Cdk inhibitors and their use as pharmaceuticals

Abstract

This disclosure relates to compounds of formula (I). Pharmaceutical compositions comprising compounds of formula (I) and methods of using and preparing them are also described.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefits of U.S. Provisional Application 63 / 081,126, filed September 21, 2020 (the entire contents of which are incorporated herein by reference), and U.S. Provisional Application 63 / 221,959, filed July 15, 2021 (the entire contents of which are incorporated herein by reference). Technical Field

[0003] This disclosure relates to CDK inhibitors and methods of their use. Background Technology

[0004] Cyclin-dependent kinases (CDKs) are a conserved family of serine / threonine kinases that play a crucial role in cell cycle and gene transcription regulation (Malumbres 2014). Within the cell cycle CDK subfamily, CDK4 and CDK6 are the major regulators controlling the transition of cells from interphase I (G1) to DNA synthesis phase (S). During this process, cyclin D protein levels increase, complexing with CDK4 / 6 and activating their kinase activity. The activated CDK4 / 6 complex phosphorylates retinoblastoma protein (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-controlled cell cycle genes and cell cycle progression (Lapenna and Giordano 2009, Asghar, Witkiewicz et al. 2015).

[0005] Given the crucial role of CDK4 / 6 in cell cycle regulation, its dysfunction is a hallmark of cancer (Hanahan and Weinberg 2011). Abnormal regulation of the CDK4 / 6 pathway is frequently observed in cancer, such as (epigenetic) inactivation of the endogenous CDK4 / 6 inhibitor p16INK4A and amplification / overexpression of CDK4 / 6 and cyclin D protein (Lapenna and Giordano 2009, Malumbres and Barbacid 2009, Asghar, Witkiewicz et al. 2015, O'Leary, Finn et al. 2016). The study has focused on CDK4 / 6 as a potential therapeutic target for cancer treatment, and the recently approved selective CDK4 / 6 inhibitors, namely palbociclib (US Food & Drug Administration. 2017), ribociclib (US Food & Drug Administration. 2017), and abemaciclib (US Food & Drug Administration. 2018), in combination with endocrine therapy for the treatment of hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, further validates this proposition.

[0006] Central nervous system (CNS) diseases such as glioblastoma (GBM) and brain metastases represent challenging malignancies with pressing unmet needs. GBM is the most common and aggressive primary brain cancer 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 is alternating in most gliomas and represents one of the most perturbed pathways (Cancer Genome Atlas Research 2008, Brennan, Verhaak et al. 2013), suggesting that CDK4 / 6 may be a good target for GBM. On the other hand, an estimated 20% of all cancer patients may develop brain metastases, yet effective treatments remain lacking (chrol, Rennert et al. 2019). Interestingly, genomic studies have also identified the CDK pathway as one of the three most frequently altered and functional genetic alterations in brain metastases (Brastianos, Carter et al. 2015, Valiente, Ahluwalia et al. 2018). However, despite positive preclinical data supporting CDK4 / 6 targeting for GBM treatment (Yin, Li et al. 2018, Bronner, Merrick et al. 2019) and initial indications of brain penetration of abecib in patients (Patnaik, Rosen et al. 2016, Sahebjam, Rhun et al. 2016), the clinical development of CDK4 / 6 inhibitors for GBM or brain metastases remains in the early stages or unsuccessful (Anders, Rhun et al. 2019, Nguyen, Searle et al. 2019, Sahebjam, Le Rhun et al. 2019), possibly because they cannot cross the blood-brain barrier (BBB) ​​(de Gooijer, Zhang et al. 2015, Parrish, Pokorny et al. 2015, Raub, Wishart et al. 2015).

[0007] Another small molecule CDK4 / 6 inhibitor is needed. Summary of the Invention

[0008] This disclosure relates to compounds of formula I:

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein

[0011] Ring A is a 5-7 membered heteroaryl group;

[0012] V = CL1R1 or N

[0013] n is 1, 2, or 3;

[0014] m is 1 or 2;

[0015] o is 1, 2, 3, 4 or 5;

[0016] Each L1 is independently a bond, O, NR, or C1-C6 alkylene, wherein R is H or C1-C6 alkyl;

[0017] Each R1 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)2NR 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)2R b ;

[0018] Each R2 is independently H, D, halogen, C1-C8 alkoxy, C1-C8 alkyl, haloalkyl, or CN, and

[0019] Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b SR b -NR c R d -NR a R c -C(O)R b -OC(O)Rb -C(O)OR b -C(O)NR c R d -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2Rb;

[0020] Each R a Independently H, D, -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)R c R b -P(O)OR c OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiR b 3. -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0021] Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0022] Each Rc Or R d Independently H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

[0023] Or R c and R d Together with the atoms attached to both, they form monocyclic or polycyclic heterocyclic alkyl groups, or monocyclic or polycyclic heterocyclic alkenyl groups;

[0024] Each R4 is independently H, D, halogen, C1-C8 alkoxy or C1-C8 alkyl, haloalkyl, and CN.

[0025] Stereoisomers of Formula I compounds, as well as their pharmaceutical salts and solvates, are also considered, described, and included herein. Methods of using Formula I compounds and pharmaceutical compositions comprising Formula I compounds are described. Detailed Implementation

[0026] This disclosure can be more fully understood by referring to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods described herein in the context of individual aspects may also be provided in combination with individual aspects. Alternatively, multiple features of the disclosed compositions and methods described in the context of individual aspects for the sake of brevity may also be provided individually or in any sub-combination.

[0027] Substituents in the compounds of the present invention are disclosed in various places throughout this specification, by group or scope. The invention is particularly intended to include each and each individual subcombination of the members of these groups and scopes. 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.

[0028] It is also desirable that the compounds of the present invention are stable. As used herein, “stable” means that the compound is robust enough to withstand separation from the reaction mixture to a useful purity, and preferably can be formulated into an effective therapeutic agent.

[0029] It should be further understood that certain features of the invention described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, many features of the invention described in the context of individual embodiments for brevity may also be provided individually or in any suitable sub-combination.

[0030] When used alone or as part of a substituent group, the term "alkyl" refers to a group having 1 to 12 carbon atoms ("C1-C1") in the group.12 The alkyl group is preferably a straight-chain or branched hydrocarbon group with 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), etc. The alkyl groups disclosed herein can be unsubstituted or substituted. Wherein the alkyl group is removed... In those alternative embodiments, the alkyl group may be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Other substituents include -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl)2, -OC(O)NH (C1-C6 alkyl), -OC(O)N (C1-C6 alkyl)2, -S(O)2NH (C1-C6 alkyl), and -S(O)2N (C1-C6 alkyl)2.

[0031] The term "halogen" or halogen refers to chlorine, fluorine, bromine, or iodine.

[0032] When used alone or as part of a substituent group, the term "cycloalkyl" refers to a group having 3 to 10 carbon atoms ("C3-C5"). 10 The cycloalkyl group, preferably a cyclic non-aromatic hydrocarbon group with 3 to 6 carbon atoms (“C3-C6”), is disclosed. The cycloalkyl groups include monocyclic groups as well as polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic cycloalkyl group, the cyclic groups may share a common atom (i.e., a spirocyclic ring). 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), adamantyl (C6), etc. 10), spiro[3.3]heptyl, bicyclo[3.3.0]octyl, etc. The cycloalkyl groups disclosed herein may be unsubstituted or substituted. In those embodiments in which the cycloalkyl groups are substituted, the cycloalkyl groups may be substituted by one, two or three substituents independently selected from -OH, -CN, amino, halogroup, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy. Other substituents include -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl)2, -OC(O)NH (C1-C6 alkyl), -OC(O)N (C1-C6 alkyl)2, -S(O)2NH (C1-C6 alkyl) and -S(O)2N (C1-C6 alkyl)2.

[0033] When used alone or as part of a substituent group, the term "heterocyclic alkyl" refers to any three- to ten-membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Heterocyclic alkyl groups disclosed herein include monocyclic groups as well as polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocyclic alkyl group, the cyclic groups may share a common atom (i.e., a spirocyclic ring). In other embodiments having at least one polycyclic heterocyclic alkyl group, the cyclic groups share two common atoms. The term C3-C6 heterocyclic alkyl refers to a heterocyclic alkyl group having three to six carbon ring atoms. 10Heterocyclic alkyl groups are heterocyclic alkyl groups having three to ten ring atoms. Heterocyclic alkyl groups can be attached to any heteroatom or carbon atom in the ring, resulting in a stable structure. Examples of suitable heterocyclic alkyl groups include, but are not limited to, aziridine, aziridine, pyrrolidinyl, dioxolane, imidazolidinyl, pyrazolyl, piperazinyl, piperidinyl, dioxane, morpholinyl, dithiazolidinyl, thiomorpholinyl, oxaziridine, ethylene oxide, oxaziridine, quinine, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, aziridine, diaziridine, oxaziridine, dioxaziridine, oxaziridine, octyl, diaziridine, oxaziridine, dioxaziridine, azirspiro[2.2]pentyl, oxaziridine[3.3]heptyl, oxaziridine[3.3]heptyl, dioxaziridine[3.3]heptyl, etc. The heterocyclic alkyl groups of this disclosure may be unsubstituted or substituted. In embodiments in which the heterocyclic alkyl group is substituted, the heterocyclic alkyl group may be substituted by one, two, or three substituents independently selected from -OH, -CN, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Other substituents include -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl)2, -OC(O)NH (C1-C6 alkyl), -OC(O)N (C1-C6 alkyl)2, -S(O)2NH (C1-C6 alkyl), and -S(O)2N (C1-C6 alkyl)2.

[0034] When used alone or as part of a substituent group, the term "heterocyclic alkenyl" refers to any three- to ten-membered monocyclic or bicyclic partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Heterocyclic alkenyl groups disclosed herein include monocyclic groups as well as polycyclic groups, such as bicyclic and tricyclic groups. In those embodiments having at least one polycyclic heterocyclic alkenyl group, the cyclic groups may share a common atom (i.e., a spirocyclic ring). In other embodiments having at least one polycyclic heterocyclic alkenyl group, the cyclic groups share two common atoms. The term C3-C6 heterocyclic alkenyl refers to a heterocyclic alkenyl group having three to six carbon atoms. 10Heterocyclic alkenyl groups refer to heterocyclic alkenyl groups having three to ten ring atoms. The heterocyclic alkenyl group can be attached to any heteroatom or carbon atom of the ring, resulting in a stable structure. The heterocyclic alkenyl groups disclosed herein can be unsubstituted or substituted. In those embodiments in which the heterocyclic alkenyl group is substituted, the heterocyclic alkenyl group can be substituted by one, two, or three substituents independently selected from -OH, -CN, amino, halogroup, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Additional substituents include -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl)2, -OC(O)NH (C1-C6 alkyl), -OC(O)N (C1-C6 alkyl)2, -S(O)2NH (C1-C6 alkyl), and -S(O)2N (C1-C6 alkyl)2.

[0035] When used alone or as part of a substituent group, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring structure comprising a carbon atom and up to five heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings may comprise a total of 5, 6, 7, 8, 9, or 10 ring atoms. (Term -C5-C) 10 A heteroaryl group refers to a heteroaryl group containing five to ten ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrole, furanyl, phenylthio (thiophene), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyranyl, furazolyl, indazinyl, indolyl, etc. The heteroaryl groups disclosed herein may be unsubstituted or substituted. In those embodiments in which the heteroaryl group is substituted, the heteroaryl group may be substituted by one, two, or three substituents independently selected from -OH, -CN, amino, halogroup, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Other substituents include -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl)2, -OC(O)NH (C1-C6 alkyl), -OC(O)N (C1-C6 alkyl)2, -S(O)2NH (C1-C6 alkyl) and -S(O)2N (C1-C6 alkyl)2.

[0036] When used alone or as part of a substituent group, the term "aryl" refers to a monocyclic or bicyclic aromatic carbocyclic structure. An aryl ring may comprise a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, etc. The aryl groups of this disclosure may be unsubstituted or substituted. In those embodiments in which the aryl group is substituted, the aryl group may be substituted by one, two, or three substituents independently selected from -OH, -CN, amino, halogroup, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Other substituents include -C(O)NH (C1-C6 alkyl), -C(O)N (C1-C6 alkyl)2, -OC(O)NH (C1-C6 alkyl), -OC(O)N (C1-C6 alkyl)2, -S(O)2NH (C1-C6 alkyl) and -S(O)2N (C1-C6 alkyl)2.

[0037] When this article uses a range of carbon atoms, such as C1-C6, it covers the entire range as well as individual numbers of carbon atoms, such as "C". 1-3 "Including C" 1-3 C 1-2 C 2-3 C1, C2, and C3. The term "C" refers to... 1-6 "Alkyl" refers to an aliphatic linking group having 1, 2, 3, 4, 5, or 6 carbon atoms, and includes, for example, -CH2-, -CH(CH3)-, -CH(CH3)-CH2-, and -C(CH3)2-. The term "-C0alkyl-" refers to a bond.

[0038] When used alone or as part of a substituent group, the term "C0-C6 alkyl" refers to an aliphatic linking group having 0, 1, 2, 3, 4, 5, or 6 carbon atoms. The term "-C1 alkyl-" refers, for example, -CH2-. The term "-C0 alkyl-" refers to a bond.

[0039] As used herein, each -C1-C6 alkyl group, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C 10 alkenyl, -C2-C6 ynyl, -C2-C 10The alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclic alkenyl, and heterocyclic alkyl groups may optionally be substituted with one, two, or three substituents independently selected from -OH, -CN, amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. Other 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)2, -S(O)2NH (C1-C6 alkyl), and -S(O)2N (C1-C6 alkyl)2.

[0040] As used herein, "alkoxy" refers to an -O-alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc.

[0041] As used in this article, "hydroxyalkyl" refers to an alkyl group that has been replaced by OH.

[0042] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended to be covered. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optical or racemic form. Methods for preparing the optical form from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are covered in this invention. Geometric isomers of the compounds of the present invention are described, and they can be isolated as mixtures of isomers or as isolated isomeric forms.

[0043] The compounds of this invention may also include tautomers. All tautomers are included.

[0044] In some embodiments, the compounds of the present invention may be present as rotational isomers. In some embodiments, the compounds of the present invention are present as a mixture of rotational isomers in any proportion. In other embodiments, the compounds of the present invention are present as a specific rotational isomer, substantially free of other rotational isomers.

[0045] The compounds of the present invention may also include all isotopes of the atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0046] In some embodiments, the compounds of the present invention and their salts are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially isolated from the environment in which they are formed or detected. Partial isolation may include, for example, compositions rich in the compounds of the present invention. Substantially isolated may include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds of the present invention or their salts. Methods for separating the compounds and their salts are conventional in the art.

[0047] This invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein 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, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts of this invention include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, 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.

[0048] As used herein, the phrase “pharmaceutically acceptable” refers to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with tissues in humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0049] "Pharmaceutical-acceptable excipients" refer to substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as inert substances, which are added to or otherwise used as a medium, carrier, or diluent to facilitate the administration of a pharmaceutical agent and are compatible with it. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0050] "Solvate" refers to the physical association of a compound of formula I with one or more solvent molecules.

[0051] "Subject" includes people. The terms "person," "patient," and "subject" are used interchangeably in this document.

[0052] In one implementation, “treatment” for any disease or condition means improving the disease or condition (i.e., preventing or reducing the development of at least one clinical symptom of the disease or its clinical symptoms). In another implementation, “treatment” means improving at least one bodily parameter that may not be discernible to the subject. In yet another implementation, “treatment” means regulating the disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing bodily parameters), or both. In yet another implementation, “treatment” means delaying the onset of the disease or condition.

[0053] "Compounds of this disclosure" and equivalent expressions are intended to include compounds of Formula I as described herein and their subgenuses, including stereoisomers (e.g., enantiomers, diastereomers) and structural isomers (e.g., tautomers) of compounds of Formula I, as well as pharmaceutically acceptable salts, where the context permits so.

[0054] As used herein, the term "isotope variant" refers to a compound that contains a proportion of an isotope at one or more atoms constituting such a compound in greater abundance than naturally occurring. For example, an "isotope variant" of a compound can be radiolabeled, i.e., containing one or more radioactive isotopes, or can be made of non-radioactive isotopes such as deuterium (…). 2 H or D), carbon-13 (H or D), carbon-13 13 C), Nitrogen-15 ( 15 The labeling is as follows: N). It should be understood that in compounds undergoing such isotopic substitution, the following atoms (when present) can vary such that, for example, any hydrogen atom can be... 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and location of such atoms can be determined within the scope of the art.

[0055] It should also be understood that compounds having the same molecular formula but different properties, or different bonding sequences of their atoms, or different spatial arrangements of their atoms are called "isomers." Isomers with different spatial arrangements of their atoms are called "stereoisomers," such as diastereomers, enantiomers, and transisomers. The compounds of this disclosure may have one or more asymmetric centers; therefore, such compounds may be produced as separate (R)- or (S)-stereoisomers at each asymmetric center, or as mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include all its stereoisomers and mixtures (racemic or otherwise). When a structure contains one chiral center but does not show a specific stereochemistry of that center, the structure comprises two enantiomers, individually or as a mixture of enantiomers. When a structure contains more than one chiral center but does not show a specific stereochemistry of that center, the structure comprises all enantiomers and diastereomers, individually or as a mixture. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0056] This disclosure relates to compounds of formula I:

[0057]

[0058] Or its pharmaceutically acceptable salts or solvates or N-oxides; ring A is a 5-7 membered heteroaryl;

[0059] V = CL1R1 or N

[0060] n is 1, 2, or 3;

[0061] m is 1 or 2;

[0062] o is 1, 2, 3, 4 or 5;

[0063] Each L1 is independently a bond, O, NR, or C1-C6 alkylene, wherein R is H or C1-C6 alkyl;

[0064] Each R1 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 Rd -S(O)R b -S(O)2NR 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)2R b ;

[0065] Each R2 is independently H, D, halogen, C1-C8 alkoxy, C1-C8 alkyl, haloalkyl, or CN, and

[0066] Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b 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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ;

[0067] Each R a Independently H, D, -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)R c R b -P(O)OR c OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiRb3, -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0068] Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0069] Each R c Or R d Independently H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;

[0070] Or R c and R d Together with the atoms attached to both, they form monocyclic or polycyclic heterocyclic alkyl groups, or monocyclic or polycyclic heterocyclic alkenyl groups;

[0071] Each R4 is independently H, D, halogen, C1-C8 alkoxy or C1-C8 alkyl, haloalkyl, and CN.

[0072] In some embodiments, ring A in formula (I) is a 5-7 membered heteroaryl group. In some embodiments, ring A is a 5-membered heteroaryl group. In other embodiments, ring A is a 6-membered heteroaryl group. In still other embodiments, ring A is a 7-membered heteroaryl group.

[0073] In some embodiments, ring A is a 5-membered heteroaryl group having at least one nitrogen atom. In some embodiments, the 5-membered heteroaryl group having at least one nitrogen atom is an imidazole. In other embodiments, ring A is a 6-membered heteroaryl group having at least one nitrogen atom. In other embodiments, the 6-membered heteroaryl group having at least two nitrogen atoms is a pyrimidine or a pyridazine.

[0074] In some embodiments, V in formula (I) is N or CL1R1. In some embodiments, V is N. In other embodiments, V is CL1R1.

[0075] In some implementations, n in equation (I) is 1, 2, or 3. In some implementations, n is 1. In other implementations, n is 2. In still other implementations, n is 3.

[0076] In some implementations, m in equation (I) is 1 or 2. In some implementations, m is 1. In other implementations, m is 2.

[0077] In some embodiments, o in formula (I) is 1, 2, 3, 4, or 5. In some embodiments, o is 1. In some embodiments, o is 2. In other embodiments, o is 3. In other embodiments, o is 4. In still other embodiments, o is 5.

[0078] In some implementations, each L in Formula I 1 Independently, it is a bond, O, NR, or C1-C6 alkylene, wherein R is H or a C1-C6 alkyl group. In some embodiments, L 1 As a key. In some implementations, L 1 For O. In some implementations, L 1 For NR. In some implementations, L 1 It is a C1-C6 alkylene group. In some embodiments, L 1 R is methylene. In some embodiments, R is H. In some embodiments, R is C1-C6 alkyl. In some embodiments, R is methyl.

[0079] In some embodiments, each R1 in Formula I 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)Rb -C(O)OR b -C(O)NR c R d -S(O)R b -S(O)2NR 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)2R b In some embodiments, R1 is H. In some embodiments, R1 is D. In some embodiments, R1 is a halogen. In some embodiments, R1 is -OH. In some embodiments, R1 is -CN. In some embodiments, R1 is NO2. In some embodiments, R1 is a -C1-C6 alkyl. In some embodiments, R1 is a -C2-C6 alkenyl. In some embodiments, R1 is a -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 heterocyclic alkenyl. 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)2NR 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)2R b etc.

[0080] In other embodiments, R1 is a heterocyclic alkyl group. In other embodiments, R1 is a 6-membered heterocyclic alkyl group. In some embodiments, R1 is a piperazine. In yet another embodiment, R1 is a 7-membered heterocyclic alkyl group. In yet another embodiment, R1 is a spirofused group. In yet another embodiment, R1 is diazaspiroheptane.

[0081] In some embodiments, each R2 in Formula I is independently H, D, a halogen, a C1-C8 alkoxy, a C1-C8 alkyl, a haloalkyl, or -CN. In some embodiments, R2 is H. In some embodiments, R2 is D. In other embodiments, R2 is a halogen. In other embodiments, R2 is fluorine. In yet another embodiment, R2 is a C1-C8 alkoxy. In yet another embodiment, R2 is a C1-C8 alkyl. In yet another embodiment, R2 is a haloalkyl. In yet another embodiment, R2 is -CN.

[0082] In some embodiments, each R3 in Formula I is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b .

[0083] In some embodiments of this disclosure, at least one R3 portion is directly bonded to the remainder of the compound of formula (I) via a carbon atom. In particularly preferred aspects of these embodiments, each R3 bonded via a carbon atom is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b .

[0084] In some embodiments of this disclosure, at least one R3 moiety is directly bonded to the remainder of the compound of formula (I) via a nitrogen atom. In a particularly preferred aspect of these embodiments, each R3 bonded via a nitrogen atom is independently H, D, oxo, -OH, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -NR c R d -NR a R c -S(O)2NR c R d or -S(O)2R b .

[0085] In some embodiments, R3 is H. In some embodiments, R3 is D. In some embodiments, R3 is a halogen. In some embodiments, R3 is an oxo group. In some embodiments, R3 is bonded to a nitrogen atom and R3 is an oxo group. 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-C1 alkyl-aryl. In other embodiments, R3 is C0-C1 alkyl-heteroaryl. In other embodiments, R3 is cycloalkyl. In other embodiments, R3 is C 3-10 Cycloalkyl. In other embodiments, R3 is cycloalkenyl. In other embodiments, R3 is heterocycloalkyl. In other embodiments, R3 is heterocycloalkenyl. In yet another embodiment, R3 is OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c -S(O)2R b Etc. In some respects, at least one R3 is a hydroxyalkyl group. In other respects, R3 is a C1-C6 alkyl group, such as isopropyl. In other respects, R3 is an oxo group. In other respects, R3 is an oxo group bonded to a nitrogen atom. In some respects, R3 is an OR group. b .

[0086] In some implementations, each R in Equation I a Independently H, D, -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)R c R b -P(O)OR c OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiRb3, -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. In some embodiments, R a For H. In some implementations, R a For D. In some implementations, R a -C(O)R b In some implementations, R a -C(O)OR c In some implementations, R a -C(O)NR c R d In some implementations, R a -C(=NR) b )NR b R c In some implementations, R a C(=NOR) b )NR b R c In some implementations, R a -C(=NCN)NR b R c .

[0087] In other implementations, R a -P(OR) c )2、-P(O)R c R b -P(O)ORc OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiR b 3, etc. In another implementation scheme, R a -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, etc.

[0088] In some implementations, each R in Equation I b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. In some embodiments, R b For H. In some implementations, R b For D. In some implementations, R b It is an -OC1-C6 alkyl group. In some embodiments, R b It is a -C2-C6 alkenyl group. In some embodiments, R b It is a -C2-C6 ynyl group. In other embodiments, R b It is aryl. In other embodiments, R b It is a cycloalkyl group. In other embodiments, R b It is cycloalkenyl. In other embodiments, R b It is a heteroaryl group. In other embodiments, R b It is a heterocyclic alkyl group. In other embodiments, R b It is a heterocyclic alkenyl group.

[0089] In some implementations, each R in Equation I c Or R d Independently, it is H, D, -OC1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. In some embodiments, R c Or R d For H. In some implementations, R c Or R d For D. In some implementations, R c Or R d -C1-C 10 Alkyl group. In some embodiments, Rc Or R d It is a -C2-C6 alkenyl group. In some embodiments, R c Or R d It is a -C2-C6 ynyl group. In other embodiments, R c Or R d It is an -OC1-C6 alkyl group. In other embodiments, R c Or R d It is an -O-cycloalkyl group. In other embodiments, R c Or R d It is aryl. In other embodiments, R c Or R d It is a cycloalkyl group. In other embodiments, R c Or R d It is cycloalkenyl. In other embodiments, R c Or R d It is a heteroaryl group. In other embodiments, R c Or R d It is a heterocyclic alkyl group. In other embodiments, R c Or R d It is a heterocyclic alkenyl group.

[0090] In another implementation, R c and R d Together with the atoms attached to both, they form a monocyclic or polycyclic heterocyclic alkyl group, or a monocyclic or polycyclic heterocyclic alkenyl group. In another embodiment, R c and R d Forming a monocyclic heterocyclic alkyl group. In another embodiment, R c and R d Polycyclic heterocyclic alkyl groups are formed. In another embodiment, R c and R d A monocyclic heterocyclic alkenyl group is formed. In another embodiment, R c and R d It forms polycyclic heterocyclic alkenyl groups.

[0091] In some embodiments, each R4 in Formula I is independently H, D, a halogen, a C1-C8 alkoxy or C1-C8 alkyl, a haloalkyl, and -CN. In some embodiments, R4 is H. In some embodiments, R4 is D. In some embodiments, R4 is a halogen. In some embodiments, R4 is a -C1-C8 alkoxy. In other embodiments, R4 is a -C1-C8 alkyl. In other embodiments, R4 is methyl. In other embodiments, R4 is a haloalkyl. In other embodiments, R4 is -CN.

[0092] 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).

[0093] In some embodiments, the compound of formula (I) is derived from the compound of formula II.

[0094]

[0095] Or its pharmaceutically acceptable salt, wherein

[0096] Each X is independently N, an N-oxide, or CR3, and at least one X is N or an N-oxide; and each of R4, R3, (R2) is... m V and (L1R1) n It is defined relative to equation (I).

[0097] In some embodiments, each X in Formula II is N. In other embodiments, one X in Formula II is an N-oxide, and all three Xs in Formula II are CR3. In other embodiments, one X in Formula II is N, and all three Xs in Formula II are CR3. In yet another embodiment, two Xs in Formula II are N, and both Xs in Formula II are CR3. In yet another embodiment, all three Xs in Formula II are N, and one X in Formula II is CR3.

[0098] In some embodiments, the compound of formula (I) is derived from the compound of formula III.

[0099]

[0100] Or its pharmaceutically acceptable salt, wherein

[0101] Each of R4, R3, (R2) m V and (L1R1) n It is defined relative to formula (I). In some embodiments, the compound of formula (I) is derived from the compound of formula IV.

[0102]

[0103] Or its pharmaceutically acceptable salt, wherein

[0104] Each of R4, R3, (R2) m V and (L1R1) n It is defined relative to equation (I).

[0105] In some embodiments, the compound of formula (I) is derived from the compound of formula V.

[0106]

[0107] Or its pharmaceutically acceptable salt, wherein

[0108] Each Y is independently either N or CR3, and at least one Y is N; and

[0109] Each of R4, R3, (R2)m, V and (L1R1)n is defined relative to equation (I).

[0110] In some embodiments, each Y in Formula V is N. In other embodiments, one Y in Formula V is N, and the other Y in Formula V is CR3. In yet another embodiment, each Y in Formula V is CR3.

[0111] In some embodiments, the compound of formula (I) is derived from the compound of formula VI.

[0112]

[0113] Or its pharmaceutically acceptable salt, wherein

[0114] Each Y is independently either N or CR3, and at least one Y is N; and

[0115] Each of R4, R3, (R2) m V and (L1R1)n are defined relative to equation (I).

[0116] In some embodiments, each Y in Formula VI is N. In other embodiments, one Y in Formula VI is N, and the other Y in Formula VI is CR3. In yet another embodiment, each Y in Formula VI is CR3.

[0117] In some embodiments, the compound of formula (I) is derived from the compound of formula VIII.

[0118]

[0119] Or its pharmaceutically acceptable salt, wherein

[0120] Each X is independently N, N-oxide, or CR3 and at least one X is N or N-oxide; and each R4, R3, R2, V, and L1R1 is defined relative to equation (I).

[0121] In some embodiments, each X in Formula VIII is N. In some embodiments, one X in Formula VIII is an N-oxide, and both X in Formula VIII are CR3. In other embodiments, one X in Formula VIII is N, and both X in Formula VIII are CR3. In other embodiments, both X in Formula VIII are N, and one X in Formula VIII is CR3.

[0122] In some embodiments, the compound of formula (I) is derived from the compound of formula IX.

[0123]

[0124] Or its pharmaceutically acceptable salt, wherein

[0125] Each X is independently N, N-oxide, or CR3 and at least one X is N or N-oxide; and each R4, R3, R2, V, and L1R1 is defined relative to equation (I).

[0126] In some embodiments, each X in Formula IX is N. In other embodiments, one X in Formula IX is an N-oxide, and one X in Formula IX is CR3. In still other embodiments, one X in Formula IX is N and one X in Formula IX is CR3.

[0127] In some embodiments, the compound of formula (I) is derived from the compound of formula X.

[0128]

[0129] Or its pharmaceutically acceptable salt, wherein

[0130] Each X is independently N, N-oxide, or CR3 and at least one X is N or N-oxide; and each R4, R3, R2, V, and L1R1 is defined relative to equation (I).

[0131] In some embodiments, X in Formula X is N. In other embodiments, X in Formula X is an N-oxide.

[0132] In some embodiments, the compound of formula (I) is derived from the compound of formula XI.

[0133]

[0134] Or its pharmaceutically acceptable salt, wherein

[0135] Each X is independently N, N-oxide, or CR3 and at least one X is N or N-oxide; and each R4, R3, R2, V, and L1R1 is defined relative to equation (I).

[0136] In some embodiments, X in Formula XI is N. In other embodiments, X in Formula XI is an N-oxide.

[0137] In some embodiments, the compound of formula (I) is derived from the compound of formula XII.

[0138]

[0139] Or its pharmaceutically acceptable salt, wherein

[0140] Y is N or CHR3; and each of R4, R3, R2, V and L1R1 is defined relative to equation (I).

[0141] In some embodiments, Y in Formula XII is N. In other embodiments, Y in Formula XII is CHR3.

[0142] In some embodiments, the compound of formula (I) is derived from the compound of formula XIII.

[0143]

[0144] Or its pharmaceutically acceptable salt, wherein

[0145] Y is N or CHR3; and each of R4, R3, R2, V and L1R1 is defined relative to equation (I).

[0146] In some embodiments, each Y in Formula XIII is N. In other embodiments, one Y in Formula XIII is N, and the other Y in Formula XIII is CR3. In yet another embodiment, each Y in Formula XIII is CR3.

[0147] In other embodiments, the compound of formula (I) is derived from the compound of formula XV.

[0148]

[0149] Or its pharmaceutically acceptable salt, wherein

[0150] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0151] In other embodiments, the compound of formula (I) is derived from the compound of formula XVI.

[0152]

[0153] Or its pharmaceutically acceptable salt, wherein

[0154] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0155] In other embodiments, the compound of formula (I) is derived from the compound of formula XVII.

[0156]

[0157] Or a pharmaceutically acceptable salt thereof, wherein each R4, R3, V and L1R1 is defined relative to formula (I).

[0158] In other embodiments, the compound of formula (I) is derived from the compound of formula XVIII.

[0159]

[0160] Or its pharmaceutically acceptable salt, wherein

[0161] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0162] In other embodiments, the compound of formula (I) is derived from the compound of formula XIX.

[0163]

[0164] Or its pharmaceutically acceptable salt, wherein

[0165] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0166] In other embodiments, the compound of formula (I) is derived from the compound of formula XX.

[0167]

[0168] Or its pharmaceutically acceptable salt, wherein

[0169] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0170] In other embodiments, the compound of formula (I) is derived from the compound of formula XXI.

[0171]

[0172] Or its pharmaceutically acceptable salt, wherein

[0173] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0174] In other embodiments, the compound of formula (I) is derived from the compound of formula XXII.

[0175]

[0176] Or its pharmaceutically acceptable salt, wherein

[0177] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0178] In other embodiments, the compound of formula (I) is derived from the compound of formula XXIII.

[0179]

[0180] Or its pharmaceutically acceptable salt, wherein

[0181] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0182] In other embodiments, the compound of formula (I) is derived from the compound of formula XXIV.

[0183]

[0184] Or its pharmaceutically acceptable salt, wherein

[0185] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0186] In other embodiments, the compound of formula (I) is derived from the compound of formula XXV.

[0187]

[0188] Or its pharmaceutically acceptable salt, wherein

[0189] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0190] In other embodiments, the compound of formula (I) is derived from the compound of formula XXVI.

[0191]

[0192] Or its pharmaceutically acceptable salt, wherein

[0193] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0194] In other embodiments, the compound of formula (I) is derived from the compound of formula XXVII.

[0195]

[0196] Or its pharmaceutically acceptable salt, wherein

[0197] Each R4, R3, V, and L1R1 is defined relative to equation (I).

[0198] In other embodiments, the compound of formula (I) is derived from the compound of formula XXIX.

[0199]

[0200] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0201] U is C(R) 10 2. NR 10 Or O;

[0202] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl group; each g and h is independently 0, 1, 2, or 3; and

[0203] Each R4, R3, V, and L1 is defined relative to equation (I).

[0204] In some implementations, W in formula XXIX is CH. In other implementations, W in formula XXIX is N.

[0205] In some implementations, U of formula XXIX is C(R) 10 2. In other implementations, U in equation XXIX is NR. 10 In another implementation, U in formula XXIX is O.

[0206] In some implementation schemes, R of formula XXIX 10 For H. In some implementations, R of formula XXIX 10 It is a halogen. In other embodiments, R of formula XXIX 10 It is fluorine. In some embodiments, R of formula XXIX 10 C 1-6 Alkyl group. In other embodiments, R of formula XIX 10 It is methyl or ethyl. In some embodiments, R of formula XXIX 10 C 1-6 Alkyl group.

[0207] In some implementations, when U of equation XXIX is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXIX is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXIX is C(R)10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXIX is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXIX is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 For hydrogen. In other embodiments, when U of formula XIX is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXIX is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0208] In some embodiments, U in formula XXIX is NCH3. In other embodiments, U in formula XXIX is NCH2CH3.

[0209] In some embodiments, g in formula XXIX is 0, 1, 2, or 3. In some embodiments, g in formula XXIX is 0. In some embodiments, g in formula XXIX is 1. In other embodiments, g in formula XXIX is 2. In other embodiments, g in formula XXIX is 3.

[0210] In some embodiments, h in formula XXIX is 0, 1, 2, or 3. In some embodiments, h in formula XXIX is 0. In some embodiments, h in formula XXIX is 1. In other embodiments, h in formula XXIX is 2. In other embodiments, h in formula XXIX is 3.

[0211] In other embodiments, the compound of formula (I) is derived from the compound of formula XXX.

[0212]

[0213] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0214] U is C(R) 10 2. NR 10 Or O;

[0215] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl groups; each g, h, j, and k is independently 0, 1, 2, or 3; and

[0216] Each R4, R3, V, and L1 is defined relative to equation (I).

[0217] In some implementations, W in formula XXX is CH. In other implementations, W in formula XXX is N.

[0218] In some implementations, U of formula XXX is C(R) 10 2. In other implementations, U in formula XXX is NR. 10 In another implementation, U in formula XXX is O.

[0219] In some implementation schemes, R of formula XXX 10 For H. In some implementations, R of formula XXX 10 It is a halogen. In other embodiments, R of formula XXX 10 It is fluorine. In some implementations, R of formula XXX 10 C 1-6 Alkyl group. In other embodiments, R of formula XXX 10 It is methyl or ethyl. In some embodiments, R of formula XXX 10 C 1-6 Alkyl group.

[0220] In some implementations, when U of equation XXX is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXX is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXX is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXX is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXX is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XXX is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXX is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0221] In some embodiments, U in formula XXX is NCH3. In other embodiments, U in formula XXX is NCH2CH3.

[0222] In some embodiments, g in formula XXX is 0, 1, 2, or 3. In some embodiments, g in formula XXX is 0. In some embodiments, g in formula XXX is 1. In other embodiments, g in formula XXX is 2. In other embodiments, g in formula XXX is 3.

[0223] In some embodiments, h in formula XXX is 0, 1, 2, or 3. In some embodiments, h in formula XXX is 0. In some embodiments, h in formula XXX is 1. In other embodiments, h in formula XXX is 2. In other embodiments, h in formula XXX is 3.

[0224] In some embodiments, j in equation XXX is 0, 1, 2, or 3. In some embodiments, j in equation XXX is 0. In some embodiments, j in equation XXX is 1. In other embodiments, j in equation XXX is 2. In other embodiments, j in equation XXX is 3.

[0225] In some embodiments, k in formula XXX is 0, 1, 2, or 3. In some embodiments, k in formula XXX is 0. In some embodiments, k in formula XXX is 1. In other embodiments, k in formula XXX is 2. In other embodiments, k in formula XXX is 3.

[0226] In other embodiments, the compound of formula (I) is derived from the compound of formula XXXI.

[0227]

[0228] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0229] U is C(R) 10 2. NR 10 Or O;

[0230] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl group; each g and h is independently 0, 1, 2, or 3; and

[0231] Each R4, R3, V, and L1 is defined relative to equation (I).

[0232] In some implementations, W in formula XXXI is CH. In other implementations, W in formula XXXI is N.

[0233] In some implementations, U of formula XXXI is C(R) 102. In other implementations, U in formula XXXI is NR. 10 In another implementation, U in formula XXXI is O.

[0234] In some implementation schemes, the R of formula XXXI 10 For H. In some implementations, R of formula XXXI 10 It is a halogen. In other embodiments, R of formula XXXI 10 It is fluorine. In some embodiments, R of formula XXXI 10 C 1-6 Alkyl group. In other embodiments, R of formula XXXI 10 It is methyl or ethyl. In some embodiments, R of formula XXXI 10 C 1-6 Alkyl group.

[0235] In some implementations, when U of equation XXXI is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXXI is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXXI is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXXI is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXXI is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XXXI is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXXI is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0236] In some embodiments, U in formula XXXI is NCH3. In other embodiments, U in formula XXXI is NCH2CH3.

[0237] In some embodiments, g in formula XXXI is 0, 1, 2, or 3. In some embodiments, g in formula XXXI is 0. In some embodiments, g in formula XXXI is 1. In other embodiments, g in formula XXXI is 2. In other embodiments, g in formula XXXI is 3.

[0238] In some embodiments, h in formula XXXI is 0, 1, 2, or 3. In some embodiments, h in formula XXXI is 0. In some embodiments, h in formula XXXI is 1. In other embodiments, h in formula XXXI is 2. In other embodiments, h in formula XXXI is 3.

[0239] In other embodiments, the compound of formula (I) is derived from the compound of formula XXXII.

[0240]

[0241] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0242] U is C(R) 10 2. NR 10 Or O;

[0243] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl groups; each g, h, j, and k is independently 0, 1, 2, or 3; and

[0244] Each R4, R3, V, and L1 is defined relative to equation (I).

[0245] In some embodiments, W in formula XXXII is CH. In other embodiments, W in formula XXXII is N.

[0246] In some implementations, U of formula XXXII is C(R) 10 2. In other embodiments, U in formula XXXII is NR. 10 In another implementation, U in formula XXXII is O.

[0247] In some implementations, R of formula XXXII 10 For H. In some implementations, R of formula XXXII 10 It is a halogen. In other embodiments, R of formula XXXII 10 It is fluorine. In some embodiments, R of formula XXXII 10 C 1-6 Alkyl group. In other embodiments, R of formula XXXII 10It is methyl or ethyl. In some embodiments, R of formula XXXII 10 C 1-6 Alkyl group.

[0248] In some implementations, when U of equation XXXII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXXII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXXII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXXII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXXII is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XXXII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXXII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0249] In some embodiments, U in formula XXXII is NCH3. In other embodiments, U in formula XXXII is NCH2CH3.

[0250] In some embodiments, g in formula XXXII is 0, 1, 2, or 3. In some embodiments, g in formula XXXII is 0. In some embodiments, g in formula XXXII is 1. In other embodiments, g in formula XXXII is 2. In other embodiments, g in formula XXXII is 3.

[0251] In some embodiments, h in formula XXXII is 0, 1, 2, or 3. In some embodiments, h in formula XXXII is 0. In some embodiments, h in formula XXXII is 1. In other embodiments, h in formula XXXII is 2. In other embodiments, h in formula XXXII is 3.

[0252] In some embodiments, j in formula XXXII is 0, 1, 2, or 3. In some embodiments, j in formula XXXII is 0. In some embodiments, j in formula XXXII is 1. In other embodiments, j in formula XXXII is 2. In other embodiments, j in formula XXXII is 3.

[0253] In some embodiments, k in formula XXXII is 0, 1, 2, or 3. In some embodiments, k in formula XXXII is 0. In some embodiments, k in formula XXXII is 1. In other embodiments, k in formula XXXII is 2. In other embodiments, k in formula XXXII is 3.

[0254] In other embodiments, the compound of formula (I) is derived from the compound of formula XXXV.

[0255]

[0256] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0257] U is C(R) 10 2. NR 10 Or O;

[0258] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl group; each g and h is independently 0, 1, 2, or 3; and

[0259] Each R4, R3, V, and L1 is defined relative to equation (I).

[0260] In some implementations, W in formula XXXV is CH. In other implementations, W in formula XXXV is N.

[0261] In some implementations, U of formula XXXV is C(R) 10 2. In other implementations, U in formula XXXV is NR. 10 In another implementation, U in formula XXXV is O.

[0262] In some implementation schemes, R of formula XXXV 10 For H. In some implementations, R of formula XXXV 10 It is a halogen. In other embodiments, R of formula XXXV 10 It is fluorine. In some embodiments, R of formula XXXV 10 C 1-6 Alkyl group. In other embodiments, R of formula XXXV 10It is methyl or ethyl. In some embodiments, R of formula XXXV 10 C 1-6 Alkyl group.

[0263] In some implementations, when U of equation XXXV is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXXV is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXXV is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XXXV is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXXV is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XXXV is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXXV is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0264] In some embodiments, U in formula XXXV is NCH3. In other embodiments, U in formula XXXV is NCH2CH3.

[0265] In some embodiments, g in formula XXXV is 0, 1, 2, or 3. In some embodiments, g in formula XXXV is 0. In some embodiments, g in formula XXXV is 1. In other embodiments, g in formula XXXV is 2. In other embodiments, g in formula XXXV is 3.

[0266] In some embodiments, h in formula XXXV is 0, 1, 2, or 3. In some embodiments, h in formula XXXV is 0. In some embodiments, h in formula XXXV is 1. In other embodiments, h in formula XXXV is 2. In other embodiments, h in formula XXXV is 3.

[0267] In other embodiments, the compound of formula (I) is derived from the compound of formula XXXVI.

[0268]

[0269] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0270] U is C(R) 10 2. NR 10 Or O;

[0271] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl groups; each g, h, j, and k is independently 0, 1, 2, or 3; and

[0272] Each R4, R3, V, and L1 is defined relative to equation (I).

[0273] In some implementations, W in formula XXXVI is CH. In other implementations, W in formula XXXVI is N.

[0274] In some implementations, U of formula XXXVI is C(R) 10 2. In other embodiments, U in formula XXXVI is NR. 10 In another implementation, U in formula XXXVI is O.

[0275] In some implementation schemes, R of formula XXXVI 10 For H. In some implementations, R of formula XXXVI 10 It is a halogen. In other embodiments, R of formula XXXVI 10 It is fluorine. In some embodiments, R of formula XXXVI 10 C 1-6 Alkyl group. In other embodiments, R of formula XXXVI 10 It is methyl or ethyl. In some embodiments, R of formula XXXVI 10 C 1-6 Alkyl group.

[0276] In some implementations, when U of equation XXXVI is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXXVI is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXXVI is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXXVI is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXXVI is C(R)10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XXXVI is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXXVI is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0277] In some embodiments, U in formula XXXVI is NCH3. In other embodiments, U in formula XXXVI is NCH2CH3.

[0278] In some embodiments, g in formula XXXVI is 0, 1, 2, or 3. In some embodiments, g in formula XXXVI is 0. In some embodiments, g in formula XXXVI is 1. In other embodiments, g in formula XXXVI is 2. In other embodiments, g in formula XXXVI is 3.

[0279] In some embodiments, h in formula XXXVI is 0, 1, 2, or 3. In some embodiments, h in formula XXXVI is 0. In some embodiments, h in formula XXXVI is 1. In other embodiments, h in formula XXXVI is 2. In other embodiments, h in formula XXXVI is 3.

[0280] In some embodiments, j in formula XXXVI is 0, 1, 2, or 3. In some embodiments, j in formula XXXVI is 0. In some embodiments, j in formula XXXVI is 1. In other embodiments, j in formula XXXVI is 2. In other embodiments, j in formula XXXVI is 3.

[0281] In some embodiments, k in formula XXXVI is 0, 1, 2, or 3. In some embodiments, k in formula XXXVI is 0. In some embodiments, k in formula XXXVI is 1. In other embodiments, k in formula XXXVI is 2. In other embodiments, k in formula XXXVI is 3.

[0282] In other embodiments, the compound of formula (I) is derived from the compound of formula XXXVII.

[0283]

[0284] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0285] U is C(R) 102. NR 10 Or O;

[0286] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy;

[0287] Each g and h is independently 0, 1, 2, or 3; and

[0288] Each R4, R3, V, and L1 is defined relative to equation (I).

[0289] In some embodiments, W in formula XXXVII is CH. In other embodiments, W in formula XXXVII is N.

[0290] In some implementations, U in equation XXXVII is C(R) 10 2. In other embodiments, U in equation XXXVII is NR. 10 In another implementation, U in formula XXXVII is O.

[0291] In some implementations, R of formula XXXVII 10 For H. In some implementations, R of formula XXXVII 10 It is a halogen. In other embodiments, R of formula XXXVII 10 It is fluorine. In some embodiments, R of formula XXXVII 10 C 1-6 Alkyl group. In other embodiments, R of formula XXXVII 10 It is methyl or ethyl. In some embodiments, R of formula XXXVII 10 C 1-6 Alkyl group.

[0292] In some implementations, when U of equation XXXVII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXXVII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXXVII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXXVII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXXVII is C(R) 10 At time 2, an R 10It is a halogen and an R 10 For hydrogen. In other embodiments, when U of formula XXXVII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXXVII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0293] In some embodiments, U in formula XXXVII is NCH3. In other embodiments, U in formula XXXVII is NCH2CH3.

[0294] In some embodiments, g in formula XXXVII is 0, 1, 2, or 3. In some embodiments, g in formula XXXVII is 0. In some embodiments, g in formula XXXVII is 1. In other embodiments, g in formula XXXVII is 2. In other embodiments, g in formula XXXVII is 3.

[0295] In some embodiments, h in formula XXXVII is 0, 1, 2, or 3. In some embodiments, h in formula XXXVII is 0. In some embodiments, h in formula XXXVII is 1. In other embodiments, h in formula XXXVII is 2. In other embodiments, h in formula XXXVII is 3.

[0296] In other embodiments, the compound of formula (I) is derived from the compound of formula XXXVIII.

[0297]

[0298] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0299] U is C(R) 10 2. NR 10 Or O;

[0300] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl groups; each g, h, j, and k is independently 0, 1, 2, or 3; and

[0301] Each R4, R3, V, and L1 is defined relative to equation (I).

[0302] In some embodiments, W in formula XXXVIII is CH. In other embodiments, W in formula XXXVIII is N.

[0303] In some implementations, U of formula XXXVIII is C(R) 10 2. In other embodiments, U in formula XXXVIII is NR. 10 In another implementation, U in formula XXXVIII is O.

[0304] In some implementations, R of formula XXXVIII 10 For H. In some implementations, R of formula XXXVIII 10 It is a halogen. In other embodiments, R of formula XXXVIII 10 It is fluorine. In some embodiments, R of formula XXXVIII 10 C 1-6 Alkyl group. In other embodiments, R of formula XXXVIII 10 It is methyl or ethyl. In some embodiments, R of formula XXXVIII 10 C 1-6 Alkyl group.

[0305] In some implementations, when U of equation XXXVIII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXXVIII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXXVIII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXXVIII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXXVIII is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XXXVIII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXXVIII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0306] In some embodiments, U in formula XXXVIII is NCH3. In other embodiments, U in formula XXXVIII is NCH2CH3.

[0307] In some embodiments, g in formula XXXVIII is 0, 1, 2, or 3. In some embodiments, g in formula XXXVIII is 0. In some embodiments, g in formula XXXVIII is 1. In other embodiments, g in formula XXXVIII is 2. In some embodiments, g in formula XXXVIII is 3.

[0308] In some embodiments, h in formula XXXVIII is 0, 1, 2, or 3. In some embodiments, h in formula XXXVIII is 0. In some embodiments, h in formula XXXVIII is 1. In other embodiments, h in formula XXXVIII is 2. In some embodiments, h in formula XXXVIII is 3.

[0309] In some embodiments, j in formula XXXVIII is 0, 1, 2, or 3. In some embodiments, j in formula XXXVIII is 0. In some embodiments, j in formula XXXVIII is 1. In other embodiments, j in formula XXXVIII is 2. In some embodiments, j in formula XXXVIII is 3.

[0310] In some embodiments, k in formula XXXVIII is 0, 1, 2, or 3. In some embodiments, k in formula XXXVIII is 0. In some embodiments, k in formula XXXVIII is 1. In other embodiments, k in formula XXXVIII is 2. In other embodiments, k in formula XXXVIII is 3.

[0311] In other embodiments, the compound of formula (I) is derived from the compound of formula XXXIX.

[0312]

[0313] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0314] U is C(R) 10 2. NR 10 Or O;

[0315] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl group; each g and h is independently 0, 1, 2, or 3; and

[0316] Each R4, R3, V, and L1 is defined relative to equation (I).

[0317] In some implementations, W in formula XXXIX is CH. In other implementations, W in formula XXXIX is N.

[0318] In some implementations, U of equation XXXIX is C(R) 10 2. In other implementations, U in equation XXXIX is NR. 10 In another implementation, U in formula XXXIX is O.

[0319] In some implementation schemes, R of formula XXXIX 10 For H. In some implementations, R of formula XXXIX 10 It is a halogen. In other embodiments, R of formula XXXVII 10 It is fluorine. In some embodiments, R of formula XXXIX 10 C 1-6 Alkyl group. In other embodiments, R of formula XXXIX 10 It is methyl or ethyl. In some embodiments, R of formula XXXIX 10 C 1-6 Alkyl group.

[0320] In some implementations, when U of equation XXXIX is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XXXIX is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XXXIX is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula XXXIX is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XXXIX is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XXXIX is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XXXIX is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0321] In some embodiments, U in formula XXXIX is NCH3. In other embodiments, U in formula XXXIX is NCH2CH3.

[0322] In some embodiments, g in formula XXXIX is 0, 1, 2, or 3. In some embodiments, g in formula XXXIX is 0. In some embodiments, g in formula XXXIX is 1. In other embodiments, g in formula XXXIX is 2. In other embodiments, g in formula XXXIX is 3.

[0323] In some embodiments, h in formula XXXIX is 0, 1, 2, or 3. In some embodiments, h in formula XXXIX is 0. In some embodiments, h in formula XXXIX is 1. In other embodiments, h in formula XXXIX is 2. In other embodiments, h in formula XXXIX is 3.

[0324] In other embodiments, the compound of formula (I) is derived from the compound of formula XL.

[0325]

[0326] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0327] U is C(R) 10 2. NR 10 Or O;

[0328] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl groups; each g, h, j, and k is independently 0, 1, 2, or 3; and

[0329] Each R4, R3, V, and L1 is defined relative to equation (I).

[0330] In some implementations, W in formula XL is CH. In other implementations, W in formula XL is N.

[0331] In some implementations, U of formula XL is C(R) 10 2. In other embodiments, U in formula XL is NR. 10 In another implementation, U in formula XL is O.

[0332] In some implementations, the R of formula XL 10 For H. In some implementations, R of formula XL 10 It is a halogen. In other embodiments, R of formula XL 10 It is fluorine. In some embodiments, R of formula XL 10 C 1-6 Alkyl group. In other embodiments, R of formula XL 10 It is methyl or ethyl. In some embodiments, R of formula XL 10C 1-6 Alkyl group.

[0333] In some implementations, when U of equation XL is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XL is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XL is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XL is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XL is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XL is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XL is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0334] In some embodiments, U in formula XL is NCH3. In other embodiments, U in formula XL is NCH2CH3.

[0335] In some embodiments, g in formula XL is 0, 1, 2, or 3. In some embodiments, g in formula XL is 0. In some embodiments, g in formula XL is 1. In other embodiments, g in formula XL is 2. In other embodiments, g in formula XL is 3.

[0336] In some embodiments, h in formula XL is 0, 1, 2, or 3. In some embodiments, h in formula XL is 0. In some embodiments, h in formula XL is 1. In other embodiments, h in formula XL is 2. In other embodiments, h in formula XL is 3.

[0337] In some embodiments, j in formula XL is 0, 1, 2, or 3. In some embodiments, j in formula XL is 0. In some embodiments, j in formula XL is 1. In other embodiments, j in formula XL is 2. In other embodiments, j in formula XL is 3.

[0338] In some embodiments, k in formula XL is 0, 1, 2, or 3. In some embodiments, k in formula XL is 0. In some embodiments, k in formula XL is 1. In other embodiments, k in formula XL is 2. In other embodiments, k in formula XL is 3.

[0339] In other embodiments, the compound of formula (I) is derived from the compound of formula XLI.

[0340]

[0341] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0342] U is C(R) 10 2. NR 10 Or O;

[0343] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl group; each g and h is independently 0, 1, 2, or 3; and

[0344] Each R4, R3, V, and L1 is defined relative to equation (I).

[0345] In some embodiments, W in formula XLI is CH. In other embodiments, W in formula XLI is N.

[0346] In some implementations, U of formula XLI is C(R) 10 2. In other embodiments, U in formula XLI is NR. 10 In another implementation, U in formula XLI is O.

[0347] In some implementations, the R of formula XLI 10 For H. In some implementations, R of formula XLI 10 It is a halogen. In other embodiments, R of formula XLI 10 It is fluorine. In some embodiments, R of formula XLI 10 C 1-6 Alkyl group. In other embodiments, R of formula XLI 10 It is methyl or ethyl. In some embodiments, R of formula XLI 10 C 1-6 Alkyl group.

[0348] In some implementations, when U of equation XLI is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLI is C(R) 10 At time 2, each R10 It is methyl. In some embodiments, when U of formula XLI is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLI is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLI is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLI is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLI is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0349] In some embodiments, U in formula XLI is NCH3. In other embodiments, U in formula XLI is NCH2CH3.

[0350] In some embodiments, g in formula XLI is 0, 1, 2, or 3. In some embodiments, g in formula XLI is 0. In some embodiments, g in formula XLI is 1. In other embodiments, g in formula XLI is 2. In other embodiments, g in formula XLI is 3.

[0351] In some embodiments, h in formula XLI is 0, 1, 2, or 3. In some embodiments, h in formula XLI is 0. In some embodiments, h in formula XLI is 1. In other embodiments, h in formula XLI is 2. In other embodiments, h in formula XLI is 3.

[0352] In other embodiments, the compound of formula (I) is derived from the compound of formula XLII.

[0353]

[0354] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0355] U is C(R) 10 2. NR 10 Or O;

[0356] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl groups; each g, h, j, and k is independently 0, 1, 2, or 3; and

[0357] Each R4, R3, V, and L1 is defined relative to equation (I).

[0358] In some embodiments, W in Formula XLII is CH. In other embodiments, W in Formula XLII is N.

[0359] In some implementations, U of formula XLII is C(R) 10 2. In other embodiments, U of formula XLII is NR. 10 In another embodiment, U in formula XLII is O.

[0360] In some implementations, the R of formula XLII 10 For H. In some implementations, R of formula XLII 10 It is a halogen. In other embodiments, R of formula XLII 10 It is fluorine. In some embodiments, R of formula XLII 10 C 1-6 Alkyl group. In other embodiments, R of formula XLII 10 It is methyl or ethyl. In some embodiments, R of formula XLII 10 C 1-6 Alkyl group.

[0361] In some implementations, when U of formula XLII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLII is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0362] In some embodiments, U in formula XLII is NCH3. In other embodiments, U in formula XLII is NCH2CH3.

[0363] In some embodiments, g in Formula XLII is 0, 1, 2, or 3. In some embodiments, g in Formula XLII is 0. In some embodiments, g in Formula XLII is 1. In other embodiments, g in Formula XLII is 2. In other embodiments, g in Formula XLII is 3.

[0364] In some embodiments, h in Formula XLII is 0, 1, 2, or 3. In some embodiments, h in Formula XLII is 0. In some embodiments, h in Formula XLII is 1. In other embodiments, h in Formula XLII is 2. In other embodiments, h in Formula XLII is 3.

[0365] In some embodiments, j in formula XLII is 0, 1, 2, or 3. In some embodiments, j in formula XLII is 0. In some embodiments, j in formula XLII is 1. In other embodiments, j in formula XLII is 2. In other embodiments, j in formula XLII is 3.

[0366] In some embodiments, k in formula XLII is 0, 1, 2, or 3. In some embodiments, k in formula XLII is 0. In some embodiments, k in formula XLII is 1. In other embodiments, k in formula XLII is 2. In other embodiments, k in formula XLII is 3.

[0367] In other embodiments, the compound of formula (I) is derived from the compound of formula XLIII.

[0368]

[0369] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0370] U is C(R) 10 2. NR 10 Or O;

[0371] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl group; each g and h is independently 0, 1, 2, or 3; and

[0372] Each R4, R3, V, and L1 is defined relative to equation (I).

[0373] In some embodiments, W in Formula XLIII is CH. In other embodiments, W in Formula XLIII is N.

[0374] In some implementations, U of formula XLIII is C(R) 10 2. In other embodiments, U in formula XLIII is NR. 10 In another embodiment, U in formula XLIII is O.

[0375] In some implementations, the R of Formula XLIII 10 For H. In some implementations, R of formula XLIII 10 It is a halogen. In other embodiments, R of formula XLIII 10 It is fluorine. In some embodiments, R of formula XLI 10 C 1-6 Alkyl group. In other embodiments, R of formula XLIII 10 It is methyl or ethyl. In some embodiments, R of formula XLIII 10 C 1-6 Alkyl group.

[0376] In some implementations, when U of formula XLIII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of formula XLIII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLIII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLIII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLIII is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLIII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLIII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0377] In some embodiments, U in Formula XLIII is NCH3. In other embodiments, U in Formula XLIII is NCH2CH3.

[0378] In some embodiments, g in Formula XLIII is 0, 1, 2, or 3. In some embodiments, g in Formula XLIII is 0. In some embodiments, g in Formula XLIII is 1. In other embodiments, g in Formula XLIII is 2. In other embodiments, g in Formula XLIII is 3.

[0379] In some embodiments, h in Formula XLIII is 0, 1, 2, or 3. In some embodiments, h in Formula XLIII is 0. In some embodiments, h in Formula XLIII is 1. In other embodiments, h in Formula XLIII is 2. In other embodiments, h in Formula XLIII is 3.

[0380] In other embodiments, the compound of formula (I) is derived from the compound of formula XLIV.

[0381]

[0382] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0383] U is C(R) 10 2. NR 10 Or O;

[0384] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkyl groups; each g, h, j, and k is independently 0, 1, 2, or 3; and

[0385] Each R4, R3, V, and L1 is defined relative to equation (I).

[0386] In some embodiments, W in formula XLIV is CH. In other embodiments, W in formula XLIV is N.

[0387] In some implementations, U of formula XLIV is C(R) 10 2. In other embodiments, U in formula XLIV is NR. 10 In another implementation, U in formula XLIV is O.

[0388] In some implementations, the R of formula XLIV 10 For H. In some implementations, R of formula XLIV 10 It is a halogen. In other embodiments, R of formula XLIV 10 It is fluorine. In some embodiments, R of formula XLIV 10 C 1-6 Alkyl group. In other embodiments, R of formula XLIV 10It is methyl or ethyl. In some embodiments, R of formula XLIV 10 C 1-6 Alkyl group.

[0389] In some implementations, when U of XLIV is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLIV is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLIV is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLIV is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLIV is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLIV is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLIV is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0390] In some embodiments, U in formula XLIV is NCH3. In other embodiments, U in formula XLIV is NCH2CH3.

[0391] In some embodiments, g in formula XLIV is 0, 1, 2, or 3. In some embodiments, g in formula XLIV is 0. In some embodiments, g in formula XLIV is 1. In other embodiments, g in formula XLIV is 2. In other embodiments, g in formula XLIV is 3.

[0392] In some embodiments, h in formula XLIV is 0, 1, 2, or 3. In some embodiments, h in formula XLIV is 0. In some embodiments, h in formula XLIV is 1. In other embodiments, h in formula XLIV is 2. In other embodiments, h in formula XLIV is 3.

[0393] In some embodiments, j in formula XLIV is 0, 1, 2, or 3. In some embodiments, j in formula XLIV is 0. In some embodiments, j in formula XLIV is 1. In other embodiments, j in formula XLIV is 2. In other embodiments, j in formula XLIV is 3.

[0394] In some embodiments, k in formula XLIV is 0, 1, 2, or 3. In some embodiments, k in formula XLIV is 0. In some embodiments, k in formula XLIV is 1. In other embodiments, k in formula XLIV is 2. In other embodiments, k in formula XLIV is 3.

[0395] In another embodiment, the compound of formula (I) is derived from the compound of formula XLV.

[0396]

[0397] Or its pharmaceutically acceptable salt, wherein

[0398] W is either CH or N;

[0399] U is C(R) 10 2. NR 10 Or O;

[0400] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0401] In some implementations, W in formula XLV is CH. In other implementations, W in formula XLV is N.

[0402] In some implementations, U of formula XLV is C(R) 10 2. In other implementations, U of formula XLV is NR. 10 In another implementation, U in formula XLV is O.

[0403] In some implementations, the R of formula XLV 10 For H. In some implementations, R of formula XLV 10 It is a halogen. In other embodiments, R of formula XLV 10 It is fluorine. In some embodiments, R of formula XLV 10 C 1-6 Alkyl group. In other embodiments, R of formula XLV 10 It is methyl or ethyl. In some embodiments, R of formula XLV 10 C 1-6Alkyl group.

[0404] In some implementations, when U of equation XLV is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLV is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLV is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLV is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLV is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLV is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLV is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0405] In some embodiments, U in formula XLV is NCH3. In other embodiments, U in formula XLV is NCH2CH3.

[0406] In another embodiment, the compound of formula (I) is derived from the compound of formula XLVI.

[0407]

[0408] Or its pharmaceutically acceptable salt, wherein

[0409] W is either CH or N;

[0410] U is C(R) 10 2. NR 10 Or O;

[0411] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0412] In some embodiments, W in formula XLVI is CH. In other embodiments, W in formula XLVI is N.

[0413] In some implementations, U of formula XLVI is C(R) 10 2. In other embodiments, U of formula XLVI is NR. 10 In another implementation, U in formula XLVI is O.

[0414] In some implementations, the R of XLVI 10 For H. In some implementations, R of formula XLVI 10 It is a halogen. In other embodiments, R of formula XLVI 10 It is fluorine. In some embodiments, R of formula XLVI 10 C 1-6 Alkyl group. In other embodiments, R of formula XLVI 10 It is methyl or ethyl. In some embodiments, R of formula XLV 10 C 1-6 Alkyl group.

[0415] In some implementations, when U of XLVI is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLVI is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLVI is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLVI is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLVI is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLVI is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLVI is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0416] In some embodiments, U in formula XLVI is NCH3. In other embodiments, U in formula XLVI is NCH2CH3.

[0417] In another embodiment, the compound of formula (I) is derived from the compound of formula XLVII.

[0418]

[0419] Or its pharmaceutically acceptable salt, wherein

[0420] W is either CH or N;

[0421] U is C(R) 10 2. NR 10 Or O;

[0422] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0423] In some embodiments, W in Formula XLVII is CH. In other embodiments, W in Formula XLVII is N.

[0424] In some implementations, U of formula XLVII is C(R) 10 2. In other embodiments, U in formula XLVII is NR. 10 In another embodiment, U in formula XLVII is O.

[0425] In some implementations, the R of formula XLVII 10 For H. In some implementations, R of formula XLVII 10 It is a halogen. In other embodiments, R of formula XLVII 10 It is fluorine. In some embodiments, R of formula XLVII 10 C 1-6 Alkyl group. In other embodiments, R of formula XLVII 10 It is methyl or ethyl. In some embodiments, R of formula XLVII 10 C 1-6 Alkyl group.

[0426] In some implementations, when U of equation XLVII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLVII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLVII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLVII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLVII is C(R)10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLVII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLVII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0427] In some embodiments, U in formula XLVII is NCH3. In other embodiments, U in formula XLVII is NCH2CH3.

[0428] In another embodiment, the compound of formula (I) is derived from the compound of formula XLVIII.

[0429]

[0430] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0431] U is C(R) 10 2. NR 10 Or O;

[0432] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0433] In some embodiments, W in formula XLVIII is CH. In other embodiments, W in formula XLVIII is N.

[0434] In some implementations, U of formula XLVIII is C(R) 10 2. In other embodiments, U of formula XLVIII is NR. 10 In another implementation, U in formula XLVIII is O.

[0435] In some implementations, the R of formula XLVIII 10 For H. In some implementations, R of formula XLVIII 10 It is a halogen. In other embodiments, R of formula XLVIII 10 It is fluorine. In some embodiments, R of formula XLVIII 10 C 1-6 Alkyl group. In other embodiments, R of formula XLVIII 10It is methyl or ethyl. In some embodiments, R of formula XLVIII 10 C 1-6 Alkyl group.

[0436] In some implementations, when U of equation XLVIII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLVIII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLVIII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLVIII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLVIII is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLVIII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLVIII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0437] In some embodiments, U of formula XLVIII is NCH3. In other embodiments, U of formula XLVIII is NCH2CH3.

[0438] In another embodiment, the compound of formula (I) is derived from the compound of formula XLIX.

[0439]

[0440] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0441] U is C(R) 10 2. NR 10 Or O;

[0442] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0443] In some implementations, W in Formula XLIX is CH. In other implementations, W in Formula XLIX is N.

[0444] In some implementations, U of formula XLIX is C(R) 10 2. In other embodiments, U in formula XLIX is NR. 10 In another implementation, U in formula XLIX is O.

[0445] In some implementations, the R of formula XLIX 10 For H. In some implementations, R of formula XLIX 10 It is a halogen. In other embodiments, R of formula XLIX 10 It is fluorine. In some embodiments, R of formula XLIX 10 C 1-6 Alkyl group. In other embodiments, R of formula XLIX 10 It is methyl or ethyl. In some embodiments, R of formula XLIX 10 C 1-6 Alkyl group.

[0446] In some implementations, when U of equation XLIX is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation XLIX is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula XLIX is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula XLIX is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula XLIX is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula XLIX is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula XLIX is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0447] In some embodiments, U in formula XLIX is NCH3. In other embodiments, U in formula XLIX is NCH2CH3.

[0448] In another embodiment, the compound of formula (I) is derived from the compound of formula L.

[0449]

[0450] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0451] U is C(R) 10 2. NR 10 Or O;

[0452] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0453] In some implementations, W in formula L is CH. In other implementations, W in formula XLIX is N.

[0454] In some implementations, U of formula L is C(R) 10 2. In other embodiments, U in formula L is NR. 10 In another implementation, U in formula L is O.

[0455] In some implementations, the R of formula L 10 For H. In some implementations, R of formula L 10 It is a halogen. In other embodiments, R of formula L 10 It is fluorine. In some embodiments, R of formula L 10 C 1-6 Alkyl group. In other embodiments, R of formula L 10 It is methyl or ethyl. In some embodiments, R of formula L 10 C 1-6 Alkyl group.

[0456] In some implementations, when U of equation L is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation L is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula L is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula L is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula L is C(R) 10 At time 2, an R10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula L is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula L is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0457] In some embodiments, U in formula L is NCH3. In other embodiments, U in formula L is NCH2CH3.

[0458] In another embodiment, the compound of formula (I) is derived from the compound of formula (I).

[0459]

[0460] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0461] U is C(R) 10 2. NR 10 Or O;

[0462] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0463] In some embodiments, W in formula LI is CH. In other embodiments, W in formula LI is N.

[0464] In some implementations, U of formula LI is C(R) 10 2. In other embodiments, U in formula LI is NR. 10 In another implementation, U in formula LI is O.

[0465] In some implementations, the R of formula LI 10 For H. In some implementations, R of formula LI 10 It is a halogen. In other embodiments, R of formula LI 10 It is fluorine. In some embodiments, R of formula LI 10 C 1-6 Alkyl group. In other embodiments, R of formula LI 10 It is methyl or ethyl. In some embodiments, R of formula LI 10 C 1-6 Alkyl group.

[0466] In some implementations, when U of equation LI is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation LI is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula LI is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula LI is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula LI is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula LI is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula LI is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0467] In some embodiments, U in formula LI is NCH3. In other embodiments, U in formula LI is NCH2CH3.

[0468] The following are particularly preferred.

[0469]

[0470] In another embodiment, the compound of formula (I) is derived from the compound of formula LII.

[0471]

[0472] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0473] U is C(R) 10 2. NR 10 Or O;

[0474] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0475] In some embodiments, W in formula LII is CH. In other embodiments, W in formula LII is N.

[0476] In some implementations, U of formula LII is C(R) 10 2. In other embodiments, U in formula LII is NR. 10 In another implementation, U in formula LII is O.

[0477] In some implementations, the R of formula LII 10 For H. In some implementations, R of formula LII 10 It is a halogen. In other embodiments, R of formula LII 10 It is fluorine. In some embodiments, R of formula LII 10 C 1-6 Alkyl group. In other embodiments, R of formula LII 10 It is methyl or ethyl. In some embodiments, R of formula LII 10 C 1-6 Alkyl group.

[0478] In some implementations, when U of formula LII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation LII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula LII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula LII is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula LII is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula LII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula LII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0479] In some embodiments, U in formula LII is NCH3. In other embodiments, U in formula LII is NCH2CH3.

[0480] The following are particularly preferred.

[0481]

[0482] In another embodiment, the compound of formula (I) is derived from the compound of formula LIII.

[0483]

[0484] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0485] U is C(R) 10 2. NR 10 Or O;

[0486] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0487] In some embodiments, W in formula LIII is CH. In other embodiments, W in formula LIII is N.

[0488] In some implementations, U of formula LIII is C(R) 10 2. In other embodiments, U in formula LIII is NR. 10 In another implementation, U in formula LIII is O.

[0489] In some implementations, R of formula LIII 10 For H. In some implementations, R of formula LIII 10 It is a halogen. In other embodiments, R of formula LIII 10 It is fluorine. In some embodiments, R of formula LIII 10 C 1-6 Alkyl group. In other embodiments, R of formula LIII 10 It is methyl or ethyl. In some embodiments, R of formula LIII 10 C 1-6 Alkyl group.

[0490] In some implementations, when U of equation LIII is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation LIII is C(R) 10 At time 2, each R 10 It is methyl. In some embodiments, when U of formula LIII is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 It is hydrogen. In some embodiments, when U of formula LIII is C(R) 10 At time 2, each R 10It is a halogen. In some embodiments, when U of formula LIII is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula LIII is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula LIII is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0491] In some embodiments, U in formula LIII is NCH3. In other embodiments, U in formula LIII is NCH2CH3.

[0492] In another embodiment, the compound of formula (I) is derived from the compound of formula LIV.

[0493]

[0494] Or its pharmaceutically acceptable salt, wherein W is CH or N;

[0495] U is C(R) 10 2. NR 10 Or O;

[0496] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0497] In some implementations, W in formula LIV is CH. In other implementations, W in formula LIV is N.

[0498] In some implementations, U of formula LIV is C(R) 10 2. In other embodiments, U of formula LIV is NR. 10 In another implementation, U in formula LIV is O.

[0499] In some implementations, the R of formula LIV 10 For H. In some implementations, R of formula LIV 10 It is a halogen. In other embodiments, R of formula LIV 10 It is fluorine. In some embodiments, R of formula LIV 10 C 1-6 Alkyl group. In other embodiments, R of formula LIV 10 It is methyl or ethyl. In some embodiments, R of formula LIV10 C 1-6 Alkyl group.

[0500] In some implementations, when U of formula LIV is C(R) 10 At time 2, each R 10 For H. In some implementations, when U of equation LIV is C(R) 10 At time 2, each R 10 For methyl. In some embodiments, when

[0501] The U of formula LIV is C(R) 10 At time 2, an R 10 It is methyl and has an R 10 For hydrogen. In some embodiments, when U of formula LIV is C(R) 10 At time 2, each R 10 It is a halogen. In some embodiments, when U of formula LIV is C(R) 10 At time 2, an R 10 It is a halogen and an R 10 It is hydrogen. In other embodiments, when U of formula LIV is C(R) 10 At time 2, each R 10 It is fluorine. In other embodiments, when U of formula LIV is C(R) 10 At time 2, an R 10 It is fluorine and an R 10 It is hydrogen.

[0502] In some embodiments, U in formula LIV is NCH3. In other embodiments, U in formula LIV is NCH2CH3.

[0503] In another embodiment, the compound of formula (I) is derived from the compound of formula LVII.

[0504]

[0505] Or its pharmaceutically acceptable salt, wherein

[0506] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0507] In some implementations, the R of formula LVII 10 For H. In some implementations, R of formula LVII 10 C 1-6 Alkyl group. In other embodiments, R of formula LVII 10It is methyl. In other embodiments, R of formula LI 10 It is an ethyl group.

[0508] The particularly preferred compound is

[0509]

[0510] In another embodiment, the compound of formula (I) is derived from the compound of formula LVIII.

[0511]

[0512] Or its pharmaceutically acceptable salt, wherein

[0513] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0514] In some implementations, the R of formula LVIII 10 For H. In some implementations, R of formula LVIII 10 C 1-6 Alkyl group. In other embodiments, R of formula LVIII 10 It is methyl. In other embodiments, R of formula LVIII 10 It is an ethyl group.

[0515] The particularly preferred compound is

[0516]

[0517] In another embodiment, the compound of formula (I) is derived from the compound of formula LIX.

[0518]

[0519] Or its pharmaceutically acceptable salt, wherein

[0520] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 alkoxy groups; and

[0521] Each R4, R3, V, and L1 is defined relative to equation (I).

[0522] In some implementations, the R of formula LIX 10 For H. In some implementations, R of formula LIX 10 C 1-6 Alkyl group. In other embodiments, R of formula LIX10 It is methyl. In other embodiments, R of formula LIX 10 It is an ethyl group.

[0523] In another embodiment, the compound of formula (I) is derived from the compound of formula LX.

[0524]

[0525] Or its pharmaceutically acceptable salt, wherein

[0526] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0527] In some implementations, the R of formula LX 10 For H. In some implementations, R of formula LX 10 C 1-6 Alkyl group. In other embodiments, R of formula LX 10 It is methyl. In other embodiments, R of formula LX 10 It is an ethyl group.

[0528] In another embodiment, the compound of formula (I) is derived from the compound of formula LXIII.

[0529]

[0530] Or its pharmaceutically acceptable salt, wherein

[0531] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0532] In some implementations, the R of formula LXIII 10 For H. In some implementations, R of formula LXIII 10 C 1-6 Alkyl group. In other embodiments, R of formula LXIII 10 It is methyl. In other embodiments, R of formula LXIII 10 It is an ethyl group.

[0533] In another embodiment, the compound of formula (I) is derived from the compound of formula LXIV.

[0534]

[0535] Or its pharmaceutically acceptable salt, wherein

[0536] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0537] In some implementations, the R of formula LXIV 10 For H. In some implementations, R of formula LXIV 10 C 1-6 Alkyl group. In other embodiments, R of formula LXIV 10 It is methyl. In other embodiments, R of formula LXIV 10 It is an ethyl group.

[0538] In another embodiment, the compound of formula (I) is derived from the compound of formula LXV.

[0539]

[0540] Or its pharmaceutically acceptable salt, wherein

[0541] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0542] In some implementations, the R of formula LXV 10 For H. In some implementations, R of formula LXV 10 C 1-6 Alkyl group. In other embodiments, R of formula LXV 10 It is methyl. In other embodiments, R of formula LXV 10 It is an ethyl group.

[0543] In another embodiment, the compound of formula (I) is derived from the compound of formula LXVI.

[0544]

[0545] Or its pharmaceutically acceptable salt, wherein

[0546] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0547] In some implementations, the R of formula LXVI10 For H. In some implementations, R of formula LXVI 10 C 1-6 Alkyl group. In other embodiments, R of formula LXVI 10 It is methyl. In other embodiments, R of formula LXVI 10 It is an ethyl group.

[0548] In another embodiment, the compound of formula (I) is derived from the compound of formula LXVII.

[0549]

[0550] Or its pharmaceutically acceptable salt, wherein

[0551] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0552] In some implementations, the R of formula LXVII 10 For H. In some implementations, R of formula LXVII 10 C 1-6 Alkyl group. In other embodiments, R of formula LXVII 10 It is methyl. In other embodiments, R of formula LXVII 10 It is an ethyl group.

[0553] In another embodiment, the compound of formula (I) is derived from the compound of formula c.

[0554]

[0555] Or its pharmaceutically acceptable salt, wherein

[0556] R 10 H, halogen (preferably fluorine), C 1-6 Alkyl or C 1-6 Alkoxy groups; and each R4, R3, V and L1 is defined relative to formula (I).

[0557] In some implementations, the R of formula LXVIII 10 For H. In some implementations, R of formula LXVIII 10 C 1-6 Alkyl group. In other embodiments, R of formula LXVIII 10 It is methyl. In other embodiments, R of formula LXVIII 10 It is an ethyl group.

[0558] In another embodiment, the compound of formula (I) is:

[0559] 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidine-2-amine;

[0560] N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0561] N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0562] 4-(3-Cyclobutyl-2,6-dimethylthiopheno[2,3-d]imidazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidine-2-amine;

[0563] 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidine-2-amine;

[0564] 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;

[0565] 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;

[0566] 4-(3-Cyclobutyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidine-2-amine;

[0567] 5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;

[0568] 4-(3-Cyclobutyl-2,6-dimethylthiopheno[2,3-d]imidazol-5-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0569] 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(3,3-difluoropyrrolidine-1-yl)pyridin-2-yl)-5-fluoropyrimidine-2-amine;

[0570] 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidine-2-amine;

[0571] 4-(3-cyclopentyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;

[0572] N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-prop-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;

[0573] 4-(7-Cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0574] 4-(3-chloro-7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0575] 2-[2-[2-[[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]prop-2-ol;

[0576] 2-[2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoroprop-2-ol;

[0577] N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-prop-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;

[0578] 4-(3-chloro-7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(1-ethylpiperidin-4-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0579] 2-[2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]prop-2-ol;

[0580] 4-(7-cyclopentyl-3-methylthiopheno[3,2-b]pyridin-2-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;

[0581] N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoro-4-(7-prop-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;

[0582] 4-(7-Cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0583] 2-[2-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoroprop-2-ol;

[0584] 4-(7-cyclopentyl-3-methylthiopheno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;

[0585] 2-[2-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]prop-2-ol;

[0586] 4-(7-cyclopentyl-3-methylthiopheno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;

[0587] 2-[2-[2-[[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoroprop-2-ol;

[0588] 4-(3-chloro-7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0589] 4-(7-cyclopentyl-3-methylthiopheno[3,2-b]pyridin-2-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;

[0590] N-(5-(2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-4-(7-cyclopentyl-3-methylthiopheno[3,2-b]pyridin-2-yl)-5-fluoropyrimidine-2-amine;

[0591] 4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0592] 4-(7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;

[0593] 4-(7-cyclopentyl-3-methylthiopheno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;

[0594] 4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;

[0595] 4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;

[0596] 4-(7-cyclopentyl-3-methylthiopheno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinylpyridin-2-yl)pyrimidin-2-amine;

[0597] 4-(7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methoxypiperidin-1-yl)pyridin-2-yl]pyrimidin-2-amine;

[0598] 4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinylpyridin-2-yl)pyrimidin-2-amine;

[0599] 4-(7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(3,3-difluoropyrrolidine-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0600] 4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2-amine;

[0601] 4-(4-cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;

[0602] 4-(4-Cyclopentylthiopheno[2,3-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0603] 4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;

[0604] 4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;

[0605] 4-(4-Cyclopentylthiopheno[2,3-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0606] 4-(7-cyclopentyl-3-methylthieno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;

[0607] 4-(4-cyclopentyl-7-methylthieno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;

[0608] N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxo-7-prop-2-ylthieno[3,2-b]pyridin-4-onthiol-2-yl)pyrimidin-2-amine;

[0609] 2-[5-fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-prop-2-ylthieno[3,2-c]pyridin-4-one;

[0610] 4-(2,6-Dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0611] 6-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine;

[0612] (4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazo-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl ketone;

[0613] 4-(2,6-Dimethyl-3-propyl-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0614] 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0615] 2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0616] 2-(2-((5-(6-ethyl-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthiopheno[3,2-c]pyridin-4(5H)-one;

[0617] 2-(2-((5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthiopheno[3,2-c]pyridin-4(5H)-one;

[0618] 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthiopheno[3,2-c]pyridin-4(5H)-one;

[0619] 2-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]oct-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;

[0620] 6-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthiopheno[2,3-d]pyrimidin-4(1H)-one;

[0621] 2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[2,3-d]pyridazine-4(5H)-one;

[0622] Or its pharmaceutically acceptable salt.

[0623] In another embodiment, the compound of formula (I) is:

[0624] N-[5-[[4-(2,2-difluoroethyl)piperazin-1-yl]methyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0625] 1-[[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl]-N,N-dimethylpyrrolidine-3-carboxamide;

[0626] 4-(2,6-Dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-pyridin-2-ylpyrimidin-2-amine;

[0627] 4-(2,6-Dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-(1-methyl-1,6-diazaspiro[3.3]hept-6-yl)pyridin-2-yl]pyrimidin-2-amine;

[0628] 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethyl-6,6-difluoro-1,4-diazacycloheptane-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0629] 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-[2,2,3,3,5,5,6,6-octadeuter-4-(trideutermethyl)piperazin-1-yl]pyridin-2-yl]pyrimidin-2-amine;

[0630] N-[5-(5,5-difluoro-7-methyl-2,7-diazaspiro[3.4]oct-2-yl)pyridin-2-yl]-4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidine-2-amine;

[0631] (6-Ethyl-2,6-diazaspiro[3.3]hept-2-yl)-[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl ketone;

[0632] N-[5-[3-(dimethylamino)azacyclobutane-1-yl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0633] N-[5-[3-(dimethylamino)pyrrolidin-1-yl]pyridin-2-yl]-4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-amine;

[0634] N-[5-(6-ethyl-3,6-diazabicyclo[3.1.1]hept-3-yl)pyridin-2-yl]-5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0635] 1-[6-[[4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino]pyridin-3-yl]-4-methylpiperazin-2-one;

[0636] 2-(5-Fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;

[0637] 2-(5-fluoro-2-((5-(7-methyl-2,7-diazaspiro[3.5]non-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0638] 2-(5-Fluoro-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;

[0639] 2-(5-Fluoro-2-((5-((3aS,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;

[0640] 2-(5-fluoro-2-((5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0641] 2-(2-((5-(5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthiopheno[3,2-c]pyridin-4(5H)-one;

[0642] 2-(5-fluoro-2-((5-(1-(methyl-d3)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0643] 2-(2-((5-(1,4-diazabicyclo[3.2.2]non-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0644] 2-(5-Fluoro-2-((5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0645] 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methyl-5-(methyl-d3)thieno[3,2-c]pyridin-4(5H)-one;

[0646] 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;

[0647] 2-(2-((5-(1-ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0648] 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0649] 2-(5-fluoro-2-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0650] 2-(2-((5-(((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0651] 2-(5-fluoro-2-((5-(2-methyl-2,7-diazaspiro[3.5]non-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0652] 2-(5-Fluoro-2-((5-(6-isopropyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0653] 2-(5-fluoro-2-((6-(1-methylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0654] 2-(5-Fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0655] 2-(5-fluoro-2-((5-(1-isopropylpyrrolidone-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one;

[0656] 7-Isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one;

[0657] 7-Isopropyl-5-methyl-2-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one;

[0658] 4-(6-((5-fluoro-4-(7-isopropyl-3,5-dimethyl-4-oxo-4,5-dihydrothiopheno[3,2-c]pyridin-2-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-1-methylpiperidine 1-oxide;

[0659] 5-Fluoro-4-(3-isopropyl-2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;

[0660] N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine;

[0661] 4-(3-Cyclopropyl-2,6-Dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(6-Ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-5-fluoropyrimidine-2-amine;

[0662] 2-(5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)-1,1,1-trifluoroprop-2-ol;

[0663] 1-(5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethyl-1-one;

[0664] 1-(5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethanol;

[0665] N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-5-fluoro-4-(3-(2-methoxypropyl-2-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidine-2-amine;

[0666] 4-(1,6-Dimethyl-3-propyl-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0667] N-(5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazine-3-amine;

[0668] 5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylazacyclobutane-3-yl)pyridin-2-yl)pyrimidin-2-amine;

[0669] 3-(2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazin-7-yl)azacyclobutane-1-carboxylic acid tert-butyl ester;

[0670] 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-(3-fluorobicyclo[1.1.1]pent-1-yl)-5-methylthieno[2,3-d]pyridazine-4(5H)-one;

[0671] 5-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3-isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine;

[0672] N-(5-(2-ethyl-2-azaspiro[3.3]hept-6-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0673] 4-(2,6-Dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[6-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0674] 5-Fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(1-methylpyrrolidone-3-yl)oxypyridin-2-yl]pyrimidin-2-amine;

[0675] 5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylmorpholino-2-yl)pyridino-2-yl)pyrimidino-2-amine;

[0676] N-[5-[1-(4-ethylpiperazin-1-yl)ethyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0677] 3-[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-1,4-dimethylpiperazin-2-one;

[0678] ((8aS)-6-(6-((5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-3(4H)-one;

[0679] 4-(2,6-Dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[4-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;

[0680] 4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;

[0681] N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-[7-prop-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]pyrimidin-2-amine;

[0682] 2-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropylthiopheno[3,2-b]pyridin-3-carboxylonitrile;

[0683] 5-Fluoro-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-4-(3-methyl-7-propyl-2-ylthieno[3,2-c]pyridin-2-yl)pyrimidin-2-amine;

[0684] N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0685] 5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine (isomer 1);

[0686] 5-Fluoro-N-[5-[1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine (isomer 2);

[0687] 4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-methoxy-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;

[0688] N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0689] N-(5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;

[0690] 5-Chloro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;

[0691] 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthiopheno[3,2-c]pyridine 5-oxide;

[0692] Or its pharmaceutically acceptable salt.

[0693] It will be apparent that compounds of Formula I (including all subgenera described herein) may have multiple stereocenters. Therefore, a variety of stereoisomers (enantiomers and diastereomers) exist for compounds of Formula I (and the subgenera described herein). This disclosure contemplates and covers every stereoisomer of any compound of Formula I (and the subgenera described herein), as well as mixtures of said stereoisomers.

[0694] Pharmaceutically acceptable salts and solvates of compounds of Formula I (including all subgenera described herein) are also within the scope of this disclosure.

[0695] This disclosure also considers isotopic variants of compounds of formula I (including all subgenera described herein).

[0696] Pharmaceutical Compositions and Administration

[0697] In some embodiments, this disclosure relates to pharmaceutical compositions comprising compounds of formula I or pharmaceutically acceptable salts or solvates thereof.

[0698] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of the disclosed compound or its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative as an active ingredient. Where desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or its coordination complex, 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), penetration enhancers, solubilizers, and adjuvants.

[0699] The pharmaceutical compositions of this invention can be administered alone or in combination with one or more other pharmaceutical agents, which are typically also administered in the form of pharmaceutical compositions. Where necessary, one or more compounds of the invention can be mixed with other pharmaceutical agents into a formulation, or the two components can be formulated into separate formulations for use alone or in combination.

[0700] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition of the present invention is less than 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%, etc. 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 number within a range that is limited by and includes any two of the above numbers) w / w, w / v, or v / v.

[0701] In some embodiments, the concentration of one or more compounds of the present invention is greater than 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%, and 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%, 0.0 3%, 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 number within a range that is limited by any two of the above numbers) w / w, w / v or v / v.

[0702] In some embodiments, the concentration of one or more compounds of the present invention is in the range of about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% 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%, about 1% to about 10% w / w, w / v, or v / v.

[0703] In some embodiments, the concentration of one or more compounds of the present invention is in the range of 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%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0704] In some embodiments, the amount of one or more compounds of the present invention is equal to or less than 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 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 number within the range that is limited by and includes any two of the above numbers).

[0705] In some embodiments, the amount of one or more compounds of the present invention is greater than 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, or 0.0035g. g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0 .0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.0 45g, 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,,0.35g,0.4g,,0.45g,0.5g,0.55g,0.6g,,0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or a number within the range specified by and including any two of the above numbers).

[0706] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001g-10g, 0.0005g-9g, 0.001g-8g, 0.005g-7g, 0.01g-6g, 0.05g-5g, 0.1g-4g, 0.5g-4g, or 1g-3g.

[0707] The compounds according to the invention are effective over a wide dosage range. For example, in adult treatment, doses of 0.01 mg / day to 1000 mg / day, 0.5 mg / day to 100 mg / day, 1 mg / day to 50 mg / day, and 5 mg / day to 40 mg / day are examples of usable doses. Exemplary doses are 10 mg / day to 30 mg / day. The exact dose will depend on the route of administration, the form of the compound administered, the subject being treated, the weight of the subject being treated, and the preferences and experience of the attending physician.

[0708] The pharmaceutical compositions of the present invention typically contain the active ingredient of the present invention (i.e., the compound disclosed herein) or its pharmaceutically acceptable salt and / or coordination complex, 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, penetration enhancers, solubilizers and adjuvants.

[0709] The following describes non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0710] Pharmaceutical compositions for oral administration .

[0711] In some embodiments, the present invention provides pharmaceutical compositions for oral administration, the pharmaceutical compositions comprising the compounds of the present invention and pharmaceutical excipients suitable for oral administration.

[0712] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, the solid pharmaceutical composition comprising: (i) an effective amount of the compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third agent.

[0713] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the present invention suitable for oral administration may be available in discrete dosage forms, such as capsules, pouches, or tablets, or liquid or aerosol sprays each containing a predetermined amount of an active ingredient, said active ingredient being a powder or granules, a solution or 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 pharmaceutical method, but all methods include the step of combining the active ingredient with a carrier constituting one or more essential components. Generally, a composition is prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a subdivided solid carrier, or both, and then, if desired, shaping the product into the desired form. For example, tablets may be prepared by compression or molding, optionally with one or more excipients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules) optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersants, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0714] This invention also includes anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means of simulating long-term storage to determine properties such as shelf life or the stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of this invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. The pharmaceutical compositions and dosage forms of this invention containing lactose can be made anhydrous if sufficient 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 properties. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0715] The active ingredient can be combined with a drug carrier in a close mixture using conventional pharmaceutical formulation techniques. The carrier can take various forms depending on the desired formulation for administration. In the preparation of compositions for oral dosage forms, in the case of oral liquid formulations (e.g., suspensions, solutions, and elixirs) or aerosols, any commonly used pharmaceutical medium can be used as a carrier, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid dosage forms, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used, although lactose is not used in some embodiments. Suitable carriers include powders, capsules, and tablets, as well as solid oral dosage forms. If desired, tablets can be coated using standard aqueous or non-aqueous techniques.

[0716] Binders suitable for 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 arabic, sodium alginate, alginic acid, other alginates, powdered astragalus gum, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0717] Examples of suitable fillers for 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, glucose binders, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0718] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant may result in tablets that disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may therefore alter the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant, neither too little nor too much, that would adversely alter the release of the active ingredient, can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary depending on the type of formulation and the method of administration, and may be readily discernible to those skilled in the art. About 0.5% to about 15% by weight, or about 1% to about 5% by weight, of disintegrant may be used in the pharmaceutical composition. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or cassava starch, other starches, pregelatinized starches, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0719] Lubricants that can be used to form the 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, condensed aerosols of synthetic silica, or mixtures thereof. Lubricants may optionally be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0720] When aqueous suspensions and / or elixirs are required for oral administration, the active ingredients therein may be combined with various sweeteners or flavorings, colorings or dyes, and, if necessary, emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0721] Tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delay-release materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented 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 an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0722] 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. That is, mixtures of hydrophilic surfactants, mixtures of lipophilic surfactants, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0723] Suitable hydrophilic surfactants typically have an HLB value of at least 10, while suitable lipophilic surfactants typically have an HLB value equal to or less than about 10. The 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 greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions.

[0724] Hydrophilic surfactants are generally considered to be compounds with HLB values ​​greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not typically applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​equal to or less than about 10. However, the HLB value of a surfactant is only a rough guideline commonly used in the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0725] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophosphatidylcholine and its derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactates; monoacetylated tartrate esters and diacetylated tartrate esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citrate esters of monoglycerides and diglycerides; and mixtures thereof.

[0726] In the above group, ionic surfactants include, for example: lecithin, lysophosphatidylcholine, phospholipids, lysophosphatidylcholine and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acylactylates; monoacetylated tartrate esters and diacetylated tartrate esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citrate esters of monoglycerides and diglycerides; and mixtures thereof.

[0727] Ionic surfactants can be ionized forms of the following substances: lecithin, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactates of fatty acids, stearoyl-2-lactic acid ester, stearoyl lactate, succinyl monoglyceride, monoacetyl / diacetyl tartrate of monoglycerides / diglycerides, citrate of monoglycerides / diglycerides, cholycylsarcosine, hexanoate, caprylate, caprate, laurate, myristate, palmitate, oleate, castor oil ester, linoleate, linolenic acid ester, stearate, lauryl sulfate, octadecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their salts and mixtures.

[0728] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltodextrins; alkyl thioglucosides; lauryl polyethylene glycol glycerides; polyoxyethylene alkyl ethers, such as polyethylene glycol alkyl ethers; polyoxyethylene alkylphenols, such as polyethylene glycol alkylphenols; polyoxyethylene 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; polyoxyethylene dehydrated sorbitol fatty acid esters, such as polyethylene glycol dehydrated sorbitol fatty acid esters; hydrophilic transesterification products of polyols with at least one of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogs; polyoxyethylene-modified vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol dehydrated sorbitol fatty acid esters and hydrophilic transesterification products of polyols with at least one of triglycerides, vegetable oils, and hydrogenated vegetable oils. Polyols can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugars.

[0729] Other hydrophilic nonionic surfactants include, but are not limited to, 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 trioleylglycerol, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 stearyl glycerol, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, and PEG-40 lauric acid. Glyceryl esters, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprylic / caprylic glyceryl ester, PEG-8 caprylic / caprylic glyceryl ester, polyglycerol-10 laurate, PEG-30 cholesterol, PEG-25 phytosterols, PEG-30 Soy sterols, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan lauryl ester, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglycerol-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamers.

[0730] By way of example only, suitable lipophilic surfactants include: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitol fatty acid esters; polyethylene glycol sorbitol fatty acid esters; sterols and sterol derivatives; polyoxyethylene-modified sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of monoglycerides and diglycerides; hydrophobic transesterification products of polyols with at least one of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Preferred lipophilic surfactants in this group include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0731] In one embodiment, the composition may contain a solubilizer to ensure good solubilization and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This is particularly important for compositions intended for non-oral use (e.g., compositions for injection). Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0732] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and their 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 with an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl PEG ether (glycogen) or methoxyPEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkyl 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 octanoate, ethyl butyrate, triacetyl triacetate, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0733] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetyl citrate, triethyl oleate, ethyl octanoate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycogen, carbitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetyl citrate, ethanol, PEG-400, glycogen, and propylene glycol.

[0734] There are no particular limitations on the amount of solubilizer that may be included. The amount of a given solubilizer may be limited to a bioacceptable amount, which can be readily determined by those skilled in the art. In some cases, it may be advantageous to include an amount of solubilizer far exceeding the bioacceptable amount, for example, to maximize the concentration of the drug, removing excess solubilizer before serving the composition to the subject using conventional techniques such as distillation or evaporation. Thus, if present, the weight ratio of the solubilizer may be 10% by weight, 25% by weight, 50% by weight, 100% by weight, or at most about 200% by weight, based on the combined weight of the drug and other excipients. Very small amounts of solubilizer, such as 5% by weight, 2% by weight, or even less, may also be used if desired. Typically, the solubilizer may be present in amounts from about 1% by weight to about 100% by weight, and more typically from about 5% by weight to about 25% by weight.

[0735] The composition may also contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-sticking agents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tension modifiers, flavoring agents, coloring agents, taste enhancers, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0736] 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, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulosic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic 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 and 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.

[0737] 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, and phosphoric acid. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulosic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0738] Injectable pharmaceutical compositions .

[0739] In some embodiments, the present invention provides an injectable pharmaceutical composition comprising the compounds of the present invention and injectable excipients. The components and amounts of the pharmaceutical preparations in the composition are as described herein.

[0740] The novel compositions of this invention that can be incorporated into the form of injectable administration include aqueous or oily suspensions or emulsions containing sesame oil,

[0741] Corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar drug carriers.

[0742] Saline solutions are also routinely used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate flowability can be maintained, for example, by using coatings (such as lecithin) to maintain the desired particle size in the dispersed state and by using surfactants. Microbial activity can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, sodium ethylmercuric thiosalicylate, etc.

[0743] A sterile injectable solution is prepared by incorporating the required amount of the compound of the present invention, along with various other ingredients listed above (as desired), into a suitable solvent, followed by filtration and sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile medium containing a basic dispersion medium and desired other ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, certain desirable preparation methods are vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any other desired ingredients from solutions that have been previously sterile filtered.

[0744] Pharmaceutical compositions for local (e.g., transdermal) delivery .

[0745] In some embodiments, the present invention provides pharmaceutical compositions for transdermal delivery, the pharmaceutical compositions comprising the compounds of the present invention and pharmaceutical excipients suitable for transdermal delivery.

[0746] The compositions of the present invention can be formulated into solid, semi-solid, or liquid forms suitable for local or topical application, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, and dimethyl sulfoxide (DMSO)-based solutions. Generally, carriers with higher density provide areas of prolonged exposure to the active ingredient. In contrast, solution formulations allow for more direct exposure of the active ingredient to the selected area.

[0747] Pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients, which are compounds that allow or facilitate the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. Many of these penetration-enhancing molecules are known to those skilled in the art of topical formulations.

[0748] Examples of such carriers and excipients include, but are not limited to, wetting agents (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, glyceryl monolaurate, sulfoxide, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0749] Another exemplary formulation used in the method of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide controlled amounts of the compounds of the present invention for continuous or discontinuous infusion, regardless of whether another formulation is used.

[0750] The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured to deliver pharmaceutical agents continuously, pulsatilely, or on demand.

[0751] Inhalation drug composition .

[0752] Compositions for inhalation or inhalation 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. The composition is preferably administered via oral or nasal inhalation for local or systemic action. Compositions preferably in pharmaceutically acceptable solvents may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask tent or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.

[0753] Other pharmaceutical compositions .

[0754] 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 spinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G., eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999); all of these references are incorporated herein by reference in their entirety.

[0755] Administration of the compounds or pharmaceutical compositions of the present invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral administration, intraduodenal administration, parenteral injection (including intravenous, intra-arterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), local application (e.g., percutaneous), rectal administration, local delivery via catheter or stent, or inhalation. The compounds can also be administered intra-adipose or intrathecally.

[0756] The amount of compound administered will depend on the subject being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the prescribing physician's judgment. However, the effective dose is in the range of about 0.001 mg / kg body weight / day to about 100 mg / kg body weight / day, preferably about 1 mg / kg / day to about 35 mg / kg / day, in single or divided doses. For a 70 kg person, this would total about 0.05 g / day to 7 g / day, preferably about 0.05 g / day to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be sufficient, while in other cases, larger doses may be used without causing any harmful side effects, for example, by dividing such larger doses into several smaller doses administered throughout the day.

[0757] In some embodiments, the compounds of the present invention are administered in a single dose.

[0758] Typically, such administration is performed by injection, such as intravenous injection, to rapidly deliver the drug. However, other routes may be appropriately used. A single dose of the compound of the present invention can also be used to treat acute conditions.

[0759] In some embodiments, the compounds of the present invention are administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times daily. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compounds of the present invention are administered together with another agent about once to about six times daily. In another embodiment, the administration of the compounds and agents of the present invention lasts for less than about seven days. In yet another embodiment, the administration lasts for more than about six, ten, fourteen, twenty-eight days, two months, six months, or one year. In some cases, continuous administration is achieved and maintained as long as necessary.

[0760] The application of the compounds of the present invention may continue as long as necessary. In some embodiments, the compounds of the present invention are applied for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the present invention are applied for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the present invention are applied on a continuous basis for a long period of time, for example, for treating chronic effects.

[0761] An effective amount of the compounds of the present invention can be administered in single or multiple doses via any acceptable mode of administration of an agent having similar efficacy, including rectal, buccal, intranasal, and percutaneous routes, via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0762] The compositions of the present invention can also be delivered via an impregnated or coated device (e.g., a stent) or a cylindrical polymer inserted into an artery. Such administration methods can, for example, help prevent or improve restenosis after procedures such as balloon angioplasty. Unbound by theory, the compounds of the present invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that lead to restenosis. The compounds of the present invention can be administered, for example, by localized delivery from a stent strut, from a stent graft, from a graft, or from a stent cover or sheath. In some embodiments, the compounds of the present invention are mixed with a matrix. This matrix can be a polymer matrix and can be used to bind the compounds to a stent. Polymer matrices suitable for this use include, for example, lactone-based polyesters or copolyesters, such as polylactide, polycaprolactone-glycolic acid, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., poly(hydroxyethyl methacrylate), polyvinylpyrrolidone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices can be non-degradable or degradable over time, releasing one or more compounds. The compounds of the present invention can be applied to the surface of a stent by various methods such as dip-coating / spin-coating, spraying, dip-coating, and / or brushing. The compounds can be applied in a solvent, and the solvent can be evaporated to form a compound layer on the stent. Alternatively, the compounds can be located within the stent or graft, for example, within microchannels or micropores. Upon implantation, the compounds diffuse out of the stent body to contact the arterial wall. Such stents can be prepared by immersing a stent manufactured to contain such micropores or microchannels in a solution of the compounds of the present invention in a suitable solvent, followed by solvent evaporation. Excess drug on the stent surface can be removed by additional brief solvent washing. In another embodiment, the compounds of the present invention can be covalently linked to the stent or graft. Covalently degradable in vivo can be used, resulting in the release of the compounds of the present invention. Any biounstable linker can be used for this purpose, such as ester, amide, or anhydride links. The compounds of the present invention can also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds can also be performed via the pericardium or via the adventitia to reduce restenosis.

[0763] For example, various support devices that can be used as described are disclosed in the following references, all of which are incorporated herein by reference: U.S. Patent 5,451,233; U.S. Patent 5,040,548; U.S. Patent 5,061,273; U.S. Patent 5,496,346; U.S. Patent 5,292,331; U.S. Patent 5,674,278; U.S. Patent 3,657,744; U.S. Patent 4,739,762; U.S. Patent 5,195,984; U.S. Patent 5,292,331; U.S. Patent 5,674,278; U.S. Patent 5,879,382; and U.S. Patent 6,344,053.

[0764] The compounds of the present invention can be administered in doses. It is known in the art that individualization of dosing regimens is essential for optimal treatment due to inter-individual variability in the pharmacokinetics of compounds. The dosage of the compounds of the present invention can be determined through conventional experiments based on this disclosure.

[0765] When the compounds of the present invention are administered in the form of a composition comprising one or more agents having a shorter half-life than the compounds of the present invention, the unit dosage form of the agents and the compounds of the present invention may be adjusted accordingly.

[0766] The pharmaceutical compositions of the present invention may be in forms suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions; forms suitable for parenteral injection, such as sterile solutions, suspensions, or emulsions; forms suitable for topical application, such as ointments or creams; or forms suitable for rectal administration, such as suppositories. The pharmaceutical compositions may be unit dosage forms suitable for a single, precise dose. The pharmaceutical compositions will include conventional drug carriers or excipients and a compound according to the present invention as the active ingredient. Furthermore, the pharmaceutical composition may include other drugs or pharmaceutical preparations, carriers, adjuvants, etc.

[0767] Exemplary parenteral formulations include solutions or suspensions of the active compound in sterile aqueous solutions (e.g., aqueous propylene glycol or glucose solutions). Such formulations may be, and appropriately, buffered if desired.

[0768] How to use

[0769] This method typically involves administering a therapeutically effective amount of the compounds of the present invention to a subject. The therapeutically effective amount of the compound combination of the present invention can vary depending on the intended application (in vitro or in vivo) or the subject being treated and the disease condition (e.g., the subject's weight and age, the severity of the disease condition, the method of administration, etc.), which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells, such as reducing proliferation or downregulating the activity of target proteins. Specific doses will vary depending on the specific compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system it carries.

[0770] As used in this article, the term "IC" 50 "IC50%" refers to the half-maximal inhibitory concentration (50% IC50) of an inhibitor in inhibiting a biological or biochemical function. This quantitative measure indicates how much of a specific inhibitor is needed to inhibit a given biological process (or a component of that process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. In other words, it is the half-maximal (50%) inhibitory concentration (IC50) of a substance (or IC50). 50 EC50 refers to the plasma concentration required to achieve 50% or more of the maximum effect in vivo.

[0771] In some implementations, the method of the present invention utilizes IC 50 CDK inhibitors with values ​​approximately or less than predetermined values, as determined in in vitro assays. In some embodiments, the CDK inhibitor inhibits IC50. 50Values ​​are approximately 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, 170 nM or less. 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 650nM or less, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1μM or less, 1.1μM or less, 1.2μM or less, 1.3μM or less, 1.4μM or less, 1.5μM or less, 1.6μM or less, 1.7μM or less, 1.8μM or less, 1.9μM or less, 2μ CDKs of 1 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 numbers within a range that are defined by and include any two of the above numbers).

[0772] In some implementations, the CDK inhibitor selectively inhibits CDKs 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 than its IC50 value against one, two, or three other CDKs (or a number within a range defined by and including any two of the above numbers).

[0773] In some implementations, the CDK inhibitor selectively inhibits CDK, with IC50 values ​​less than approximately 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, and 2... 00nM, 225nM, 250nM, 275nM, 300nM, 325nM, 350nM, 375nM, 400nM, 425nM, 450nM, 475nM, 5 00nM, 550nM, 600nM, 650nM, 700nM, 750nM, 800nM, 850nM, 900nM, 950nM, 1μM, 1.1μM, 1.2 μM, 1.3μM, 1.4μM, 1.5μM, 1.6μM, 1.7μM, 1.8μM, 1.9μM, 2μM, 5μM, 10μM, 15μM, 20μM, 25μM , 30μM, 40μM, 50μM, 60μM, 70μM, 80μM, 90μM, 100μM, 200μM, 300μM, 400μM or 500μM (or any of the above (Any two numbers that define and include the range of any two numbers above), and the IC50 value 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 than its IC50 value for one, two, or three other CDKs (or a number that defines and includes the range of any two numbers above).

[0774] The method of this invention can be used to treat CDK-related disease conditions. Any disease condition directly or indirectly caused by abnormal CDK activity or expression levels can be a anticipated disease condition.

[0775] Various disease conditions associated with CDK have been reported. CDK involves, for example, autoimmune diseases, neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease, and ischemic diseases), inflammatory diseases, viral infections, and cancers such as 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.

[0776] Non-limiting examples of such conditions include, but are not limited to, acanthoma, acinar cell carcinoma, acoustic neuroma, acral lentigines melanoma, acral hidradenoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myeloid leukemia, acute promyelocytic leukemia, amelomas, adenocarcinoma, adenoid cystic carcinoma, and adenocarcinoma. enoma), odontogenic adenomatoid tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft tissue sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdomyosarcoma, basal cell carcinoma, basal cell carcinoma, B-cell leukemia, B-cell lymphoma, Bellini ductal carcinoma (Bellini) Duct carcinoma, bile duct cancer, bladder cancer, blastoma, bone cancer, bone tumor, brainstem glioma, brain tumor, breast cancer, Brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, brown tumor, Burkitt's lymphoma, cancer of unknown primary location, carcinoid tumor, carcinoma, carcinoma in situ, penile cancer, carcinoma of unknown primary location. Site), carcinosarcoma, Castleman's disease, embryonal tumors of the central nervous system, cerebellar astrocytoma, brain astrocytoma, cervical cancer, chondrocyte carcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myeloid leukemia, chronic myelodysplastic disease, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, degos disease, dermatofibrosarcoma protuberans, dermoid cyst, connective tissue proliferative small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, endometrial cancerUterine Cancer, endometrioid tumors, enteropathy-associated T-cell lymphoma, ependymoblastoma, epidermoid carcinoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, olfactory neuroblastoma, Ewing family tumor, Ewing family sarcoma, Ewing's sarcoma, germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, extramammary Paget's disease, fallopian tube cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, gallbladder cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors. Tumors, gastrointestinal stromal tumors, germ cell tumors, germ cell tumors, gestational choriocarcinoma, gestational trophoblastic tumors, giant cell tumors of bone, glioblastoma multiforme, gliomas, gliomatosis, glomus tumors, glucagonomas, gonadal germ cell tumors, ovarian granulosa cell tumors, hairy cell leukemia, head and neck cancer, heart cancer, hemoglobinopathies such as β-thalassemia and sickle cell disease (SCD), angioblastomas, hemangiopericytomas, angiosarcomas, hematologic malignancies, hepatocellular carcinoma, hepatosplenic T-cell lymphomas, hereditary breast cancer and ovarian cancer syndromes, Hodgkin's lymphoma. Lymphoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi's sarcoma, renal cell carcinoma, Klatskin tumor, Krukenberg tumor, laryngeal cancer, laryngeal cancerCancer), malignant lentigines melanoma, leukemia, lip and oral cancer, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelial carcinoma, lymphocytic leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant fibrous histiocytoma, bone malignant fibrous histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdomyosarcoma, malignant salamander tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, mastocytosis, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid carcinoma, medulloblastoma, medulloblastoma, medullary epithelioma, melanoma, melanoma, meningioma, Merkel cell carcinoma. Carcinoma, mesothelioma, mesothelioma, occult primary metastatic squamous neck carcinoma, metastatic urothelial carcinoma, mixed Mullerian tumor, monocytic leukemia, oral cancer, myxoma, multiple endocrine adenoma syndrome, multiple myeloma, multiple myeloma, mycosis fungoides, myelodysplastic disorders, myelodysplastic syndrome, myeloid leukemia, myeloid sarcoma, myeloproliferative disorders, myxoma, nasal cavity carcinoma, nasopharyngeal carcinoma, nasopharyngeal carcinoma, vegetation, schwannoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma. Lymphoma, non-Hodgkin lymphoma, non-melanoma skin cancer, non-small cell lung cancer, eye tumors, oligodendroastrocytoma, oligodendroglioma, eosinophilic adenoma, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumors, ovarian low-malignant potential tumors, Paget's disease of the breast, superior sulcus tumor, pancreatic cancer.Cancer), papillary thyroid carcinoma, papilloma, paraganglioma, sinus carcinoma, parathyroid carcinoma, penile cancer, perivascular epithelioid cell tumor, pharyngeal carcinoma, pheochromocytoma, intermediately differentiated pineal parenchymal tumor, pineoblastoma, pituitary cell tumor, pituitary adenoma, pituitary adenoma, plasma cell tumor, pleural pulmonary blastoma, polyembryoma, precursor T-cell lymphoma, primary central nervous system lymphoma, primary exudative lymphoma, primary hepatocellular carcinoma, primary liver cancer, primary peritoneal carcinoma, primitive neuroectodermal tumor, prostate cancer, peritoneal pseudomyxoma, rectal cancer, renal cell carcinoma, respiratory tract cancer involving the NUT gene on chromosome 15, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, Richter's transformation Transformation), sacrococcygeal teratoma, salivary gland tumor, sarcoma, Schwannomatosis, sebaceous gland carcinoma, secondary tumor, seminoma, serous tumor, Sertoli-stromal cell tumor, sex cord-stromal tumor, Sezary syndrome (Syndrome), signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestinal cancer, soft tissue sarcoma, somatostatinoma, sootypic warts, spinal cord tumors, spinal tumors, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial diffuse melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-mesenchymal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphoblastic leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, advanced lymphoma, testicular cancer, theca cell tumor, laryngeal cancer, thymic carcinoma, thymoma, thyroid cancer, renal pelvis and ureter transitional cell carcinoma, transitional cell carcinoma, urachal carcinoma, urethral cancer, urogenital cancer, uterine sarcoma, uveal melanoma, vaginal cancer, Verner-Morison syndrome (syndrome), verrucous carcinoma, optic pathway glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.

[0777] In some implementations, the method is used to treat diseases 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 carcinoma.

[0778] In other embodiments, the method is used to treat diseases selected from the group consisting of: breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

[0779] In other embodiments, the method is used to treat diseases selected from: leukemia, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic osteomyeloid leukemia, hairy cell leukemia, spinal dysplasia, myeloproliferative disorders, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or epidermoid carcinoma.

[0780] The compounds disclosed herein, and pharmaceutical compositions comprising them, may be administered alone or in combination with medical therapies to treat any of the said diseases. Medical therapies include, for example, surgery and radiation therapy (e.g., gamma radiation therapy, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, whole-body radioisotopes).

[0781] In other respects, the compounds disclosed herein and the pharmaceutical compositions comprising them may be administered alone or in combination with one or more other pharmaceutical agents to treat any of the said diseases.

[0782] In other methods, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with agonists of nuclear receptor agents.

[0783] In other methods, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with antagonists of nuclear receptor agents.

[0784] In other methods, the compounds of this disclosure and pharmaceutical compositions comprising them may be administered in combination with antiproliferative agents.

[0785] In some embodiments, this disclosure relates to a method for treating CDK4-mediated and CDK6-mediated conditions in patients of need, the method comprising administering to the patient a compound of formula I (including all subgenus described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I (including all subgenus described herein).

[0786] In some implementations, CDK4-mediated and CDK6-mediated conditions are cancers. In some implementations, 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 metastases.

[0787] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a 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.

[0788] In some implementations, the cancer is prostate cancer. In some implementations, the cancer is chronic lymphocytic leukemia. In some implementations, the cancer is lymphoma. In some implementations, the cancer is myeloma. In some implementations, the cancer is acute myeloid leukemia. In some implementations, the cancer is secondary pancreatic cancer. In some implementations, the cancer is secondary brain metastasis.

[0789] In some implementations, the breast cancer is HR+ / HER2- or HR+ / HER2+ advanced or metastatic breast cancer. In some implementations, the breast cancer is HR+ / HER2- advanced breast cancer. In some implementations, the breast cancer is HR+ / HER2- metastatic breast cancer. In some implementations, the breast cancer is HR+ / HER2+ advanced breast cancer. In some implementations, the breast cancer is HR+ / HER2+ metastatic breast cancer.

[0790] In some embodiments, the malignant brain tumor is a glioblastoma, astrocytoma, or 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.

[0791] In some embodiments, a pharmaceutical composition comprising a compound of formula I (including all subgenera described herein) or a pharmaceutically acceptable salt thereof is administered to a patient. In some embodiments, administration is oral.

[0792] combination therapy

[0793] For the treatment of 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, such as gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole-body radioisotopes. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, benzamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib. Bustezomib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate, filgrastim, fluxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide Acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mecaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase, pegfilgrastim, pemetrexedDisodium, pentostatin, piperobromidine, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malate The following are listed: maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronate.

[0794] In some embodiments, the compounds of the present invention can be used in combination with therapeutic agents that target epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetyltransferase 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.

[0795] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with targeted therapies including JAK kinase inhibitors (e.g., ruxotinib), PI3 kinase inhibitors (including PI3K-δ selective and broad-spectrum PI3K inhibitors), MEK inhibitors, cyclin-dependent kinase inhibitors (including CDK4 / 6 inhibitors and CDK9 inhibitors), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., pabisostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo- and extra-terminal family (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.

[0796] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor, such as 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 the immune checkpoint molecule is a PD-L1 inhibitor, such as 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 the immune checkpoint molecule is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0797] 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).

[0798] For the treatment of autoimmune or inflammatory conditions, the compounds of the present invention can be used in combination with corticosteroids such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.

[0799] For the treatment of autoimmune or inflammatory conditions, the compounds of this invention can be combined with immunosuppressants such as fluocinolone acetonide. Rimexolone (AL-2178, Vexol, Alcon) or cyclosporine Combined administration.

[0800] In some embodiments, this disclosure relates to the methods described herein, which further include administering an additional therapeutic agent to a patient. 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.

[0801] 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 other embodiments, the additional therapeutic agent is an alkylating agent.

[0802] 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.

[0803] In another embodiment, the PRMT5 inhibitor is a compound disclosed in U.S. Patent Application Publication 2020 / 0148692 (filed January 16, 2020); U.S. Patent Application Publication 2019 / 0284193 (filed April 5, 2019); and U.S. Patent Application Publication 2019 / 0048014 (filed August 9, 2018); each of which is hereby incorporated herein by reference in its entirety.

[0804] In some implementations, the PRMT5 inhibitor is:

[0805] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisosperm-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof;

[0806] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-7-chloroisosperm-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof;

[0807] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloroisosperman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof;

[0808] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-difluoroisosperm-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof;

[0809] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5,6-difluoroisosperm-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof;

[0810] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-5-fluoroisochroman-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof;

[0811] (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 solvation thereof;

[0812] (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-dichloroisosperm-1-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof;

[0813] (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 solvation thereof;

[0814] (2S,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 solvation thereof;

[0815] (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 solvation thereof;

[0816] (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 solvation thereof;

[0817] (2S,3S,4R,5R)-2-((R)-6,7-dichloroisocyanuran-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol, or a pharmaceutically acceptable salt or solvation thereof.

[0818] In some implementations, 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 solvation thereof.

[0819] synthesis

[0820] The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0821] The reactions used to prepare the compounds of the present invention can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially unreactive with the starting materials (reactants), intermediates, or products at temperatures in which the reaction takes place, for example, temperatures in the range of the solvent's freezing temperature to its boiling point. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, those skilled in the art can select a suitable solvent for that particular reaction step.

[0822] The preparation of the compounds of this invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection, as well as the selection of suitable protecting groups. The chemical properties of protecting groups can be found, for example, in TW Greene and PGM Uts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), the full text of which is incorporated herein by reference.

[0823] The reaction can be monitored using any suitable method known in the art. For example, product formation can be monitored using spectroscopic techniques such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Monitoring by infrared spectroscopy, spectrophotometry (e.g., UV-visible light), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin-layer chromatography.

[0824] As used herein, the terms “ambient temperature,” “room temperature,” and “rt” are understood in the art and generally refer to temperature, such as reaction temperature, which is approximately the temperature of the room in which the reaction takes place, for example, a temperature of approximately 20°C to approximately 30°C.

[0825] The compounds of the present invention can be prepared using a variety of preparation reactions known in the literature. The following schemes provide general guidance for the preparation of the compounds of the present invention. Those skilled in the art will understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry 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.

[0826] The following examples are provided to illustrate some of the concepts described within this disclosure. While the examples are intended to provide implementation methods, they should not be considered as limiting the more general implementation methods described herein.

[0827] Example

[0828] General synthesis procedure

[0829] The compound of formula (I) can be protected by 1-1 (where W) 1 The compound is prepared as a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) as shown in Scheme I. Compound 1-1 can be prepared under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) chloride and a base, such as K3PO4) or under standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(O)) or under standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(O) or [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) chloride) with compound 1-2 (where M 1 Coupling with boric acid, borate esters, potassium trifluoroborate, or a suitably substituted metal, such as Sn(Bu)3 or ZnCl, yields compounds 1-3, wherein W 2 The compounds are halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs). Coupling of compounds 1-3 with amines 1-4 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of palladium catalysts such as XPhos Pd G2 and bases such as K3PO4) can provide compounds of formula (I).

[0830] Alternatively, compound 1-1 can be converted into suitable compounds 1-5 (e.g., M). 2 For B(OH)2, Bpin, BF3K, Sn(Me)3, Sn(Bu)3 or ZnCl), and then coupled to 1-6 (where W) under standard Suzuki conditions (e.g. in the presence of a palladium catalyst such as [1,1′-bis(diphenylphosphine)ferrocene]dichloro-palladium(II) and a base such as K3PO4) or under standard Stille conditions (e.g. in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O)) or under standard Negishi conditions (e.g. in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) or [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II)) (where W) 3 By using halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs), compounds 1-3 are obtained, which can be used to synthesize compounds of formula (I).

[0831] Option I

[0832]

[0833] The intermediate used to synthesize the compound 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 metallized in the presence of a strong base such as lithium diisopropylamino or lithium butylene and a suitable reagent (e.g., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane, hexamethylditin, trimethyltin chloride, or zinc chloride) to give compound 1-5.

[0834] Option II

[0835]

[0836] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme III. Compound 3-1 (wherein W) 4 Coupling of a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) with an amine 3-2 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)) can provide 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, a MeOH solution of H2 in the presence of a transition metal catalyst (e.g., palladium / carbon), a MeOH / H2O solution of Fe / NH4Cl, or an EtOH / H2O solution of sodium dithionite. Compound 3-4 can be used in scheme I to obtain the compound of formula (I).

[0837] Option III

[0838]

[0839] The intermediate used to synthesize the compound of formula (I) can be obtained from compound 4-1 (where M) as described in scheme IV. 3 Rx, Ry, and Rz are boric acid, borate esters, potassium trifluoroborate, or suitably substituted metals, such as Sn(Bu)3 or ZnCl; Rx, Ry, and Rz are independently H, D, C1-C5 alkyl, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-heterocyclic alkyl, wherein the C1-C5 alkyl, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-heterocyclic alkyl may be optionally substituted; and optionally, R x and R zThese compounds, together with the olefins to which they are attached, can form cycloalkenyl or heterocyclic alkenyl groups. Compound 4-1 can be prepared with compound 4-2 (where Y... 1 Coupling of a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf or OMs) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and a base such as K3PO4) or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(O) or [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)) yields compound 4-3. Alkene 4-3 can be converted to compound 4-4 under reducing conditions such as, but not limited to, an alcoholic solvent (e.g., MeOH or EtOH) solution of H2 in the presence of a transition metal catalyst (e.g., palladium / carbon).

[0840] Option IV

[0841]

[0842] The intermediate used to synthesize the compound of formula (I) can be, as described in scheme V, compound 5-1 (wherein Rv and Rw are independently H, D, C1-C5 alkyl, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4, 5, 6, or 7 heterocyclic alkyl, wherein the C1-C5 alkyl, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4, 5, 6, or 7 heterocyclic alkyl can be optionally substituted, and optionally, R... v and R w It can be prepared by forming cyclic ketones together with the carbons attached to both of them. It is also prepared with amines 5-2 (where R... q The reaction of a C1-C6 alkyl group with a reducing agent (e.g., in the presence of a reducing agent such as sodium triacetoxyborohydride and optionally an acid such as acetic acid) under standard conditions for reductive amination can yield compound 5-3. Hydrolysis of ester 5-3 under standard conditions (e.g., in the presence of a base such as NaOH or an acid such as HCl) can yield carboxylic acid 5-4. Amine 5-4 can react with compound 5-5 (wherein, when compound 5-5 is an acyl chloride, Y...) 1Coupling of compounds 5-5 with Cl) or -OC (=O)Rs (where Rs are C1-C6 alkyl groups when compounds 5-5 are anhydrides) under suitable conditions (e.g., in the presence of a base such as triethylamine and an optional catalyst such as 4-(dimethylamino)pyridine) yields amides 5-6. Under standard conditions, such as in the presence of diphenylphosphohydrazine and a base such as triethylamine, the Curtius rearrangement of compounds 5-6, followed by exposure to aqueous conditions (e.g., dioxane / water), yields compounds 5-7. Cyclization of 5-7 under suitable conditions, such as in the presence of a dehydrating agent (e.g., phosphorus oxychloride), can provide compounds 5-8.

[0843] Option V

[0844]

[0845] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme VI. Carboxylic acid 6-1 can be converted to a suitable acyl chloride 6-2 under standard conditions (e.g., in the presence of a reagent such as oxalyl chloride or thionyl chloride and optionally a catalyst such as N,N-dimethylformamide). The reaction with hydroxylamine or its salt (e.g., NH2OH·HCl) under suitable conditions (e.g., in the presence of a base such as sodium hydroxide) can give isohydroxamic acid 6-3. Compound 6-3 can be acylated with acyl chloride 6-4 (wherein Rp is a C1-C6 alkyl group) under suitable conditions (e.g., in the presence of a base such as triethylamine) to give compound 6-5. Compound 6-5 can be reacted with compound 6-6 (wherein Rp is a C1-C6 alkyl group) to give compound 6-5. g and R h Each independently as R 3 Under standard transition metal-catalyzed CH activation conditions (e.g., in the presence of a rhodium catalyst such as pentamethylcyclopentadienylrhodium(III) chloride dimer and a base such as cesium acetate), compounds 6-8 are given. Alternatively, compound 6-5 can be coupled with compound 6-6 (where R... g and R h Each independently as R 3 Coupling under standard transition metal-catalyzed CH activation conditions (e.g., in the presence of a rhodium catalyst such as pentamethylcyclopentadienyl rhodium(III) chloride dimer and a base such as cesium acetate) yields compounds 6-8 (where R... g and R h Each is H). Dehydration halogenation of compounds 6-8 (e.g., by treatment with reagents such as POCl3 or POBr3) yields compounds 6-9 (where Y is H). 2 Halogens (e.g., Cl or Br).

[0846] Solution VI

[0847]

[0848] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme VII. Carbonyl compound 7-1 (wherein R) i The C1-C5 alkyl group, 5-7 aryl group, 5-7 heteroaryl group, cycloalkyl group, or 4-, 5-, 6-, or 7-membered heterocyclic alkyl group can be optionally substituted with organometallic reagent 7-2 (wherein M... 4 Suitable metals (e.g., Li, MgCl, MgBr, ZnCl or ZnR) j And R j The compound is a C1-C5 alkyl, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-heterocyclic alkyl group, wherein the C1-C5 alkyl group, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-heterocyclic alkyl group may optionally be substituted, to give alcohol 7-3. Alternatively, compound 7-1 can be reacted with silane 7-4 (wherein Y, ... 3 It reacts with halogens (e.g., F or Br) or H) to convert to alcohols 7-5 (where Z is 7-5). 1 It is a fluoroalkyl group (e.g., CF3 or CF2H).

[0849] Option VII

[0850]

[0851] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme VIII. Oxidation of compound 8-1 under standard conditions, such as in the presence of a peroxyacid (e.g., mCPBA) or a peroxide (e.g., a urea-hydrogen peroxide adduct), yields N-oxide 8-2.

[0852] Scheme VIII

[0853]

[0854] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme IX. Thiophene 9-1 and compound 9-2 (wherein Y 4 The reaction of a halogen (e.g., Cl or Br) under standard conditions, such as in the presence of a Lewis acid (e.g., aluminum chloride), yields compound 9-3. Ketone 9-3 can react with compound 9-4 (where R...) o and Rr Each of the compounds (individually C1-C6 alkyl groups) reacts under standard conditions in the presence of a base (e.g., sodium hydride, butyllithium, or isopropyl magnesium chloride) to give α,β-unsaturated ester 9-5. Hydrolysis of ester 9-5 under standard conditions (e.g., in the presence of a base such as NaOH or an acid such as HCl) can provide carboxylic acid 9-6. Under standard conditions, such as in the presence of diphenylphosphohydrazine and a base such as triethylamine, the Coulters rearrangement of compound 9-6, followed by cyclization under standard conditions, yields compound 9-7. With halide 9-8 (where Y... 5 Alkylating compound 9-7 with a halide (e.g., Cl, Br, or I) and Rn being a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C1 alkyl-aryl, C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group can provide compound 9-9.

[0855] Solution IX

[0856]

[0857] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme X. Compound 3-1 is mixed with compound 10-1 (where x and y are independently 0, 1, 2, or 3; where Q...). 1 H or a protecting group, such as Boc, Cbz, Bn, PMB, Trt, acetamido, or trifluoroacetamido; and wherein M is... 5 Coupling with boric acid, borate esters, potassium trifluoroborate, or suitably substituted metals, such as Sn(Bu)3 or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and a base such as K3PO4 or K2CO3) or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions (e.g., in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(O) or [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)) and then optionally deprotecting can provide compound 10-2. With halide 10-3 (where Y... 6 It is a halogen (e.g., Cl, Br, or I) or a pseudohalogen (e.g., OTf, OTs, or OMs) and R aAlkylating an amine 10⁻² with a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C1 alkyl-aryl, C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group can provide a compound 10⁻⁴. Compound 10⁻⁴ can be reduced to an amine 10⁻⁵ under standard reducing conditions, such as, but not limited to, H₂ in the presence of a transition metal catalyst (e.g., palladium / carbon or platinum oxide (IV)).

[0858] Alternatively, amine 10-2 reacts with compound 10-6 (wherein R) under standard conditions for reductive amination (e.g., in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride and optionally an acid such as acetic acid) under standard conditions for reductive amination. b and R c Each of the following is independently H, D, C1-C6 alkyl, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-heterocyclic alkyl, wherein the C1-C5 alkyl, 5-7 aryl, 5-7 heteroaryl, cycloalkyl, or 4-, 5-, 6-, or 7-heterocyclic alkyl may be optionally substituted, and optionally, R b and R c Reactions with the carbon atoms attached to both of them (which can form cyclic ketones) can provide compound 10⁻⁷. Compound 10⁻⁷ can be reduced to amine 10⁻⁸ under standard reducing conditions, such as, but not limited to, H₂ in the presence of a transition metal catalyst (e.g., palladium / carbon or platinum oxide (IV)).

[0859] Option X

[0860]

[0861] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme XI. Halide 11-1 (wherein W...) 3 Metallization of halogens (e.g., Br or I) under standard metal-halogen exchange conditions, followed by addition to pyrimidine 11-2 (where W 2 Compound 11-3 can be provided in halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs). Compound 11-3 can be oxidized to heteroaromatic compound 1-3 under standard oxidation conditions, such as, but not limited to, in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone.

[0862] Option XI

[0863]

[0864] Compounds of formula (I) can be prepared from compounds 1-3, as shown in scheme XII. Compounds 1-3 can be reacted under standard nucleophilic aromatic substitution conditions (e.g., in the presence of anhydrous NH3 or NH4OH (aqueous solution)) or under standard Buchwald-Hartwig amination conditions (e.g., in the presence of an ammonia substitute such as benzophenone imine, lithium bis(trimethylsilyl)amide, or tert-butyl carbamate; a palladium catalyst such as Pd2(dba)3; a ligand such as XPhos or XantPhos; and an optional base such as Cs2CO3) or under standard Ullman coupling conditions (e.g., in the presence of an ammonia source such as NH3 or ammonium bicarbonate and a copper catalyst such as CuO, CuSO4, or CuI) to give aminopyrimidine 12-1. Compound 12-1 reacts with halide 12-2 (wherein W 5 Coupling of halogens (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs) under standard Buchwald-Hartwig amination conditions (e.g., in the presence of palladium catalysts such as XPhos Pd G2 or BrettPhos Pd G3 and bases such as sodium tert-butoxide or K3PO4) can provide compounds of formula (I).

[0865] Solution XII

[0866]

[0867] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme XIII. Reduction of ester 13-1 (where Rs is a -C1-C6 alkyl group) under standard conditions (e.g., in the presence of lithium aluminum hydride) provides compound 13-2. Acylation of compound 13-2 with acid anhydride 13-3 (where Rt is a C1-C6 alkyl group) under standard conditions (e.g., in the presence of potassium acetate), followed by nitrosylation / cyclization under standard conditions, such as in the presence of an alkyl nitrite (e.g., isoamyl nitrite), yields compound 13-4. Hydrolysis of acylthiophene pyrazole 13-4 under standard conditions (e.g., in the presence of a base such as NaOH or an acid such as HCl) provides thiophene pyrazole 13-5. Compound 13-5 can be halogenated with a suitable reagent such as iodine, bromine, or N-bromosuccinimide, optionally in the presence of a base (e.g., potassium carbonate or sodium hydroxide), to give compound 13-6 (where W... 6 For halogens (e.g., Br or I). Using electrophilic reagent 13-7 (where Y... 8Alkylating thiophene-pyrazole 13-6 with a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf, OTs, or OMs) or other leaving group (e.g., dimethyloxonium) and Ru being a -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C1 alkyl-aryl, C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group can provide compound 13-8. Heteroaryl halides 13-8 can be coupled with suitable compounds 13-9 (e.g., M6 being B(OH)2, Bpin, BF3K, Sn(Me)3, Sn(Bu)3, or ZnCl) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and a base such as K3PO4) or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) or [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)) to give compounds 13-10.

[0868] Option XIII

[0869]

[0870] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme XIV. Under standard conditions, such as in the presence of a Lewis acid (e.g., AlCl3), it is prepared with an acyl halide 14-1 (where R... k It is H, D, F, C1-C8 alkoxy, C1-C8 alkyl, fluoroalkyl, or CN and Y 9 Friedel-Crafts acylation of compound 2-1 with a halogen (e.g., Cl or Br) yields ketone 14-2. Compound 14-2 reacts with acetal 14-3 (where R...) 1 Condensation of H, D, -C1-C8 alkoxy, -C1-C8 alkyl, fluoroalkyl, or CN yields compound 14-4. Condensation of compound 14-4 with guanidine or one of its salts (e.g., guanidine hydrochloride) optionally in the presence of a base (e.g., K2CO3) yields aminopyrimidine 14-5.

[0871] Solution XIV

[0872]

[0873] The intermediate used to synthesize the compound of formula (I) can be prepared as described in scheme XV. Compound 13-8 can be coupled with compound 4-1 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and a base such as K3PO4) or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O)) or standard Negishi conditions (e.g., in the presence of a palladium(O) catalyst such as tetrakis(triphenylphosphine)palladium(O) or [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)) to give compound 15-1. Alkene 15-1 can be converted to compound 15-2 under reducing conditions such as, but not limited to, an alcoholic solvent (e.g., MeOH or EtOH) solution of H2 in the presence of a transition metal catalyst (e.g., palladium / carbon).

[0874] Solution XV

[0875]

[0876] Example 1.4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidine-2-amine

[0877]

[0878] Step 1: Methyl 2-(cyclopentylamino)-4-methylthiophene-3-carboxylate

[0879]

[0880] NaBH(OAc)3 (18.382 g, 86.7 mmol, 2.50 equivalents) was added in portions to methyl 2-amino-4-methylthiophene-3-carboxylate (5.940 g, 34.7 mmol, 1.00 equivalents), cyclopentanone (7.556 g, 86.7 mmol, 2.50 equivalents), and acetic acid (5.209 g, 86.7 mmol, 2.50 equivalents) in a solution of DCE (120 mL). The resulting suspension was stirred at ambient temperature for 18 h. The reaction mixture was slowly poured into a 10% Na2CO3 solution (200 mL) and stirred until gas escape stopped. The organic layer was separated, and the aqueous layer was extracted with DCM (50 mL × 3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid chromatography (80 g) (0-5% MTBE / heptane) to give the title compound as a colorless oil (5.221 g, 21.8 mmol, 62.9% yield). f =0.6 (10% MTBE / heptane). C 12 H 18 NO2S[M+H] + The calculated LCMS value is m / z = 240.1; the measured value is 240.0.

[0881] Step 2.2-(cyclopentylamino)-4-methylthiophene-3-carboxylic acid

[0882]

[0883] NaOH powder (8.276 g, 218.2 mmol, 10.0 equivalent) was dissolved in H₂O (30 mL), and the resulting aqueous solution was slowly added at ambient temperature to methyl 2-(cyclopentylamino)-4-methylthiophene-3-carboxylate (5.221 g, 21.8 mmol, 1.00 equivalent) in a solution of MeOH (30 mL). The reaction mixture was heated at 80 °C for 18 h. The organic solvent was evaporated under reduced pressure. The remaining aqueous solution was diluted with H₂O (30 mL), acidified with 4N HCl solution (to pH 3–4), and extracted with MTBE (50 mL × 3). The combined organic phases were washed with H₂O (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, and evaporated under vacuum to give the title compound (4.175 g, 18.5 mmol, 85.0% yield) as an amber solid. f =0.3 (30% MTBE / heptane). C 11 H 16 NO2S[M+H] + The calculated LCMS value is m / z = 226.1; the measured value is 226.0.

[0884] Step 3.2-(N-cyclopentylacetamido)-4-methylthiophene-3-carboxylic acid

[0885]

[0886] Acetic anhydride (4.729 g, 46.3 mmol, 2.50 equivalents) was added dropwise to a solution of 2-(cyclopentylamino)-4-methylthiophene-3-carboxylic acid (4.175 g, 18.5 mmol, 1.00 equivalents), Et3N (5.625 g, 55.6 mmol, 3.00 equivalents), and DMAP (226 mg, 1.85 mmol, 0.10 equivalents) in DCM (50 mL). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was poured into a cold saturated NH4Cl solution (100 mL). The organic layer was separated, and the aqueous layer was extracted twice with DCM (50 mL). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by silica gel rapid chromatography (0-50% EtOAc / heptane as eluent) to give the title compound (3.897 g, 14.6 mmol, 78.8% yield) as a yellow, viscous, oily substance. f =0.2 (50% EtOAc / heptane). C 13 H 18 NO3S[M+H] + The calculated LCMS value is m / z = 268.1; the measured value is 268.0.

[0887] Step 4. N-(3-amino-4-methylthiophen-2-yl)-N-cyclopentylacetamide

[0888]

[0889] 3.897 g of 2-[acetyl(cyclopentyl)amino]thiophene-3-carboxylic acid. 14.6DPPA (10.029 g, 36.4 mmol, 2.50 equivalents) was added dropwise to a solution of 1,4-dioxane (40 mL) and Et3N (7.375 g, 72.9 mmol, 5.00 equivalents). The reaction mixture was stirred at room temperature for 1 h. H2O (40 mL) was added and the reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and 2 M NaOH solution (20 mL) was added, and the resulting mixture was stirred further at room temperature for 30 min. The reaction mixture was poured into a saturated NH4Cl solution (30 mL) and extracted with DCM (50 mL × 3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0890] Step 5.3-Cyclopentyl-2,6-dimethyl-3H-thiopheno[2,3-d]imidazole

[0891]

[0892] At ambient temperature, POCl3 (2.782 g, 18.1 mmol, 1.00 equivalence) was added dropwise to a solution of N-(3-amino-4-methylthiophene-2-yl)-N-cyclopentylacetamide (crude product, from the previous step, 4.118 g, 17.3 mmol, 1.00 equivalence) in toluene (40 mL). The resulting solution was heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature and poured into a 10% Na2CO3 solution. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 mL × 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0%–75% EtOAc and 0.1% Et3N / heptane) to give the title compound (1.547 g, 7.02 mmol, 40.6% yield) as an amber oil. f =0.2 (50% EtOAc / heptane). C 12 H 17 N2S[M+H] + The calculated LCMS value is m / z = 221.1; the measured value is 221.0.

[0893] Step 6.3-Cyclopentyl-2,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-3H-thiopheno[2,3-d]imidazolium

[0894]

[0895] At -78 °C, a solution of LDA (1.29 mL, 9.74 mmol, 5.00 equivalent) in THF and hexane (1.40 M) was added dropwise to a solution of 3-cyclopentyl-2,6-dimethylthiopheno[2,3-d]imidazole (429 mg, 1.95 mmol, 1.00 equivalent) and 4,4,5,5-tetramethyl-2-prop-2-yloxy-1,3,2-dioxoboronylcyclopentane (725 mg, 3.89 mmol, 2.00 equivalent) in THF (10 mL). The reaction mixture was stirred at -78 °C and monitored by LCMS. When LCMS analysis indicated complete consumption of the starting material (approximately 1 h), the reactants were quenched by dropwise addition of saturated NH4Cl (15 mL). The resulting mixture was extracted with CHCl3 / iPrOH (1:1, 20 mL × 3). The combined organic phases were washed with H₂O (10 mL) and brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was used in the next step without further purification. 18 H 28 The calculated LCMS value of BN2O2S[M+H is m / z = 347.2; the measured value is 347.1.

[0896] Step 7.5-(2-chloro-5-fluoropyrimidin-4-yl)-3-cyclopentyl-2,6-dimethyl-3H-thiopheno[2,3-d]imidazolium

[0897]

[0898] 2,6-Dichloro-5-uracil (285 mg, 1.71 mmol, 1.00 equivalent), Pd(dppf)Cl2 (62 mg, 0.09 mmol, 0.05 equivalent), K3PO4 (1.449 g, 6.83 mmol, 4.00 equivalent), and H2O (2 mL) were added to a 1,4-dioxane solution (8 mL) of crude borate ester. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 6 h, at which point TLC analysis showed the disappearance of the starting material. The reaction mixture was cooled to ambient temperature and partitioned between H2O (15 mL) and EtOAc (15 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (15 mL × 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by rapid column chromatography (0-50% EtOAc / heptane) to give the title compound as a yellow solid (120 mg, 0.34 mmol, 20.0% yield). f = 0.25 (50% EtOAc / heptane). C 16 H 17 ClFN4S[M+H] +The calculated LCMS value is m / z = 351.1; the measured value is 351.0.

[0899] Step 8.4 -(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethyl-piperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidine-2-amine

[0900] A suspension of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-cyclopentyl-2,6-dimethylthiopheno[2,3-d]imidazole (70.0 mg, 0.20 mmol, 1.00 equivalent), 5-(4-ethylpiperazin-1-yl)pyridine-2-amine (41.0 mg, 0.20 mmol, 1.00 equivalent), XPhos Pd G2 (7.9 mg, 0.01 mmol, 0.05 equivalent), and K3PO4 (169.0 mg, 0.80 mmol, 4.00 equivalent) in 1,4-dioxane (2 mL) was heated at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was cooled to room temperature and TFA (2 drops) was added. The inorganic salts were filtered off and the filtrate was subjected to preparative HPLC at C2. 18 Purification on a column (6%–80% MeCN / H2O) yielded the title compound as its hydrochloride (46.2 mg, 0.09 mmol, 43.6% yield), a pale yellow solid. 1 H NMR(300MHz,CD3OD)δ8.81(d,J=3.0Hz,1H),8.28(dd,J=9.7,2.8Hz,1H),7.95(d ,J=2.7Hz,1H),7.59(d,J=9.6Hz,1H),5.15–5.02(m,1H),3.97(t,J=10.8Hz,2H) ,3.74(t,J=10.6Hz,2H),3.40–3.33(m,2H),3.28–3.24(m,2H),2.89(s,3H),2.7 4(d,J=3.1Hz,3H),2.46–2.33(m,2H),2.27–1.78(m,7H),1.44(t,J=7.3Hz,3H). C 27 H 34 FN8S[M+H] + The calculated LCMS value is m / z = 521.3; the measured value is 520.9.

[0901] The embodiments listed in Tables 1-1 and 1-2 are synthesized according to a procedure similar to that of Embodiment 1.

[0902]

[0903] Table 1-1: Examples 2-13

[0904]

[0905]

[0906] Table 1-2: Examples 2-13

[0907]

[0908]

[0909]

[0910] Example 14. N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-prop-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine

[0911]

[0912] Step 1: 7-Prop-1-en-2-ylthiopheno[3,2-b]pyridine

[0913]

[0914] A mixture of 7-chlorothieno[3,2-b]pyridine (2.0 g, 11.79 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (3.0 g, 17.69 mmol), K3PO4 (7.5 g, 35.37 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (862.7 mg, 1.18 mmol) in 1,4-dioxane (20 mL) and water (6 mL) was bubbled with N2 for 5 min and stirred overnight at 100 °C. LCMS showed that the starting material was consumed. Solids were removed by filtration, and the filtrate was concentrated to dryness. The residue was dissolved in EtOAc (50 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0-25%) to give the title compound (1.71 g, 82.8% yield). C 10 H 10 NS[M+H] + The calculated LCMS value is m / z = 176.1; the measured value is 175.9.

[0915] Step 2: 7-Isopropylthiopheno[3,2-b]pyridine

[0916]

[0917] A mixture of 7-prop-1-en-2-ylthieno[3,2-b]pyridine (1.8 g, 10.15 mmol) and Pd / C (180.0 mg, 0.17 mmol) in methanol (20 mL) was stirred overnight under H2 atmosphere. LCMS showed that the starting material was consumed. The solids were removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0–25%) to give the title compound (1.53 g, 84.0% yield). 10 H 12 NS[M+H] + The calculated LCMS value is: m / z = 178.1 / 179.1; the measured value is: 178.2 / 179.4.

[0918] Step 3: (7-prop-2-ylthiopheno[3,2-b]pyridin-2-yl)boronic acid

[0919]

[0920] At -78 °C, n-BuLi (0.81 mL, 2.03 mmol) was added dropwise to a solution of 7-prop-2-ylthieno[3,2-b]pyridine (300.0 mg, 1.69 mmol) in THF (5 mL). The reaction mixture was stirred at -78 °C for 1 h. Then, 4,4,5,5-tetramethyl-2-prop-2-yloxy-1,3,2-dioxoborane (629.7 mg, 3.38 mmol) was added dropwise. The resulting mixture was stirred from -78 °C to room temperature overnight. LCMS showed that the starting material was consumed. The reactants were quenched with saturated NH4Cl solution (5 mL) and extracted with IPA / CHCl3 (1:3, 5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (330 mg) as a crude mixture, which was used in the next reaction without further purification.

[0921] Step 4: 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-propyl-2-ylthiopheno[3,2-b]pyridine

[0922]

[0923] A mixture of (7-prop-2-ylthieno[3,2-b]pyridin-2-yl)boronic acid (330.0 mg, 1.49 mmol), 2,6-dichloro-5-fluorouracil (373.8 mg, 2.24 mmol), K3PO4 (950.5 mg, 4.48 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (109.2 mg, 0.15 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was bubbled with N2 for 5 min and stirred overnight at 100 °C. LCMS showed that the starting material was consumed. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (10 mL), washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (5%–60%) to give the title compound (180.0 mg, 39.2% yield). 14 H 11 ClFN3S[M+H] + The calculated LCMS value is m / z = 308.0; the measured value is 307.9.

[0924] Step 5: N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-prop-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine

[0925] 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-propyl-2-ylthiopheno[3,2-b]pyridine (18.0 A mixture of 5-(4-ethylpiperazin-1-yl)pyridin-2-amine (18.1 mg, 0.09 mmol), K3PO4 (37.2 mg, 0.18 mmol), and XPhos PdG2 (4.6 mg, 0.01 mmol) in 1,4-dioxane (1 mL) was bubbled with N2 for 5 min and stirred overnight at 100 °C. LC-MS showed that the starting material was consumed. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a C18 column by elution with MeCN / H2O (5%–100%) and 0.1% TFA to give the title compound (8.2 mg, 27.2% yield) as its TFA salt. 1H NMR(300MHz,CD3OD)δ8.82(d,J=2.8Hz,1H),8.74(dd,J=5.1,2.1Hz,1H),8.4 8(t,J=2.0Hz,1H),8.20(dd,J=9.7,2.6Hz,1H),7.95(s,1H),7.69(d,J=9.5Hz ,1H),7.52(dd,J=5.1,2.0Hz,1H),3.35(d,J=1.8Hz,1H),3.33–3.32(m,8H), 3.31(s,2H),1.52(d,J=2.1Hz,3H),1.50(d,J=2.3Hz,3H),1.47–1.40(m,3H). C 25 H 29 FN7S[M+H] + The calculated LCMS value is: m / z = 478.2 / 479.2; the measured value is: 477.9 / 479.3.

[0926] Example 15.4-(7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[0927]

[0928] Step 1: 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0929]

[0930] The mixture of tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (500.0 mg, 1.56 mmol) and TFA (5.0 mL, 65.34 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (300 mg, 87.3% yield) was used in the next step without further purification. 10 H 13 N4O2[M+H] + The calculated LC-MS value is m / z = 221.2; the measured value is 220.9.

[0931] Step 2: 6-Ethyl-2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

[0932]

[0933] A mixture of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (500.0 mg, 2.27 mmol), triethylamine (0.63 mL, 4.54 mmol), acetic acid (0.01 mL, 0.23 mmol), acetaldehyde (500.1 mg, 11.35 mmol), and NaBH3CN (713.4 mg, 11.35 mmol) in methanol (5 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure. HCl (1 N, 10 mL) was added to the result, and the aqueous mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (300 mg, 53.2% yield), which was used directly in the next step without further purification. 12 H 17 N4O2[M+H] + The calculated LC-MS value is m / z = 249.3; the measured value is 249.0.

[0934] Step 3: 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridine-2-amine

[0935]

[0936] A mixture of 6-ethyl-2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (500.0 mg, 2.01 mmol) and Pd / C (60% H2O, 50 mg) in ethanol (10 mL) was stirred overnight under H2 atmosphere. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was analyzed by preparative HPLC on a C18 column (30 × 250 mm, 10 μm) using a mobile phase of 0 to 10% MeCN / H2O (t R Purification was performed over 15 minutes to obtain the title compound (240 mg, 54.6% yield). 12 H 19 N4[M+H] + The calculated LC-MS value is m / z = 219.2; the measured value is 218.9.

[0937] Step 4: 4-(7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[0938] The title compound was synthesized using a procedure similar to those outlined in steps 1-5 of Example 14. 1H NMR (300MHz, DMSO-d6) δ10.24(s,1H),8.78(d,J=3.0Hz,1H),8.71(d,J=4.8Hz,1H),8.30(s,1H),7.96(d,J=9.0Hz,1H),7.64(d,J=2.5Hz,1H),7.43( d,J=4.7Hz,1H),7.21(d,J=8.9Hz,1H),4.41–4.31(m,2H),4.27–4.19(m,2 H),4.13(s,2H),4.03(s,2H),2.20(m,3H),2.05–1.95(m,2H),1.84(m,6H). C 28 H 31 FN7S[M+H] + The calculated LC-MS values ​​are: m / z = 516.2 / 517.2; the measured values ​​are 516.2 / 517.2.

[0939] Example 16. 4-(3-chloro-7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[0940]

[0941] Step 1: 7-(cyclopenten-1-yl)thiopheno[3,2-b]pyridine

[0942]

[0943] A mixture of 7-chlorothieno[3,2-b]pyridine (1.02 g, 6.01 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (1.75 g, 9.02 mmol), K3PO4 (3.83 g, 18.04 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (439.98 mg, 0.60 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was bubbled with N2 for 5 min and stirred overnight at 100 °C. LC-MS showed that the starting material was consumed. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0-20%) to give the title compound (1.1 g, 91% yield) as a colorless oil. 12 H 12 NS[M+H] +The calculated LC-MS value is m / z = 202.0; the measured value is 201.9.

[0944] Step 2: 7-Cyclopentylthiopheno[3,2-b]pyridine

[0945]

[0946] A mixture of 7-(cyclopenten-1-yl)thieno[3,2-b]pyridine (1.1 g, 5.46 mmol) and Pd / C (10 wt% Pd, 200.0 mg, 0.19 mmol) in methanol (20 mL) was stirred overnight under H2 atmosphere. LCMS showed that the starting material was consumed. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0-20%) to give the title compound (1.0 g, 90.0% yield) as a colorless oil. 12 H 14 NS[M+H] + The calculated LC-MS value is m / z = 204.0; the measured value is 203.9.

[0947] Step 3: 3-Chloro-7-cyclopentylthiopheno[3,2-b]pyridine

[0948]

[0949] A mixture of 7-cyclopentylthiopheno[3,2-b]pyridine (300.0 mg, 1.48 mmol) and 1-chloropyrrolidine-2,5-dione (236.46 mg, 1.77 mmol) in trifluoromethanesulfonic acid (1.0 mL, 11.33 mmol) was stirred overnight at room temperature. LCMS showed that the starting material was consumed. The mixture was poured into a cold NaHCO3 solution (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0–20%) to give the title compound (276 mg, 78.7% yield, by HPLC ratio 3:1) as a mixture with dichloro compounds. 12 H 13 ClNS[M+H] + The calculated LCMS value is: m / z = 238.05 / 240.04; the measured value is: 238.3 / 240.0.

[0950] Step 4: 4-(3-chloro-7-cyclopentylthiopheno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[0951] The title compound was synthesized using a procedure similar to those outlined in steps 3-5 of Example 14. 1 H NMR (300MHz, CD3OD) δ8.93(d,J=2.2Hz,1H),8.78(d,J=4.9Hz,1H),8.32–8.22(m,1H),7.94(s,1H),7.64–7.54(m,2H),3.96(d ,J=9.4Hz,2H),3.75(s,2H),3.50–3.43(m,1H),3.32(m,6H),2.30(d,J=8.8Hz,2H),2.01–1.81(m,6H),1.44(t,J=7.2Hz,3H). C 27 H 30 ClFN7S[M+H] + The calculated LCMS value is: m / z = 538.2 / 540.2; the measured value is: 538.1 / 540.3.

[0952] Example 17.2-[2-[2-[[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]prop-2-ol

[0953]

[0954] Step 1: 1-Thiopheno[3,2-b]pyridin-7-yl ethyl ketone

[0955]

[0956] A mixture of 7-chlorothieno[3,2-b]pyridine (1.21 g, 7.13 mmol), tributyl(1-ethoxyvinyl)tin (3.61 mL, 10.7 mmol), and tetrakis(triphenylphosphine)palladium(0) (824 mg, 0.713 mmol) in 1,4-dioxane (25 mL) was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and 2N HCl (aqueous solution) (10 mL) was added. The mixture was stirred further overnight. The mixture was neutralized with saturated NaHCO3 (aqueous solution) (10 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–50% EtOAc / heptane) to give the title compound as a white solid (601 mg, 3.39 mmol, 47.5% yield).

[0957] C9H8NOS[M+H] +The calculated LCMS value is m / z = 178.0; the measured value is 178.1.

[0958] Step 2: 2-Thiopheno[3,2-b]pyridin-7-ylprop-2-ol

[0959]

[0960] A mixture of methyl magnesium chloride solution (0.86 mL, 2.59 mmol) and 1-thieno[3,2-b]pyridin-7-yl ethyl ketone (153.0 mg, 0.86 mmol) in THF (2 mL) was stirred at room temperature for 2 h. LCMS showed that the starting material was consumed. The reaction mixture was quenched with saturated NH4Cl solution (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (5%–50%) to give the title compound (112.0 mg, 67.1% yield). 10 H 12 NOS[M+H] + The calculated LCMS value is m / z = 194.0; the measured value is 193.9.

[0961] Step 3: 2-[2-[2-[[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thiopheno[3,2-b]pyridin-7-yl]prop-2-ol

[0962] The title compound was synthesized using a procedure similar to those outlined in steps 3-5 of Example 14. 25 H 29 FN7OS[M+H] + The calculated LCMS value is: m / z = 494.2 / 495.2; the measured value is: 494.0 / 495.4.

[0963] Example 18.2-[2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoroprop-2-ol

[0964]

[0965] Step 1: 1,1,1-trifluoro-2-thieno[3,2-b]pyridin-7-ylprop-2-ol

[0966]

[0967] A solution of tetrabutylammonium fluoride (0.1 mL, 0.10 mmol) was added to a solution of 1-thieno[3,2-b]pyridin-7-yl ethyl ketone (88.0 mg, 0.50 mmol) in THF (2 mL), followed by the dropwise addition of trimethyl(trifluoromethyl)silane (91.8 mg, 0.65 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 5 min and then at room temperature for 2 h. The mixture was cooled to 0 °C and a solution of tetrabutylammonium fluoride (0.1 mL, 0.10 mmol) and water (0.1 mL, 5.55 mmol) were added. The resulting mixture was stirred at room temperature for 30 min. LCMS showed that the starting material was consumed. The reactants were quenched with brine (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (5%–50%) to give the title compound (80.0 mg, 65.2% yield). 10 H9F3NOS[M+H] + The calculated LCMS value is: m / z = 248.04 / 249.04; the measured value is: 248.1 / 249.3.

[0968] Step 2: 2-[2-[2-[[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoroprop-2-ol

[0969] The title compound was synthesized using a procedure similar to those outlined in steps 3-5 of Example 14. 1 H NMR (300MHz, CD3OD) δ8.75(t,J=4.2Hz,2H),8.41(d,J=1.8Hz,1H),7.64(dd,J=9.4,2.8Hz,1H),7.58–7.51(m,2H),7.47(d,J=2. 7Hz, 1H), 4.51 (d, J = 11.2Hz, 2H), 4.30 (d, J = 14.6Hz, 4H), 4.18 (s, 2H), 3.25 (d, J = 7.1Hz, 2H), 1.94 (s, 3H), 1.23 (t, J = 7.2Hz, 3H). C 26 H 26 F4N7OS[M+H] + The calculated LCMS value is: m / z = 560.2 / 561.2; the measured value is: 560.0 / 561.3.

[0970] The embodiments listed in Tables 2-1 and 2-2 are synthesized according to procedures similar to those of Embodiment 14 (Method 1), Embodiment 15 (Method 2), Embodiment 16 (Method 3), Embodiment 17 (Method 4), or Embodiment 18 (Method 5).

[0971]

[0972] Table 2-1: Examples 19-41

[0973]

[0974]

[0975]

[0976] Table 2-2: Examples 19-41

[0977]

[0978]

[0979]

[0980]

[0981]

[0982] Example 42.4-(4-cyclopentylthiopheno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-) 2-yl)pyrimidin-2-amine

[0983]

[0984] Step 1: 4-(cyclopenten-1-yl)thiopheno[2,3-b]pyridine

[0985]

[0986] A mixture of 4-chlorothieno[2,3-b]pyridine (696.0 mg, 4.10 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (1194.5 mg, 6.15 mmol), K3PO4 (2612.8 mg, 12.31 mmol), and 1,1'-[bis(diphenylphosphine)ferrocene]dichloropalladium(II) (300.2 mg, 0.41 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was bubbled with N2 for 5 min and stirred at 100 °C for 6 h. LCMS showed that the starting material was consumed. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0-20%) to give the title compound (775.0 mg, 93.8% yield). 12 H 12 NS[M+H] + The calculated LCMS value is m / z = 202.1; the measured value is 201.9.

[0987] Step 2: 4-Cyclopentylthiopheno[2,3-b]pyridine

[0988]

[0989] A mixture of 4-(cyclopenten-1-yl)thieno[2,3-b]pyridine (930.0 mg, 4.62 mmol) and Pd / C (10 wt% Pd, 180.0 mg, 0.17 mmol) in methanol (30 mL) and acetic acid (3 mL) was stirred for 24 h under H2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0–15%) to give the title compound (565.0 mg, 60.2% yield). 12 H 14 NS[M+H] + The calculated LCMS value is m / z = 204.1; the measured value is 203.9.

[0990] Step 3: 4-(4-cyclopentylthiopheno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2-amine

[0991] The title compound was synthesized using a procedure similar to those outlined in steps 3-5 of Example 14. 1 H NMR (300MHz, CD3OD) δ8.77(d,J=3.3Hz,1H),8.57(d,J=5.0Hz,1H),8.45(s,1H),8.18(dd,J=9.7,2.9Hz,1H),7.79(d,J=2.7Hz,1H),7.54 (d,J=9.6Hz,1H),7.44(d,J=5.0Hz,1H),3.94–3.84(m,4H),3.73–3.63(m,1H),3.27–3.22(m,4H),2.33–2.18(m,2H),1.98–1.78(m,6H). C 25 H 26 FN6OS[M+H] + The calculated LCMS value is: m / z = 477.2 / 478.2; the measured value is: 477.0 / 478.3.

[0992] The embodiments listed in Tables 3-1 and 3-2 are synthesized according to a procedure similar to that of Embodiment 42.

[0993]

[0994] Table 3-1: Examples 43-47

[0995]

[0996] Table 3-2: Examples 43-47

[0997]

[0998]

[0999] Example 48.4-(7-cyclopentyl-3-methylthiopheno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methyl) Piperazine-1-yl)pyridin-2-yl)pyrimidin-2-amine

[1000]

[1001] Step 1.4-Methylthiophene-2-carbonyl chloride

[1002]

[1003] Oxaloyl chloride (2.631 g, 1.778 mL, 20.7 mmol, 1.25 equivalents) was added dropwise to a solution of 4-methylthiophene-2-carboxylic acid (2.358 g, 16.6 mmol, 1.00 equivalents) in DMF (61 mg, 64 μL, 0.83 mmol, 0.05 equivalents) at 0 °C. The resulting pale green solution was heated to ambient temperature and stirred for 4 h, at which point LC-MS analysis (quenched with morpholine) indicated complete consumption of formic acid. The reaction mixture was concentrated under reduced pressure and dried under high vacuum. The crude acyl chloride was used directly without further purification.

[1004] Step 2. N-hydroxy-4-methylthiophene-2-carboxamide

[1005]

[1006] A solution of crude 4-methylthiophene-2-carbonyl chloride from step 1 in THF (10 mL) was added dropwise at 0 °C to a suspension of NH₂OH·HCl (4.615 g, 66.4 mmol, 4.00 equivalents) and NaOH (3.320 g, 83.0 mmol, 5.00 equivalents) in THF (10 mL) and H₂O (20 mL). The resulting mixture was slowly heated to ambient temperature and stirred for 2 h. The reaction mixture was acidified with 2N HCl (pH 3) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated NaHCO₃ solution (30 mL), H₂O (30 mL), and brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The crude product obtained as a yellow solid was used in the next step without further purification. C₆H₈NO₂S[M+H] + The calculated LCMS value is m / z = 158.0; the measured value is 158.1.

[1007] Step 3.4-Methyl-N-(neovaleroxy)thiophene-2-carboxamide

[1008]

[1009] Trimethylacetyl chloride (1.951 g, 16.6 mmol, 1.00 equivalent) was added dropwise to a solution of crude N-hydroxy-4-methylthiophene-2-carboxamide (from step 2) and Et3N (2.016 g, 2.777 mL, 19.9 mmol, 1.20 equivalent) in THF (25 mL) at 0 °C. The resulting orange suspension was warmed to ambient temperature and stirred for 18 h. The pale yellow emulsion reaction mixture was concentrated to 1 / 3 of its original volume and partitioned between H2O (30 mL) and EtOAc (30 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (5%–20% EtOAc, 10% DCM / heptane) to give the title compound as a white solid (3.732 g, 15.5 mmol, three-step yield 93.2%). f =0.4 (30% EtOAc / heptane). C 11 H 16 NO3S[M+H] + The calculated LCMS value is m / z = 242.1; the measured value is 242.0.

[1010] Step 4.3-Methylthiopheno[2,3-c]pyridin-7(6H)-one

[1011]

[1012] A suspension of [(4-methylthiophene-2-carbonyl)amino]2,2-dimethylpropionate (1.316 g, 5.45 mmol, 1.00 equivalent), CsOAc (1.050 g, 5.45 mmol, 1.00 equivalent), [Cp*RhCl2]2 (101 mg, 0.16 mmol, 0.03 equivalent), and vinyl acetate (704 mg, 8.18 mmol, 1.50 equivalent) in anhydrous MeOH (15 mL) was stirred at 45 °C under a nitrogen atmosphere for 18 h. The reactants were diluted with H2O (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-50% EtOAc / heptane, containing 0.1% Et3N) to give the title compound as an orange-red solid (527 mg, 3.19 mmol, 58.5% yield). f = 0.25 (50% EtOAc / heptane). C8H8NOS[M+H] +The calculated LCMS value is m / z = 166.0; the measured value is 166.1.

[1013] Step 5.7 Chloro-3-methylthiopheno[2,3-c]pyridine

[1014]

[1015] A mixture of 3-methyl-6H-thieno[2,3-c]pyridin-7-one (527 mg, 3.19 mmol, 1.00 equivalent) and POCl3 (2.935 mg, 19.1 mmol, 6.00 equivalent) was heated at 100 °C for 3 h, at which point LCMS indicated complete consumption of the starting material. Excess POCl3 was evaporated under reduced pressure, and the residue was partitioned between 10% Na2CO3 solution (20 mL) and EtOAc (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic phases were washed with 10% Na2CO3 solution (10 mL), H2O (10 mL), and brine (10 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The oily residue was purified by rapid silica gel column chromatography (0-50% EtOAc / heptane) to give the title compound as a yellow solid (332 mg, 1.81 mmol, 56.7% yield). f = 0.3 (50% EtOAc / heptane). C8H7ClNS[M+H] + The calculated LCMS value is m / z = 184.0; the measured value is 184.1.

[1016] Step 6.7-(cyclopent-1-en-1-yl)-3-methylthiopheno[2,3-c]pyridine

[1017]

[1018] A suspension of 7-chloro-3-methylthieno[2,3-c]pyridine (332 mg, 1.81 mmol, 1.00 equivalent), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronacyclopentane (526 mg, 2.71 mmol, 1.50 equivalent), Pd(dppf)Cl2 (66 mg, 0.09 mmol, 0.05 equivalent), and K3PO4 (1.535 g, 7.23 mmol, 4.00 equivalent) in 1,4-dioxane (8 mL) and H2O (2 mL) was stirred at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was cooled to ambient temperature and then partitioned between H2O (30 mL) and EtOAc (15 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (15 mL × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by rapid silica gel column chromatography (0-25% MTBE / heptane) to give the title compound as a colorless oil (308 mg, 1.43 mmol, 79.0% yield). f =0.4 (30% MTBE / heptane). C 13 H 14 NS[M+H] + The calculated LCMS value is m / z = 216.1; the measured value is 216.0.

[1019] Step 7.7 - Cyclopentyl-3-methylthiopheno[2,3-c]pyridine

[1020]

[1021] A solution of 7-(cyclopenten-1-yl)-3-methylthiopheno[2,3-c]pyridine (308 mg, 1.43 mmol) in MeOH (5 mL) was cooled at 0 °C. Pd / C (10 wt% Pd, 31 mg, 0.29 mmol) was added, and the reaction flask was evacuated and purged with hydrogen. The reaction mixture was warmed to room temperature and stirred for 4 h. The solid was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (5 mL × 2). The combined filtrates were concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (0–25% MTBE / heptane) to give the title compound (305 mg, 1.40 mmol, 98.1% yield) as a pale yellow solid. f =0.3 (25% MTBE / heptane). C 13 H 16 NS[M+H] + The calculated LCMS value is m / z = 218.1; the measured value is 218.0.

[1022] Step 8.4-(7-cyclopentyl-3-methylthiopheno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine

[1023] The title compound was synthesized using a procedure similar to those outlined in steps 3-5 of Example 14. 27 H 31 FN7S[M+H] + The calculated LCMS value is m / z = 504.2; the measured value is 504.0.

[1024] Example 49. 4-(4-cyclopentyl-7-methylthiopheno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methyl) Piperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

[1025]

[1026] Step 1: 4-(cyclopent-1-en-1-yl)-7-methylthiopheno[3,2-d]pyrimidine

[1027]

[1028] 4-Chloro-7-methylthieno[3,2-d]pyrimidine (800 mg, 4.33 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (1.37 mL, 6.5 mmol), Pd(dppf)Cl2 (169 mg, 0.26 mmol), and K3PO4 (3679 mg, 17.33 mmol) were weighed into a 40-mL vial. Then 1,4-dioxane (8 mL) and water (2 mL) were added. The mixture was purged with N2 for 2 minutes. It was then heated overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4. The solution was concentrated to dryness, and the residue was purified by automated rapid column chromatography on a pre-packed silica column (40 g) using EtOAc / heptane (5%–70%) to give the title compound as a white solid (840 mg, 3.88 mmol, 89.6% yield). 12 H 13 N2S[M+H] + The calculated LC-MS value is m / z = 217.08; the measured value is 217.04.

[1029] Step 2: 4-Cyclopentyl-7-methylthiopheno[3,2-d]pyrimidine

[1030]

[1031] Three drops of AcOH were added to a suspension of 4-(cyclopenten-1-yl)-7-methylthieno[3,2-d]pyrimidine (800.0 mg, 3.7 mmol) and Pd / C (5 wt% Pd, 100.0 mg, 0.94 mmol) in methanol (20 mL). The mixture was stirred overnight under a H2 atmosphere. The solvent was removed under vacuum. The residue was purified by rapid silica gel column chromatography (0-30% EtOAc / heptane, containing 0.1% Et3N) to give the title compound as a white solid (720 mg, 3.30 mmol, 89.2% yield). 12 H 15 N2S[M+H] + The calculated LC-MS value is m / z = 219.10; the measured value is 219.08.

[1032] Step 3: 4-(4-cyclopentyl-7-methylthiopheno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

[1033] The title compound was synthesized using a procedure similar to those outlined in steps 3-5 of Example 14. 1 ¹H NMR (300MHz, methanol-d⁴) δ 9.50–9.05 (m, 1H), 9.04–8.91 (m, 1H), 8.46–8.30 (m, 2H), 7.68–7.55 (m, 1H), 3.67 (d, J = 12.1 Hz, 2H), 3.35 (s, 3H), 3.22 (d, J = 12.9 Hz, 2H), 2.94 (s, 3H), 2.75 (dd, J = 14.4, 3.1 Hz, 2H), 2.44–1.78 (m, 12H). C 27 H 30 FN7S[M+H] + The calculated LC-MS value is m / z = 504.23; the measured value is 504.03.

[1034] Example 50. N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxo-7-prop-2-ylthiazolyl) Fern[3,2-b]pyridin-4-onthiol-2-yl)pyrimidin-2-amine

[1035]

[1036] Step 1: 2-(2-chloro-5-fluoropyrimidin-4-yl)-4-oxo-7-prop-2-ylthieno[3,2-b]pyridine-4-onium

[1037]

[1038] A mixture of 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-propyl-2-ylthieno[3,2-b]pyridine (20.0 mg, 0.06 mmol) and mCPBA (16.82 mg, 0.10 mmol) in DCM (3 mL) was stirred at room temperature for 1 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (2 mL × 3). The combined organic layers were concentrated and analyzed by preparative HPLC on a C18 column using a mobile phase of 20% to 100% MeCN / H2O (t). R Purification was performed for 15 minutes to obtain the title compound (9.1 mg, 43%) as a bright yellow solid. 1 H NMR (300MHz, CDCl3) δ8.72(d,J=1.7Hz,1H),8.63(d,J=2.4Hz,1H),8.32(d,J =6.5Hz,1H),7.20(d,J=6.5Hz,1H),3.33–3.17(m,1H),1.45(d,J=6.9Hz,6H).

[1039] Step 2: N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxo-7-prop-2-ylthieno[3,2-b]pyridin-4-onthiol-2-yl)pyrimidin-2-amine

[1040] The title compound was synthesized using a procedure similar to those outlined in step 5 of Example 14. 1 H NMR (300MHz, CD3OD) δ8.85(d,J=3.0Hz,1H),8.61(d,J=0.9Hz,1H),8.48(d,J=6.5Hz,1H),8.24(dd,J=9.6,2.9Hz,1H),7.94(d,J=2.7Hz,1H),7.5 9(d,J=9.6Hz,1H),7.53(d,J=6.5Hz,1H),4.05–3.86(m,2H),3.85–3.64 (m,2H),3.40–3.24(m,7H),1.49(d,J=6.9Hz,6H),1.43(t,J=7.3Hz,3H). C 25 H 29 FN7OS[M+H] + The calculated LC-MS values ​​are: m / z = 494.2 / 495.2; the measured values ​​are 494.1 / 495.3.

[1041] Example 51.2-[5-fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3, 5-Dimethyl-7-propyl-2-ylthieno[3,2-c]pyridin-4-one

[1042]

[1043] Step 1: 1-(5-bromo-4-methylthiophen-2-yl)-2-methylprop-1-one

[1044]

[1045] Isobutyryl chloride (1.32 g, 12.43 mmol) was added dropwise to a suspension of aluminum chloride (1.66 g, 12.43 mmol) in DCM (20 mL) at 0 °C, followed by the slow addition of 2-bromo-3-methylthiophene (2.0 g, 11.3 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (0–10%) to give the title compound (2.11 g, 75.2%). 1 H NMR (300MHz, CDCl3) δ7.39 (s, 1H), 3.35–3.19 (m, 1H), 2.22 (s, 3H), 1.21 (d, J = 6.9Hz, 6H).

[1046] Step 2: Ethyl (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoate

[1047]

[1048] At 0 °C, triethyl phosphonoacetate (2.11 g, 9.4 mmol) was added dropwise to a suspension of sodium hydride (407.8 mg, 10.2 mmol) in THF (20 mL). The reaction mixture was stirred at 0 °C for 30 min, and then at room temperature for 30 min. A solution of 1-(5-bromo-4-methylthiophene-2-yl)-2-methylprop-1-one (2.1 g, 8.5 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (2.01 g), which was used in the next reaction without further purification.

[1049] Step 3: (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoic acid

[1050]

[1051] A solution of sodium hydroxide (1.26 g, 31.52 mmol) in water (10 mL) was added dropwise to a solution of ethyl (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoate (2.01 g, 6.3 mmol) in methanol (10 mL). The reaction mixture was stirred at 65 °C for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (20 mL) and acidified with 2N HCl solution (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.30 g), which was used in the next reaction without further purification.

[1052] Step 4: 2-Bromo-3-methyl-7-propyl-2-yl-5H-thienro[3,2-c]pyridin-4-one

[1053]

[1054] Diphenylphosphoazide (1.86 g, 6.74 mmol) was added dropwise to a solution of (E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoic acid (1.30 g, 4.50 mmol) and triethylamine (1.93 g, 13.49 mmol) in diphenyl ether (10 mL). The reaction mixture was stirred at room temperature for 30 min and heated at 180 °C for 30 min. The reaction mixture was quenched with 1 N NaOH solution (10 mL) and stirred at room temperature for 30 min. The reaction mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (5-90%) to give the title compound (0.45 g, 35.0%). 1 H NMR (300MHz, CDCl3) δ10.75 (s, 1H), 6.95 (s, 1H), 3.00–2.76 (m, 1H), 2.64 (s, 3H), 1.31 (d, J = 6.9Hz, 6H).

[1055] Step 5: 2-Bromo-3,5-dimethyl-7-prop-2-ylthieno[3,2-c]pyridin-4-one

[1056]

[1057] Cesium carbonate (239.1 mg, 0.73 mmol) was added to a solution of 2-bromo-3-methyl-7-prop-2-yl-5H-thieno[3,2-c]pyridin-4-one (105.0 mg, 0.37 mmol) in DMF (1 mL), followed by iodomethane (104.2 mg, 0.73 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (2 mL) and extracted with EtOAc (2 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography using EtOAc / heptane (5–70%) to give the title compound (75.0 mg, 68.1% yield). 1 H NMR (300MHz, CDCl3) δ7.03 (s, 1H), 3.71 (s, 3H), 3.00–2.78 (m, 1H), 2.60 (s, 3H), 1.34 (d, J = 6.9Hz, 6H).

[1058]

[1059] Step 6: 2-(2-chloro-5-fluoropyrimidin-4-yl)-3,5-dimethyl-7-prop-2-ylthieno[3,2-c]pyridin-4-one

[1060] To a solution of 2-bromo-3,5-dimethyl-7-prop-2-ylthieno[3,2-c]pyridin-4-one (130.0 mg, 0.43 mmol) and pinacol diboronate (164.9 mg, 0.65 mmol) in 1,4-dioxane (3 mL), KOAc (127.5 mg, 1.3 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichlorochloride (1:1) (31.7 mg, 0.04 mmol) were added. The reaction mixture was purged with N2 for 5 min and stirred at 100 °C for 1 h. LCMS showed that the starting material was consumed. The reaction mixture was cooled to room temperature and a solution of K3PO4 (275.8 mg, 1.3 mmol) in water (1 mL) was added. The resulting mixture was stirred at room temperature for 30 min. Next, 2,6-dichloro-5-fluorouracil (108.4 mg, 0.65 mmol) and 1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.7 mg, 0.04 mmol) were added. The reaction mixture was purged with N2 for 5 min and stirred overnight at 100 °C. LC-MS showed that the starting material was consumed. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a C18 column by elution with MeCN / H2O (20%–100%) to give the title compound (14.1 mg, 9.2% yield). 16 H 16 ClFN3OS[M+H]+ The calculated LCMS value is: m / z = 352.07 / 354.07; the measured value is: 352.0 / 353.9.

[1061] Step 7: 2-[5-fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-propyl-2-ylthieno[3,2-c]pyridin-4-one

[1062] The title compound was synthesized using a procedure similar to those outlined in step 5 of Example 14. 1 H NMR (300MHz, CD3OD) δ8.77(d,J=2.7Hz,1H),8.23(dd,J=9.6,3.0Hz,1H),7.91(d,J=2.9Hz,1H),7.59(d,J=9. 6Hz,1H),7.46(s,1H),3.63(s,3H),4.00–3.10(m,8H),3.05–2.93(m,4H),2.85(s,3H),1.40(d,J=7.0Hz,6H). C 26 H 31 FN7OS[M+H] + The calculated LCMS value is: m / z = 508.2 / 509.2; the measured value is: 508.2 / 509.4.

[1063] Example 52: 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[1064]

[1065] Step 1. Methyl 2-(isopropylamino)-4-methylthiophene-3-carboxylate

[1066]

[1067] Sodium triacetoxyborohydride (13.5 g, 63.7 mmol) was added in portions to a mixture of methyl 2-amino-4-methylthiophene-3-carboxylate (7.27 g, 42.5 mmol), 2-methoxyprop-1-ene (4.6 g, 63.7 mmol), and acetic acid (3.64 mL, 63.7 mmol) in DCE (140 mL). The resulting mixture was stirred for 4 h. The reaction mixture was slowly poured into 10% Na₂CO₃ (aqueous solution) and stirred until gas escape stopped (30 min). The organic layer was separated, and the aqueous layer was extracted with DCM (60 mL × 3). The combined organic layers were washed with 10% Na₂CO₃ (aqueous solution) (60 mL), water (60 mL), and brine (60 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-10% MTBE / heptane) to give the title compound as a colorless oil (7.81 g, 36.6 mmol, 86.1% yield). 10 H 16 NO2S[M+H] + The calculated LCMS value is m / z = 214.1; the measured value is 214.2.

[1068] Step 2.2-(isopropylamino)-4-methylthiophene-3-carboxylic acid

[1069]

[1070] A solution of NaOH (8.78 g, 220 mmol) in water (70 mL) was added to a solution of methyl 2-(isopropylamino)-4-methylthiophene-3-carboxylate (7.81 g, 36.6 mmol) in methanol (70 mL). The reaction mixture was heated at 70 °C for 18 h. The organic solvent was removed under reduced pressure. The remaining aqueous mixture was diluted with water (20 mL), acidified to pH 3 with 2N HCl, and extracted with MTBE (30 mL × 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (6.26 g, 31.4 mmol, 85.8% yield) as an amber solid, which was used in the next step without further purification. C9H 14 NO2S[M+H] + The calculated LCMS value is m / z = 200.1; the measured value is 200.1.

[1071] Step 3.2-(N-isopropylacetamido)-4-methylthiophene-3-carboxylic acid

[1072]

[1073] Acetic anhydride (7.43 mL, 78.6 mmol) was added dropwise to a mixture of 2-(isopropylamino)-4-methylthiophene-3-carboxylic acid (6.26 g, 31.4 mmol), triethylamine (13.1 mL, 94.3 mmol), and 4-(dimethylamino)pyridine (0.38 g, 3.14 mmol) in DCM (60 mL). The resulting light amber solution was stirred for 18 h. The reaction mixture was poured into water (80 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed successively with water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0–50% EtOAc / heptane) to give the title compound (4.71 g, 19.5 mmol, 62.1% yield) as a yellow, viscous oil. 11 H 16 NO3S[M+H] + The calculated LCMS value is m / z = 242.1; the measured value is 242.1.

[1074] Step 4. N-(3-amino-4-methylthiophen-2-yl)-N-isopropylacetamide

[1075]

[1076] Diphenylphosphoazide (8.05 g, 29.2 mmol) was added dropwise to a mixture of 2-(N-isopropylacetamido)-4-methylthiophene-3-carboxylic acid (4.71 g, 19.5 mmol) and triethylamine (8.15 mL, 58.5 mmol) in 1,4-dioxane (25 mL) over 30 min. The resulting mixture was stirred for 1 h. Water (25 mL) was added, and the reaction mixture was heated at 100 °C for 18 h. After cooling to room temperature, 2N NaOH (aqueous solution) (10 mL) was added. The resulting mixture was stirred for 15 min and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated to give the title compound, which was used in the next step without further purification. 10 H 17 N2OS[M+H] + The calculated LCMS value is m / z = 213.1; the measured value is 213.1.

[1077] Step 5.3 - Isopropyl-2,6-dimethyl-3H-thiopheno[2,3-d]imidazole

[1078]

[1079] POCl3 (3.29 mg, 21.5 mmol) was slowly added to a solution of crude N-(3-amino-4-methylthiophene-2-yl)-N-isopropylacetamide (from step 4) in toluene (40 mL) at room temperature, and the mixture was then heated at 100 °C for 18 h. The reaction mixture was poured into ice-cold 10% Na2CO3 (aqueous solution) with vigorous stirring. The organic layer was separated, and the aqueous layer was extracted with EtOAc (40 mL × 3). The combined organic layers were washed with 10% Na2CO3 (aqueous solution) (40 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–75% EtOAc / heptane, containing 0.1% NEt3) to give the title compound (2.88 g, 14.8 mmol, two-step yield 75.9%) as a red oil. 10 H 15 N2S[M+H] + The calculated LCMS value is m / z = 195.1; the measured value is 195.1.

[1080] Step 6.3 - Isopropyl-2,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-3H-thiopheno[2,3-d]imidazolium

[1081]

[1082] At -78 °C, a solution of lithium diisopropylamino (5.43 mL, 41.0 mmol) (2.0 M in THF / ethylbenzene / hexane) was added dropwise to a mixture of 3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole (1.60 g, 8.21 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoborane (4.19 mL, 20.5 mmol) in THF (50 mL). The mixture was stirred at -78 °C. After 4 h, the reactants were quenched by dropwise addition of saturated NH4Cl (aqueous solution) (75 mL) at 0 °C. The mixture was extracted with EtOAc (75 mL × 3) and 1:1 CHCl3 / iPrOH (75 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used in the next step without further purification. 16 H 26 BN2O2S[M+H] + The calculated LCMS value is m / z = 321.2; the measured value is 321.1.

[1083] Step 7.5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2,6-dimethyl-3H-thiopheno[2,3-d]imidazole

[1084]

[1085] A suspension of 2,6-dichloro-5-fluorouracil (1.77 g, 10.6 mmol), 3-isopropyl-2,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3H-thieno[2,3-d]imidazole (from step 6), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (323 mg, 0.44 mmol), and K3PO4 (7.50 g, 35.4 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was heated at 100 °C under a nitrogen atmosphere for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0-75% EtOAc / heptane, containing 0.1% NEt₃) and then by preparative HPLC at C₂O₃. 18 Further purification on a column (15%–60% MeCN / H₂O, containing 0.1% TFA) yielded the title compound as a yellow solid in its TFA salt form (1.57 g, 3.58 mmol, two-step yield 43.7%). 14 H 15 ClFN4S[M+H] + The calculated LCMS value is m / z = 325.1; the measured value is 325.0.

[1086] Step 8.4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[1087] A suspension of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazolium TFA salt (500 mg, 1.14 mmol), XPhos Pd G2 (121 mg, 0.15 mmol), K3PO4 (980 mg, 4.62 mmol), and 5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridine-2-amine (437 mg, 2.0 mmol) in 1,4-dioxane (10 mL) and DMSO (1 mL) was heated at 100 °C under a nitrogen atmosphere for 5 h. The reaction mixture was cooled to room temperature, diluted with MeOH (5 mL), filtered, and purified by preparative HPLC on a C18 column (5%–40% MeCN / H2O, containing 0.1% TFA) to give the title compound in its TFA salt form (701 mg, 0.955 mmol, 62.0% yield). 1 H NMR (300MHz, methanol-d4) δ8.47(d,J=3.5Hz,1H),7.95(d,J=9.0Hz,1H),7.58(d,J=2.8Hz,1H),7.22(dd,J=9.1,2.9Hz,1H),4.81–4.76 (m,1H),4.41(s,4H),4.16(s,4H),3.30(q,J=7.3Hz,2H),2.65(s,3H),2.64(s,3H),1.62(d,J=6.7Hz,6H),1.26(t,J=7.2Hz,3H). C 26 H 32 FN8S[M+H] + The calculated LC-MS value is m / z = 507.2; the measured value is 506.9.

[1088] Example 53: 6-(6-ethyl-2-) , 6-Diazaspiro[3.3]hept-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-) Dimethyl-3H-thieneno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazine-3-amine

[1089]

[1090] Step 1. 5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

[1091]

[1092] To a suspension of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole (138 mg, 0.426 mmol) in 2-propanol (2 mL), an aqueous solution of NH4OH (2.0 mL, 0.42 mmol, 33%) was added. The resulting mixture was stirred in a sealed tube at 100 °C for 2 days. After cooling to room temperature, volatiles were removed under vacuum. The residue was purified by preparative HPLC on a C18 column (15%–60% MeCN / H2O, containing 0.1% TFA) to give the title compound as a yellow solid in the form of its TFA salt (122 mg, 0.291 mmol, 68.4% yield). 14 H 17 FN5S[M+H] + The calculated LCMS value is m / z = 306.1; the measured value is 305.9.

[1093] Step 2. 6-(6-chloropyridazine-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[1094]

[1095] To a solution of 3,6-dichloropyridazine (500 mg, 3.36 mmol) in 1,4-dioxane (10 mL), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (665 mg, 3.36 mmol), K3PO4 (2.14 g, 10.1 mmol), and XPhos Pd G2 (264 mg, 0.34 mmol) were added. The mixture was stirred at 100 °C under a N2 atmosphere for 24 h. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10%–90% EtOAc / heptane) to give the title compound (545 mg, 1.75 mmol, 52.1% yield). 14 H 20 ClN4O2[M+H] + The calculated LCMS values ​​are: m / z = 311.1, 313.1; the measured values ​​are 311.1, 313.0.

[1096] Step 3.2-(6-chloropyridazine-3-yl)-2,6-diazaspiro[3.3]heptane

[1097]

[1098] TFA (5.0 mL, 65 mmol) was added to a solution of 6-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (545 mg, 1.75 mmol) in DCM (5 mL). The mixture was stirred for 3 h and then concentrated under reduced pressure to give the title compound (350 mg, 1.66 mmol, 94.9% yield). C9H 12 ClN4[M+H] + The calculated LCMS value is m / z = 211.0; the measured value is 211.1.

[1099] Step 4.2-(6-chloropyridazin-3-yl)-6-ethyl-2,6-diazaspiro[3.3]heptane

[1100]

[1101] Triethylamine (0.46 mL, 3.32 mmol), acetaldehyde (365 mg, 8.31 mmol), acetic acid (100 mg, 1.66 mmol), and sodium cyanoborohydride (1.04 g, 16.6 mmol) were added to a solution of 2-(6-chloropyridazine-3-yl)-2,6-diazaspiro[3.3]heptane (350 mg, 1.66 mmol) in MeOH (4 mL). The mixture was stirred overnight at room temperature. Water (10 mL) was added, and the resulting 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, 75.9% yield). C 11 H 16 ClN4[M+H] + The calculated LCMS value is m / z = 239.1; the measured value is 239.2.

[1102] Step 5.6-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine

[1103] A suspension of 5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine (53 mg, 0.17 mmol), 2-(6-chloropyridazin-3-yl)-6-ethyl-2,6-diazaspiro[3.3]heptane (38 mg, 0.16 mmol), sodium tert-butoxide (61 mg, 0.63 mmol), and BrettPhos Pd G3 (7.2 mg, 0.010 mmol, CAS: 1470372-59-8) in 1,4-dioxane (1 mL) was heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature and diluted with MeOH (2 mL). The solid salt was removed by filtration, and the filtrate was purified by preparative HPLC on a C-18 column (6%-80% MeCN / H2O, containing 0.1% TFA) to give the title compound as a yellow solid in the form of TFA salt (25 mg, 0.034 mmol, 21% yield). 1 H NMR (300MHz, CD3OD) δ8.71(d,J=3.0Hz,1H),8.13(d,J=9.8Hz,1H),7.53(d,J=9.9Hz,1H),5.03–4.97(m,1H),4.55 –4.29(m,8H),3.28–3.23(m,2H),2.83(s,3H),2.69(d,J=3.1Hz,3H),1.66(d,J=6.6Hz,6H),1.22(t,J=7.2Hz,3H). C 25 H 31 FN9S[M+H] + The calculated LCMS value is m / z = 508.2; the measured value is 508.0.

[1104] Example 54: ( 4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-propyl-2-ylthieno[2,3-d]) [imidazol-5-yl]pyrimidin-2-yl]amino]pyridin-3-yl]methyl ketone

[1105]

[1106] Step 1. (6-Aminopyridin-3-yl)(4-ethylpiperazin-1-yl)methyl ketone

[1107]

[1108] A solution of 6-aminonicotinic acid (200 mg, 1.45 mmol) in 1,4-dioxane (10 mL) was added with thionyl chloride (0.1 mL, 1 mmol). While stirring at room temperature for 3 h, 1-ethylpiperazine (0.19 mL, 1.5 mmol) was added. The mixture was stirred for another 24 h. Water (10 mL) and solid NaHCO3 were added to adjust the pH to >8. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a C18 column (10%–100% MeCN / H2O) to give the title compound (149 mg, 0.637 mmol, 43.9% yield). 12 H 19 N4O[M+H] + The calculated LCMS value is m / z = 235.3; the measured value is 235.2.

[1109] Step 2. (4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl] methyl ketone

[1110] The TFA salt of the title compound was synthesized using a procedure similar to those outlined in step 8 of Example 1. 1 HNMR (300MHz, methanol-d4) δ8.69(d,J=3.1Hz,1H),8.53–8.49(m,1H),8.19(d,J=8.9Hz,1H),8.12(dd,J=8.9,2.2Hz,1H),8.09(d,J= 0.9Hz,1H),5.10–4.91(m,1H),3.88–3.34(m,6H),3.30–3.15(m,4H),2.87(s,3H),1.71(d,J=6.7Hz,6H),1.40(t,J=7.3Hz,3H). C 25 H 30 FN8OS[M+H] + The calculated LCMS value is m / z = 509.2; the measured value is 509.0.

[1111] Example 55: 4-(2,6-dimethyl-3-prop-2-ylthiopheno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl- 2,6-Diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[1112]

[1113] Step 1: 2,4-Dimethylthiophene-3-amine

[1114]

[1115] A solution of methyl 3-amino-4-methylthiophene-2-carboxylate (30.0 g, 175 mmol) in dioxane (20 mL) was added over 10 min to a stirred solution of lithium aluminum hydride (13.3 g, 350 mmol) in 1,4-dioxane (250 mL). The resulting mixture was stirred at 100 °C for 30 min. The reaction mixture was cooled to room temperature and diluted with MTBE (300 mL). The reaction mixture was quenched by sequentially adding water (60 mL), 15% NaOH (aqueous solution) (60 mL), and water (180 mL). After stirring for 30 min, the reaction mixture was extracted with EtOAc (200 mL × 2), and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (23.0 g, 181 mmol) as an orange oil. This substance was used in the next step without further purification. LC-MS: C6H 10 NS's [M+H] + Calculated value: 128.1; Measured value: 128.0.

[1116] Step 2.1-(6-methylthiopheno[3,2-c]pyrazol-1-yl)acetone

[1117]

[1118] KOAc (17.74 g, 180.8 mmol) was added to a solution of 2,4-dimethylthiophene-3-amine (23.0 g, 181 mmol) in toluene (250 mL), followed by dropwise addition of acetic anhydride (34.18 mL, 361.6 mmol). Isoamyl nitrite (36.15 mL, 271.2 mmol) was added dropwise over 10 min while heating to 80 °C. The mixture was then heated at 95 °C for 1 h. The reaction mixture was quenched by adding saturated NaHCO3 (aqueous solution) (50 mL). The reaction mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (5%–30% EtOAc / heptane) to give the title compound (31.9 g, 177 mmol, 97.8% yield) as an orange solid. LCMS (C18 column; 0.8 mL / min; MeCN / H2O, containing 0.1% formic acid; 5% for 1 min, 5%-95% for 4 min, 95% for 2 min) R =3.57 min. LCMS calculated value of C6H7N2S[M+H-COCH3]+: m / z = 139.0; measured value: 138.9.

[1119] Step 3. 6-Methyl-1H-thieno[3,2-c]pyrazole

[1120]

[1121] Concentrated HCl (143 mL, 1.72 mol) was added to a solution of 1-(6-methylthiopheno[3,2-c]pyrazol-1-yl)ethyl ketone (31 g, 0.17 mol) in ethanol (120 mL) and water (120 mL). The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with water (50 mL) and quenched with NaHCO3 to pH 8-9. The reaction mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (3%-30% EtOAc / heptane) to give the title compound (23 g, 0.16 mol, 95% yield) as a viscous brown solid. LCMS (C18 column; 0.8 mL / min; MeCN / H2O, containing 0.1% formic acid; 5% 1 min, 5%-95% 4 min, 95% 2 min) R = 3.32 min. C6H7N2S[M+H] + The calculated LCMS value is m / z = 139.0; the measured value is 138.9.

[1122] Step 4.3 - Iodo-6-methyl-1H-thieno[3,2-c]pyrazole

[1123]

[1124] K₂CO₃ (48.4 g, 350 mmol) and iodine (44.5 g, 175 mmol) were added to a solution of 6-methyl-1H-thieno[3,2-c]pyrazole (22 g, 160 mmol) in methanol (200 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched by adding 10% Na₂S₂O₃ (aqueous solution) (50 mL), and the reaction mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0–30% EtOAc / heptane) to give the title compound (37 g, 140 mmol, 88% yield) as a red solid. C₆H₆IN₂S[M+H] + The calculated LCMS value is m / z = 264.9; the measured value is 264.8.

[1125] Step 5.3 - Iodo-2,6-dimethylthiopheno[3,2-c]pyrazole

[1126]

[1127] A suspension of 3-iodo-6-methyl-1H-thieno[3,2-c]pyrazole (30 g, 114 mmol) and NaHCO3 (19.1 g, 227 mmol) in DCM (400 mL) was added to a vial containing trimethyloxonium tetrafluoroborate (17.6 g, 119 mmol). After stirring at room temperature for 1 h, the reaction mixture was quenched with water (200 mL). The reaction mixture was extracted with EtOAc (200 mL × 3), and the combined organic phases were dried over Na2SO4, filtered, and the residue was purified by silica gel chromatography (5%–50% EtOAc / heptane) to give the title compound (29 g, 100 mmol, 92% yield). C7H8IN2S[M+H] + The calculated LCMS value is m / z = 278.9; the measured value is 278.8.

[1128] Step 6: 2,6-Dimethyl-3-prop-1-en-2-ylthiopheno[3,2-c]pyrazole

[1129]

[1130] The title compound was synthesized using a procedure similar to those outlined in step 1 of Example 14. 10 H 13 N2S[M+H] + The calculated LCMS value is m / z = 193.1; the measured value is 193.0.

[1131] Step 7.2,6-Dimethyl-3-propyl-2-ylthiopheno[3,2-c]pyrazole

[1132]

[1133] 5% Pd / C (0.77 g, 7.3 mmol) was added to a stirred solution of 2,6-dimethyl-3-prop-1-en-2-ylthieno[3,2-c]pyrazole (14 g, 73 mmol) in acetic acid (100 mL). H2 was introduced into the reaction vessel, and the reaction mixture was stirred in a Parr shaker for 3 days. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated. The residue was purified by silica gel chromatography (5%–30% EtOAc / heptane) to give the title compound (11.8 g, 60.7 mmol, 83.1% yield). 10 H 15 N2S[M+H] + The calculated LCMS value is m / z = 195.1; the measured value is 195.0.

[1134] Step 8.2,6-Dimethyl-3-propyl-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)thiopheno[3,2-c]pyrazole

[1135]

[1136] The title compound was synthesized using a procedure similar to those outlined in step 6 of Example 52. 16 H 26 BN2O2S[M+H] + The calculated LCMS value is m / z = 321.2; the observed value is 321.0.

[1137] Step 9.5-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-dimethyl-3-propyl-2-ylthieno[3,2-c]pyrazole

[1138]

[1139] The title compound was synthesized using a procedure similar to those outlined in step 7 of Example 52. 14 H 15 ClFN4S[M+H] + The calculated LCMS values ​​are: m / z = 325.1, 327.1; the measured values ​​are: 324.8, 326.8.

[1140] Step 10.4-(2,6-dimethyl-3-prop-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]hept-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

[1141] The title compound was synthesized using a procedure similar to those outlined in step 8 of Example 1. Purification by silica gel chromatography (1%–10% MeOH / DCM) and recrystallization in EtOAc yielded the title compound as a pale yellow solid. 1 HNMR(300MHz,DMSO-d6)δ9.70(s,1H),8.62(d,J=2.8Hz,1H),7.94(d,J=8.9Hz,1H),7.59(d,J=2.9Hz,1H),6.95(dd,J=8.9,3.0Hz,1H),4.00(s ,3H),3.95(s,4H),3.91(s,4H),3.40–3.25(m,1H),2.87(q,J=7.2Hz,2H),2.40(d,J=3.4Hz,3H),1.32(d,J=6.8Hz,6H),0.99(t,J=7.1Hz,3H). C 26 H32 FN8S[M+H] + The calculated LCMS value is m / z = 507.2; the measured value is 507.0.

[1142] Example 56: 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- Isopropyl-3,5-dimethylthiopheno[3,2-c]pyridine-4(5H)-one

[1143]

[1144] Step 1. 6-Nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-tert-butyl formate

[1145]

[1146] N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (12.0 g, 38.8 mmol), 5-bromo-2-nitropyridine (7.80 g, 38.4 mmol), sodium carbonate (15.9 g, 115 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloro(II) (2.51 g, 3.84 mmol) were suspended in 1,4-dioxane (120 mL) and water (40.0 mL) under an inert atmosphere. The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography using EtOAc / heptane (10%–60%, containing 0.1% Et3N) to give the title compound as a brown solid (9.20 g, 30.1 mmol, 78.4% yield). 15 H 20 N3O4[M+H] + The calculated LCMS value is m / z = 306.1; the measured value is 306.1.

[1147] Step 2.6-Nitro-1',2',3',6'-Tetrahydro-3,4'-Bipyridine

[1148]

[1149] 11.0 g (36.0 mmol) of tert-butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate was dissolved in DCM (30.0 mL) and cooled to 0 °C. Trifluoroacetic acid (10.0 mL, 131 mmol) was slowly added at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and then diluted with water (10.0 mL). The solution was lyophilized and used directly without further purification to give crude TFA salt of the title compound (18.6 g) as a yellow solid. 10 H 12 N3O2[M+H] + The calculated LCMS value is m / z = 206.1; the measured value is 206.0.

[1150] Step 3.1'-Methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine

[1151]

[1152] Formaldehyde (24.9 mL, 335 mmol, 37 wt% in H₂O) and crude TFA salt of 6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine (18.6 g) were dissolved in DCM (60 mL) at room temperature. The mixture was stirred for 30 min and the reaction mixture was cooled to 0 °C. Sodium triacetoxyborohydride (14.2 g, 66.9 mmol) was added in portions at 0 °C. The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated sodium bicarbonate (aqueous solution) (60.0 mL) and sodium carbonate was added until no more gas was observed to escape. The organic phase was separated and the aqueous layer was extracted with DCM (30.0 mL × 2). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction sequence in steps 2-3 was repeated with an additional portion of tert-butyl 6-nitro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (2.5 mmol in step 2), and the crude products from both sequences were combined for purification. Purification by silica gel chromatography using MeOH / DCM (0-50%) yielded the free base of the title compound as a yellow solid (8.10 g, 36.9 mmol, quantitative yield in two steps). 1 H NMR (300MHz, DMSO-d6) δ8.74(d,J=2.1Hz,1H),8.29–8.16(m,2H),6.57(t,J=3.6Hz,1H),3.09–3.03(m,2H),2.60–2.52(m,4H),2.27(s,3H). C 11 H 14 N3O2[M+H]+ The calculated LCMS value is: m / z = 220.1; the measured value is: 220.0.

[1153] The free base was dissolved in EtOAc (50.0 mL), DCM (5.00 mL), and MeOH (5.00 mL). Then, HCl solution (37.0 mL, 74.0 mmol, 2N in iPrOAc) was added. The reaction mixture was stirred at room temperature for 2 h. The precipitate was collected by filtration and dried under reduced pressure to give the hydrochloride salt of the title compound as a white solid (9.46 g, 32.4 mmol, yield 90.1%).

[1154] Step 4.5-(1-Methylpiperidin-4-yl)pyridin-2-amine

[1155]

[1156] In a 500 mL reaction vessel, 1'-methyl-6-nitro-1',2',3',6'-tetrahydro-3,4'-bipyridine hydrochloride (9.46 g, 32.4 mmol) was dissolved in MeOH (150 mL). Palladium / carbon (0.875 g, 0.822 mmol, 10 wt%) and glacial acetic acid (1.00 mL, 17.5 mmol) were added sequentially at room temperature. The reaction vessel was sealed in a Parr shaker and hydrogen gas (60 psi) was introduced into the vessel. The reaction mixture was mixed overnight. The hydrogen atmosphere was removed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The dark residue was dissolved in DCM (30.0 mL) and neutralized with sodium hydroxide (3.39 g, 84.8 mmol). The organic layer was washed with water (30.0 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using MeOH / DCM (0-50%, containing 0.1% Et3N) to give the title compound as a grayish-white solid (6.10 g, 31.9 mmol, 98.5% yield). 1 H NMR (300MHz, DMSO-d6) δ7.74(d,J=2.2Hz,1H),7.23(dd,J=8.5,2.4Hz,1H),6.36(d,J=8.5Hz,1H),5.62 (s,2H),2.81(d,J=11.4Hz,2H),2.40–2.16(m,1H),2.15(s,3H),2.00–1.75(m,2H),1.64–1.47(m,4H). C 11 H 18 N3[M+H] + The calculated LCMS value is m / z = 192.1; the measured value is 192.1.

[1157] Step 5.2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one

[1158]

[1159] Butyllithium (5.20 mL, 13.0 mmol, 2.5 M in hexane) was added dropwise to a solution of 2-bromo-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one (2.60 g, 8.66 mmol, Example 51, step 5) at -78 °C. The reaction mixture was stirred at -78 °C for 20 min. Then, 2-chloro-5-fluoropyrimidine (1.38 g, 10.4 mmol) was added in a single batch. The reaction mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with saturated NH4Cl (aqueous solution) and diluted with DCM (30.0 mL). The mixture was warmed to room temperature and the two phases were separated. The organic layer was removed, and the aqueous layer was extracted with DCM (30.0 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated.

[1160] 2,3-Dichloro-5,6-dicyano-p-benzoquinone (1.86 g, 8.20 mmol) was added to THF (30.0 mL) containing the crude residue. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM (30.0 mL), washed with hot potassium carbonate (10 wt% aqueous solution) (30.0 mL × 2), dried over sodium sulfate, and concentrated. The crude residue was purified by preparative HPLC using a C18 column (20%–100% MeCN / 0.1% TFA (aqueous solution)) to give the title compound as a grayish-white solid in the form of a TFA salt (1.35 g, 2.90 mmol, 35.3% yield). 16 H 16 ClFN3OS[M+H] + The calculated LCMS values ​​are: m / z = 352.1, 354.1; the measured values ​​are: 352.0, 353.9.

[1161] Step 6.2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthiopheno[3,2-c]pyridin-4(5H)-one

[1162] To a solution of 2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one TFA salt (1.20 g, 2.58 mmol) and 5-(1-methylpiperidin-4-yl)pyridin-2-amine (0.783 g, 4.09 mmol) in 1,4-dioxane (24.0 mL), K3PO4 (2.17 g, 10.2 mmol) and XPhos Pd G2 (268 mg, 0.341 mmol, CAS 1310584-14-5) were added. The reaction vessel was sealed, and the mixture was degassed with N2 (3×). The reaction mixture was heated at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The dark residue was purified by preparative HPLC on a C18 column (10%–50% MeCN / 0.1% TFA (aqueous solution)) to give the title compound in the form of a TFA salt. The TFA salt was neutralized with saturated NaHCO3 (aqueous solution) (20.0 mL), and the aqueous layer was extracted with DCM (20.0 mL × 3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1N HCl (2.20 mL, 2.20 mmol, 1.05 equivalents), and the solvent was removed by lyophilization to give the title compound hydrochloride as a yellow solid (1.21 g, 2.23 mmol, 86.5% yield). 1 H NMR(300MHz,DMSO-d6)δ10.46(br s,1H),10.31(br s,1H),8.75(d,J=2.5Hz,1H),8.21(d,J=2.4Hz,1H),8.12(d,J=8.7Hz,1H),7.71(dd,J=8.8,2.4Hz,1H),7.55(s,1H),3...

Claims

1. A compound of Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, or Formula XXVII: Formula XXVII or a pharmaceutically acceptable salt thereof, wherein V = CL1R1or N, each L1is independently a bond, O, NR, or C1-C6alkylene, wherein R is H or C1-C6alkyl; each R4is independently H, D, halogen, C1-C8alkoxy, or C1-C8alkyl, haloalkyl, or CN. each R1is independently H, D, halogen, -OH, -CN, -NO2, -Ci-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, 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)2NR 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)2R b ; Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ; Each R a Independently H, D, -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)R c R b -P(O)OR c OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiR b 3. -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R c Or R d Independently H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 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; 2. A compound of Formula XXIX, Formula XXX, Formula XXXI, or Formula XXXII: Formula XXXI Formula XXXII or a pharmaceutically acceptable salt thereof; wherein V = CL1R1or N, each L1is independently a bond, O, NR, or C1-C6alkylene, wherein R is H or C1-C6alkyl; each R4is independently H, D, halogen, C1-C8alkoxy, or C1-C8alkyl, haloalkyl, or CN; W is CH or N; each R1is independently H, D, halogen, -OH, -CN, -NO2, -Ci-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, 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)2NR 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)2R b ; Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ; Each R a Independently H, D, -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)R c R b -P(O)OR c OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiR b 3. -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R c Or R d Independently H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 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; each g, h, j, and k is independently 0, 1, 2, or 3.

3. A compound of Formula XXXV, Formula XXXVI, Formula XXXVII, Formula XXXVIII, Formula XXXIX, Formula XL, Formula XLI, Formula XLII, Formula XLIII, or Formula XLIV: Formula XXXV Formula XXXVI Formula XXXVII Formula XXXVIII Formula XXXIX Formula XL Formula XLI Formula XLII Formula XLIII Formula XLIV or a pharmaceutically acceptable salt thereof; wherein U is C(R 10 )2, NR 10 or O; R 10 is H, fluoro, C 1-6 alkyl or C 1-6 alkoxy; and V = CL1R1or N, each L1is independently a bond, O, NR, or C1-C6alkylene, wherein R is H or C1-C6alkyl; each R4is independently H, D, halogen, C1-C8alkoxy, or C1-C8alkyl, haloalkyl, or CN; W is CH or N; each g, h, j, and k is independently 0, 1, 2, or 3. each R1is independently H, D, halogen, -OH, -CN, -NO2, -Ci-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, 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)2NR 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)2R b ; Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ; each R is independently H, D, -C(O)R a , -C(O)OR b , -C(O)NR c R c , -C(=NR d )NR b R b , -C(=NOR c )NR b R b , -C(=NCN)NR c R b , -P(OR c )2, -P(O)R c R c , -P(O)OR b , -P(O)(NR c R b )2, -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)2NR c R d , SiR b 3, -Ci-C 10 alkyl, -C2-C 10 alkenyl, -C2-C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; each R c or R d independently H, D, -Ci-C 10 alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -OCi-C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 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; 4. A compound of Formula XLV, Formula XLVI, Formula XLVII, Formula XLVIII, Formula XLIX, or Formula L: Formula XLV Formula XLVI Formula XLVII Formula XLVIII Formula XLIX Formula L or a pharmaceutically acceptable salt thereof; wherein V = CL1R1or N, U is C(R 10 )2, NR 10 or O; R 10 H, fluoro, C 1-4 alkyl or C 1-4 alkoxy; and each L1is independently a bond, O, NR, or C1-C6alkylene, wherein R is H or C1-C6alkyl; each R4is independently H, D, halogen, C1-C8alkoxy, or C1-C8alkyl, haloalkyl, or CN; W is CH or N; 5. A compound of Formula LI, Formula LII, Formula LIII, or Formula LIV: Formula LI Formula LII Formula LIII Formula LIV or a pharmaceutically acceptable salt thereof; wherein V = CL1R1or N, each R1is independently H, D, halogen, -OH, -CN, -NO2, -Ci-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, 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)2NR 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)2R b ; Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ; each R is independently H, D, -C(O)R a , -C(O)OR b , -C(O)NR c R c , -C(=NR d )NR b R b , -C(=NOR c )NR b R b , -C(=NCN)NR c R b , -P(OR c )2, -P(O)R c R c , -P(O)OR b , -P(O)(NR c R b )2, -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)2NR c R d , -SiR b 3, -Ci-C 10 alkyl, -C2-C 10 alkenyl, -C2-C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; each R c or R d independently H, D, -Ci-C 10 alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -OCi-C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 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; each L1is independently a bond, O, NR, or C1-C6alkylene, wherein R is H or C1-C6alkyl; each R4is independently H, D, halogen, C1-C8alkoxy, or C1-C8alkyl, haloalkyl, or CN; U is C(R 10 )2, NR 10 or O; R 10 is H, fluoro, C 1-4 alkyl or C 1-4 alkoxy. W is CH or N; 6. A compound, which is a compound of Formula LVII, Formula LVIII, Formula LIX, or Formula LX: Formula LVII Formula LVIII Formula LIX Formula LX or a pharmaceutically acceptable salt thereof; wherein V = CL1R1or N, each L1is independently a bond, O, NR, or C1-C6alkylene, wherein R is H or C1-C6alkyl; each R1is independently H, D, halogen, -OH, -CN, -NO2, -Ci-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, 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)2NR 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)2R b ; Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ; Each R a Independently H, D, -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)R c R b -P(O)OR c OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiR b 3. -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R c Or R d Independently H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 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; each R4is independently H, D, halogen, C1-C8alkoxy, or C1-C8alkyl, haloalkyl, or CN; ​ U is C(R 10 )2, NR 10 or O; R 10 H, fluoro, C 1-4 alkyl or C 1-4 alkoxy. ​ ​ ​ ​ each R1is independently H, D, halogen, -OH, -CN, -NO2, -Ci-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, 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)2NR 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)2R b ; Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ; each R is independently H, D, -C(O)R a , -C(O)OR b , -C(O)NR c R c , -C(=NR d )NR b R b , -C(=NOR c )NR b R b , -C(=NCN)NR c R b , -P(OR c )2, -P(O)R c R c , -P(O)OR b , -P(O)(NRR c ))2, -OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)2NR c R d , SiR b 3, -Ci-C 10 alkyl, -C2-C 10 alkenyl, -C2-C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R c Or R d Independently H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 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 10 is H, C 1-6 alkyl or C 1-6 alkoxy.

7. A compound of Formula LXIII, Formula LXIV, Formula LXV, Formula LXVI, Formula LXVII, or Formula LXVIII: or a pharmaceutically acceptable salt thereof; wherein V = CL1R1or N, each L1is independently a bond, O, NR, or C1-C6alkylene, wherein R is H or C1-C6alkyl; each R1is independently H, D, halogen, -OH, -CN, -NO2, -Ci-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, 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)2NR 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)2R b ; Each R3 is independently H, D, halogen, oxo group, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, C0-C1 alkyl-aryl, C0-C1 alkyl-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -OR a -OR b -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 -S(O)R b -S(O)2NR c R d -S(O)(=NR) b )R b -SF5, -P(O)R b R b -P(O)(OR) b (OR) b -B(OR) d (OR) c ) or -S(O)2R b ; Each R a Independently H, D, -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)R c R b -P(O)OR c OR b -S(O)R b -S(O)NR c R d -S(O)2R b -S(O)2NR c R d SiR b 3. -C1-C 10 Alkyl, -C2-C 10 alkenyl, -C2-C 10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R b Independently, it is H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl; Each R c Or R d Independently H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 ynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, 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; each R4is independently H, D, halogen, C1-C8alkoxy, or C1-C8alkyl, haloalkyl, or CN; R 10 is H, C 1-4 alkyl or C 1-4 alkoxy.

8. A compound which is: 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4- ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl- 3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl- 3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-[5-(4- ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(3-cyclopentyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(3-cyclopentyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4- methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-prop-2-ylthieno[3,2- b]pyridin-2-yl)pyrimidin-2-amine; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoro-4-(7-prop-2- ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoro-4-(7-prop-2- ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; ​ ​ ​ ​ ​ 2-[2-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 2-[2-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 2-[2-[2-[[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol; 4-(3-chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine; 4-(7-cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(7-cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine; 4-(7-cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine; 4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine; 4-(7-cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methoxypiperidin-1-yl)pyridin-2-yl]pyrimidin-2-amine; 4-(7-cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2- amine; 4-(7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-5- fluoropyrimidin-2-amine; 4-(4-cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2- amine; 4-(4-cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin- 2-amine; 4-(4-cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin- 2-amine; 4-(4-cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin- 2-amine; 4-(4-cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine; 4-(4-cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]- 5-fluoropyrimidin-2-amine; 4-(7-cyclopentyl-3-methylthieno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2- yl)pyrimidin-2-amine; 4-(4-cyclopentyl-7-methylthieno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2- yl)pyrimidin-2-amine; N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxo-7-prop-2-ylthieno[3,2-b]pyridinium-4- yl)pyrimidin-2-amine; 2-[5-fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-prop-2- ylthieno[3,2-c]pyridin-4-one; 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2- yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine; 6-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3- d]imidazol-5-yl)pyrimidin-2-yl)pyridazine-3-amine; (4-ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5- yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone; 4-(2,6-dimethyl-3-prop-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan- 2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine; 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5- dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one; 2-(2-((5-(6-ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4- yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one; 2-(2-((5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl- 5-methylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3- methylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)- 7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 6-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-1- isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one; 2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one; or a pharmaceutically acceptable salt thereof.

9. A compound, which is: N-[5-[[4-(2,2-difluoroethyl)piperazin-1-yl]methyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-prop-2- ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; 1-[[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl]-N,N-dimethylpyrrolidine-3-carboxamide; 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-pyridin-2-ylpyrimidin-2-amine; 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridin-2-yl]pyrimidin-2-amine; 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethyl-6,6-difluoro-1,4-diazepan-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine; 4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteromethyl)piperazin-1-yl]pyridin-2-yl]pyrimidin-2-amine; N-[5-(5,5-difluoro-7-methyl-2,7-diazaspiro[3.4]octan-2-yl)pyridin-2-yl]-4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-amine; (6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-[6-[[5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone; N-[5-[3-(dimethylamino)azetidin-1-yl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; N-[5-[3-(dimethylamino)pyrrolidin-1-yl]pyridin-2-yl]-4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-amine; N-[5-(6-ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl]-5-fluoro-4-(2-methyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; 1-[6-[[4-(2,6-dimethyl-3-prop-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino]pyridin-3-yl]-4-methylpiperazin-2-one; 2-(5-fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-((3aS,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(2-((5-(5-ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(l-(methyl-d3)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(2-((5-(l,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(l-(tetrahydrofuran-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methyl-5-(methyl-d3)thieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one; 2-(2-((5-(l-ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 2-(5-fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one; 7-isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)thieno[3,2-c]pyridin-4(5H)-one; 7-isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)thieno[3,2-c]pyridin-4(5H)-one; 4-(6-((5-fluoro-4-(7-isopropyl-3,5-dimethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-2- yl)pyrimidin-2-yl)amino)pyridin-3-yl)-1-methylpiperidine 1-oxide; 5-fluoro-4-(3-isopropyl-2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(1- methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine; N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-2H- thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine; 4-(3-cyclopropyl-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(6-ethyl-2,6- diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 2-(5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6- dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)-1,1,1-trifluoropropan-2-ol; 1-(5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6- dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-one; 1-(5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6- dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-ol; N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-(2- methoxypropan-2-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine; 4-(1,6-dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin- 2-yl]-5-fluoropyrimidin-2-amine; N-(5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin- 3-amine; 5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-amine; 3-(2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin- 4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazin-7-yl)azetidine-1-carboxylic acid tert- butyl ester; 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-(3- fluorobicyclo[1.1.1]pentan-1-yl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one; 5-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4- yl)-3-isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine; N-(5-(2-ethyl-2-azaspiro[3.3]oct-6-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl- 3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; 4-(2,6-Dimethyl-3-propyl-2H-thieno[2,3-d]imidazol-5-yl)-N-[6-(4-ethylpiperazin-1- yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine; 5-Fluoro-4-(2-methyl-3-propyl-2H-thieno[2,3-d]imidazol-5-yl)-N-[5-(1- methylpyrrolidin-3-yl)oxypyridin-2-yl]pyrimidin-2-amine; 5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4- methylmorpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine; N-[5-[1-(4-ethylpiperazin-1-yl)ethyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propyl- 2H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; 3-[6-[[5-Fluoro-4-(2-methyl-3-propyl-2H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2- yl]amino]pyridin-3-yl]-1,4-dimethylpiperazin-2-one; ((8aS)-6-(6-((5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5- yl)pyrimidin-2-yl)amino)pyridin-3-yl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-3(4H)- one; 4-(2,6-Dimethyl-3-propyl-2H-thieno[2,3-d]imidazol-5-yl)-N-[4-(4-ethylpiperazin-1- yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine; 4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-4- yl)pyridin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine; N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-[7-propyl-3- (trifluoromethyl)thieno[3,2-b]pyridin-2-yl]pyrimidin-2-amine; 2-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7- isopropylthieno[3,2-b]pyridine-3-carbonitrile; 5-Fluoro-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-4-(3-methyl-7-propyl- thieno[3,2-c]pyridin-2-yl)pyrimidin-2-amine; N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-methyl-3-propyl- 2H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; 5-fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-prop-2-ylthieno[2,3- d]imidazol-5-yl)pyrimidin-2-amine (Isomer 1); 5-fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-prop-2-ylthieno[2,3- d]imidazol-5-yl)pyrimidin-2-amine (Isomer 2); 4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-methoxy-N-(5-(1- methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine; N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-3H- thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-3H- thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; 5-chloro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1- methylpiperidin-3-yl)pyridin-2-yl)pyrimidin-2-amine; 2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7- isopropyl-3-methylthieno[3,2-c]pyridine 5-oxide; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. Use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for inhibiting CDK4 and CDK6.

12. Use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for treating a CDK4-mediated and CDK6-mediated disorder in a patient in need thereof.

13. The use according to claim 12, wherein the CDK4-mediated and CDK6-mediated disorder is cancer.

14. The use according to claim 13, wherein 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 lymphatic leukemia, lymphoma, myeloma, acute myeloid leukemia, secondary pancreatic cancer, or secondary brain metastasis.

15. The use according to claim 14, wherein 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.

16. The use of claim 12, wherein the medicament is an orally administered medicament.

17. A compound which is: or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 which is:

19. A pharmaceutical composition comprising a compound of claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. Use of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19, in the manufacture of a medicament for inhibiting CDK4 and CDK6.

21. Use of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19, in the manufacture of a medicament for treating a CDK4-mediated and CDK6-mediated disorder in a patient in need thereof.

22. The use of claim 21, wherein the CDK4-mediated and CDK6-mediated disorder is cancer.

23. The use of claim 22, wherein 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 lymphatic leukemia, lymphoma, myeloma, acute myelogenous leukemia, secondary pancreatic cancer, or secondary brain metastasis.

24. The use of claim 23, wherein 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.

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