.

[0219] In some embodiments, W in formula XIV is CR 11 In other embodiments, W in formula XIV is N.

[0220] In some embodiments, U of formula XIV is C(R 11 In other embodiments, U in formula XIV is NR 10 In still other embodiments, U in formula XIV is O.

[0221] In some embodiments, R of Formula XIV 11 is H. In some embodiments, R of formula XIV 11 is D. In some embodiments, R of formula XIV 11 In some embodiments, R of formula XIV is fluoro. 11 is C 1~6 In another embodiment, R of formula XIV is alkyl. 11 is methyl or ethyl. In some embodiments, R of Formula XIV 11 is C1~6 It is an alkoxide.

[0222] In some embodiments, R of Formula XIV 10 is H. In some embodiments, R of formula XIV 10 is D. In some embodiments, R of formula XIV 10 is C 1~6 In another embodiment, R of formula XIV is alkyl. 10 is methyl or ethyl. In some embodiments, R of Formula XIV 10 is haloalkyl.

[0223] In some embodiments, U of Formula XIV is C(R 11 )2, then each R 11 is H. In some embodiments, U in formula XIV is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of Formula XIV is C(R 11 )2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U in formula XIV is C(R 11 )2, then each R 10 is halogen. In some embodiments, U in Formula XIV is C(R 11 )2, then one R 11 is a halogen and one R 11 is hydrogen. In other embodiments, U in formula XIV is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U of formula XIV is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0224] In some embodiments, U of formula XIV is NCH. In other embodiments, U of formula XIV is NCH.

[0225] In some embodiments, R4 of Formula XIV is H. In some embodiments, R4 of Formula XIV is D. In some embodiments, R4 of Formula XIV is methyl. In some embodiments, R4 of Formula XIV is haloalkyl.

[0226] In some embodiments, R5 of Formula XIV is H. In some embodiments, R5 of Formula XIV is D. In some embodiments, R5 of Formula XIV is methyl. In some embodiments, R5 of Formula XIV is haloalkyl.

[0227] In some embodiments, g in Formula XIV is 0, 1, 2, or 3. In some embodiments, g in Formula XIV is 0. In some embodiments, g in Formula XIV is 1. In other embodiments, g in Formula XIV is 2. In other embodiments, g in Formula XIV is 3.

[0228] In some embodiments, h in Formula XIV is 0, 1, 2, or 3. In some embodiments, h in Formula XIV is 0. In some embodiments, h in Formula XIV is 1. In other embodiments, h in Formula XIV is 2. In other embodiments, h in Formula XIV is 3.

[0229] In some embodiments, the compound of Formula (I) is a compound of Formula XV:

[0230] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a and (R6) qis defined for formula (I), and L1 is a bond, —CH2—, or C═O; V is CR 11 or N, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R 10 H, D, C 1~6 alkyl, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, and R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; Each g, h, j, and k is independently 0, 1, 2, or 3.

[0231] In some embodiments, E in formula XV is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in Formula XV is a bond. In some embodiments, E in Formula XV is -O-. In some embodiments, E in Formula XV is -S-. In some embodiments, E in Formula XV is C(R a )2. In some embodiments, E in Formula XV is —C(═O)NR—. In some embodiments, E in Formula XV is NR a is.

[0232] In some embodiments, L1 of formula XV is a bond. In some embodiments, L1 of formula XV is -CH2-. In some embodiments, L1 of formula XV is C=O.

[0233] In some embodiments, V of formula XV is CR 11 In other embodiments, V in formula XV is N.

[0234] In some embodiments, W of formula XV is CR 11 In other embodiments, W in formula XV is N.

[0235] In some embodiments, U of formula XV is C(R 11 In other embodiments, U of formula XV is NR 10 In still other embodiments, U in formula XV is O.

[0236] In some embodiments, R of Formula XV 11 is H. In some embodiments, R of formula XV 11 is D. In some embodiments, R of formula XV 11 In some embodiments, R of formula XV is fluoro. 11 is C 1~6 In another embodiment, R of formula XV is alkyl. 11 is methyl or ethyl. In some embodiments, R of formula XV 11 is C 1~6 It is an alkoxide.

[0237] In some embodiments, R of Formula XV 10 is H. In some embodiments, R of formula XV 10 is D. In some embodiments, R of formula XV 10 is C 1~6 In another embodiment, R of formula XV is alkyl. 10 is methyl or ethyl. In some embodiments, R of formula XV 10 is haloalkyl.

[0238] In some embodiments, U of Formula XV is C(R 11 )2, then each R 11 is H. In some embodiments, U of formula XV is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of Formula XV is C(R 11)2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U of formula XV is C(R 11 )2, then each R 10 is halogen. In some embodiments, U of Formula XV is C(R 11 )2, then one R 11 is a halogen and one R 11 is hydrogen. In other embodiments, U of formula XV is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U of formula XV is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0239] In some embodiments, U of formula XV is NCH. In other embodiments, U of formula XV is NCH.

[0240] In some embodiments, R4 of Formula XV is H. In some embodiments, R4 of Formula XV is D. In some embodiments, R4 of Formula XV is methyl. In some embodiments, R4 of Formula XV is haloalkyl.

[0241] In some embodiments, R5 of Formula XV is H. In some embodiments, R5 of Formula XV is D. In some embodiments, R5 of Formula XV is methyl. In some embodiments, R5 of Formula XV is haloalkyl.

[0242] In some embodiments, g in Formula XV is 0, 1, 2, or 3. In some embodiments, g in Formula XV is 0. In some embodiments, g in Formula XV is 1. In other embodiments, g in Formula XV is 2. In other embodiments, g in Formula XV is 3.

[0243] In some embodiments, h in Formula XV is 0, 1, 2, or 3. In some embodiments, h in Formula XV is 0. In some embodiments, h in Formula XV is 1. In other embodiments, h in Formula XV is 2. In other embodiments, h in Formula XV is 3.

[0244] In some embodiments, j in Formula XV is 0, 1, 2, or 3. In some embodiments, j in Formula XV is 0. In some embodiments, j in Formula XV is 1. In other embodiments, j in Formula XV is 2. In other embodiments, j in Formula XV is 3.

[0245] In some embodiments, k in Formula XV is 0, 1, 2, or 3. In some embodiments, k in Formula XV is 0. In some embodiments, k in Formula XV is 1. In other embodiments, k in Formula XV is 2. In other embodiments, k in Formula XV is 3.

[0246] In some embodiments, the compound of formula (I) is a compound of formula XVI:

[0247] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a and (R6) q is defined in relation to formula (I), L1 is a bond, -CH2-, or C=O, and V is CR 11 or N, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R 10 H, D, C1~6 alkyl, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, and R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; Each g and h is independently 0, 1, 2, or 3.

[0248] In some embodiments, E in Formula XVI is a bond, —O—, —S—, —C(Ra) 2 , —C(═O)NR—, or NR a In some embodiments, E in Formula XVI is a bond. In some embodiments, E in Formula XVI is -O-. In some embodiments, E in Formula XVI is -S-. In some embodiments, E in Formula XVI is C(R a )2. In some embodiments, E in Formula XVI is —C(═O)NR—. In some embodiments, E in Formula XVI is NR a is.

[0249] In some embodiments, L1 of Formula XVI is a bond. In some embodiments, L1 of Formula XVI is -CH2-. In some embodiments, L1 of Formula XVI is C=O.

[0250] In some embodiments, V in Formula XVI is CR 11 In other embodiments, V in formula XVI is N.

[0251] In some embodiments, W in formula XVI is CR 11 In other embodiments, W in formula XVI is N.

[0252] In some embodiments, U in Formula XVI is C(R 11 In other embodiments, U in formula XVI is NR 10In still other embodiments, U in formula XVI is O.

[0253] In some embodiments, R of Formula XVI 11 is H. In some embodiments, R of Formula XVI 11 is D. In some embodiments, R of Formula XVI 11 In some embodiments, R of Formula XVI is fluoro. 11 is C 1~6 In another embodiment, R of formula XVI is alkyl. 11 is methyl or ethyl. In some embodiments, R of Formula XVI 11 is C 1~6 It is an alkoxide.

[0254] In some embodiments, R of Formula XVI 10 is H. In some embodiments, R of Formula XVI 10 is D. In some embodiments, R of Formula XVI 10 is C 1~6 In another embodiment, R of formula XVI is alkyl. 10 is methyl or ethyl. In some embodiments, R of Formula XVI 10 is haloalkyl.

[0255] In some embodiments, U in Formula XVI is C(R 11 )2, then each R 11 is H. In some embodiments, U in Formula XVI is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of Formula XVI is C(R 11 )2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U in Formula XVI is C(R 11 )2, then each R 10 is halogen. In some embodiments, U in Formula XVI is C(R 11)2, then one R 11 is a halogen and one R 11 is hydrogen. In other embodiments, U in formula XVI is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U in formula XVI is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0256] In some embodiments, U of formula XVI is NCH. In other embodiments, U of formula XVI is NCH.

[0257] In some embodiments, R4 of Formula XVI is H. In some embodiments, R4 of Formula XVI is D. In some embodiments, R4 of Formula XVI is methyl. In some embodiments, R4 of Formula XVI is haloalkyl.

[0258] In some embodiments, R5 of Formula XVI is H. In some embodiments, R5 of Formula XVI is D. In some embodiments, R5 of Formula XVI is methyl. In some embodiments, R5 of Formula XVI is haloalkyl.

[0259] In some embodiments, g in Formula XVI is 0, 1, 2, or 3. In some embodiments, g in Formula XVI is 0. In some embodiments, g in Formula XVI is 1. In other embodiments, g in Formula XVI is 2. In other embodiments, g in Formula XVI is 3.

[0260] In some embodiments, h in Formula XVI is 0, 1, 2, or 3. In some embodiments, h in Formula XVI is 0. In some embodiments, h in Formula XVI is 1. In other embodiments, h in Formula XVI is 2. In other embodiments, h in Formula XVI is 3.

[0261] In some embodiments, the compound of formula (I) is a compound of formula XVII:

[0262] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a and (R6) q is defined in relation to formula (I), L1 is a bond, -CH2-, or C=O, and V is CR 11 or N, W is CR 11 or N, U is C(R 11 )2, NR 10 , or O, R 10 H, D, C 1~6 alkyl, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, and R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; Each g, h, j, and k is independently 0, 1, 2, or 3.

[0263] In some embodiments, E in Formula XVII is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR aIn some embodiments, E in Formula XVII is a bond. In some embodiments, E in Formula XVII is -O-. In some embodiments, E in Formula XVII is -S-. In some embodiments, E in Formula XVII is C(Ra)2. In some embodiments, E in Formula XVII is -C(=O)NR-. In some embodiments, E in Formula XVII is NR a is.

[0264] In some embodiments, L1 of Formula XVII is a bond. In some embodiments, L1 of Formula XVII is -CH2-. In some embodiments, L1 of Formula XVII is C=O.

[0265] In some embodiments, V of Formula XVII is CR 11 In other embodiments, V in formula XVII is N.

[0266] In some embodiments, W of Formula XVII is CR 11 In other embodiments, W in formula XVII is N.

[0267] In some embodiments, U of Formula XVII is C(R 11 In other embodiments, U in formula XVII is NR 10 In still other embodiments, U in formula XVII is O.

[0268] In some embodiments, R of Formula XVII 11 is H. In some embodiments, R of Formula XVII 11 is D. In some embodiments, R of Formula XVII 11 In some embodiments, R of Formula XVII is fluoro. 11 is C 1~6 In another embodiment, R of Formula XVII is alkyl. 11 is methyl or ethyl. In some embodiments, R of Formula XVII11 is C 1~6 It is an alkoxide.

[0269] In some embodiments, R of Formula XVII 10 is H. In some embodiments, R of Formula XVII 10 is D. In some embodiments, R of Formula XVII 10 is C 1~6 In another embodiment, R of Formula XVII is alkyl. 10 is methyl or ethyl. In some embodiments, R of Formula XVII 10 is haloalkyl.

[0270] In some embodiments, U of Formula XVII is C(R 11 )2, then each R 11 is H. In some embodiments, U of Formula XVII is C(R 11 )2, then each R 11 is methyl. In some embodiments, U of Formula XVII is C(R 11 )2, then one R 11 is methyl and one R 11 is hydrogen. In some embodiments, U of Formula XVII is C(R 11 )2, then each R 10 is halogen. In some embodiments, U of Formula XVII is C(R 11 )2, then one R 11 is a halogen and one R 11 is hydrogen. In other embodiments, U of Formula XVII is C(R 11 )2, then each R 11 is fluoro. In other embodiments, U of Formula XVII is C(R 11 )2, then one R 11 is fluoro and one R 11 is hydrogen.

[0271] In some embodiments, U of formula XVII is NCH. In other embodiments, U of formula XVII is NCH.

[0272] In some embodiments, R4 of Formula XVII is H. In some embodiments, R4 of Formula XVII is D. In some embodiments, R4 of Formula XVII is methyl. In some embodiments, R4 of Formula XVII is haloalkyl.

[0273] In some embodiments, R5 of Formula XVII is H. In some embodiments, R5 of Formula XVII is D. In some embodiments, R5 of Formula XVII is methyl. In some embodiments, R5 of Formula XVII is haloalkyl.

[0274] In some embodiments, g in Formula XVII is 0, 1, 2, or 3. In some embodiments, g in Formula XVII is 0. In some embodiments, g in Formula XVII is 1. In other embodiments, g in Formula XVII is 2. In other embodiments, g in Formula XVII is 3.

[0275] In some embodiments, h in Formula XVII is 0, 1, 2, or 3. In some embodiments, h in Formula XVII is 0. In some embodiments, h in Formula XVII is 1. In other embodiments, h in Formula XVII is 2. In other embodiments, h in Formula XVII is 3.

[0276] In some embodiments, j in Formula XVII is 0, 1, 2, or 3. In some embodiments, j in Formula XVII is 0. In some embodiments, j in Formula XVII is 1. In other embodiments, j in Formula XVII is 2. In other embodiments, j in Formula XVII is 3.

[0277] In some embodiments, k in Formula XVII is 0, 1, 2, or 3. In some embodiments, k in Formula XVII is 0. In some embodiments, k in Formula XVII is 1. In other embodiments, k in Formula XVII is 2. In other embodiments, k in Formula XVII is 3.

[0278] In some embodiments, the compound of Formula (I) is a compound of Formula XVIII:

[0279] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a and L1 is a bond, -CH2-, or C=O, and V is CR 11 or N, W is CR 11 or N, R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, R 10 H, D, C 1~6 alkyl, or haloalkyl.

[0280] In some embodiments, E in Formula XVIII is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in Formula XVIII is a bond. In some embodiments, E in Formula XVIII is -O-. In some embodiments, E in Formula XVIII is -S-. In some embodiments, E in Formula XVIII is C(R a)2. In some embodiments, E in Formula XVIII is —C(═O)NR—. In some embodiments, E in Formula XVIII is NR a is.

[0281] In some embodiments, L1 in Formula XVIII is a bond. In some embodiments, L1 in Formula XVIII is -CH2-. In some embodiments, L1 in Formula XVIII is C=O.

[0282] In some embodiments, V in Formula XVIII is CR 11 In other embodiments, V in formula XVIII is N.

[0283] In some embodiments, W in formula XVIII is CR 11 In other embodiments, W in formula XVIII is N.

[0284] In some embodiments, R4 of Formula XVIII is H. In some embodiments, R4 of Formula XVIII is D. In some embodiments, R4 of Formula XVIII is methyl. In some embodiments, R4 of Formula XVIII is haloalkyl.

[0285] In some embodiments, R5 of Formula XVIII is H. In some embodiments, R5 of Formula XVIII is D. In some embodiments, R5 of Formula XVIII is methyl. In some embodiments, R5 of Formula XVIII is haloalkyl.

[0286] In some embodiments, R of Formula XVIII 10 is H. In some embodiments, R of Formula XVIII 10 is D. In some embodiments, R of Formula XVIII 10 is C 1~6 In another embodiment, R of Formula XVIII is alkyl. 10is methyl or ethyl. In some embodiments, R of Formula XVIII 10 is haloalkyl.

[0287] In some embodiments, R of Formula XVIII 11 is H. In some embodiments, R of Formula XVIII 11 is D. In some embodiments, R of Formula XVIII 11 In some embodiments, R of Formula XVIII is fluoro. 11 is C 1~6 In another embodiment, R of Formula XVIII is alkyl. 11 is methyl or ethyl. In some embodiments, R of Formula XVIII 11 is C 1~6 It is an alkoxide.

[0288] In some embodiments, the compound of Formula (I) is a compound of Formula XIX:

[0289] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a wherein L1 is a bond, —CH2—, or C═O; V is CR 11 or N, R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; R 10 is H or C 1~6 is alkyl, R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 It is an alkoxide.

[0290] In some embodiments, E in Formula XIX is a bond, —O—, —S—, C(Ra )2, -C(=O)NR-, or NR a In some embodiments, E in Formula XIX is a bond. In some embodiments, E in Formula XIX is -O-. In some embodiments, E in Formula XIX is -S-. In some embodiments, E in Formula XIX is C(Ra)2. In some embodiments, E in Formula XIX is -C(=O)NR-. In some embodiments, E in Formula XIX is NR a is.

[0291] In some embodiments, L1 of formula XIX is a bond. In some embodiments, L1 of formula XIX is -CH2-. In some embodiments, L1 of formula XIX is C=O.

[0292] In some embodiments, V of formula XIX is CR 11 In other embodiments, V in formula XIX is N.

[0293] In some embodiments, R4 of Formula XIX is H. In some embodiments, R4 of Formula XIX is D. In some embodiments, R4 of Formula XIX is methyl. In some embodiments, R4 of Formula XIX is haloalkyl.

[0294] In some embodiments, R5 of Formula XIX is H. In some embodiments, R5 of Formula XIX is D. In some embodiments, R5 of Formula XIX is methyl. In some embodiments, R5 of Formula XIX is haloalkyl.

[0295] In some embodiments, R of Formula XIX 10 is H. In some embodiments, R of formula XIX 10 is D. In some embodiments, R of formula XIX 10 is C 1~6 In another embodiment, R of formula XIX is alkyl. 10is methyl or ethyl. In some embodiments, R of formula XIX 10 is haloalkyl.

[0296] In some embodiments, R of Formula XIX 11 is H. In some embodiments, R of formula XIX 11 is D. In some embodiments, R of formula XIX 11 In some embodiments, R of formula XIX is fluoro. 11 teeth, C 1~6 In another embodiment, R of formula XIX is alkyl. 11 is methyl or ethyl. In some embodiments, R of formula XIX 11 is C 1~6 It is an alkoxide.

[0297] In some embodiments, the compound of formula (I) is a compound of formula XX:

[0298] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a wherein L1 is a bond, —CH2—, or C═O; V is CR 11 or N, W is CR 11 or N, R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 alkoxide, R 10 H, D, C 1~6 It is alkyl.

[0299] In some embodiments, E in formula XX is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in formula XX is a bond. In some embodiments, E in formula XX is -O-. In some embodiments, E in formula XX is -S-. In some embodiments, E in formula XX is C(R a )2. In some embodiments, E in formula XX is -C(=O)NR-. In some embodiments, E in formula XX is NRa.

[0300] In some embodiments, L1 of formula XX is a bond. In some embodiments, L1 of formula XX is -CH2-. In some embodiments, L1 of formula XX is C=O.

[0301] In some embodiments, V of formula XX is CR 11 In other embodiments, V in formula XX is N.

[0302] In some embodiments, W of formula XX is CR 11 In other embodiments, W in formula XX is N.

[0303] In some embodiments, R4 of formula XX is H. In some embodiments, R4 of formula XX is D. In some embodiments, R4 of formula XX is methyl. In some embodiments, R4 of formula XX is haloalkyl.

[0304] In some embodiments, R5 of formula XX is H. In some embodiments, R5 of formula XX is D. In some embodiments, R5 of formula XX is methyl. In some embodiments, R5 of formula XX is haloalkyl.

[0305] In some embodiments, R of formula XX 10is H. In some embodiments, R of formula XX 10 is D. In some embodiments, R of Formula XVIII 10 is C 1~6 In another embodiment, R of formula XX is alkyl. 10 is methyl or ethyl. In some embodiments, R of formula XX 10 is haloalkyl.

[0306] In some embodiments, R of formula XX 11 is H. In some embodiments, R of formula XX 11 is D. In some embodiments, R of formula XX 11 In some embodiments, R of formula XX is fluoro. 11 is C 1~6 In another embodiment, R of formula XX is alkyl. 11 is methyl or ethyl. In some embodiments, R of formula XX 11 is C 1~6 It is an alkoxide.

[0307] In some embodiments, the compound of formula (I) is a compound of formula XXI:

[0308] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a wherein L1 is a bond, —CH2—, or C═O; V is CR 11 or N, R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; R 10 is H or C 1~6 is alkyl, R 11 H, D, Fluor, C 1~6Alkyl or C 1~6 It is an alkoxide.

[0309] In some embodiments, E in formula XXI is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in formula XXI is a bond. In some embodiments, E in formula XXI is -O-. In some embodiments, E in formula XXI is -S-. In some embodiments, E in formula XXI is C(R a )2. In some embodiments, E in formula XXI is —C(═O)NR—. In some embodiments, E in formula XXI is NR a is.

[0310] In some embodiments, L1 of formula XXI is a bond. In some embodiments, L1 of formula XXI is -CH2-. In some embodiments, L1 of formula XXI is C=O.

[0311] In some embodiments, V of formula XXI is CR 11 In other embodiments, V in formula XXI is N.

[0312] In some embodiments, R4 of Formula XXI is H. In some embodiments, R4 of Formula XXI is D. In some embodiments, R4 of Formula XXI is methyl. In some embodiments, R4 of Formula XXI is haloalkyl.

[0313] In some embodiments, R5 of Formula XXI is H. In some embodiments, R5 of Formula XXI is D. In some embodiments, R5 of Formula XXI is methyl. In some embodiments, R5 of Formula XXI is haloalkyl.

[0314] In some embodiments, R of Formula XXI 10is H. In some embodiments, R of formula XXI 10 is D. In some embodiments, R of formula XXI 10 is C 1~6 In another embodiment, R of formula XXI is alkyl. 10 is methyl or ethyl. In some embodiments, R of formula XXI 10 is haloalkyl.

[0315] In some embodiments, R of Formula XXI 11 is H. In some embodiments, R of formula XXI 11 is D. In some embodiments, R of formula XXI 11 In some embodiments, R of formula XXI is fluoro. 11 teeth, C 1~6 In another embodiment, R of formula XXI is alkyl. 11 is methyl or ethyl. In some embodiments, R of formula XXI 11 is C 1~6 It is an alkoxide.

[0316] In some embodiments, the compound of formula (I) is a compound of formula XXII:

[0317] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR a wherein L1 is a bond, —CH2—, or C═O; V is CR 11 or N, W is CR 11 or N, R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; R 11 H, D, Fluor, C1~6 Alkyl or C 1~6 alkoxide, R 10 H, D, C 1~6 alkyl, or haloalkyl.

[0318] In some embodiments, E in Formula XXII is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in Formula XXII is a bond. In some embodiments, E in Formula XXII is -O-. In some embodiments, E in Formula XXII is -S-. In some embodiments, E in Formula XXII is C(R a )2. In some embodiments, E in Formula XXII is —C(═O)NR—. In some embodiments, E in Formula XXII is NR a is.

[0319] In some embodiments, L1 in formula XXII is a bond. In some embodiments, L1 in formula XXII is -CH2-. In some embodiments, L1 in formula XXII is C=O.

[0320] In some embodiments, V in formula XXII is CR 11 In other embodiments, V in formula XXII is N.

[0321] In some embodiments, W in formula XXII is CR 11 In other embodiments, W in formula XXII is N.

[0322] In some embodiments, R4 of Formula XXII is H. In some embodiments, R4 of Formula XXII is D. In some embodiments, R4 of Formula XXII is methyl. In some embodiments, R4 of Formula XXII is haloalkyl.

[0323] In some embodiments, R5 of Formula XXII is H. In some embodiments, R5 of Formula XXII is D. In some embodiments, R5 of Formula XXII is methyl. In some embodiments, R5 of Formula XXII is haloalkyl.

[0324] In some embodiments, R of Formula XXII 10 is H. In some embodiments, R of Formula XXII 10 is D. In some embodiments, R of Formula XXII 10 is C 1~6 In another embodiment, R of Formula XXII is alkyl. 10 is methyl or ethyl. In some embodiments, R of Formula XXII 10 is haloalkyl.

[0325] In some embodiments, R of Formula XXII 11 is H. In some embodiments, R of Formula XXII 11 is D. In some embodiments, R of Formula XXII 11 In some embodiments, R of Formula XXII is fluoro. 11 is C 1~6 In another embodiment, R of Formula XXII is alkyl. 11 is methyl or ethyl. In some embodiments, R of Formula XXII 11 is C 1~6 It is an alkoxide.

[0326] In some embodiments, the compound of Formula (I) is a compound of Formula XXIII:

[0327] [ka] or a pharmaceutically acceptable salt thereof, wherein: E is a bond, -O-, -S-, C(R a )2, -C(=O)NR a - or NR aand L1 is a bond, —CH2—, or C═O; V is CR 11 or N, R4 is H, D, Me, or haloalkyl; R5 is H, D, Me, or haloalkyl; R 10 H, D, C 1~6 alkyl, or haloalkyl; R 11 H, D, Fluor, C 1~6 Alkyl or C 1~6 It is an alkoxide.

[0328] In some embodiments, E in Formula XXIII is a bond, —O—, —S—, C(R a )2, -C(=O)NR-, or NR a In some embodiments, E in Formula XXIII is a bond. In some embodiments, E in Formula XXIII is -O-. In some embodiments, E in Formula XXIII is -S-. In some embodiments, E in Formula XXIII is C(R a )2. In some embodiments, E in Formula XXIII is —C(═O)NR—. In some embodiments, E in Formula XXIII is NR a is.

[0329] In some embodiments, L1 in formula XXIII is a bond. In some embodiments, L1 in formula XXIII is -CH2-. In some embodiments, L1 in formula XXIII is C=O.

[0330] In some embodiments, V in formula XXIII is CR 11In other embodiments, V in Formula XXIII is N. In some embodiments, R4 in Formula XXIII is H. In some embodiments, R4 in Formula XXIII is D. In some embodiments, R4 in Formula XXIII is methyl. In some embodiments, R4 in Formula XXIII is haloalkyl.

[0331] In some embodiments, R5 of Formula XXIII is H. In some embodiments, R5 of Formula XXIII is D. In some embodiments, R5 of Formula XXIII is methyl. In some embodiments, R5 of Formula XXIII is haloalkyl.

[0332] In some embodiments, R of Formula XXIII 10 is H. In some embodiments, R of Formula XXIII 10 is D. In some embodiments, R of Formula XXIII 10 is C 1~6 In another embodiment, R of formula XXIII is alkyl. 10 is methyl or ethyl.

[0333] In some embodiments, R of Formula XXIII 11 is H. In some embodiments, R of Formula XXIII 11 is D. In some embodiments, R of Formula XXIII 11 In some embodiments, R of Formula XXIII is fluoro. 11 is C 1~6 In another embodiment, R of formula XXIII is alkyl. 11 is methyl or ethyl. In some embodiments, R of Formula XXIII 11 is C 1~6 It is an alkoxide.

[0334] In still further embodiments, the compound of formula (I) is 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one, or a pharmaceutically acceptable salt thereof.

[0335] In still further embodiments, the compound of formula (I) is 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 3'-chloro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-3'-(trifluoromethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-chloro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-ethyl-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-isopropylpyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(5-methyl-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-[5-methyl-2-[[5-(1-methylpiperidin-3-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, 5'-ethyl-2'-[5-methyl-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(1-ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-3'-(trifluoromethyl)spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 3'-chloro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclo-propane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1-ethylpyrrolidin-3-yl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclo-propane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-((3aS,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 5-methyl-2-[4-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]spiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-methylpyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-methylpyrimidin-4-yl]-3,5-dimethylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 5-methyl-2-[5-methyl-2-[[5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[5-chloro-2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[5-chloro-2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2'-(5-fluoro-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1-(2,2-difluoroethyl)piperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(4-methyl-piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1-ethyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 5-methyl-2-[4-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]spiro[6H-thieno[3,2-c]pyridin-7,1'-cyclobutan]-4-one, 5-methyl-2-[5-methyl-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[6H-thieno[3,2-c]pyridin-7,1'-cyclobutan]-4-one, 2-[5-chloro-2-[[5-(1-methyl-piperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclobutan]-4-one, 2'-(5-fluoro-2-((5-(6-(methyl-d3)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-5'-(methyl-d3)-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-morpholino-pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2-[2-[[5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one, 2-[5-fluoro-2-[[5-[4-methyl-2-(trifluoromethyl)piperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one, 2'-[5-fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3'-methyl-5'-(trideuteriomethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, 2'-[2-[[5-(1-ethylpyrrolidin-3-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, (E)-2'-(2-((5-(1-(but-2-en-1-yl)pyrrolidin-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2-[5-fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3-methyl-spiro[5H-thieno[2,3-c]pyrrole-6,1'-cyclopropan]-4-one, 5'-ethyl-2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2''-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5''-methyl-5'',6''-dihydro-4''H-dispiro[cyclopropane-1,1'-cyclobutane-3',7''-thieno[3,2-c]pyridin]-4''-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-2,3,5,5',6,6'-hexahydro-4'H-spiro[pyran-4,7'-thieno[3,2-c]pyridin]-4'-one, 5'-methyl-2'-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(2-ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2-[2-[[6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one, 2'-(5-fluoro-2-((6-(1-isopropylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 3,3-difluoro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3,3-difluoro-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one 2-[2-[[5-(4-ethyl-2-oxopiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one, 2-[5-fluoro-2-[[6-(1-methylpiperidin-4-yl)pyridazin-3-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one, or and pharmaceutically acceptable salts thereof.

[0336] In still further embodiments, the compound of formula (I) is 6'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methyl-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-isoquinolin]-1'-one, 6'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2'-methyl-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-isoquinolin]-1'-one, 6'-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methyl-2',3'-dihydro-1'H-spiro[cyclo-pentane-1,4'-isoquinolin]-1'-one, 6'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methyl-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinolin]-1'-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-1',5'-dimethyl-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[3,2-c]pyridin]-4'(1'H)-one, 6'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methylspiro[cyclopentane-1,1'-isoindolin]-3'-one, 6'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2'-methylspiro[cyclopentane-1,1'-isoindolin]-3'-one, or and pharmaceutically acceptable salts thereof.

[0337] It will be apparent that compounds of Formula I, including all subgenera described herein, may possess multiple stereocenters. As a result, multiple stereoisomers (enantiomers and diastereomers) of compounds of Formula I (and the subgenera described herein) exist. The present disclosure contemplates and includes each stereoisomer of any compound of Formula I (and the subgenera described herein), as well as mixtures of such stereoisomers.

[0338] Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of this disclosure.

[0339] Isotopic variations of the compounds of Formula I (including all subgenera described herein) are also contemplated by the present disclosure.

[0340] Pharmaceutical Compositions and Methods of Administration In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0341] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof, as the active ingredient. If desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof, as well as one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0342] The subject pharmaceutical compositions can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of pharmaceutical compositions. If desired, one or more compounds of the present invention and the other drugs can be mixed in a preparation, or both components can be formulated in separate preparations and used separately or in combination at the same time.

[0343] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, less than 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a range defined by any two of the above numbers, inclusive) w / w, w / v, or v / v.

[0344] In some embodiments, the concentration of one or more compounds of the present invention is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%18%, 17.75%, 17.50%, 17.25%17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%15%, 14.75%, 14. 50%, 14.25%14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%11%, 10.75%, 10.50%, 10.25%10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.0 greater than 2%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a range defined by any two of the above numbers inclusive) w / w, w / v, or v / v.

[0345] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.0 The range is 8% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0346] In some embodiments, the concentration of one or more compounds of the present invention ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0347] In some embodiments, the amount of one or more compounds of the present invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g , 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or a range defined by and inclusive of any two of the foregoing values).

[0348] In some embodiments, the amount of one or more compounds of the present invention is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0. 0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008 g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0 .045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g , 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.45g, 0.35g, 0.4g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g , 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or a number within a range defined by any two of the above numbers, inclusive).

[0349] In some embodiments, the amount of one or more compounds of the present invention ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0350] The compounds according to the present invention are effective over a wide dosage range. For example, in the treatment of an adult, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician.

[0351] Pharmaceutical compositions of the present invention typically contain an active ingredient of the present invention (i.e., a compound of the present disclosure) or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions, and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0352] Non-limiting exemplary pharmaceutical compositions and methods for preparing them are described below.

[0353] A pharmaceutical composition for oral administration. In some embodiments, the present invention provides an oral pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0354] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration containing (i) an effective amount of a compound of the present invention, optionally (ii) an effective amount of a second pharmaceutical agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third pharmaceutical agent.

[0355] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions of the present invention suitable for oral administration can be provided as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surface active or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0356] Because water can accelerate the degradation of some compounds, the present invention also encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, water can be added (e.g., 5%) in pharmaceutical applications as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of a formulation over time. Anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, allowing them to be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0357] The active ingredient can be combined in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms, depending on the form of preparation desired for administration. In preparing compositions for oral dosage forms, any pharmaceutical medium can be used as a carrier, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, etc., and disintegrants can be used in some embodiments for oral solid preparations without the use of lactose. For example, suitable carriers include powders, capsules, and tablets, as well as solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0358] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as gum acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0359] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0360] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Using too much disintegrant can produce tablets that disintegrate in the bottle. Using too little can result in insufficient disintegration, which can alter the rate and extent of release of the active ingredient from the dosage form. Therefore, dosage forms of the compounds disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discerned by those skilled in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0361] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0362] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0363] Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0364] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0365] Suitable hydrophilic surfactants will generally have an HLB value of at least 10, while suitable lipophilic surfactants will generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0366] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guideline that is generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0367] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0368] Among the aforementioned groups, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0369] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactyl esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate , succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroylcarnitine, palmitolcarnitine, myristoylcarnitine, and ionized forms of salts and mixtures thereof.

[0370] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic interesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, polyoxyethylene sterols, derivatives and analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, polyethylene glycol sorbitan fatty acid esters, and hydrophilic interesterification products of polyols and at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0371] Other hydrophilic nonionic surfactants include PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG -20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-4 0 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glyceride, PEG-8 Caprate / Caprylate Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soysterol, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, PO Examples of suitable glycerin-based copolymers include, but are not limited to, PEG-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol, PEG 15-100 octylphenol, and poloxamer.

[0372] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, mono- and diglyceride lactic acid derivatives, the hydrophobic transesterification product of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, fat-soluble vitamins / vitamin derivatives, and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of polyols and at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0373] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as injection compositions. Solubilizing agents may also be added to increase the solubility of hydrophilic drugs and / or other components (e.g., surfactants) or to maintain the composition as a stable or homogeneous solution or dispersion.

[0374] Examples of suitable solubilizers include alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- These include, but are not limited to, alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0375] Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyalkylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0376] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biologically acceptable amount, which can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize drug concentration, it may be advantageous to include an amount of solubilizer that far exceeds the biologically acceptable amount, with the excess solubilizer being removed using conventional techniques such as distillation or evaporation before providing the composition to a subject. Thus, when present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, or 1%, can also be used. Typically, the solubilizer can be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0377] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0378] In addition, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharmaceutically acceptable acids (e.g., acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.). Salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0379] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0380] Injectable pharmaceutical compositions. In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the drugs in the composition are as described herein.

[0381] Forms into which the novel compositions of the present invention can be incorporated for administration by injection include sesame oil, corn oil, cottonseed oil, or peanut oil, as well as aqueous or oily suspensions or emulsions containing elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0382] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc.

[0383] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount into a suitable solvent with various other ingredients as listed above, as needed, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and the other necessary ingredients listed above.For the preparation of sterile powder for sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying, which produces powder of active ingredient with any other desired ingredients from the solution that has been previously sterile-filtered.

[0384] Pharmaceutical compositions for topical delivery (eg, transdermal). In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0385] The composition of the present invention can be formulated into a solid, semi-solid or liquid form suitable for local or topical administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, carriers with higher density can provide areas with prolonged exposure to active ingredients.In contrast, solution formulations can provide more rapid exposure of active ingredients to selected areas.

[0386] The pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients, which are compounds that allow for increased penetration of or assist in the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those skilled in the art of topical formulation.

[0387] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0388] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without other agents.

[0389] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0390] Pharmaceutical compositions for inhalation. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure respirator. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0391] Other pharmaceutical compositions. Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill,20037ybg;Goodman and Gilman,eds.,The Pharmacological Basis of Therapeutics,Tenth Edition,McGraw Hill,2001;Remingtons Pharmaceutical Sciences,20th Ed.,Lippincott Williams & Wilkins.,2000;Martindale,The Extra Pharmacopoeia,Thirty-Second Edition(The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties.

[0392] The compounds or pharmaceutical compositions of the present invention can be administered by any method that allows delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, administration via local delivery by catheter or stent, or administration via inhalation. The compounds can also be administered intraadiposely or intrathecally.

[0393] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. However, effective dosages range from about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this amounts to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned range may be more than sufficient, while in other cases, even higher doses may be used without causing adverse side effects, for example, by dividing such higher doses into several smaller doses for administration throughout the day.

[0394] In some embodiments, the compounds of the invention are administered in a single dose.

[0395] Typically, such administration is by injection, e.g., intravenous injection, to rapidly introduce the drug. However, other routes may be used as appropriate. A single dose of the compound of the present invention may also be used to treat acute conditions.

[0396] In some embodiments, the compound of the present invention is administered in multiple doses. Dosing can be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing can be about once per month, once every two weeks, once per week, or once every other day. In another embodiment, the compound of the present invention and another agent are administered together about once per day to about six times per day. In another embodiment, administration of the compound of the present invention and another agent continues for less than about seven days. In yet another embodiment, administration continues for more than about six days, ten days, fourteen days, twenty-eight days, two months, six months, or one year. In some cases, continuous administration is achieved and maintained as long as necessary.

[0397] Administration of the compounds of the invention can continue for as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered chronically, for example, to treat chronic effects.

[0398] An effective amount of a compound of this invention can be administered by any of the accepted modes of administration for drugs with similar utilities, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant, in either a single dose or multiple doses.

[0399] The compositions of the present invention can also be delivered via impregnated or coated devices, such as stents, or cylindrical polymers inserted into the artery. Such administration methods can help prevent or improve restenosis after treatments such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compounds of the present invention can be administered by local delivery, for example, from the struts of a stent, from a stent graft, from a graft, or from the cover or sheath of a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymer matrix and can serve to bind the compound to the stent. Suitable polymer matrices for such uses include, for example, lactone-based polyesters or copolyesters (e.g., polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-LLA)), polysiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices can be non-degradable or can degrade over time, releasing the compound. The compounds of the present invention can be applied to the surface of the stent by various methods, such as dipping / spin coating, spray coating, dip coating, and / or brush coating. The compound can be applied in a solvent, and the solvent can evaporate to form a layer of the compound on the stent. Alternatively, the compound can be disposed within the body of the stent or graft, for example, within microchannels or micropores. Upon implantation, the compound diffuses from the stent body and contacts the arterial wall. Such stents can be prepared by immersing a stent, fabricated to contain such micropores or microchannels, in a solution of the compound of the present invention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent can be removed via a further brief solvent wash. In yet another embodiment, the compounds of the present invention can be covalently bonded to a stent or graft. A covalent linker can be used that decomposes in vivo, resulting in the release of the compounds of the present invention. For such purposes, any biolabile bond, such as an ester, amide, or anhydride bond, can be used. The compounds of the present invention can also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds by pericarded or adventitial application of the formulations of the present invention can also be performed to reduce restenosis.

[0400] Various stent devices that may be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. Patent No. 5,451,233, U.S. Patent No. 5,040,548, U.S. Patent No. 5,061,273, U.S. Patent No. 5,496,346, U.S. Patent No. 5,292,331, U.S. Patent No. 5,674,278, U.S. Patent No. 3,657,744, U.S. Patent No. 4,739,762, U.S. Patent No. 5,195,984, U.S. Patent No. 5,292,331, U.S. Patent No. 5,674,278, U.S. Patent No. 5,879,382, U.S. Patent No. 6,344,053.

[0401] The compound of the present invention can be administered in dosage.It is known in the art that due to the inter-subject variability in compound pharmacokinetics, individualized dosage regimen is necessary for optimal treatment.The dosage of the compound of the present invention can be found by routine experimentation in light of the present disclosure.

[0402] When a compound of the invention is administered in a composition containing one or more drugs, and the drugs have a shorter half-life than the compound of the invention, the unit dosage forms of the drugs and the compounds of the invention may be adjusted accordingly.

[0403] The subject pharmaceutical compositions may be in a form suitable for oral administration as, for example, tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions; parenteral injection as a sterile solution, suspension, or emulsion; topical administration as an ointment or cream; or rectal administration as a suppository. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dosage. The pharmaceutical composition comprises a conventional pharmaceutical carrier or excipient and a compound according to the present invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0404] Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0405] How to use The method typically involves administering a therapeutically effective amount of a compound of the present invention to a subject. The therapeutically effective amount of the combination of compounds of the present invention can vary depending on the intended use (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight and age, the severity of the disease state, the mode of administration, etc.), and can be easily determined by one skilled in the art. The term also applies to a dose that induces a specific response in target cells (e.g., reduced proliferation or down-regulation of the activity of a target protein). The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0406] As used herein, "IC 50The term "half-maximal inhibitory concentration" refers to the half-maximal inhibitory concentration of an inhibitor in inhibiting a biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to half-inhibit a given biological process (or a component of the process, i.e., an enzyme, a cell, a cellular receptor, or a microorganism). In other words, it is the half-maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50). EC50 refers to the plasma concentration required to obtain >50% of the maximal effect in vivo.

[0407] In some embodiments, the subject methods utilize CDK inhibitors that have IC50 values ​​at or below about a predetermined value, as determined in an in vitro assay. In some embodiments, the CDK inhibitor has an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less. Bottom, 170nM or less, 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less, 65 Inhibits CDK with an IC50 value of 0 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM or less, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less, 1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μM or less, 2 μM or less, 5 μM or less, 10 μM or less, 15 μM or less, 20 μM or less, 25 μM or less, 30 μM or less, 40 μM or less, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM or less (or a range defined by, and including, any two of the foregoing values).

[0408] In some embodiments, the CDK inhibitor selectively inhibits a CDK with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times lower (or a number within a range defined by and including any two of the above numbers) than its IC50 value for one, two, or three other CDKs.

[0409] In some embodiments, the CDK inhibitor is at or below about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 260 nM, 270 nM, 280 nM, 290 nM, 300 nM, 310 nM, 320 nM, 330 nM, 340 nM, 350 nM, 360 nM, 370 nM, 380 nM, 390 nM, 400 nM, 410 nM, 420 nM, 430 nM, 440 nM, 450 nM, 460 nM, 470 nM, 480 nM, 490 nM, 500 nM, 510 nM, 520 nM, 530 nM, 540 nM, 550 nM, 560 nM, 570 nM, 580 nM, 590 nM, 600 nM, 610 nM, 620 nM, 630 nM, 640 nM, 650 nM, 660 nM, 670 nM, 680 nM, 690 nM, 700 nM, 710 nM, 720 nM, 730 nM, 740 nM, 750 75nM, 300nM, 325nM, 350nM, 375nM, 400nM, 425nM, 450nM, 475nM, 500nM, 550nM, 600nM, 650nM , 700nM, 750nM, 800nM, 850nM, 900nM, 950nM, 1μΜ, 1.1μΜ, 1.2μΜ, 1.3μΜ, 1.4μΜ, 1.5μΜ, 1.6μΜ , 1.7 μM, 1.8 μM, 1.9 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM (or within a range defined by and including any two of the above numbers) The compound selectively inhibits the CDK with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times (or a number within a range defined by and including any two of the above numbers) less than its IC50 value for one, two, or three other CDKs.

[0410] The subject methods are useful for treating disease states associated with CDKs. Any disease state that results directly or indirectly from abnormal activity or expression levels of a CDK may be a disease state of interest.

[0411] Various disease states associated with CDKs have been reported, including autoimmune diseases, neurodegeneration (e.g., Parkinson's disease, Alzheimer's disease, and ischemia), inflammatory diseases, viral infections, and cancer (e.g., colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, or pancreatic cancer).

[0412] Non-limiting examples of such conditions include acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acral hidradenoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, enamel, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatous odontogenic tumor, adrenocortical tumor, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancer, AIDS-related lymphoma, Alveolar soft part sarcoma, acute myeloid leukemia, acute promyelocytic leukemia, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell carcinoma, B-cell lymphoma, Bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer, Brenner tumor, bronchial tumor, bronchoalveolar carcinoma, Brown tumor, Burkitt lymphoma, cancer of unknown primary origin, carcinoid tumor, carcinoma, penile cancer, cancer of unknown primary origin, Carcinosarcoma, Castleman's disease, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, bile duct cancer, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Degos disease, dermatofibrosarcoma protozoanoma, dermoid cyst, decidual small round cell tumor, diffuse large B-cell lymphoma, decidual neuroepithelial tumor, germ cell carcinoma, endodermal sinus tumor, endometrial carcinoma, endometrioid tumor, intestinal-associated tumor T-cell lymphoma, ependymoblastoma, ependymoma, epidermoid carcinoma, parathyroid sarcoma, erythroblastic leukemia, esophageal cancer, esthesioneublastoma, Ewing family of tumors, Ewing family of sarcoma, Ewing sarcoma, extracranial germ cell tumor, extracarinal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fetal, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, gallbladder cancer, ganglioneuroma, radiculouroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germ cell tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone,Glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), hemangioblastoma, hemangiopericytoma, angiosarcoma, hematologic malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, hereditary breast and ovarian cancer syndrome, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, kidney cancer, Klatskin tumor, Krukenberg tumor, laryngeal cancer, lentigo maligna, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, luteoma, lymphangioma , lymphangiosarcoma, lymphoepithelioma, lymphocytic leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma of bone, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant Triton tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, mastocytosis, breast germ cell tumor, breast tumor, medullary thyroid carcinoma, medulloblastoma, medulloepithelioma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, occult squamous cell carcinoma, metastatic urothelial carcinoma, mixed Mullerian tumor, monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease myelodysplastic syndrome, myeloid leukemia, myelosarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, nasopharyngeal carcinoma, neoplasms, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, non-small cell lung cancer, ophthalmic tumors, oligodendroglioma, oligodendroglioma, optic nerve sheath meningioma, oral cavity cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian Epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant potential tumor, Paget's disease of the breast, Pancoast tumor, pancreatic cancer, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, sinus cancer, parathyroid cancer, penile cancer, hemangioperiepithelioma, pharyngeal cancer, pheochromocytoma, intermediately differentiated pineal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasma cell neoplasm, alveolar germinoma, polyembryomatous tumor, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary pleural effusion lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal cancer,Primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma, respiratory tract cancer involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation, sacral teratoma, salivary gland carcinosarcoma, Schwannomatosis, sebaceous gland carcinoma, secondary neoplasms, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, Sézary syndrome, signet ring cell tumor, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatinoma, soot warts, spinal cord tumor, spinal cord tumor, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, Table These include, but are not limited to, superficial spreading melanoma, superficial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocytic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, peripheral lymphatic vessel carcinoma, testicular cancer, sarcoma, pharyngeal cancer, thymic carcinoma, thymoma, thyroid cancer, renal pelvis and ureteral transitional cell carcinoma, transitional cell carcinoma, urethral cancer, urinary tract neoplasms, uterine sarcoma, uveal melanoma, vaginal cancer, Berner-Morrison syndrome, warty carcinoma, visual pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, and combinations thereof.

[0413] In some embodiments, the method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid cancer.

[0414] In other embodiments, the method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0415] In other embodiments, the method is for treating a disease selected from acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, leukemia, such as acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or epidermoid carcinoma.

[0416] The compounds of the present disclosure, as well as pharmaceutical compositions comprising them, can be administered alone or in combination with medical therapies, including, for example, surgery and radiation therapy, such as gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes, to treat any of the diseases described.

[0417] In other aspects, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with one or more other agents to treat any of the diseases described.

[0418] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an agonist of a nuclear receptor agent.

[0419] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with an antagonist of a nuclear receptor agent.

[0420] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with an anti-proliferative agent.

[0421] In some embodiments, the present disclosure is directed to a method of treating CDK4- and CDK6-mediated disorders in a patient in need of such treatment, comprising administering to the patient a compound of Formula I, including all subgenera described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, including all subgenera described herein.

[0422] In some embodiments, the CDK4- and CDK6-mediated disorder is cancer, hi some embodiments, the cancer is breast cancer, malignant brain tumor, colon cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis.

[0423] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is malignant brain tumor. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer.

[0424] In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is chronic lymphocytic leukemia. In some embodiments, the cancer is leukemia or lymphoma. In some embodiments, the cancer is myeloma. In some embodiments, the cancer is acute myeloid leukemia. In some embodiments, the cancer is secondary pancreatic cancer. In some embodiments, the cancer is secondary brain metastasis.

[0425] In some embodiments, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer. In some embodiments, the breast cancer is HR+ / HER2- advanced breast cancer. In some embodiments, the breast cancer is HR+ / HER2- metastatic breast cancer. In some embodiments, the breast cancer is HR+ / HER2+ advanced breast cancer. In some embodiments, the breast cancer is HR+ / HER2+ metastatic breast cancer.

[0426] In some embodiments, the malignant brain tumor is a glioblastoma, an astrocytoma, or a pontine glioma. In some embodiments, the malignant brain tumor is a glioblastoma. In some embodiments, the malignant brain tumor is an astrocytoma. In some embodiments, the malignant brain tumor is a pontine glioma.

[0427] In some embodiments, the patient is administered a pharmaceutical composition comprising a compound of Formula I, including all subgenera described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the administration is oral.

[0428] Combination therapy To treat cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds of the present invention can also be used in combination with medical therapies such as surgery or radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, and whole-body radioisotopes). Examples of suitable chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bortezomib, intravenous busulfan, oral busulfan, castellon, capecitabine, carboplatin, carmustine, and cetaxel. Cimab, chlorambucil, cisplatin, cladribine, cloharabine, cyclophosphamide, cicarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, exemestane , fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, hisrelin acetate, ibritumomab tiuxetan acetate, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, irinotecan, lapatinib ditosylate, lenalidomide, lebrozole, leucovorin, leuproreductase acetate Lolide, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspagase, pegfilgrastim, pemetrexed disodium, pentostatin,Examples of the anticoagulant include pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

[0429] In some embodiments, the compounds of the present invention can be used in combination with therapeutic agents targeting epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors, and DNA methyltransferase inhibitors. Histone deacetylase inhibitors include, for example, vorinostat. Histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs), such as PRMT5, PRMT1, and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0430] For the treatment of cancer and other proliferative diseases, the compounds of the invention may be used in combination with targeted therapies including JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors, including PI3K-delta selective and broad-spectrum PI3K inhibitors, cyclin-dependent kinase inhibitors, including MEK inhibitors, CDK4 / 6 inhibitors and CDK9 inhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo- and extra-terminal family member (BET) inhibitors, BTK inhibitors (e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g., venetoclax), dual BCL2 family inhibitors (e.g., BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

[0431] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), or PDR001. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0432] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0433] For the treatment of autoimmune or inflammatory conditions, the compounds of the invention may be administered in combination with a corticosteroid (eg, triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone).

[0434] For the treatment of autoimmune or inflammatory conditions, the compounds of the invention may be administered in combination with immunosuppressants such as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).

[0435] In some embodiments, the present disclosure is directed to a method described herein, further comprising administering to the patient an additional therapeutic agent, in some embodiments, the additional therapeutic agent is a PRMT5 inhibitor, a HER2 kinase inhibitor, an aromatase inhibitor, an estrogen receptor antagonist, or an alkylating agent.

[0436] In some embodiments, the additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the additional therapeutic agent is a HER2 kinase inhibitor. In other embodiments, the additional therapeutic agent is an aromatase inhibitor. In other embodiments, the additional therapeutic agent is an estrogen receptor antagonist. In yet other embodiments, the additional therapeutic agent is an alkylating agent.

[0437] In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the estrogen receptor antagonist is fulvestrant. In other embodiments, the alkylating agent is temozolomide.

[0438] In still other embodiments, the PRMT5 inhibitor is a compound disclosed in U.S. Patent Application Publication No. 2020 / 0148692 (filed January 16, 2020), U.S. Patent Application Publication No. 2019 / 0284193 (filed April 5, 2019), and U.S. Published Patent Application No. 2019 / 0048014 (filed August 9, 2018), each of which is incorporated herein in its entirety.

[0439] In some embodiments, the PRMT5 inhibitor is (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt or solvate thereof, (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-7-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-difluoroisochroman-1-yl)tetrahydrofuran-3,4-diol (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5,6-difluoroisochroman-1-yl)tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt or solvate thereof, ... (2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-dichloroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2 S,3S,4R,5R)-2-((R)-6,7-difluoroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2S,3S,4R,5R)-2-((R)-5,6-difluoroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof, or (2S,3S,4R,5R)-2-((R)-6,7-dichloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof.

[0440] In some embodiments, the PRMT5 inhibitor is (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvate thereof.

[0441] synthesis The compounds of the present invention (including salts thereof) may be prepared using known organic synthesis techniques, and may be synthesized according to any of a number of possible synthetic routes.

[0442] The reaction for preparing the compounds of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can range from the freezing temperature of the solvent to the boiling point of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Depending on the specific reaction step, a suitable solvent for a specific reaction step can be selected by those skilled in the art.

[0443] The preparation of the compounds of the present invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by one skilled in the art. For the chemistry of protecting groups, see, for example, T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0444] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), or mass spectrometry, or by chromatography, e.g., high performance liquid chromatography (HPLC) or thin-layer chromatography.

[0445] The expressions "ambient temperature," "room temperature," and "rt," as used herein, are understood in the art and generally refer to a temperature that is about the temperature of the room in which a reaction is carried out, e.g., a temperature of about 20°C to about 30°C, e.g., the reaction temperature.

[0446] The compounds of the present invention can be prepared using a number of prior reactions known in the literature.The following schemes provide general guidance related to the preparation of the compounds of the present invention.Those skilled in the art will understand that they can use their general knowledge of organic chemistry to modify or optimize the preparations shown in the schemes to prepare various compounds of the present invention.Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0447] The following examples are provided to illustrate some of the concepts described within this disclosure and are considered to provide embodiments, but should not be considered to limit the more general embodiments described herein.

[0448] Example General synthetic procedure Compounds of formula (I) can be prepared by reacting W as shown in Scheme I 1 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs). Compound 1-1 can be prepared from an optionally protected compound 1-1, in which M is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs). Compound 1-1 can be prepared from M under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)] and a base such as K3PO4), under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). 1is a boronic acid, boronic ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3, Sn(Me)3, or ZnCl to give W 2 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), to give compounds 1-3. Compounds 1-3 can be coupled with amines 1-4 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as XPhos Pd G3 and a base such as CsCO3 or K3PO4) to give compounds of formula (I).

[0449] Alternatively, compound 1-1 can be converted to the appropriate compound 1-5 (e.g., M2 is B(OH)2, Bpin, BF3K, Sn(Me)3, Sn(Bu)3, or ZnCl) and then reacted with W under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as K3PO4), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). 3 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) to give compound 1-3, which can be used to synthesize compounds of formula (I).

[0450] [ka]

[0451] Intermediates for the synthesis of compounds of Formula (I) can be prepared as described in Scheme II. Compound 2-1 can be halogenated with a suitable reagent, such as N-bromosuccinimide or N-iodosuccinimide, to give compound 1-1. Alternatively, compound 2-1 can be metallated in the presence of a strong base, such as lithium diisopropylamide or butyllithium, and an appropriate reagent (e.g., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, hexamethylditin, trimethyltin chloride, or zinc chloride) to give compound 1-5.

[0452] [ka]

[0453] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme III. W can be reacted with W under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as XPhos Pd G2 and a base such as K3PO4) or under standard conditions for nucleophilic aromatic substitution, optionally in the presence of a base (e.g., diisopropylethylamine). 4 Compound 3-1, where is a halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be coupled with amine 3-2 to give compound 3-3. Nitro compound 3-3 can be reduced to amino compound 3-4 under standard reducing conditions, such as, but not limited to, H, in the presence of a transition metal catalyst (e.g., palladium on charcoal) in MeOH, Fe / NHCl in MeOH / HO, or sodium dithionite in EtOH / HO.

[0454] [ka]

[0455] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme IV. Compound 3-1 can be prepared by reacting compound 3-2 with compound 3-3, where x and y are independently 0, 1, 2, or 3, and Q is 0, 1, 2, or 3, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II)] and a base such as KPO or KCO), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). 1 is H or a protecting group such as Boc, Cbz, Bn, PMB, Trt, acetamide, or trifluoroacetamide, and M 3 is a boronic acid, boronic ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu) or ZnCl, followed by optional deprotection to give compound 4-2. Amine 4-2 can be converted to X by cleavage under standard conditions (e.g., in the presence of a base such as potassium carbonate). d is a halide (e.g., Cl, Br, or I) or a pseudohalide (e.g., OTf, OTs, or OMs), and R x is a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C1alk-aryl, C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group to afford compound 4-4. Compound 4-4 can be reduced to amine 4-5 under standard reducing conditions, such as, but not limited to, H2, in the presence of a transition metal catalyst (e.g., palladium on charcoal or platinum(IV) oxide).

[0456] Alternatively, amine 4-2 can be reacted with R y and R z are each independently H, D, —C1-C6 alkyl, 5- to 7-membered aryl, 5- to 7-membered heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-membered heterocycloalkyl, which C1-C5 alkyl, 5- to 7-membered aryl, 5- to 7-membered heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-membered heterocycloalkyl may be optionally substituted, and optionally R y and R z can be reacted with compound 4-6, which can form a cyclic ketone together with the carbon to which they are both attached, to give compound 4-7. Compound 4-7 can be reduced to amine 4-8 under standard reducing conditions, such as, but not limited to, H2, in the presence of a transition metal catalyst (e.g., palladium on charcoal or platinum(IV) oxide).

[0457] [ka]

[0458] Compounds of formula (II) can be prepared from optionally protected compounds 5-1, where W1 is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs), as shown in Scheme V. Compound 5-1 can be coupled with compound 5-2, where M is a boronic acid, boronic ester, potassium trifluoroborate, or an appropriately substituted metal such as Sn(Bu)3, Sn(Me)3, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)] and a base such as K3PO4), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)), to give W 2 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), to give compound 5-3. Compound 5-3 can be coupled with amine 5-4 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as XPhos Pd G3 and a base such as CsCO3 or K3PO4) to give compound of formula (II).

[0459] Alternatively, compound 5-1 can be reacted with a suitable compound 5-5 (e.g., M 2is converted to B(OH), Bpin, BF, K, Sn(Me), Sn(Bu), or ZnCl, followed by cleavage of W under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as KPO), or under standard Stille conditions (e.g., in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)), or under standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). 3 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) to give compound 5-3, which can be used to synthesize compounds of formula (II).

[0460] [ka]

[0461] Intermediates for the synthesis of compounds of Formula (I) can be prepared as described in Scheme VI. Compound 6-1 can be halogenated with a suitable reagent, such as N-bromosuccinimide or N-iodosuccinimide, to give compound 5-1. Alternatively, compound 6-1 can be metallated in the presence of a strong base, such as lithium diisopropylamide or butyllithium, and an appropriate reagent (e.g., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, hexamethylditin, trimethyltin chloride, or zinc chloride) to give compound 5-5.

[0462] [ka]

[0463] Intermediates for the synthesis of compounds of Formula (I) can be prepared as described in Scheme VII. Thiophene 7-1 can be lithiated with a strong base, such as butyllithium, followed by addition to ketone 7-2, where w is 0, 1, 2, or 3 and z is 1, 2, or 3, to afford alcohol 7-3. Lactone formation under standard conditions, such as in the presence of benzenesulfonyl chloride and pyridine, or in the presence of an acid (e.g., tosylic acid), or in the presence of a coupling reagent (e.g., N,N'-dicyclohexylmethanediimine or HATU) and, optionally, an additive (e.g., 1-hydroxybenzotriazole) and, optionally, a base (e.g., pyridine or N,N-diisopropylethylamine), can afford lactone 7-4. Exposure of compound 7-4 to ammonia under standard conditions, such as elevated temperature and pressure, can afford lactam 7-5. Lactam 7-5 can be alkylated with a suitable compound 7-6, where Xa is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OMs, OTs, or OTf), in the presence of a base such as NaH to provide compound 7-7.

[0464] Alternatively, compound 7-3 can be converted to R w Dehydration in the presence of alcohol 7-8, where ##STR00001## is a C1-C4 alkyl group, can give compound 7-9. Exposure of compound 7-9 to ammonia under standard conditions of elevated temperature and pressure can give lactam 7-5.

[0465] [ka]

[0466] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme VIII. Nitrile 8-1 can be reacted with X in the presence of a base such as sodium hydride. b and X cAlkylation with a suitable compound 8-2, where u and v are independently a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OMs, OTs, or OTf), and u and v are independently 1, 2, or 3, can provide compound 8-3. Reduction of nitrile 8-3 under standard conditions, such as in the presence of a reducing agent (e.g., lithium aluminum hydride or borane tetrahydrofuran complex), can provide amine 8-4. Reaction of compound 8-4 under standard conditions, such as in the presence of a phosgene source (e.g., triphosgene) and a base (e.g., NaHCO3), can provide isocyanate 8-5. Compound 8-5 can undergo intramolecular Friedel-Crafts acylation in the presence of a Lewis acid (e.g., aluminum trichloride) to give lactam 8-6. Lactam 8-6 can be alkylated with a suitable compound 7-6 in the presence of a base such as NaH to give compound 8-7.

[0467] [ka]

[0468] Intermediates for the synthesis of compounds of Formula (I) can be prepared as described in Scheme IX. Nitrile 8-3 can be reduced under standard conditions, such as in the presence of a reducing agent (e.g., diisobutylaluminum hydride or lithium triethoxyaluminum hydride), followed by hydrolysis under standard aqueous workup, such as under acidic conditions (e.g., aqueous HCl), to afford aldehyde 9-1. Aldehyde 9-1 can be reacted with R to afford nitrile 8-3 in the presence of a base (e.g., butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, KH, methylmagnesium bromide, potassium tert-butoxide, triethylamine, or KCO). e is a C1-C4 alkyl group; or R f is an aryl group, and X - is a halide anion (e.g., Cl - or Br- Olefination with a Wittig reagent 9-3, such as a counteranion, can provide acrylate 9-4. Conjugate reduction of acrylate 9-4 under standard conditions, such as in the presence of a hydride source (e.g., polymethylhydrosiloxane) and a catalyst (e.g., CuCl), can provide ester 9-5.

[0469] Compound 9-5 can be hydrolyzed in aqueous medium under basic conditions (e.g., LiOH, NaOH, or KOH) or acidic conditions (e.g., HCl or H2SO4) to form acid 9-6. Acid 9-6 can be converted to acyl chloride 9-7 under standard conditions, such as in the presence of a suitable reagent (e.g., thionyl chloride or oxalyl chloride) and, optionally, in the presence of a catalyst such as DMF. Compound 9-7 can undergo intramolecular Friedel-Crafts acylation in the presence of a Lewis acid (e.g., aluminum trichloride) to give cyclic ketone 9-8. Schmidt rearrangement of ketone 9-8 under standard conditions, such as in the presence of an azide source (e.g., sodium azide) and an acid (e.g., H2SO4), can give lactam 9-9. Alkylation of lactam 9-9 with an appropriate compound 7-6 in the presence of a base such as NaH can give compound 9-10.

[0470] [ka]

[0471] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme X. Carboxylic acid 10-1 can be reduced to primary alcohol 10-2 in the presence of a reducing agent such as lithium aluminum hydride. Alcohol 10-2 can be prepared by the reaction of Y acan be converted to compound 10-3, where is a halogen (e.g., Cl, Br, or I) under standard deoxygenative halogenation conditions (e.g., in the presence of a suitable reagent such as thionyl chloride, phosphorus tribromide, or triphenylphosphine and iodine) or a pseudohalogen (e.g., OTf, OTs, or OMs) under standard sulfonylation conditions (e.g., in the presence of an electrophile such as methanesulfonyl chloride, p-toluenesulfonyl chloride, or triflic anhydride and a base such as triethylamine). Nucleophilic displacement of compound 10-3 with a cyanide salt (e.g., NaCN or KCN) can provide nitrile 8-1.

[0472] [ka]

[0473] Intermediates for the synthesis of compounds of formula (II) can be prepared as described in Scheme XI. Under standard conditions, such as in the presence of a Lewis acid (e.g., AlCl), R k is H, D, F, C1-C8 alkoxide, —C1-C8 alkyl, fluoroalkyl, or CN, and Y 9 Friedel-Crafts acylation of compound 6-1 with acid halide 11-1, where R is a halogen (e.g., Cl or Br), can provide ketone 11-2. 1 is H, D, —C1-C8 alkoxide, —C1-C8 alkyl, fluoroalkyl, or CN to give compound 11-4. Compound 11-4 can then be condensed with guanidine or one of its salts (e.g., guanidine hydrochloride), optionally in the presence of a base (e.g., KCO), to give aminopyrimidine 11-5.

[0474] [ka]

[0475] Compounds of formula (II) can be prepared from compound 5-3 as shown in Scheme XII. Compound 5-3 can be reacted under standard nucleophilic aromatic substitution conditions (e.g., in the presence of anhydrous NH or NHOH (aq)), or standard Buchwald-Hartwig amination conditions (e.g., in the presence of an ammonia surrogate such as benzophenone imine, lithium bis(trimethylsilyl)amide, or tert-butyl carbamate, a palladium catalyst such as Pd(dba), a ligand such as XPhos or XantPhos, and optionally a base such as CsCO), or standard Ullmann coupling conditions (e.g., in the presence of an ammonia source such as NH or ammonium bicarbonate and a copper catalyst such as CuO, CuSO, or CuI) to provide aminopyrimidine 12-1. Compound 12-1 can be converted to W under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as XPhos Pd G2 or BrettPhos Pd G3 and a base such as sodium tert-butoxide or K3PO4). 5 Coupling with a halide 12-2, where is a halogen (eg, Cl, Br, or I) or pseudohalogen (eg, OTf or OMs), can provide compounds of formula (II).

[0476] [ka]

[0477] Intermediates for the synthesis of compounds of Formula (II) can be prepared as described in Scheme XIII. Amide coupling of thiophene 7-1 with a suitable amine 13-1 in the presence of a coupling reagent (e.g., N,N'-dicyclohexylcarbodiimide or HATU) and, optionally, an additive (e.g., 1-hydroxybenzotriazole or 4-dimethylaminopyridine) and, optionally, a base (e.g., pyridine or N,N-diisopropylethylamine) can provide amide 13-2. Lithiation of thiophene 13-2 with a strong base such as butyllithium followed by addition to a formyl transfer reagent such as N,N-dimethylformamide, N-methoxy-N-methylformamide, or N-formylmorpholine can provide aldehyde 13-3. Reduction of aldehyde 13-3 under standard conditions, such as in the presence of a reducing agent (e.g., sodium borohydride, lithium aluminum hydride, or borane tetrahydrofuran complex), can provide alcohol 13-4. Alcohol 13-4 can be halogenated with a suitable reagent, such as thionyl chloride, phosphorus tribromide, or triphenylphosphine and iodine, to give compound 13-5, where Xe is a halogen (e.g., Cl, Br, or I). Compound 13-5 can be ring-closed under basic conditions (e.g., in the presence of sodium hydride and lithium bis(trimethylsilyl)amide) to give lactam 13-6. Lactam 13-6 can be alkylated with compound 8-2 in the presence of a base, such as sodium hydride or lithium diisopropylamide, to give compound 13-7.

[0478] [ka]

[0479] Intermediates for the synthesis of compounds of Formula (I) can be prepared as described in Scheme XIV. Nitriles 14-1, where Xi is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be alkylated with a suitable compound 8-2 in the presence of a base such as sodium hydride to give compound 14-2. Nitriles 14-2 can be reduced under standard conditions, such as in the presence of a reducing agent (e.g., lithium aluminum hydride or borane tetrahydrofuran complex), to give amines 14-3. Compound 14-3 can be reacted with a phosgene source (e.g., triphosgene) in the presence of a base (e.g., NaHCO) to give isocyanates 14-4. Compound 14-4 can undergo intramolecular Friedel-Crafts acylation in the presence of a Lewis acid (e.g., FeCl or AlCl) to give lactams 14-5. Lactam 14-5 can be alkylated with a suitable compound 7-6 in the presence of a base such as NaH to give compound 14-6.

[0480] [ka]

[0481] Example 1. 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0482] [ka]

[0483] Step 1. 2-(1-(isocyanatomethyl)cyclopentyl)thiophene

[0484] [ka]

[0485] To a vial containing triphosgene (0.15 g, 0.50 mmol) was added CHCl (1.5 mL). After cooling the reaction to 0° C., 1-(2-thienyl)cyclopentanemethanamine (0.16 mL, 1.0 mmol) and saturated aqueous NaHCO (1.5 mL) were added sequentially. The reaction was stirred at room temperature overnight. The reaction was diluted with CHCl (10 mL) and the layers were separated. The organic layer was washed with brine, dried over NaSO, filtered, and used directly in the next step. 11 H 14 LCMS calculated for NOS[M+H]+: m / z=208.1, found: 208.0.

[0486] Step 2. 5',6'-Dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0487] [ka]

[0488] The solution of 2-(1-(isocyanatomethyl)cyclopentyl)thiophene in CHCl from step 1 was added to a vial containing AlCl (0.13 g, 1.0 mmol). The resulting mixture was heated at 50° C. for 1 h. The reaction mixture was poured into saturated aqueous NHCl and extracted with CHCl. ​​The organic layer was separated, washed with brine, dried over NaSO, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (50% EtOAc in hexanes) to afford the title compound (0.10 g, 0.50 mmol, 50% yield over two steps) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.41 (d, J=5.2Hz, 1H), 7.11 (d, J=5.2Hz, 1H), 6.42 (s, 1H), 3.43 (d, J=2.7Hz, 2H), 2.05-1.68 (m, 8H). C 11 H 14LCMS calculated for NOS[M+H]+: m / z=208.1, found: 208.0.

[0489] Step 3. 5'-Methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0490] [ka]

[0491] A vial was charged with 5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one (80 mg, 0.39 mmol) and NaH (31 mg, 60% in mineral oil). The vial was evacuated and backfilled with N2. Tetrahydrofuran (4 mL) was then added to the vial, and the reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of iodomethane (48 μL, 0.78 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was quenched with saturated aqueous NH4Cl, and the reaction mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (35% EtOAc in hexanes) to afford the title compound (66 mg, 0.30 mmol, 77% yield) as a white solid. C 12 H 16 NOS [M+H] + LCMS calculated for: m / z=222.1, found: 222.0.

[0492] Step 4. 2'-Bromo-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0493] [ka]

[0494] 5'-Methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one (66 mg, 0.30 mmol) and N-bromosuccinimide (53 mg, 0.30 mmol) were dissolved in MeCN (3 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (20% EtOAc in hexanes) to give the title compound (72 mg, 0.24 mmol, 80% yield) as a pale yellow solid. 12 H 15 BrNOS[M+H] + LCMS calculated value for: m / z=300.0 / 302.0, found value: 299.8 / 301.8.

[0495] Step 5. 2'-(2-chloro-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]

[0496] [ka]

[0497] To a vial was added 2'-bromo-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one (72 mg, 0.24 mmol), 2,6-dichloro-5-fluororacil (0.12 g, 0.73 mmol), hexamethylditin (0.10 mL, 0.49 mmol), and Pd(PPh3)4 (42 mg, 0.037 mmol). The vial was evacuated and refilled with N2 three times. 1,4-Dioxane (12 mL) was then added, and the reaction mixture was heated at 100 °C for 24 h. The reaction mixture was cooled to room temperature, and saturated aqueous KF solution (9.7 mL, 0.97 mmol, 0.10 M) was added. The mixture was stirred at room temperature for 10 min and then filtered through Celite. The filtrate was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (35% EtOAc in hexanes) to afford the title compound (26 mg, 0.074 mmol, 30% yield) as a white solid. 16 H 16 LCMS calculated for ClFN3OS[M+H]+: m / z = 352.1, found: 351.9.

[0498] Step 6. Tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0499] [ka]

[0500] A mixture of 5-fluoro-2-nitropyridine (0.30 g, 2.1 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.42 g, 2.1 mmol), and DIPEA (0.36 mL, 6.3 mmol) in DMF (4 mL) was stirred at 80 °C overnight. The reaction mixture was slowly poured into ice water (30 mL). The precipitate was collected via filtration and dried to give the title compound (0.63 g, 1.9 mmol, 92% yield) as a yellow solid. 15H 21 LCMS calculated for N4O4[M+H]+: m / z = 321.2, found 321.0.

[0501] Step 7. 2-(6-Nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0502] [ka]

[0503] A mixture of tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (500 mg, 1.6 mmol) and TFA (5.0 mL, 65 mmol) in DCM (10 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue, 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (300 mg, 1.4 mmol, 87% yield), was used in the next step without further purification. 10 H 13 LC-MS calculated for N4O2 [M+H]+: m / z = 221.2, found 220.9.

[0504] Step 8. 6-Ethyl-2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0505] [ka]

[0506] A mixture of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (500 mg, 2.3 mmol), triethylamine (0.63 mL, 4.5 mmol), acetic acid (0.010 mL, 0.23 mmol), acetaldehyde (500 mg, 11 mmol), and NaBHCN (713 mg, 11 mmol) in methanol (5 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure. HCl (1N, 10 mL) was added to the resulting material, and the aqueous mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (300 mg, 1.2 mmol, 53% yield), which was used directly in the next step without further purification. 12 H 17 N4O2[M+H] + LC-MS calculated for: m / z=249.3, found 249.0.

[0507] Step 9. 5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine

[0508] [ka]

[0509] A mixture of 6-ethyl-2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (500 mg, 2.0 mmol) and Pd / C (50 mg, 0.047 mmol, 10%) in ethanol (10 mL) was stirred overnight under an H atmosphere. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC on a C18 column (5-50% MeCN in 0.1% TFA (aq), pH=2) to give the title compound (240 mg, 1.1 mmol, 55% yield). 12 H 19 LC-MS calculated for N4[M+H]+: m / z=219.2, found 218.9.

[0510] Step 10. 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one A suspension of 2'-(2-chloro-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one (20 mg, 0.057 mmol), 5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine (25 mg, 0.11 mmol), XPhos Pd G3 (7.2 mg, 0.0085 mmol), and Cs2CO3 (56 mg, 0.17 mmol) in 1,4-dioxane (2 mL) was heated at 100 °C for 18 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, and TFA (0.044 mL) was added. The mixture was filtered, and the filter frit was washed with MeOH. The filtrate was purified by preparative HPLC on a C18 column (6-80% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (17 mg, 0.032 mmol, 56% yield) as a yellow solid. 1 H NMR (400(MHz, CD3OD) δ8.65(d, J=3.1Hz, 1H), 8.23(s, 1H), 7.63(d, J=9.9Hz, 1H), 7.56-7.47(m, 2H), 4.58-4.43(m, 2H), 4.38-4.2 C 28 H 33 LCMS calculated for FN7OS[M+H]+: m / z = 534.2, found: 534.1.

[0511] Example 2. 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0512] [ka]

[0513] Step 1. tert-Butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0514] [ka]

[0515] 5-Bromo-2-nitropyridine (15 g, 74 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (25 g, 81 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.6 g, 2.2 mmol), and potassium carbonate (41 g, 295 mmol) in 1,4-dioxane (160 mL) and water (40 mL) were stirred at 100 °C for 2 h under a N atmosphere. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was diluted with water (100 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (80 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-100% DCM in heptane) to give the title compound (18 g, 59 mmol, 80% yield) as a yellow solid. 15 H 20 LCMS calculated for N3O4 [M+H]+: m / z = 306.1, found: 306.0.

[0516] Step 2. 6-Nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine

[0517] [ka]

[0518] To a solution of tert-butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (9.2 g, 30 mmol) in DCM (90 mL) was added TFA (90 mL) slowly at room temperature. The resulting orange solution was stirred at room temperature for 4 hours. The volatiles were evaporated in vacuo to give the title compound (8.0 g) as the TFA salt, which was used directly without further purification. 10 H 12 LCMS calculated for N3O2 [M+H]+: m / z = 206.1, found: 206.0.

[0519] Step 3. 1'-Methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine

[0520] [ka]

[0521] To a solution of 6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine (6.2 g, 30 mmol), paraformaldehyde (5.4 g, 180 mmol), and acetic acid (11 g, 180 mmol) in methanol (60 mL) was added NaCNBH (11 g, 180 mmol) portionwise over 30 minutes at room temperature. The resulting dark solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was adjusted to pH 8 with 10% Na2CO3 (aq). The mixture was extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (0-80% MeOH in MTBE) to give the title compound (5.1 g, 23 mmol, 77% yield) as a yellow solid. C10 H 14 LCMS calculated for N3O2 [M+H]+: m / z = 220.1, found: 220.0.

[0522] Step 4. 5-(1-methylpiperidin-4-yl)pyridin-2-amine

[0523] [ka]

[0524] To a solution of 1'-methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine (9.1 g, 42 mmol) in methanol (500 mL) was added 10% Pd / C (2.0 g, 19 mmol). The mixture was hydrogenated at 100 psi and 45 °C for 5 days. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0 to 80% MeOH in MTBE) to give the title compound (5.6 g, 29 mmol, 70% yield) as a white solid. 1 H NMR (300MHz, CD3OD) δ7.77(d, J=2.3Hz, 1H), 7.41(dd, J=8.6, 2.4Hz, 1H), 6.58(d, J=8.6Hz, 1 H), 3.32-3.30(m, 1H), 2.78-2.67(m, 2H), 2.64(s, 3H), 2.62-2.54(m, 2H), 1.97-1.78(m, 4H). C 11 H 18 LCMS calculated for N3[M+H]+: m / z=192.2, found: 192.2.

[0525] Step 5. 2'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one A suspension of XPhos Pd G3 (9.4 mg, 0.011 mmol), Cs2CO3 (72 mg, 0.22 mmol), 5-(1-methylpiperidin-4-yl)pyridin-2-amine (28 mg, 0.15 mmol), and 2'-(2-chloro-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one (26 mg, 0.074 mmol) in 1,4-dioxane (2 mL) was heated at 100 °C for 18 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, and TFA (0.056 mL) was added. The reaction mixture was filtered, and the filter frit was washed with MeOH. The filtrate was purified by preparative HPLC on a C18 column (6-80% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (18 mg, 0.035 mmol, 47% yield) as a yellow solid. 1 H NMR (400MHz, CD3OD) δ8.72(d, J=3.2Hz, 1H), 8.30-8.25(m, 2H), 8.24(d, J=1.7Hz , 1H), 7.66(d, J=9.5Hz, 1H), 3.73-3.65(m, 2H), 3.61(s, 2H), 3.26-3.16(m, 2H), 3.15(s, 3H), 3.13-3.03(m, 1H), 2.96(s, 3H), 2.28-2.19(m, 2H), 2.13-2.00(m, 4H), 1.99-1.85(m, 6H). C 27 H 32 LCMS calculated for FN6OS[M+H]+: m / z=507.2, found: 507.0.

[0526] Example 3. 2'-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0527] [ka]

[0528] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10, using 5-(4-ethylpiperazin-1-yl)pyridin-2-amine instead of 5-(6-ethylethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine. 1 H NMR (400MHz, CD3OD) δ8.68(d, J=3.2Hz, 1H), 8.24(d, J=1.7Hz, 1H), 8.17(dd, J=9.6, 3.0Hz, 1H), 7.94(d, J=2.9Hz, 1H), 7.65 (d, J=9.6Hz, 1H), 4.04-3.62(m, 4H), 3.61(s, 2H), 3.46-3.16(m, 6H), 3.15(s, 3H), 2.14-1.85(m, 8H), 1.43(t, J=7.3Hz, 3H). C 27 H 33 LC-MS calculated for FN7OS [M+H] + : m / z = 522.2, found 522.0.

[0529] Example 4. 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0530] [ka]

[0531] The title compound was synthesized by procedures similar to those outlined in Example 1, steps 1-10. 29 H 35 LC-MS calculated for FN7OS [M+H] + : m / z = 548.3, found 548.2.

[0532] Example 5. 2'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0533] [ka]

[0534] The title compound was synthesized by procedures similar to those outlined in Example 1, steps 1-5 and Example 2, step 5. 1 H NMR (400MHz, CD3OD) δ8.70(d, J=3.1Hz, 1H), 8.26(d, J=5.7Hz, 2H), 8.21(d, J=9.1Hz, 1H), 7.75(d, J=9.0Hz, 1H), 3.75-3 .63(m, 4H), 3.26-3.05(m, 3H), 3.17(s, 3H), 2.97(s, 3H), 2.25(d, J=14.2Hz, 2H), 2.08-1.86(m, 4H), 1.83-1.47(m, 8H). C 28 H 34 LC-MS calculated for FN6OS[M+H]+: m / z = 521.2, found 521.1.

[0535] Example 6. 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0536] [ka]

[0537] Step 1. N,4-Dimethylthiophene-3-carboxamide

[0538] [ka]

[0539] Triethylamine (13.8 mL, 99.0 mmol) was added to a solution of 4-methyl-3-thiophenecarboxylic acid (3.52 g, 24.8 mmol), HATU (10.4 g, 27.2 mmol), and methylamine hydrochloride (2.51 g, 37.1 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 2 h. The reaction was diluted with water (25 mL) and the layers were separated. The organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-30% EtOAc / heptane) to afford the title compound (3.50 g, 22.5 mmol, 91.1% yield) as a clear oil. CH 10 LCMS calculated for NOS[M+H]+: m / z=156.1, found: 156.0.

[0540] Step 2. 2-Formyl-N,4-dimethylthiophene-3-carboxamide

[0541] [ka]

[0542] n-Butyllithium (18.0 mL, 44 mmol, 2.5 M in THF) was added dropwise over 30 minutes to a solution of N,4-dimethylthiophene-3-carboxamide (2.73 g, 17.6 mmol) in THF (30.0 mL) at −78° C. The reaction was stirred at −78° C. for 1 hour. N,N-Dimethylformamide (6.81 mL, 87.9 mmol) was added dropwise to the reaction mixture over 15 minutes. The solution was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0° C. and diluted with saturated NH4Cl(aq) (30.0 mL). The reaction mixture was extracted with EtOAc (2×30.0 mL) and DCM (2×30.0 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give the title compound, which was used in the next step without further purification. CH 10 NO2S[M+H] + LCMS calculated for: m / z=184.0, found: 184.0.

[0543] Step 3. 2-(Hydroxymethyl)-N,4-dimethylthiophene-3-carboxamide

[0544] [ka]

[0545] To a solution of 2-formyl-N,4-dimethylthiophene-3-carboxamide (from Step 2) in methanol (20.0 mL) was added sodium borohydride (0.666 g, 17.6 mmol) portionwise at 0 °C. The reaction was stirred for 30 min. The mixture was carefully quenched with saturated NH4Cl(aq) (35.0 mL) while stirring at 0 °C. The white solid was filtered off and collected. The filtrate was extracted with EtOAc (2 × 20.0 mL) and DCM (2 × 20.0 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–100% EtOAc / heptane) to afford the title compound (1.84 g, 9.93 mmol, 56.4% yield over two steps) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ7.87(s, 1H), 6.95(s, 1H), 5.51(t, J=5.5Hz, 1H), 4.56(d, J=5.5Hz, 2H), 2.67(d, J=4.6Hz, 3H), 2.09(s, 3H). C8H 10 NOS [M-OH] + LCMS calculated for: m / z=168.1, found: 167.9.

[0546] Step 4. 2-(Chloromethyl)-N,4-dimethylthiophene-3-carboxamide

[0547] [ka]

[0548] Thionyl chloride (1.08 mL, 14.9 mmol) was added dropwise to a solution of 2-(hydroxymethyl)-N,4-dimethylthiophene-3-carboxamide (1.84 g, 9.93 mmol) in DCM (30.0 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NaHCO3 (aq) (30.0 mL) and extracted with DCM (3×30.0 mL). The combined organics were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated to give the title compound, which was used in the next step without further purification. CH 10 NOS[M-Cl] + LCMS calculated for: m / z=168.1, found: 167.9.

[0549] Step 5. 3,5-Dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

[0550] [ka]

[0551] Lithium bis(trimethylsilyl)amide (11.2 mL, 11 mmol, 1.0 M in THF) was added dropwise to a solution of 2-(chloromethyl)-N,4-dimethylthiophene-3-carboxamide (from Step 4) in THF (36.0 mL) at -78 °C. The reaction was stirred at -78 °C for 1 h. The reaction was quenched with saturated NaHCO (aq) (20.0 mL), and the reaction mixture was extracted with EtOAc (3 x 20.0 mL). The combined organics were washed with brine (30.0 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% EtOAc / heptane) to afford the title compound (0.605 g, 3.62 mmol, 38.8% yield over two steps) as a pale yellow oil. CH 10 LCMS calculated for NOS[M+H]: m / z=168.1, found: 168.0

[0552] Step 6. 3',5'-Dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0553] [ka]

[0554] Lithium diisopropylamide (5.43 mL, 11 mmol, 2.0 M in THF) was added dropwise to a solution of 3,5-dimethyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one (0.605 g, 3.62 mmol) in THF (30.0 mL) at -78 °C and stirred for 20 minutes. 1,2-Dibromoethane (0.627 mL, 7.24 mmol) was added, and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C, and the reaction was quenched with saturated NH4Cl (aq). The mixture was extracted with DCM (3 × 30.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-30% EtOAc / heptane) to afford the title compound (0.278 g, 1.44 mmol, 39.8% yield) as a pale yellow solid. 10 H 12 LCMS calculated for NOS[M+H]+: m / z=194.1, found: 194.1.

[0555] Step 7. 2'-Bromo-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0556] [ka]

[0557] N-Bromosuccinimide (0.266 g, 1.51 mmol) was added to a solution of 3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (0.278 g, 1.44 mmol) in acetonitrile (5.00 mL) at room temperature and stirred for 30 minutes. The mixture was concentrated, and the crude residue was purified by silica gel chromatography (0-40% EtOAc / heptane) to afford the title compound (0.338 g, 1.24 mmol, 86.3% yield) as a pale yellow solid. 10 H 11 BrNOS[M+H] + LCMS calculated values ​​for: m / z = 272.0, 274.0, found values: 271.8, 273.8.

[0558] Step 8. 2'-(2-chloro-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0559] [ka]

[0560] A solution of 2'-bromo-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (0.306 g, 1.12 mmol), hexamethylditin (0.466 mL, 2.25 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.195 g, 0.169 mmol) in 1,4-dioxane (10.0 mL) was heated at 100 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and 2,6-dichloro-5-fluorouracil (0.413 g, 2.47 mmol) was added. The reaction mixture was stirred at 100 °C overnight. After cooling to room temperature, a solution of potassium fluoride (0.261 g, 4.50 mmol) in water (30.0 mL) was added to the reaction mixture. Ethyl acetate (50.0 mL) was added and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-45% EtOAc / heptane) to afford the title compound (0.220 g, 0.679 mmol, 60.4% yield) as a yellow solid. 14 H 12 ClFN3OS[M+H] + LCMS calculated values ​​for: m / z = 324.0, 326.0, found values: 323.9, 325.8.

[0561] Step 9. 2'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one 2'-(2-chloro-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (0.260 g, 0.803 mmol), 5-(1-methylpiperidin-4-yl)pyridin-2-amine (0.230 g, 1.20 mmol, Example 2, Step 4), XPhos Pd G2 (0.102 g, 0.120 mmol, CAS number: 1310584-14-5), and KPO in 1,4-dioxane (8.00 mL). 4(A suspension of 1.31 g (4.02 mmol) of HCl (H O ) was heated at 100°C for 18 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and TFA (2 drops) was added. The inorganic salts were filtered off, and the filtrate was purified by preparative HPLC on a C18 column (10-40% MeCN in 0.1% TFA (aq)) to give the title compound as a yellow solid, the TFA salt (0.128 g, 0.181 mmol, 23%). 1 H NMR (400MHz, CD3OD) δ8.70(d, J=3.0Hz, 1H), 8.24(s, 1H), 8.15(d, J=9.0Hz, 1H), 7.78(d, J=9.0Hz, 1H), 3.71-3.63(m, 2H), 3.24-3.15(m, 2H), 3.10-3.00 (m, 1H), 2.95(s, 3H), 2.87(s, 3H), 2.75(d, J=2.5Hz, 3H), 2.26-2.19(m, 2H), 2.06-1.96(m, 2H), 1.93(dd, J=6.2, 8.6Hz, 2H), 1.53(dd, J=6.0, 8.2Hz, 2H). C 25 H 28 FN6OS[M+H] + LCMS calculated for: m / z=479.2, found: 479.2.

[0562] Examples 7 to 19 Examples 7-19 listed in Tables 1 and 2 were synthesized following procedures similar to Example 6. All examples in these tables were prepared as TFA salts unless otherwise noted.

[0563] [ka]

[0564] [Table 1]

[0565] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0566] [Table 2-5] [Table 2-6]

[0567] Example 20. 2'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0568] [ka]

[0569] Step 1. 5-Methyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one

[0570] [ka]

[0571] The title compound is synthesized by procedures similar to those outlined in Example 6, steps 1-5. C7H8NOS[M+H] + LCMS calculated for: m / z=154.0, found: 153.9.

[0572] Step 2. 5'-Methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0573] [ka]

[0574] The title compound is synthesized by a procedure similar to that outlined in Example 6, Step 6, using 1,4-diiodobutane instead of 1,2-dibromoethane. 11 H 14 NOS [M+H] + LCMS calculated for: m / z=208.1, found: 208.0.

[0575] Step 3. 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one The title compound is synthesized by procedures similar to those outlined in Example 6, steps 7-9. 26 H 30 FN6OS[M+H] + LCMS calculated for: m / z=493.2, found: 493.1.

[0576] Examples 21 to 27 Examples 21-27 listed in Tables 3 and 4 are synthesized following procedures similar to Example 20. All examples in these tables were prepared as TFA salts unless otherwise noted.

[0577] [ka]

[0578] [Table 3]

[0579] [Table 4-1] [Table 4-2] [Table 4-3]

[0580] Example 28. 2'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0581] [ka]

[0582] Step 1. (4-Methylthiophen-2-yl)methanol

[0583] [ka]

[0584] Lithium aluminum hydride (2.10 g, 55.4 mmol) was added slowly to a solution of 4-methylthiophene-2-carboxylic acid (7.50 g, 52.8 mmol) in MTBE (105 mL) while maintaining the temperature of the reaction mixture at 25-30 °C. The reaction was stirred for 30 min. The reaction mixture was cooled to 0 °C and quenched by the sequential addition of water (2.10 mL) and a solution of 1 N NaOH (aq) (8.40 mL). The suspension was diluted with MTBE, dried over sodium sulfate, filtered, and concentrated. The crude residue, containing the title compound (6.70 g) as a colorless oil, was used without further purification. 1H NMR (400MHz, CDCl3) δ6.85(q, J=1.2Hz, 1H), 6.83(d, J=1.4Hz, 1H), 4.77(s, 2H), 2.24(d, J=1.0Hz, 3H).

[0585] Step 2. 2-(Chloromethyl)-4-methylthiophene

[0586] [ka]

[0587] Thionyl chloride (4.56 mL, 62.7 mmol) was added dropwise to a solution of crude (4-methylthiophen-2-yl)methanol (6.70 g, from Step 1) in THF (130.0 mL) at room temperature. The reaction was heated at 50° C. for 90 minutes. The reaction mixture was cooled to room temperature and concentrated. The crude residue was diluted with DCM (30.0 mL) and cooled to 0° C. before adding saturated NaHCO3 (aq) (50.0 mL). The two phases were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated. The crude residue contained the title compound (6.87 g) as a yellow oil and was used without further purification. 1 H NMR (400MHz, CDCl3) δ6.90(s, 1H), 6.88(p, J=1.2Hz, 2H), 4.75(s, 2H), 2.23(d, J=1.0Hz, 3H).

[0588] Step 3. 2-(4-methylthiophen-2-yl)acetonitrile

[0589] [ka]

[0590] Sodium cyanide (5.12 g, 104 mmol) was added to a solution of crude 2-(chloromethyl)-4-methylthiophene (6.87 g) in DMF (105.0 mL) at room temperature. The reaction was heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with water (300 mL) and MTBE (100 mL). The two phases were separated, and the aqueous layer was extracted with MTBE (100 mL × 2). The combined organic layers were washed with water (100 mL × 2), dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–40% EtOAc / hexanes) to afford the title compound (5.15 g, 37.5 mmol, 71.8% yield over three steps) as a brown oil. 1 H NMR (400MHz, CDCl3) δ6.87(s, 1H), 6.83(t, J=1.3Hz, 1H), 3.85(d, J=1.1Hz, 2H), 2.23(d, J=1.1Hz, 3H).

[0591] Step 4. 1-(4-methylthiophen-2-yl)cyclopropane-1-carbonitrile

[0592] [ka]

[0593] Sodium hydride (4.47 g, 112 mmol) was added portionwise to a solution of 2-(4-methylthiophen-2-yl)acetonitrile (6.14 g, 44.7 mmol) in DMF (110 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, and then 1,2-dibromoethane (4.26 mL, 49.2 mmol) was added dropwise. The dark mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with water (300 mL) and DCM (100 mL). The two phases were separated, and the aqueous layer was extracted with DCM (100 mL × 4). The organic layers were combined, washed with water (100 mL × 2), dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–40% EtOAc / hexanes) to afford the title compound (5.40 g, 33.1 mmol, 74.0% yield) as an orange oil. 1H NMR (400MHz, CDCl3) δ6.89(d, J=1.5Hz, 1H), 6.75(t, J=1.3Hz, 1H), 2.21(d, J=1.1Hz, 3H), 1.79-1.67(m, 2H), 1.48-1.37(m, 2H). C9H 10 NS[M+H] + LCMS calculated for: m / z=164.1, found: 163.8.

[0594] Step 5. (1-(4-methylthiophen-2-yl)cyclopropyl)methanamine

[0595] [ka]

[0596] Lithium aluminum hydride (1.60 g, 42.0 mmol) was added slowly to a solution of 1-(4-methylthiophen-2-yl)cyclopropane-1-carbonitrile (6.54 g, 40.0 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was quenched by the sequential addition of water (1.60 mL) and 1N NaOH (aq) (6.40 mL) at 0° C. The suspension was diluted with EtOAc, dried over sodium sulfate, filtered, and concentrated. The crude residue contained the title compound (6.70 g) as an orange oil and was used without further purification. CH 14 NS[M+H] + LCMS calculated for: m / z = 168.1, found 168.0.

[0597] Step 6. 2-(1-(isocyanatomethyl)cyclopropyl)-4-methylthiophene

[0598] [ka]

[0599] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 1. 10 H 12NOS [M+H] + LCMS calculated for: m / z = 194.1, found 193.9.

[0600] Step 7. 3'-Methyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0601] [ka]

[0602] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 2. 10 H 12 NOS [M+H] + LCMS calculated for: m / z = 194.1, found 194.0.

[0603] Step 8. 3',5'-Dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0604] [ka]

[0605] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 3. 11 H 14 NOS [M+H] + LCMS calculated for: m / z = 208.1, found 208.0.

[0606] Step 9. 2'-Bromo-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0607] [ka]

[0608] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 4. 11 H 13 BrNOS[M+H] + LCMS calculated values ​​for: m / z = 286.0, 288.0, found values ​​285.8, 287.8.

[0609] Step 10. 2'-(2-chloro-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0610] [ka]

[0611] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 5. Purification via slurry in 1:1 EtOAc / hexanes afforded the title compound. 15 H 14 ClFN3OS[M+H] + LCMS calculated values ​​for: m / z = 338.0, 340.0, found values ​​338.0, 339.9.

[0612] Step 11. 2'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. It was isolated as the TFA salt. 1H NMR (400MHz, DMSO-d6) δ10.54(s, 1H), 9.57(s, 1H), 8.73(d, J=2.6Hz, 1H), 8.21( d, J=2.4Hz, 1H), 8.01(d, J=8.8Hz, 1H), 7.81(dd, J=8.9, 2.4Hz, 1H), 3.62-3.44(m , 4H), 3.07(q, J=11.6Hz, 2H), 2.97(s, 3H), 2.89-2.75(m, 4H), 2.55(d, J=3.3Hz, 3H), 2.10-1.98(m, 2H), 1.96-1.74(m, 2H), 1.46-1.22(m, 2H), 1.18-0.97(m, 2H). C 26 H 30 FN6OS[M+H] + LCMS calculated for: m / z=493.2, found: 493.1.

[0613] Examples 29 to 45 Examples 29-45 listed in Tables 5 and 6 were synthesized following procedures similar to Example 28. All examples in these tables were prepared as TFA salts unless otherwise noted.

[0614] [ka]

[0615] [Table 5-1]

[0616] [Table 5-2]

[0617] [Table 6-1] [Table 6-2] [Table 6-3]

[0618] [Table 6-4] [Table 6-5] [Table 6-6]

[0619] [Table 6-7]

[0620] Example 46. 2'-(5-fluoro-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0621] [ka]

[0622] Step 1. 1-(Thiophen-2-yl)cyclobutane-1-carbonitrile

[0623] [ka]

[0624] Sodium hydride (60 wt%, 4.87 g, 122 mmol) was added portionwise to a solution of 2-thiopheneacetonitrile (6.00 g, 48.7 mmol) in THF (25.0 mL), and the mixture was stirred at room temperature for 15 minutes. 1,3-Diiodopropane (6.15 mL, 53.6 mmol) was then added dropwise. The dark mixture was stirred for 2 hours. The reaction was quenched with water (50.0 mL), and the mixture was extracted with MTBE (50.0 mL). The two phases were separated, and the aqueous layer was extracted with MTBE (50.0 mL × 2). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–20% EtOAc / hexanes) to afford the title compound (6.80 g, 41.7 mmol, 85.5% yield) as a dark oil. 1 H NMR (400MHz, CDCl3) δ7.28(dd, J=5.1, 1.2Hz, 1H), 7.09(dd, J=3.6, 1.2Hz, 1H), 6.98(dd, J=5 .1, 3.6Hz, 1H), 3.00-2.83(m, 2H), 2.78-2.57(m, 2H), 2.47-2.28(m, 1H), 2.25-2.07(m, 1H).

[0625] Step 2. (1-(thiophen-2-yl)cyclobutyl)methanamine

[0626] [ka]

[0627] The title compound was synthesized by a procedure similar to that outlined in Example 28, Step 5. 14 NS[M+H] + LCMS calculated for: m / z = 168.1, found 168.0.

[0628] Step 3. 5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-amine

[0629] [ka]

[0630] The title compound was synthesized as the TFA salt by a procedure similar to that outlined in Example 1, steps 6-9. 1 H NMR (400MHz, DMSO-d6) δ7.49(d, J=3.0Hz, 1H), 6.98(dd, J=8.9, 3.1Hz, 1H), 6.45(d, J=8.6Hz, 1H), 5.03(s, 2H), 3.55(d , J=5.8Hz, 2H), 3.33(d, J=11.1Hz, 3H), 3.19(d, J=10.9Hz, 2H), 2.47-2.32(m, 1H), 1.97(s, 3H), 1.55(d, J=8.1Hz, 1H).

[0631] Step 4. 2'-(5-fluoro-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one The title compound was synthesized by procedures similar to those outlined in Example 1, steps 1-5 and 10. It was isolated as the TFA salt. 1 H NMR (400MHz, DMSO-d6) δ10.42(s, 0.5H), 10.17-9.99(m, 1H), 9.08(s, 0.5H), 8.67(d, J=3.2Hz, 1H), 8.00(dd, J= 9.2, 5.4Hz, 1H), 7.93(d, J=1.9Hz, 1H), 7.90(d, J=3.1Hz, 1H), 7.53-7.42(m, 1H), 4.56-4.47(m, 1H), 4.37(d, J=6 .3Hz, 1H), 3.90(dd, J=19.3, 12.1Hz, 2H), 3.82-3.66(m, 4H), 3.43-3.29(m, 0.5H), 3.05(d, J=5.2Hz, 1.5H), 3.04 (s, 3H), 2.91-2.79(m, 0.5H), 2.53(d, J=3.8Hz, 1.5H), 2.38-2.21(m, 4H), 2.20-2.11(m, 1H), 2.09-1.93(m, 2H). C 26 H 29 FN7OS[M+H] +LCMS calculated for: m / z=506.2, found: 506.1.

[0632] Examples 47 to 60 Examples 47-60 listed in Tables 7 and 8 were synthesized following procedures similar to Example 46. All examples in these tables were prepared as TFA salts unless otherwise noted.

[0633] [ka]

[0634] [Table 7]

[0635] [Table 8-1] [Table 8-2] [Table 8-3]

[0636] [Table 8-4] [Table 8-5]

[0637] Examples 61 to 65 Examples 61-65 listed in Tables 9 and 10 were synthesized following procedures similar to those for Examples 1 and 2. All examples in these tables were prepared as TFA salts unless otherwise noted.

[0638] [ka]

[0639] [Table 9]

[0640] [Table 10-1] [Table 10-2]

[0641] Example 66. 6'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methyl-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-isoquinolin]-1'-one

[0642] [ka]

[0643] Step 1. 6'-Bromo-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-isoquinolin]-1'-one

[0644] [ka]

[0645] To a solution of triphosgene (222 mg, 0.750 mmol) in DCM (2.5 mL) was added 1-(3-bromophenyl)cyclopentanemethanamine (0.290 mL, 1.50 mmol) at 0 °C, followed by the slow addition of NaHCO3 (aq) (2.0 mL, 1.50 mmol, 0.75 M). The reaction mixture was stirred at room temperature for 2 h. The two layers were separated. The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was diluted with DCM (15 mL), and FeCl3 (243 mg, 1.50 mmol) was added. The reaction mixture was heated at 50 °C for 1 h. The reaction mixture was poured into saturated NH4Cl (aq) and diluted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc / hexanes) to afford the title compound (80.5 mg, 0.286 mmol, 19.1%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.95(d, J=8.2Hz, 1H), 7.48(d, J=8.4Hz, 1H), 7.44(s, 1H), 6.58(s, 1H), 3.37(d, J=2.7Hz, 2H), 2.00-1.71(m, 8H). C 13 H 15 BrNO[M+H] + LCMS calculated value for: m / z=280.0 / 282.0, found value: 280.0 / 282.0.

[0646] Step 2. 6'-Bromo-2'-methyl-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-isoquinolin]-1'-one

[0647] [ka]

[0648] The title compound is synthesized by a procedure similar to that outlined in Example 1, Step 3. 14 H 17 BrNO[M+H] + LCMS calculated values ​​for: m / z = 294.0, 296.0, found values: 293.9, 295.8.

[0649] Step 3. 6'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methyl-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-isoquinolin]-1'-one The title compound is synthesized by procedures similar to those outlined in Example 1, steps 5 and 10. 1 H NMR (400MHz, CD3OD) δ8.64(d, J=3.3Hz, 1H), 8.07-7.94(m, 3H), 7.57(dd, J=9.3, 2.7Hz, 1H), 7.42-7.35(m, 2H), 4.41(d, J=11.2Hz, 2H), 4. 21(d, J=11.0Hz, 2H), 4.18(s, 2H), 4.08(s, 2H), 3.43(s, 2H), 3.17(q, J=7.3Hz, 2H), 3.10(s, 3H), 1.92-1.73(m,8H), 1.13(t, J=7.2Hz, 3H). C 30 H 35 FN7O[M+H] + LCMS calculated for: m / z=528.3, found: 528.1.

[0650] Examples 67 to 69 The examples listed in Tables 11 and 12 were synthesized following procedures similar to Example 66. All examples in these tables were prepared as TFA salts unless otherwise stated.

[0651] [ka]

[0652] [Table 11]

[0653] [Table 12]

[0654] Example 70. 2'-[5-Fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3'-methyl-5'-(trideuteriomethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0655] [ka]

[0656] Step 1. N-[(4-methoxyphenyl)methyl]-4-methylthiophene-3-carboxamide

[0657] [ka]

[0658] To a solution of 4-methyl-3-thiophenecarboxylic acid (15.0 g, 105 mmol) in THF (200 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (13.9 g, 137 mmol). After the mixture was stirred at room temperature for 30 minutes, 4-methoxybenzylamine (15.9 g, 116 mmol) was added dropwise at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was poured into 1N HCl (aq) (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (2–35% EtOAc / heptane) to give the title compound (15.5 g, 59.3 mmol, 56.2% yield). 14 H 16 NO2S[M+H] + LC-MS calculated for: m / z=262.1, found: 262.1.

[0659] Step 2. 2-Formyl-N-[(4-methoxyphenyl)methyl]-4-methylthiophene-3-carboxamide

[0660] [ka]

[0661] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 2. 15 H 16 NO3S[M+H] + LC-MS calculated value for: m / z=290.1, found value: 290.0.

[0662] Step 3. 2-(Hydroxymethyl)-N-[(4-methoxyphenyl)methyl]-4-methylthiophene-3-carboxamide

[0663] [ka]

[0664] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 3. 15 H 18 NO3S[M+Na] + LC-MS calculated value for: m / z=314.1, found value: 314.0.

[0665] Step 4. 2-(Chloromethyl)-N-[(4-methoxyphenyl)methyl]-4-methylthiophene-3-carboxamide

[0666] [ka]

[0667] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 4. 15 H 16 NO2S[M-Cl] + LCMS calculated for: m / z=274.1, found: 274.0.

[0668] Step 5. 5-[(4-methoxyphenyl)methyl]-3-methyl-6H-thieno[2,3-c]pyrrol-4-one

[0669] [ka]

[0670] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 5. 15 H 16 NO2S[M+H] + LC-MS calculated for: m / z = 274.1, found 274.1.

[0671] Step 6. 3-Methyl-5,6-dihydrothieno[2,3-c]pyrrol-4-one

[0672] [ka]

[0673] A solution of 5-[(4-methoxyphenyl)methyl]-3-methyl-6H-thieno[2,3-c]pyrrol-4-one (1.00 g, 3.66 mmol) in TFA (20 mL) was stirred at 70 °C overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a C18 column (5-50% MeCN / 0.1% TFA (aq)) to give the title compound (215 mg, 1.40 mmol, 38.4% yield). C7H8NOS[M+H] + LC-MS calculated value for m / z = 154.0, found value: 154.1

[0674] Step 7. 3-Methyl-5-(trideuteriomethyl)-6H-thieno[2,3-c]pyrrol-4-one

[0675] [ka]

[0676] A mixture of 3-methyl-5,6-dihydrothieno[2,3-c]pyrrol-4-one (300 mg, 1.96 mmol), iodomethane-d3 (0.24 mL, 3.9 mmol), and cesium carbonate (1.40 g, 4.31 mmol) in DMF (5 mL) was stirred at 70 °C overnight. The reaction was poured into brine (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (5–40% EtOAc / heptane) to give the title compound (225 mg, 1.32 mmol, 67.5% yield). C8H7D3NOS[M+H] + LC-MS calculated for: m / z=171.1, found: 171.2.

[0677] Step 8. 3'-Methyl-5'-(trideuteriomethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0678] [ka]

[0679] A solution of 3-methyl-5-(trideuteriomethyl)-6H-thieno[2,3-c]pyrrol-4-one (200 mg, 1.17 mmol) in THF (15 mL) was sparged with N for 10 minutes and then cooled to -78 °C. Lithium diisopropylamide (1.76 mL, 3.52 mmol, 2.0 M in THF / heptane / ethylbenzene) was added dropwise. The reaction mixture was stirred at -78 °C for 20 minutes, after which 1-bromo-2-chloroethane (0.29 mL, 3.5 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred at room temperature for 1 hour. The reaction was again degassed with N and cooled to -78 °C. An additional portion of lithium diisopropylamide (1.76 mL, 3.52 mmol, 2.0 M in THF / heptane / ethylbenzene) was added dropwise. After stirring for 20 min, 1-bromo-2-chloroethane (0.290 mL, 3.52 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into cold saturated NH4Cl(aq) (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (2–35% EtOAc / heptane) to give the title compound (75.1 mg, 0.382 mmol, 32.5% yield). C 10 H9D3NOS[M+H] + LC-MS calculated for: m / z=197.1, found: 197.2.

[0680] Step 9. 2'-Bromo-3'-methyl-5'-(trideuteriomethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0681] [ka]

[0682] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 7. 10 H8D3BrNOS[M+H] +LC-MS calculated values ​​for: m / z = 275.0, 277.0, found values: 274.9, 276.9.

[0683] Step 10. 2'-(2-chloro-5-fluoropyrimidin-4-yl)-3'-methyl-5'-(trideuteriomethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0684] [ka]

[0685] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 8. 14 H9D3ClFN3OS[M+H] + LC-MS calculated values ​​for: m / z = 327.1, 329.1, found values: 326.9, 328.9.

[0686] Step 11. 2'-[5-Fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3'-methyl-5'-(trideuteriomethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 9. It was isolated as the TFA salt. 1 H NMR (300MHz, CD3OD) δ8.72(d, J=3.0Hz, 1H), 8.25(s, 1H), 8.21(dd, J=9.1, 2.1Hz, 1H), 7.73(d, J=9.0Hz, 1H), 3.73-3.62(m, 2H), 3.27-3.11 (m, 2H), 3.08-3.01(m, 1H), 2.95(s, 3H), 2.76(d, J=2.5Hz, 3H), 2.28-2.18(m, 2H), 2.10-1.96(m, 2H), 1.96-1.88(m, 2H), 1.58-1.49(m, 2H). C 25 H 25 D3FN6OS[M+H] + LC-MS calculated for: m / z=482.2, found: 482.2.

[0687] Example 71. 2'-[2-[[5-(1-ethylpyrrolidin-3-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0688] [ka]

[0689] Step 1. tert-Butyl 3-(6-nitropyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0690] [ka]

[0691] The title compound was synthesized by a procedure similar to that outlined in Example 2, Step 1. 14 H 18 LC-MS calculated for N3O4 [M+H+]: m / z = 292.1, found 292.0.

[0692] Step 2. tert-Butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate

[0693] [ka]

[0694] A mixture of tert-butyl 3-(6-nitropyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.91 g, 6.52 mmol) and palladium on carbon (200 mg, 0.19 mmol, 10 wt%) in MeOH (25 mL) and THF (5.0 mL) was stirred under an atmosphere of H for 24 hours. The mixture was filtered through Celite®, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (10-30% EtOAc / heptane containing 10% MeOH) to give the title compound (1.36 g, 5.06 mmol, 77.6% yield). 14 H 22 N3O2[M+H + LCMS calculated for m / z = 264.2, found 264.1.

[0695] Step 3. tert-Butyl 3-[6-[[4-(3',5'-dimethyl-4'-oxospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-2'-yl)-5-fluoropyrimidin-2-yl]amino]pyridin-3-yl]pyrrolidine-1-carboxylate

[0696] [ka]

[0697] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. 28 H 32 FN6O3S[M+H] + LCMS calculated for: m / z=551.2, found: 551.2.

[0698] Step 4. 2'-[5-Fluoro-2-[(5-pyrrolidin-3-ylpyridin-2-yl)amino]pyrimidin-4-yl]-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0699] [ka]

[0700] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 7, and purified by preparative HPLC on a C18 column (10-40% MeCN / 0.1% TFA (aq)) to afford the title compound as the TFA salt. 23 H 24 FN6OS[M+H] + LCMS calculated for: m / z=451.2, found: 451.0.

[0701] Step 5. 2'-[2-[[5-(1-ethylpyrrolidin-3-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0702] To a solution of 2'-[5-fluoro-2-[(5-pyrrolidin-3-ylpyridin-2-yl)amino]pyrimidin-4-yl]-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one (45.0 mg, 0.0999 mmol) in DCM (2 mL) was added acetaldehyde (22.0 mg, 0.499 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (63.5 mg, 0.300 mmol) was added. The resulting mixture was stirred for 30 minutes. The reaction was quenched with saturated NaHCO3 (aq) (5 mL). The reaction mixture was stirred for 10 minutes and extracted with DCM (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC on a C18 column (10-40% MeCN / 0.1% TFA (aq)) to afford the title compound as a TFA salt (17.4 mg, 0.0354 mmol, 35.4% yield) as an off-white solid. 1H NMR (300MHz, CD3OD) δ8.73(d, J=3.0Hz, 1H), 8.36-8.28(m, 2H), 7.73(d, J=9.6Hz, 1H), 4.13-3.61(m, 5H), 2.87(s, 3H), 2.77(d, J= 2.4Hz, 3H), 2.68-2.51(m, 2H), 2.39-2.13(m, 2H), 1.92(dd, J=8.4, 6.3Hz, 2H), 1.53(dd, J=8.0, 6.0Hz, 2H), 1.40(t, J=7.5Hz, 3H). C 25 H 28 FN6OS[M+H] + LCMS calculated for: m / z=479.2, found: 479.2.

[0703] Example 72 (E)-2'-(2-((5-(1-(but-2-en-1-yl)pyrrolidin-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0704] [ka]

[0705] The title compound was isolated as a by-product from the procedure described in Example 71, Step 5. 27 H 30 FN6OS[M+H] + LCMS calculated value for: 505.2, found value: 505.3.

[0706] Example 73. 2-[5-Fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3-methylspiro[5H-thieno[2,3-c]pyrrole-6,1'-cyclopropan]-4-one

[0707] [ka]

[0708] Step 1. 5'-[(4-methoxyphenyl)methyl]-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0709] [ka]

[0710] The title compound was synthesized by procedures similar to those outlined in Example 6, steps 1-6. 17 H 18 NO2S[M+H] + LC-MS calculated value: 300.1, found value: 300.1

[0711] Step 2. 2'-Bromo-5'-[(4-methoxyphenyl)methyl]-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0712] [ka]

[0713] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 7. 17 H 17 BrNO2S[M+H] + LC-MS calculated values ​​for: 378.0, 380.0, found values: 377.9, 379.9.

[0714] Step 3. 2'-(2-chloro-5-fluoropyrimidin-4-yl)-5'-[(4-methoxyphenyl)methyl]-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0715] [ka]

[0716] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 8. 21 H 18 ClFN3O2S[M+H] + LC-MS calculated values ​​for: 430.1, 432.1, found values: 430.0, 431.9.

[0717] Step 4. 2'-[5-Fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-5'-[(4-methoxyphenyl)methyl]-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one

[0718] [ka]

[0719] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 9. 32 H 34 LC-MS calculated for FN6O2S[M+H]+: 585.2, found: 585.2.

[0720] Step 5. 2-[5-Fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3-methylspiro[5H-thieno[2,3-c]pyrrole-6,1'-cyclopropan]-4-one The title compound was synthesized by a procedure similar to that outlined in Example 70, Step 6. 1 H NMR (300MHz, CD3OD) δ8.74(d, J=3.0Hz, 1H), 8.33-8.24(m, 2H), 7.64(d, J=9.0Hz, 1H), 3.68(d, J=12.3Hz, 2H), 3.26-3.02(m, 4 H), 2.95(s, 3H), 2.76(d, J=2.4Hz, 3H), 2.27-2.17(m, 2H), 2.14-1.95(m, 2H), 1.76(dd, J=9.0, 6.0Hz, 2H), 1.61-1.53(m, 2H). C 24 H 26LC-MS calculated for FN6OS[M+H]+: 465.2, found: 465.1.

[0721] Example 74. 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-1',5'-dimethyl-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[3,2-c]pyridin]-4'(1'H)-one

[0722] [ka]

[0723] Step 1. Ethyl 1-(aminomethyl)cyclopentane-1-carboxylate

[0724] [ka]

[0725] To a solution of ethyl 1-cyanocyclopentane-1-carboxylate (10.0 g, 59.8 mmol) in ethanol (30 mL) was added Raney nickel (1.43 g, 24.3 mmol, slurry in water, Aldrich, 221678). The mixture was stirred under an atmosphere of H2 at room temperature for 48 h. The mixture was filtered through Celite and concentrated. The crude residue was dissolved in DCM, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-20% MeOH / DCM) to afford the title compound (7.30 g, 42.6 mmol, 71.0% yield) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ4.13(q, J=7.1Hz, 2H), 2.80(s, 2H), 2.09-1.97(m, 2H), 1.86(s, 2H), 1.74-1.43(m, 6H), 1.24(t, J=7.1Hz, 3H). R f =0.2 (10% MeOH / DCM, ninhydrin staining).

[0726] Step 2. Ethyl 1-((2,2,2-trifluoroacetamido)methyl)cyclopentane-1-carboxylate

[0727] [ka]

[0728] To a solution of ethyl 1-(aminomethyl)cyclopentane-1-carboxylate (2.01 g, 11.7 mmol) in ethyl trifluoroacetate (20.0 mL, 168 mmol) was added triethylamine (2.44 mL, 17.5 mmol). The mixture was heated at 50 °C for 1 h. The solvent was removed under reduced pressure. The residue was diluted with saturated NaHCO (aq) (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound (3.12 g, 11.7 mmol) as a colorless oil, which was used directly in the next step without further purification. R f = 0.1 (30% EtOAc / hexane).

[0729] Step 3. Ethyl 1-((2,2,2-trifluoro-N-methylacetamido)methyl)cyclopentane-1-carboxylate

[0730] [ka]

[0731] To a solution of ethyl 1-[[(2,2,2-trifluoroacetyl)amino]methyl]cyclopentane-1-carboxylate (2.40 g, 8.98 mmol) in THF (30 mL) was added sodium hydride (1.08 g, 26.9 mmol, 60 wt% dispersion in mineral oil) followed by iodomethane (1.68 mL, 26.9 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated NH4Cl (aq) (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the title compound (2.53 g, 8.98 mmol) as a colorless oil, which was used directly in the next step without further purification. C 12 H 19 F3NO3[M+H] + LCMS calculated for: m / z = 282.1, found 282.0.

[0732] Step 4. Ethyl 1-((methylamino)methyl)cyclopentane-1-carboxylate

[0733] [ka]

[0734] To a suspension of ethyl 1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]cyclopentane-1-carboxylate (2.00 g, 7.10 mmol) in methanol (15 mL) and water (7.5 mL) was added Na2CO3 (1.51 g, 14.2 mmol). The mixture was stirred at room temperature overnight. The mixture was poured into water (20 mL) and extracted with CHCl3 (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-30% MeOH / DCM) to afford the title compound (558 mg, 3.01 mmol, 42.0% yield over three steps) as a colorless oil. C 10 H 20 NO2[M+H] + LCMS calculated for: m / z = 186.1, found 185.9.

[0735] Step 5. Ethyl 1-((3-ethoxy-N-methyl-3-oxopropanamido)methyl)cyclopentane-1-carboxylate

[0736] [ka]

[0737] To a solution of ethyl 1-((methylamino)methyl)cyclopentane-1-carboxylate (256.8 mg, 1.386 mmol) in DCM (2 mL) was added ethyl 3-chloro-3-oxopropanoate (288 μL, 2.25 mmol). The mixture was cooled to 0 °C, and triethylamine (0.63 mL, 4.5 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with HO (2 mL) and extracted with DCM (2 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0–65% EtOAc / heptane) to afford the title compound (286 mg, 0.956 mmol, 69% yield) as a pale green oil. 1 H NMR (300MHz, CDCl3) δ4.25-4.11(m, 4H), 3.75(s, 2H), 3.43(s, 2H), 2.93(s, 3H), 2.12-1.94(m, 2H), 1.77-1.56(m, 6H), 1.32-1.23(m, 6H).

[0738] Step 6. 7-Methyl-7-azaspiro[4.5]decane-8,10-dione

[0739] [ka]

[0740] To a solution of ethyl 1-((3-ethoxy-N-methyl-3-oxopropanamido)methyl)cyclopentane-1-carboxylate (621 mg, 2.07 mmol) in toluene (10 mL) was added sodium ethoxide (1.26 mL, 3.26 mmol, 20 wt % in ethanol). The mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature, and HO (10 mL) was added. The aqueous layer was removed, and the organic layer was extracted with HO (10 mL × 2). The combined aqueous layers were acidified to pH < 1 with 4 N HCl (aq) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude residue was dissolved in MeCN (6 mL) containing 2% HO and stirred at 80° C. for 2 h. The solvent was evaporated and the crude residue was purified by silica gel chromatography (0-20% MeOH / DCM) to afford the title compound (360 mg, 1.99 mmol, 96.1%) as an off-white solid. 10 H 15 GCMS calculated for NO2[M]+: m / z = 181.1, found 181.1.

[0741] Step 7: 2-chloro-4-(1-ethoxyethenyl)-5-fluoropyrimidine

[0742] [ka]

[0743] To a solution of tributyl(1-ethoxyvinyl)tin (1.34 mL, 3.97 mmol) and 2,6-dichloro-5-fluorouracil (553 mg, 3.31 mmol) in toluene (6.00 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (194 mg, 0.265 mmol). The mixture was stirred at 100 °C for 3 hours. KF (1.00 g, 17.2 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was then added, and the mixture was stirred overnight. The mixture was filtered, and the two phases were separated. The aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 10% EtOAc / heptane) to give the title compound (268 mg, 1.32 mmol, 39.9% yield). GC-MS calculated for C8H8ClFN2O[M]+: m / z = 202.0, found 202.1.

[0744] Step 8: 2-Bromo-1-(2-chloro-5-fluoropyrimidin-4-yl)ethan-1-one

[0745] [ka]

[0746] To a solution of 2-chloro-4-(1-ethoxyethenyl)-5-fluoropyrimidine (1.94 g, 9.59 mmol) in THF (15 mL) and water (6 mL) was added N-bromosuccinimide (1.71 g, 9.59 mmol). The reaction mixture was stirred at room temperature for 10 minutes. To the mixture were added hexane (8 mL) and EtOAc (8 mL), followed by HO (6 mL). The organic layer was removed, and the aqueous layer was extracted with EtOAc (15 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0% to 45%, EtOAc / heptane) to afford the title compound (2.40 g, 9.47 mmol, 98.7% yield) as a colorless solid. GC-MS calculated for C6H3BrClFN2O[M]+: m / z = 251.9, 253.9, found 252.0, 254.0.

[0747] Step 9. 2'-(2-chloro-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[3,2-c]pyridin]-4'(1'H)-one

[0748] [ka]

[0749] To a solution of 7-methyl-7-azaspiro[4.5]decane-8,10-dione (105 mg, 0.579 mmol) in ethanol (1 mL) was added 2-bromo-1-(2-chloro-5-fluoropyrimidin-4-yl)ethan-1-one (3.29 mL, 0.582 mmol, 1.77 M in ethanol), followed by NHOAc (59.7 mg, 0.775 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the crude residue was purified by preparative HPLC on a C18 column (10-55% MeCN / 0.1% TFA (aq)) to give the title compound (47 mg, 0.14 mmol, 24% yield). 16 H 17 LCMS calculated m / z for ClFN4O[M+H]+ = 335.1, found 334.9.

[0750] Step 10. 2'-(2-chloro-5-fluoropyrimidin-4-yl)-1',5'-dimethyl-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[3,2-c]pyridin]-4'(1'H)-one

[0751] [ka]

[0752] To a solution of 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylspiro[1,6-dihydropyrrolo[3,2-c]pyridin-7,1'-cyclopentan]-4-one (41.9 mg, 0.125 mmol) and K2CO3 (87 mg, 0.63 mmol) in acetone (3 mL) was added dimethyl sulfate (118 μL, 1.25 mmol). The mixture was stirred at room temperature for 24 hours. An additional portion of dimethyl sulfate (118 μL, 1.25 mmol) was added to the mixture, and the mixture was stirred for an additional 2 days. The mixture was filtered, concentrated, and purified by preparative HPLC on a C18 column (10-70% MeCN / 0.1% TFA (aq)) to give the title compound (32.5 mg, 0.0932 mmol, 74.6% yield) as a colorless solid. 17 H 19 LCMS calculated for ClFN4O[M+H]+: m / z = 349.1, found 348.9.

[0753] Step 10. 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-1',5'-dimethyl-5',6'-dihydrospiro[cyclopentane-1,7'-pyrrolo[3,2-c]pyridin]-4'(1'H)-one The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. It was isolated as the TFA salt. 1H NMR (400MHz, methanol-d4) δ8.58(d, J=3.6Hz, 1H), 8.25-8.17(m, 2H), 7.66(d, J=8.8Hz, 1H), 7.40(d, J=4.0Hz, 1H), 4.05(s, 3H), 3.71 -3.64(m, 2H), 3.41(s, 2H), 3.23-3.14(m, 2H), 3.06(s, 3H), 2.94(s, 3H), 2.27-2.18(m, 2H), 2.16-2.09(m, 2H), 2.08-1.82(m, 9H). C 28 H 35 LCMS calculated m / z for FN7O[M+H]+ = 504.3, found 504.2.

[0754] Example 75. 5'-Ethyl-2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-cpyridin]-4'-one

[0755] [ka]

[0756] The title compound was synthesized by procedures similar to those outlined in Example 1, steps 1-10. 30 H 37 FN7OS[M+H] + LCMS calculated value for: 562.3, found value: 562.1.

[0757] Example 76. 2"-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5"-methyl-5'',6"-dihydro-4"H-dispiro[cyclopropane-1,1'-cyclobutane-3',7"-thieno[3,2-c]pyridin]-4"-one

[0758] [ka]

[0759] Step 1. (5-(thiophen-2-yl)spiro[2.3]hexan-5-yl)methanamine

[0760] [ka]

[0761] The title compound was synthesized by a procedure similar to that outlined in Example 28, steps 4-5, using 1,1-bis(bromomethyl)cyclopropane instead of 1,2-dibromoethane in step 4. 11 H 16 NS[M+H] + LCMS calculated for: 194.1, found: 194.2.

[0762] Step 2. 2″-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5″-methyl-5′,6″-dihydro-4″H-dispiro[cyclopropane-1,1′-cyclobutane-3′,7″-thieno[3,2-c]pyridin]-4″-one The title compound was synthesized by procedures similar to those outlined in Example 1. 1 H NMR (400MHz, CD3OD) δ8.56(d, J=3.2Hz, 1H), 8.13(d, J=1.8Hz, 1H), 7.56(dd, J=9 .5, 2.8Hz, 1H), 7.39(d, J=6.0Hz, 1H), 7.38(s, 1H), 4.40(d, J=11.2Hz, 2H), 4.26 -4.13(m, 4H), 4.08(s, 2H), 3.78(s, 2H), 3.17(q, J=7.2Hz, 2H), 3.05(s, 3H), 2.4 4(d, J=12.8Hz, 2H), 2.32(d, J=12.6Hz, 2H), 1.13(t, J=7.2Hz, 3H), 0.54(s, 4H). C 29 H 33 FN7OS[M+H] + LCMS calculated value for: 546.2, found value: 546.1.

[0763] Example 77. 2'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-2,3,5,5',6,6'-hexahydro-4'H-spiro[pyran-4,7'-thieno[3,2-c]pyridin]-4'-one

[0764] [ka]

[0765] The title compound was synthesized by a procedure similar to that outlined in Example 28, steps 6-11, using (4-(thiophen-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (CombiBlock, QJ-3597) instead of (1-(4-methylthiophen-2-yl)cyclopropyl)methanamine in step 6. 1 H NMR (400MHz, CD3OD) δ8.69(d, J=3.1Hz, 1H), 8.27(d, J=1.8Hz, 2H), 8.15(dd, J=8.9, 2.4Hz, 1H), 7.84(d, J=9.0Hz, 1H), 3.97-3.89(m, 2H), 3 .88-3.80(m, 4H), 3.73-3.64(m, 2H), 3.26-3.20(m, 2H), 3.18(s, 3H), 3.10-3.03(m, 1H), 2.97(s, 3H), 2.29-2.20(m, 2H), 2.08-1.89(m, 6H). C 27 H 32 FN6O2S[M+H] + LCMS calculated value for: 523.2, found value: 523.1.

[0766] Example 78. 6'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methylspiro[cyclopentane-1,1'-isoindolin]-3'-one

[0767] [ka]

[0768] Step 1. 6'-Bromo-2'-methylspiro[cyclopentane-1,1'-isoindolin]-3'-one

[0769] [ka]

[0770] Sodium hydride (80.0 mg, 2.00 mmol, 60 wt% dispersion in mineral oil) and 5-bromo-2,3-dihydro-2-methyl-1H-isoindol-1-one (90.4 mg, 0.400 mmol) were suspended in anhydrous THF (10 mL) and stirred at room temperature for 30 minutes. 1,4-Diiodobutane (0.260 mL, 2.00 mmol) was added, and the reaction was stirred for 24 hours. The reaction was poured into saturated NH4Cl (aq) and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0–30% EtOAc / hexanes) to afford the title compound (80.0 mg, 0.286 mmol, 71.4%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.68 (d, J=8.2Hz, 1H), 7.60-7.54 (m, 2H), 3.04 (s, 3H), 2.15-1.88 (m, 8H). C 13 H 15 BrNO[M+H] + LCMS calculated for: m / z=280.0 / 282.0, found: 279.9 / 281.9.

[0771] Step 2. 6'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2'-methylspiro[cyclopentane-1,1'-isoindolin]-3'-one The title compound was synthesized by procedures similar to those outlined in Example 1, steps 5 and 10. 1H NMR (400MHz, CD3OD) δ8.66(d, J=3.2Hz, 1H), 8.19(s, 1H), 8.14(d, J=8.1Hz, 1H), 7.80(d, J=8.0Hz, 1H), 7.57(dd, J=9.4, 2.8Hz, 1H), 7.43-7.31(m, 2H), 4.41(d, J=11.3Hz, 2H), 4.21(d, J=10.9Hz, 2H), 4.18(s, 2H), 4.08(s, 2H), 3 .17(q, J=7.3Hz, 2H), 3.02(s, 3H), 2.23-1.78(m, 8H), 1.13(t, J=7.2Hz, 3H). C 29 H 33 FN7O[M+H] + LCMS calculated for: m / z=514.3, found: 514.1.

[0772] Example 79. 6'-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2'-methylspiro[cyclopentane-1,1'-isoindolin]-3'-one

[0773] [ka]

[0774] The title compound was synthesized by procedures similar to those outlined in Example 78, steps 1-2. 1 H NMR (400MHz, CD3OD) δ8.72 (d, J=3.1Hz, 1H), 8.23-8.12 (m, 4H), 7.81 (d, J=8.0Hz, 1H), 7.55 (d, J=9.4Hz, 1H), 3. 58(d, J=12.4Hz, 2H), 3.10(t, J=12.6Hz, 2H), 3.02(s, 3H), 3.01-2.92(m, 1H), 2.85(s, 3H), 2.21-1.83(m, 12H). C 28 H 32 FN6O[M+H] + LCMS calculated for: m / z=487.3, found: 487.1.

[0775] Example 80. 5'-Methyl-2'-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0776] [ka]

[0777] Step 1. 5'-Methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0778] [ka]

[0779] The title compound was synthesized by procedures similar to those outlined in Example 6, steps 1-6. 10 NOS [M+H] + LC-MS calculated value for: 180.1, found value: 180.0.

[0780] Step 2. 5'-Methyl-2'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one

[0781] [ka]

[0782] To a solution of 5'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-4'(5'H)-one (94.0 mg, 0.520 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.210 mL, 1.05 mmol) in THF (1.7 mL) was added lithium diisopropylamide (0.79 mL, 1.57 mmol, 2.0 M in THF / heptane / ethylbenzene) over 15 min at -78 °C. After stirring for 90 min at room temperature, saturated NH4Cl(aq) (10 mL) was added and the mixture was extracted with EtOAc (5 mL). The title compound was observed. C 15 H 21 BNO3S [M+H] + LC-MS calculated for: 306.1, found: 306.0. The organic layer was removed and the aqueous layer was extracted with 1:3 isopropanol / chloroform (5 mL x 4). The combined organic layers were concentrated to give a dark oil which was used without further purification.

[0783] Step 3. 2'-(2-chloro-5-methylpyrimidin-4-yl)-5'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0784] [ka]

[0785] A mixture of 5'-methyl-2'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,6'-thieno[2,3-c>]pyrrole]-4'(5'H)-one from Step 2, 2,4-dichloro-5-methylpyrimidine (from Step 2), KPO (334 mg, 1.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.4 mg, 0.0525 mmol), 1,4-dioxane (4 mL), and water (1 mL) was sparged with N for 10 minutes. The reaction vessel was then capped, and the reaction mixture was heated at 100 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-40%, EtOAc / heptane) to afford the title compound (17.0 mg, 0.0556 mmol, 10.7% yield over two steps). 14 H 13 ClN3OS[M+H] + LCMS calculated values ​​for: 306.0, 308.0, found values: 306.1, 308.1.

[0786] Step 4. 5'-Methyl-2'-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 9. It was isolated as the TFA salt. 25 H 29 N6OS[M+H] + LC-MS calculated for: 461.2, found: 461.2.

[0787] Example 81. 2'-(2-((5-(2-ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0788] [ka]

[0789] Step 1. tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

[0790] [ka]

[0791] A vial was charged with tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2.55 g, 12.0 mmol), imidazole (2.44 g, 35.9 mmol), triphenylphosphine (6.27 g, 23.9 mmol), and iodine (4.55 g, 17.9 mmol). Toluene (40 mL) was then added. The mixture was refluxed for 1 h. The mixture was cooled to room temperature, washed with HO (40 mL), dried over NaSO, filtered, and concentrated to give a colorless solid. The crude residue was purified by silica gel chromatography (0–20% EtOAc / heptane) to give the title compound (3.55 g, 10.9 mmol, 91.8% yield) as a colorless solid. f =0.7 (20% EtOAc / hexane).

[0792] Step 2. tert-Butyl 6-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0793] [ka]

[0794] A vial was charged with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (82.1 mg, 0.373 mmol), tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (120.5 mg, 0.3729 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.3 mg, 0.0373 mmol), and KPO (237.4 mg, 1.119 mmol). 1,4-Dioxane (3 mL) and water (1 mL) were then added. The mixture was heated at 100 °C overnight. The mixture was concentrated and partitioned between DCM (10 mL) and water (10 mL). The biphasic mixture was then filtered through a syringe filter. The organic layer was separated and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-10% MeOH / DCM) to give the title compound (40.1 mg, 0.138 mmol, 37.0% yield). 16 H 24 N3O2[M+H] + LCMS calculated for: m / z=290.2, found: 290.0.

[0795] Step 3. tert-Butyl 6-(6-((4-(3',5'-dimethyl-4'-oxo-4',5'-dihydrospiro[cyclopropane-1,6'-thieno[2,3-c]pyrrole]-2'-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0796] [ka]

[0797] The title compound was synthesized by a procedure similar to that outlined in Example 6, Step 9. 30 H 34 FN6O3S[M+H] + LCMS calculated for: m / z=577.2, found: 577.5.

[0798] Step 4. 2'-(2-((5-(2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one

[0799] [ka]

[0800] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 7. 25 H 26 FN6OS[M+H] + LCMS calculated for: m / z=477.2, found: 477.2.

[0801] Step 5. 2'-(2-((5-(2-ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 8. 1 H NMR (300MHz, methanol l-d4) δ8.73(d, J=3.0Hz, 1H), 8.28(dd, J=9.0, 2.1Hz, 1H), 8.20-8.15(m, 1H), 7.60( d, J=9.0Hz, 1H), 4.46(dd, J=10.8, 2.5Hz, 1H), 4.21(d, J=10.5, 2H), 4.03(d, J=10.8Hz, 1H), 3.62(p, J= 9.0Hz, 1H), 3.24(q, J=7.0Hz, 2H), 2.86(s, 3H), 2.84-2.80(m, 1H), 2.77(d, J=2.4Hz, 3H), 2.74-2.66(m , 1H), 2.60-2.43(m, 2H), 1.92(dd, J=8.7, 6.0Hz, 2H), 1.54(d, J=8.4, 6.0Hz, 2H), 1.21(t, J=7.2Hz, 3H). C27 H 30 FN6OS[M+H] + LCMS calculated for: m / z=505.2, found: 505.0.

[0802] Example 82. 2-[2-[[6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one

[0803] [ka]

[0804] Step 1. tert-Butyl 6-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0805] [ka]

[0806] To a solution of 3,6-dichloropyridazine (500 mg, 3.36 mmol) in 1,4-dioxane (10 mL) was added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (665 mg, 3.36 mmol), KPO (2.14 g, 10.1 mmol), and XPhos Pd G (264 mg, 0.340 mmol, CAS 1310584-14-5). The mixture was stirred at 100 °C for 24 h. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (10–90% EtOAc / heptane) to give the title compound (545 mg, 1.75 mmol, 52.3% yield). C 14 H 20 ClN4O2[M+H] +LCMS calculated for: m / z = 311.1, 313.1, found 311.1, 313.0.

[0807] Step 2. 2-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane

[0808] [ka]

[0809] To a solution of tert-butyl 6-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (545 mg, 1.75 mmol) in DCM (5 mL) was added TFA (5.0 mL, 65 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the crude material containing the title compound was carried forward without further purification. C9H 11 ClN4[M+H] + LCMS calculated for: m / z = 211.1, found 211.1.

[0810] Step 3. 2-(6-chloropyridazin-3-yl)-6-ethyl-2,6-diazaspiro[3.3]heptane

[0811] [ka]

[0812] To a solution of 2-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane (350 mg, 1.66 mmol) in methanol (4 mL) was added triethylamine (0.462 mL, 3.32 mmol), acetaldehyde (366 mg, 8.31 mmol), acetic acid (100 mg, 1.66 mmol), and sodium cyanoborohydride (1.04 g, 16.6 mmol). The mixture was stirred at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (300 mg, 1.26 mmol, 75.6% yield). C 11 H 16 LCMS calculated for ClN4[M]+: m / z = 239.1, found 239.1.

[0813] Step 4. N-[6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-yl]-1,1-diphenylmethanimine

[0814] [ka]

[0815] To a solution of 2-(6-chloropyridazin-3-yl)-6-ethyl-2,6-diazaspiro[3.3]heptane (360 mg, 1.51 mmol) in toluene (7.2 mL) was added benzophenone imine (410 mg, 2.26 mmol), tris(dibenzylindeneacetone)dipalladium(0) (51.4 mg, 0.151 mmol), rac-BINAP (141 mg, 0.231 mmol, CAS 98327-87-8), and sodium tert-butoxide (435 mg, 4.52 mmol). The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and diluted sequentially with water (30 mL) and EtOAc (30 mL). The organic layer was removed, and the aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (20% to 100% EtOAc / heptane, then 0% to 30% MeOH / EtOAc) to afford the title compound (210 mg, 0.548 mmol, 36.3% yield) as a white solid. 24 H 26 N5[M+H] + LCMS calculated for: m / z=384.2, found: 384.2.

[0816] Step 5. 6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-amine

[0817] [ka]

[0818] To a solution of N-[6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-yl]-1,1-diphenylmethanimine (1.38 g, 3.60 mmol) in DCM (15 mL) was slowly added trifluoroacetic acid (15.0 mL, 196 mmol). The resulting mixture was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure and then co-evaporated with toluene. The residue was purified by preparative HPLC (0%-60% MeCN / 0.1% TFA (aqueous)) on a C18 column. After concentration, the material was partitioned between 10 mL of 1:3 isopropyl alcohol / CHCl3 and 10 mL of saturated sodium bicarbonate solution. The organic layer was removed, and the aqueous layer was extracted with 1:3 isopropyl alcohol / CHCl3 (10 mL × 5). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further purified by silica gel chromatography (0-40% MeOH / DCM) to afford the title compound (200 mg, 0.912 mmol, 25.3% yield) as a white solid. 1 H NMR (300MHz, CD3OD) δ6.91(d, J=9.4Hz, 1H), 6.80(d, J=9.4Hz, 1H), 4.06(s, 4H), 3.44(s, 4H), 2.53(q, J=7.2Hz, 2H), 0.99(t, J=7.2Hz, 3H). C 11 H 18 N5[M+H] + LCMS calculated for: m / z=220.2, found: 220.1.

[0819] Step 6. 2-[2-[[6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one To a nitrogen-sparged solution of 2-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one (50.0 mg, 0.142 mmol), 6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-amine (37.4 mg, 0.171 mmol), and potassium phosphate tribasic (90.5 mg, 0.426 mmol) in 1,4-dioxane (4.75 mL) was added XPhos Pd G2 (11.2 mg, 0.0142 mmol). The reaction was sealed and stirred at 100 °C for 48 h. The reaction mixture was cooled to room temperature, filtered, diluted with MeCN, and purified via preparative HPLC on a C18 column (11-31% MeCN / 0.1% TFA (aq)) to afford the title compound as a yellow powder, TFA salt (21.7 mg, 0.0245 mmol, 17.2% yield). 1 H NMR (400MHz, DMSO-d6) δ9.99(s, 1H), 8.70(d, J=3.1Hz, 1H), 8.19(d, J=9.7Hz, 1H), 7.93(d, J=1.9Hz, 1H), 7.44(d, J=9.8Hz, 1H), 4.50-4.31(m,6 H), 4.25(dd, J=11.2, 6.5Hz, 2H), 3.53(s, 2H), 3.18(p, J=7.0Hz, 2H), 3.02(s, 3H), 2.06-1.94(m, 2H), 1.90-1.75(m, 6H), 1.07(t, J=7.2Hz, 3H). C 27 H 32 FN8OS[M+H] + LCMS calculated for: m / z=535.2, found: 535.1.

[0820] Example 83. 2'-(5-Fluoro-2-((6-(1-isopropylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0821] [ka]

[0822] Step 1. tert-Butyl 4-(6-aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0823] [ka]

[0824] N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (2.63 g, 8.49 mmol), 6-chloropyridazin-3-amine (1.00 g, 7.72 mmol), KPO (4.92 g, 23.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.565 g, 0.772 mmol) were suspended in 1,4-dioxane (15.0 mL) and water (5.00 mL). The reaction mixture was heated at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (30.0 mL). The mixture was extracted with EtOAc (30.0 mL × 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was suspended in DCM (20.0 mL) and the solid was collected by filtration to give the title compound (1.65 g, 5.97 mmol, 77.4% yield) as a white solid. 1 H NMR (300MHz, CDCl3) δ7.39(d, J=9.3Hz, 1H), 6.73(d, J=9.3Hz, 1H), 6.32(s, 1H), 4. 69(s, 2H), 4.12(q, J=3.1Hz, 2H), 3.64(t, J=5.7Hz, 2H), 2.76(s, 2H), 1.49(s, 9H).

[0825] Step 2. tert-Butyl 4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate

[0826] [ka]

[0827] tert-Butyl 4-(6-aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.60 g, 5.79 mmol) was dissolved in MeOH (30.0 mL). Palladium on carbon (0.800 g, 0.751 mmol, 10 wt%) and acetic acid (2.00 mL, 34.8 mmol) were added sequentially. The reaction vessel was sealed in a Parr shaker and charged with H (60 psi). The reaction mixture was shaken overnight. The H2 atmosphere was removed, the mixture was filtered, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (50-100% EtOAc in heptane, then 0-30% MeOH in EtOAc) to give the title compound (610 mg, 2.19 mmol, 37.8% yield). 14 H 23 N4O2[M+H] + LCMS calculated for: m / z=279.2, found: 279.0.

[0828] Step 3. tert-Butyl 4-(6-((4-(3',5'-dimethyl-4'-oxo-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-2'-yl)-5-fluoropyrimidin-2-yl)amino)pyridazin-3-yl)piperidine-1-carboxylate

[0829] [ka]

[0830] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. 29 H 35 FN7O3S[M+H] + LCMS calculated for: m / z=580.2, found: 580.1.

[0831] Step 4. 2'-(5-Fluoro-2-((6-(piperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0832] [ka]

[0833] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 7. 24 H 27 FN7OS[M+H] + LCMS calculated for: m / z=480.2, found: 480.1.

[0834] Step 5. 2'-(5-Fluoro-2-((6-(1-isopropylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one Potassium carbonate (120 mg, 0.85 mmol) and 2-iodopropane (26 μL, 0.26 mmol) were added to a solution of 2′-(5-fluoro-2-((6-(piperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-3′,5′-dimethyl-5′,6′-dihydro-4′H-spiro[cyclopropane-1,7′-thieno[3,2-c]pyridin]-4′-one (100 mg, 0.21 mmol) in DMF (1.10 mL) at room temperature. The mixture was stirred for 20 hours. The crude reaction was diluted with methanol, filtered, and concentrated. The crude residue was purified by preparative HPLC on a C18 column (14-34% MeCN / 0.1% TFA (aq)) to afford the title compound as the TFA salt (3.9 mg, 0.0046 mmol, 2.20% yield). 27 H 33 FN7OS[M+H] + LCMS calculated for: m / z=522.2, found: 522.1.

[0835] Example 84. 3,3-Difluoro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0836] [ka]

[0837] Step 1. 3,3-Dimethoxy-1-(thiophen-2-yl)cyclobutane-1-carbonitrile

[0838] [ka]

[0839] Sodium hydride (1.62 mg, 40.6 mmol, 60 wt% dispersion in mineral oil) and 1,3-ibromo-2,2-dimethoxypropane (4.68 g, 17.9 mmol) were added to a solution of 2-thiopheneacetonitrile (2.00 g, 16.2 mmol) in DMF (40 mL) at room temperature. The reaction mixture was heated at 60 °C for 18 h. The reaction was quenched with water (50 mL), and the mixture was diluted with EtOAc (50 mL). The two phases were separated, and the aqueous layer was extracted with EtOAc (50 mL × 2). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0 to 40% EtOAc in hexanes) to afford the title compound (2.90 g, 13.0 mmol, 80.0% yield) as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ7.28(dd, J=5.1, 1.3Hz, 1H), 7.13(dd, J=3.6, 1.3Hz, 1H), 6.97(dd, J=5.1, 3.6Hz, 1H) ), 3.26(s, 3H), 3.18(s, 3H), 3.17-3.14(m, 1H), 3.13-3.10(m, 1H), 2.79-2.76(m, 1H), 2.75-2.72(m, 1H).

[0840] Step 2. 3,3-Dimethoxy-1-(thiophen-2-yl)cyclobutane-1-carbonitrile

[0841] [ka]

[0842] Hydrochloric acid (aq) (0.832 mL, 9.99 mmol, 12 M) was added to a solution of 3,3-dimethoxy-1-(thiophen-2-yl)cyclobutane-1-carbonitrile (446 mg, 2.0 mmol) in 1:1 acetone / water (6.60 mL) at room temperature. The reaction mixture was heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (10.0 mL) and DCM (10.0 mL). The two phases were separated, and the aqueous phase was extracted with DCM (10.0 mL × 2). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (350 mg, 1.97 mmol, 98.9% yield) as a gray oil. 1 H NMR (400MHz, CDCl3) δ7.35(dd, J=5.1, 1.2Hz, 1H), 7.19(dd, J=3.6, 1.2Hz, 1H), 7.03(dd, J=5 .1, 3.6Hz, 1H), 4.16-4.10(m, 1H), 4.10-4.05(m, 1H), 3.80-3.75(m, 1H), 3.75-3.70(m, 1H).

[0843] Step 3. 3,3-Difluoro-1-(thiophen-2-yl)cyclobutane-1-carbonitrile

[0844] [ka]

[0845] Diethylaminosulfur trifluoride (0.650 mL, 4.93 mmol) was added to a solution of 3,3-dimethoxy-1-(thiophen-2-yl)cyclobutane-1-carbonitrile (349 mg, 1.97 mmol) in DCM (10.0 mL) at room temperature. The reaction mixture was stirred for 18 h. The reaction mixture was poured into saturated NaHCO3 (aq) (20.0 mL) and diluted with DCM (10.0 mL). The two phases were separated, and the aqueous layer was extracted with DCM (10.0 mL × 2). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0–20% EtOAc in hexanes) to afford the title compound (313 mg, 1.57 mmol, 79.8% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.34(d, J=5.2Hz, 1H), 7.16(d, J=3.7Hz, 1H), 7.02(dd, J=5.2, 3.6Hz, 1H), 3.63-3.46(m, 2H), 3.33-3.15(m, 2H).

[0846] Step 5. (3,3-Difluoro-1-(thiophen-2-yl)cyclobutyl)methanamine

[0847] [ka]

[0848] Lithium aluminum hydride (62.6 mg, 1.65 mmol) was added to a solution of 3,3-difluoro-1-(thiophen-2-yl)cyclobutane-1-carbonitrile (313 mg, 1.57 mmol) in THF (5.00 mL) at room temperature. After stirring for 30 minutes, the reaction was quenched by the sequential addition of water (0.070 mL) and 1N NaOH (aq) (0.280 mL). The suspension was diluted with EtOAc and dried over sodium sulfate. The resulting mixture was filtered and concentrated. The crude residue containing the title compound as a colorless oil was used without further purification. CH 12F2NS[M+H] + LCMS calculated for: m / z = 204.1, found 203.9.

[0849] Step 6. 2'-Bromo-3,3-difluoro-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0850] [ka]

[0851] The title compound is synthesized by procedures similar to those outlined in Example 1, steps 1-4. It was isolated as the major component of a mixture. 1 H NMR (400MHz, CDCl3) δ7.37 (s, 1H), 3.66 (d, J=1.3Hz, 2H), 3.11 (s, 3H), 2.92-2.73 (m, 4H). C 11 H 11 BrF2NOS[M+H] + LCMS calculated for: m / z=322.0 / 324.0, found: 321.8, 323.7.

[0852] Step 7. 3,3-Difluoro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one The title compound was synthesized by procedures similar to those outlined in Example 1, steps 5 and 10. It was isolated as the TFA salt. 1H NMR (400MHz, DMSO-d6) δ10.23(s, 1H), 9.35(s, 1H), 8.73(d, J=3.1Hz, 1H), 8.21( d, J=2.5Hz, 1H), 8.13(d, J=8.7Hz, 1H), 7.95(d, J=1.9Hz, 1H), 7.72(dd, J=8.7, 2 .5Hz, 1H), 3.80(s, 2H), 3.54(d, J=12.0Hz, 2H), 3.24-3.05(m, 4H), 3.04(s, 3H), 2.99-2.88(m, 3H), 2.83(d, J=4.7Hz, 3H), 2.14-2.00(m, 2H), 1.94-1.73(m, 2H). C 26 H 28 F3N6OS[M+H] + LCMS calculated for: m / z=529.2, found: 529.0.

[0853] Example 85. 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3,3-difluoro-5'-methyl-5',6'-dihydro-4"H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one

[0854] [ka]

[0855] The title compound was synthesized by a procedure similar to that outlined in Example 84. It was isolated as the TFA salt. 1H NMR (400MHz, DMSO-d6) δ9.90(s, 1H), 9.79(s, 1H), 8.65(d, J=3.1Hz, 1H), 7.93(d, J=1 .8Hz, 1H), 7.90(d, J=9.0Hz, 1H), 7.61(d, J=3.0Hz, 1H), 7.08(dd, J=9.1, 3.0Hz, 1H), 4 .35(dd, J=11.4, 6.3Hz, 2H), 4.21(dd, J=11.6, 6.0Hz, 2H), 4.09(s, 2H), 4.00(s, 2H), 3 .79(s, 2H), 3.24-3.09(m, 4H), 3.03(s, 3H), 3.00-2.85(m, 2H), 1.07(t, J=7.2Hz, 3H). C 27 H 29 F3N7OS[M+H] + LCMS calculated for: m / z=556.2, found: 556.0.

[0856] Example 86. 2-[2-[[5-(4-ethyl-2-oxopiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one

[0857] [ka]

[0858] Step 1: 4-ethyl-1-(6-nitropyridin-3-yl)piperazin-2-one

[0859] [ka]

[0860] A solution of 5-bromo-2-nitropyridine (1050 mg, 5.16 mmol), 4-ethyl-2-piperazinone hydrochloride (850 mg, 5.16 mmol), and cesium carbonate (3360 mg, 10.3 mmol) in 1,4-dioxane (25 mL) was sparged with N for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (88.0 mg, 0.258 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (257 mg, 0.444 mmol) were added, and the solution was sparged with N for an additional 10 minutes. The reaction was stirred at 105 °C overnight. The reaction mixture was cooled to room temperature, diluted with water (40 mL) and EtOAc (40 mL), and filtered through Celite. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-20% MeOH / DCM) to afford the title compound (992 mg, 3.96 mmol, 76.8% yield) as an orange solid. 11 H 15 N4O3[M+H] + LCMS calculated for: m / z=251.1, found: 251.0.

[0861] Step 2. 1-(6-aminopyridin-3-yl)-4-ethylpiperazin-2-one

[0862] [ka]

[0863] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 9. 11 H 17 NO[M+H] + LCMS calculated for: m / z = 221.1, found 221.0.

[0864] Step 3. 2-[2-[[5-(4-ethyl-2-oxopiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10, to provide the title compound as the TFA salt. 27 H 31 FN7O2S[M+H] + LCMS calculated for: m / z = 536.2, found 536.1.

[0865] Example 87. 2-[5-Fluoro-2-[[6-(1-methylpiperidin-4-yl)pyridazin-3-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one

[0866] [ka]

[0867] Step 1. 2-[5-Fluoro-2-[(6-piperidin-4-ylpyridazin-3-yl)amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one

[0868] [ka]

[0869] The title compound was synthesized by procedures similar to those outlined in Example 83, steps 1-4. 25 H 29 FN7OS[M+H] + LCMS calculated for: m / z = 494.2, found 494.0.

[0870] Step 2. 2-[5-Fluoro-2-[[6-(1-methylpiperidin-4-yl)pyridazin-3-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one To a solution of 2-[5-fluoro-2-[(6-piperidin-4-ylpyridazin-3-yl)amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one (165 mg, 0.340 mmol) in methanol (1.75 mL) was added acetic acid (0.110 mL, 2.01 mmol) and formaldehyde (0.16 mL, 2.01 mmol, 37 wt % in water). The reaction was stirred at room temperature for 15 minutes. Sodium cyanoborohydride (126 mg, 2.01 mmol) was added in portions, and the reaction mixture was stirred for 18 hours. The reaction mixture was filtered through Celite, concentrated, and purified by preparative HPLC on a C18 column (14-34% MeCN / 0.1% TFA (aq)) to give the title compound as the TFA salt (2.10 mg, 0.00257 mmol, 0.767% yield). 26 H 31 FN7OS[M+H] + LCMS calculated for: m / z=508.2, found: 508.1.

[0871] Example A: Enzyme activity and cytotoxicity assays CDK4 / cyclin D1 enzyme activity assay The inhibitory activity of the compounds was evaluated in vitro using a TR-FRET assay in white 384-well low-volume microplates (Greiner Bio-One). CDK4 / cyclin D1-catalyzed phosphorylation of the peptides was measured in the presence and absence of the compounds. IC 50 Determination: Recombinant protein complex CDK4 / cyclin D1 expressed from insect cells was purchased from ProQinase. Test compounds were dissolved in DMSO at 0.1 mM and 9 doses of IC 50The assay was performed in the 1000-well mode. The reaction mixture was prepared by mixing CDK4 / cyclin D1 (1 nM final), ULight-4E-BP1 (100 nM final, Perkinelmer, TRF0128-D), and ATP (2 mM final) in assay buffer (20 mM HEPES pH 7.4, 1 mM EGTA, 0.05% BSA, 0.005% Tween 20, and 1 mM TCEP). The compound of interest in DMSO was added to each well in 3-fold serial dilutions using a dispenser (TECAN D300E). After preincubation at room temperature for 20 minutes, the reaction was initiated by adding MgCl (10 mM final). After incubation at 37°C...

Claims

1. Formula I: 【Chemistry 1】 [In the formula, Ring A is a 3- to 8-membered cycloalkyl or heterocycloalkyl ring; Ring B is a 6-membered aryl or a 5- to 6-membered heteroaryl, and Ring B optionally contains 1, 2, or 3 R ４ is substituted with a substituent, Z is O, S, NR ｂ , N.O.R. ｂ or N-CN, V is CL １ R １ or N, n is 1, 2 or 3; m is 1 or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, 5, or 6; Each L １ are independently a bond, O, -C(O), S, NR, C ２ ~C ６ Alkylyne or C ２ ~C ６ alkylene, R is H or C １ ~C ６ is alkyl, Each R １ are independently H, D, halogen, -OH, -CN, -NO ２ , -C １ ~C ６ Alkyl, C １～６ Alkoxide, -C ２ ~C ６ Alkenyl, -C ２ ~C ６ Alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ａ , -SR ａ , -NR ｃ R ｄ , -NR ａ R ｃ , -C(O)R ｂ , -OC(O)R ｂ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ , -S(O)R ｂ , -S(O) ２ N.R. ｃ R ｄ , -S(O)(=NR ｂ ) R ｂ , -SF ５ , -P(O)R ｂ R ｂ , -P(O)(OR ｂ ) (OR ｂ ), -B(OR ｃ ) (OR ｄ ), or -S(O) ２ R ｂ and Each R ２ are independently H, D, halogen, C １ ~C ８ Alkoxide, C １ ~C ８ alkyl, haloalkyl, or CN; Each R ３ are independently H, D, halogen, -OH, -CN, -NO ２ , -C １ ~C ６ Alkyl, -C ２ ~C ６ Alkenyl, -C ２ ~C ６ Alkynyl, C ０～ C １ alk-aryl, C ０～ C １ alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -OR ａ , -SR ｂ , -NR ｃ R ｄ , -NR ａ R ｃ , -C(O)R ｂ , -OC(O)R ｂ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ , or -B(OR ｄ ) (OR ｃ ) and Each R ４ are independently H, D, halogen, C １ ~C ８ Alkoxide, C １ ~C ８ alkyl, haloalkyl, or CN; Each R ａ are independently H, D, -C(O)R ｂ , -C(O)OR ｃ , -C(O)NR ｃ R ｄ , -C(=NR ｂ ) N.R. ｂ R ｃ , -C(=NOR ｂ ) N.R. ｂ R ｃ , -C(=NCN)NR ｂ R ｃ -P(OR ｃ ) ２ , -P(O)OR ｃ OR ｂ , -S(O) ２ R ｂ , -S(O) ２ N.R. ｃ R ｄ , SiR ｂ ３ , -C １ ~C １０ Alkyl, -C ２ ~C １０ Alkenyl, -C ２ ~C １０ Alkynyl, C ０～ C １ alk-aryl, cycloalkyl, cycloalkenyl, C ０～ C １ alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R ｂ are independently H, D, -C １ ~C ６ Alkyl, -C ２ ~C ６ Alkenyl, -C ２ ~C ６ Alkynyl, C ０～ C １ alk-aryl, cycloalkyl, cycloalkenyl, C ０～ C １ alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R ｃ Or R ｄ are independently H, D, -C １ ~C １０ Alkyl, -C ２ ~C ６ Alkenyl, -C ２ ~C ６ Alkynyl, -OC １ ~C ６ Alkyl, -O-cycloalkyl, aryl, C １ alk-aryl, heteroaryl, cycloalkyl, cycloalkenyl, C １ alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Or R ｃ and R ｄ together with the atom to which they are both attached form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl group; R ５ But, H, D, OR ｂ , C １～４ alkyl, １～４ the alkyl may be substituted with at least one of halogen, —OH, —CN, or an amine, or may be a cycloalkyl; R ６ are independently H, D, halogen, -OH, -CN, -NO ２ , -C １ ~C ６ Alkyl, -C ２ ~C ６ Alkenyl, -C ２ ~C ６ Alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR ａ , -SR ａ , -NR ｃ R ｄ , -NR ａ R ｃ , -C(O)R ｂ , -OC(O)R ｂ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ , -S(O)R ｂ , -S(O) ２ N.R. ｃ R ｄ , -S(O)(=NR ｂ ) R ｂ , -SF ５ , -P(O)R ｂ R ｂ , -P(O)(OR ｂ ) (OR ｂ ), -B(OR ｃ ) (OR ｄ ), or -S(O) ２ R ｂ is] or a pharma- ceutically acceptable salt or solvate or N-oxide thereof.

2. Formula II: 【Chemistry 2】 or a pharma- ceutically acceptable salt, solvate, or N-oxide thereof.

2. The compound of claim 1, wherein the compound is:

3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, solvate or N-oxide thereof, wherein Z is O.

4. (a) Formula III: 【Chemistry 3】 or a pharma- ceutically acceptable salt or solvate or N-oxide thereof; (b) Formula IV: 【Chemistry 4】 or a pharma- ceutically acceptable salt or solvate or N-oxide thereof; (c) a compound of formula V, formula VI, formula VII, formula VIII, formula IX, formula X, or formula XI: 【Chemistry 5】 [In the formula, E is a bond, -O-, -S-, C(R a ) 2 , -(C═O)NR a -, or NR a ] or a pharma- ceutically acceptable salt, solvate or N-oxide thereof.

4. The compound according to any one of claims 1 to 3, which is a compound of the formula:

5. Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII: 【Chemistry 6】 [In the formula, E is a bond, -O-, -S-, C(R a ) 2 , -(C═O)NR a -, or NR a ; L 1 is a bond, —CH 2 —, or C═O; V is CR 11 or N; W is CR 11 or N; U is C(R 11 ) 2 , NR 10 , or O; R 11 is H, D, fluoro, C 1-6 alkyl, or C 1-6 alkoxide; R 4 is H, D, methyl, or haloalkyl; R 5 is H, D, methyl, or haloalkyl; R 10 is H, D, C 1-6 alkyl, or haloalkyl; Each g, h, j, and k is independently 0, 1, 2, or 3. or a pharma- ceutically acceptable salt or solvate or N-oxide thereof, Optionally, the compound of formula XVIII, formula XIX, formula XX, formula XXI, formula XXII, or formula XXIII: 【Chemistry 7】 [In the formula, E is a bond, -O-, -S-, C(R a ) 2 , -(C═O)NR-, or NR a ; L 1 is a bond, —CH 2 —, or C═O; V is CR 11 or N; W is CR 11 or N; R 11 is H, D, fluoro, C 1-6 alkyl, or C 1-6 alkoxide; R 10 is H, D, C 1-6 alkyl, or haloalkyl; R 4 is H, D, Me, or haloalkyl; R 5 is H, D, Me, or haloalkyl. or a pharma- ceutically acceptable salt, solvate or N-oxide thereof.

5. The compound according to any one of claims 1 to 4, which is a compound of the formula: (a) At least one R 1 is a group of formula Y: 【Chemistry 8】 [In the formula, 【Chemistry 9】 is the point of attachment to L 1 ; W is CR 11 or N; U is C(R 11 ) 2 , NR 10 , or O; R 10 is H, D, C 1-6 alkyl, or haloalkyl; R 11 is H, D, fluoro, C 1-6 alkyl, or C 1-6 alkoxide; R 12 is H, D, fluoro, C 1-6 alkyl, or C 1-6 alkoxide; t is 0, 1, 2, 3, 4, 5, or 6; each g and h is independently 0, 1, 2, or 3; Is it a group of (b) at least one R 1 is 【Chemistry 10】 wherein R 10 is H or C 1-6 alkyl; 【Chemistry 11】 is the point of attachment to L 1 . is a group selected from 6. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate or N-oxide thereof.

7. At least one R 1 is represented by formula Z: 【Chemistry 12】 [In the formula, 【Chemistry 13】 is the point of attachment to L 1 ; W is CH or N; U is C(R 11 ) 2 , NR 10 , or O; R 10 is H, D, C 1-6 alkyl, or haloalkyl; R 11 is H, D, fluoro, C 1-6 alkyl, or C 1-6 alkoxide; R 12 is H, D, fluoro, C 1-6 alkyl, or C 1-6 alkoxide; t is 0, 1, 2, 3, 4, 5, or 6; Each g, h, j, and k is independently 0, 1, 2, or 3. Based on Optionally, At least one R 1 is 【Chemistry 14】 wherein R 10 is H or C 1-6 alkyl; 【Chemistry 15】 is the point of attachment to L 1 . The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, solvate or N-oxide thereof, wherein R is a group selected from the group consisting of:

8. 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one, or a pharma- ceutically acceptable salt, solvate or N-oxide thereof.

8. The compound according to any one of claims 1 to 7, which is a compound of the formula:

9. 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 3'-chloro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-3'-(trifluoromethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-chloro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-ethyl-3'-methylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-isopropylpyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(5-methyl-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-[5-methyl-2-[[5-(1-methylpiperidin-3-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, 5'-ethyl-2'-[5-methyl-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 5'-ethyl-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(1-ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-3'-(trifluoromethyl)spiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 3'-chloro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methylspiro[cyclopentane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclo-propane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1-ethylpyrrolidin-3-yl)pyridin-2-yl)amino)-5-fluoro-pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclo-propane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-((3aS,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 5-methyl-2-[4-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]spiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-methylpyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-methylpyrimidin-4-yl]-3,5-dimethylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 5-methyl-2-[5-methyl-2-[[5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[5-chloro-2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2-[5-chloro-2-[[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopropan]-4-one, 2'-(5-fluoro-2-((5-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1-(2,2-difluoroethyl)piperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(4-methyl-piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1-ethyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 5-methyl-2-[4-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]-5-(trifluoromethyl)pyrimidin-2-yl]spiro[6H-thieno[3,2-c]pyridine-7,1'-cyclobutan]-4-one, 5-methyl-2-[5-methyl-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]spiro[6H-thieno[3,2-c]pyridin-7,1'-cyclobutan]-4-one, 2-[5-chloro-2-[[5-(1-methyl-piperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclobutan]-4-one, 2'-(5-fluoro-2-((5-(6-(methyl-d3)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-(methyl-d3)-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-morpholino-pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(5-fluoro-2-((5-(1-methyl-piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopentane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2-[2-[[5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one, 2-[5-fluoro-2-[[5-[4-methyl-2-(trifluoromethyl)piperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one, 2'-[5-fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3'-methyl-5'-(trideuteriomethyl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, 2'-[2-[[5-(1-ethylpyrrolidin-3-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'-one, (E)-2'-(2-((5-(1-(but-2-en-1-yl)pyrrolidin-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2-[5-fluoro-2-[[5-(1-methylpiperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3-methyl-spiro[5H-thieno[2,3-c]pyrrole-6,1'-cyclopropan]-4-one, 5'-ethyl-2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5',6'-dihydro-4'H-spiro[cyclohexane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2''-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5''-methyl-5'',6''-dihydro-4''H-dispiro[cyclopropane-1,1'-cyclobutane-3',7''-thieno[3,2-c]pyridin]-4''-one, 2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-2,3,5,5',6,6'-hexahydro-4'H-spiro[pyran-4,7'-thieno[3,2-c]pyridin]-4'-one, 5'-methyl-2'-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)spiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2'-(2-((5-(2-ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3',5'-dimethylspiro[cyclopropane-1,6'-thieno[2,3-c]pyrrol]-4'(5'H)-one, 2-[2-[[6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridazin-3-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one, 2'-(5-fluoro-2-((6-(1-isopropylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-3',5'-dimethyl-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-thieno[3,2-c]pyridin]-4'-one, 3,3-difluoro-2'-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one, 2'-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3,3-difluoro-5'-methyl-5',6'-dihydro-4'H-spiro[cyclobutane-1,7'-thieno[3,2-c]pyridin]-4'-one 2-[2-[[5-(4-ethyl-2-oxopiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridine-7,1'-cyclopentan]-4-one, 2-[5-fluoro-2-[[6-(1-methylpiperidin-4-yl)pyridazin-3-yl]amino]pyrimidin-4-yl]-5-methylspiro[6H-thieno[3,2-c]pyridin-7,1'-cyclopentan]-4-one, or a pharma- ceutically acceptable salt, solvate or N-oxide thereof.

8. The compound according to any one of claims 1 to 7, which is a compound of the formula:

10. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or N-oxide thereof, which is: embedded image

11. The compound described in claim 10, which is:

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt or solvate or N-oxide thereof, and a pharma- ceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 for treating CDK4-mediated and CDK6-mediated disorders in a patient in need of such treatment.

14. the CDK4- and CDK6-mediated disorder is cancer; Optionally, the cancer is breast cancer, malignant brain tumor, colon cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis; Optionally, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer and the malignant brain tumor is glioblastoma, astrocytoma, or pontine glioma.

15. the patient is administered the pharmaceutical composition; Optionally, the administration is oral administration.

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