Heterocyclic compounds, compositions thereof, and methods of treatment thereof

Abstract

Provided herein are compounds having the following structure: # imgabs0 # or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof, wherein the substituents are as defined herein; compositions comprising an effective amount of a compound; and methods of inhibiting the activity of cyclin-dependent kinases.

Description

Technical Field

[0001] Provided herein are compounds useful for inhibiting cyclin-dependent kinases, methods of treating cancer using the compounds disclosed herein, and pharmaceutical compositions comprising the compounds. Background Art

[0002] Human kinases are a large class of enzymes that add phosphate groups (PO43-) to other molecules in the human body [1. FASEB J. 1995 May; 9 (8): 576-96. 2. Enzyme Res. 2011; 2011: 794089.]. There are more than 500 kinase encoding genes in the human genome, as well as their substrates, including proteins, lipids and nucleic acids [3. Cell Signal. 2004 September; 16 (9): 983-9. 4. Cell. 2017 August 10; 170 (4): 605-635.]. Kinase dysregulation is found in many diseases, including cancer, autoimmune diseases, neurological disorders, diabetes and cardiovascular diseases. For example, mutated kinases can become constitutively active, causing various cellular abnormalities, leading to the occurrence or growth of cancer. The use of small molecule inhibitors to inhibit kinase activity has been shown to be a successful approach for treating cancer and other diseases [5. Expert Rev Anticancer Ther. 2018 Dec; 18(12): 1249-1270.]. To date, more than 70 kinase inhibitors have been approved as drugs by the FDA, EMA or CDE [6. Nat Rev Drug Discov. 2018 May; 17(5): 353-377.].

[0003] The protein kinase family accounts for most of the kinase superfamily. For protein targets, protein kinases can phosphorylate amino acids including serine, threonine, tyrosine and histidine. [7. Science. December 6, 2002; 298 (5600): 1912-34.] Protein kinases play a major role in cell activation through the reversible phosphorylation and dephosphorylation of proteins, through the antagonism of kinases and phosphatases, and are an important component of cell signal transduction because the phosphorylated and non-phosphorylated states of target proteins can have different activity levels. [8. Biochimie. December 2014; 107 Pt B: 167-87. 9. Clin Transl Oncol. March 2006; 8 (3): 153-60.]. Different protein kinases, including EGFR, BTK, ALK, JAK, PI3K and CDK, have been shown to be good targets for cancer drug development.

[0004] Overactivated cell cycle is a common feature of human cancer [10. Nat Rev Cancer. 2009 March; 9(3): 153-66.]. Cyclin is one of the most important core cell cycle regulators. Four basic types of cyclins are found in humans, including G1 cyclins, G1 / S cyclins, S cyclins, and M cyclins. In order to drive the cell cycle forward, cyclins must activate or inactivate many target proteins in the cell. These cyclins mainly drive cell cycle events by cooperating with a family of enzymes called cyclin-dependent kinases (Cdk). Cdk kinases are inactive by themselves, but binding to cyclins can activate them, making the CDK / cyclin complex a functional full enzyme and allowing it to modify target proteins [11. Orphanet J Rare Dis. 2020 August 6; 15(1): 203. 12. J Mol Biol. 1999 April 16; 287(5): 821-8.]. There are 26 serine / threonine protein kinases that form the CDK and CDK-like branches of the CMGC subfamily of the human kinase group; 21 of these are classified as CDKs. Of the CDKs identified so far, CDK1, CDK2, CDK4, and CDK6 are thought to directly regulate the cell cycle primarily by phosphorylating and inactivating the RB protein and releasing the E2F transcription factor, while the E2F downstream pathway is critical in regulating the initiation of DNA replication. CDK4 / 6 is critical for early G1 initiation and G1 / S transition. [13. Cell Death Differ. 1998 Feb; 5(2): 132-40. 14. Oncogene. 2016 Sep 15; 35(37): 4829-35.] CDK4 / 6-related pathways are often dysregulated in a variety of different cancer types, such as breast cancer, lung cancer, and pancreatic cancer. There are 4 approved CDK4 / 6 inhibitors, including palbociclib, ribociclib, abemaciclib and trilaciclib, all of which have been approved by the FDA or CDE and can be used alone or in combination with endocrine therapy to treat HR+, Her2- breast cancer. This approach has shown good efficacy in clinical practice, but CDK4 / 6 inhibitors can more or less cause hematopoietic toxicity such as neutropenia and leukopenia, which greatly limits the clinical application of CDK4 / 6 inhibitors.Emerging data suggest that inhibition of CDK6 / cyclin D3 may cause the hematologic toxicity observed in the clinic [15. Cell. 2004 Aug 20;118(4):493-504. 16. Haematologica. 2021 Oct 1;106(10):2624-2632.], whereas CDK4 / cyclin D1 is an oncogenic driver in different cancers [17. Nat Commun. 2019 Dec 20;10(1):5817. 18. 18. Cancer Cell. 2006 Jan;9(1):23-32.]. The development of CDK4-selective inhibitors may offer several advantages, including improved efficacy, reduced hematologic toxicity, and expanded clinical applications in many cancers, including but not limited to breast, lung, pancreatic, prostate, bone, liver, and endometrial cancers.

[0005] Since the protein structures of CDK4 and CDK6 are highly homologous, there is still a great need to develop CDK4-selective inhibitors. Most of the previously reported compounds are CDK4 / 6 dual inhibitors. Here, we report compounds with high CDK4 selectivity over all other kinases including CDK6, which may lead to better efficacy, improved toxicity profiles and the potential to overcome resistance mechanisms, etc.

[0006] Citation or identification of any reference in this section shall not be construed as an admission that such reference is prior art to the present application. Summary of the invention

[0007] Provided herein are compounds having the following formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof,

[0010] in:

[0011] R a and R b are each independently hydrogen or substituted or unsubstituted C 1-8 alkyl;

[0012] or R a and R b With R a and R b The nitrogen atoms to which they are attached together form a substituted or unsubstituted non-aromatic heterocyclic group;

[0013] R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted saturated cycloalkylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl; or

[0014] R 1 and R 2 With R 1 and R 2 The atoms to which they are attached together form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted non-aromatic heterocyclic group.

[0015] Provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof and a pharmaceutically acceptable carrier, excipient or vehicle.

[0016] Provided herein is a method for inhibiting the activity of a CDK kinase in a cell, the method comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof. In one embodiment, the CDK kinase is CDK4 kinase.

[0017] Provided herein is a method of treating or preventing a cancer responsive to CDK activity, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein. In one embodiment, the CDK is CDK4 kinase. DETAILED DESCRIPTION

[0018] definition

[0019] The term "CDK" as used herein refers to a cell cycle-dependent protein kinase protein, which is a member of the protein kinase family that regulates the cell cycle. Known CDKs include CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, and CDK11. A "CDK inhibitor" is a substance that (i) directly interacts with CDK, such as by binding to CDK, and (ii) reduces the expression or activity of CDK. The term also includes variants of naturally occurring CDKs (including CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, and CDK11).

[0020] As used herein and in the specification and appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents unless the context clearly dictates otherwise.

[0021] As used herein, and unless otherwise indicated, the terms "about" and "approximately" when used in conjunction with the dose, amount, or weight percentage of an ingredient of a composition or dosage form, mean a dose, amount, or weight percentage that one of ordinary skill in the art considers to provide a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage. In certain embodiments, the terms "about" and "approximately" when used herein encompass doses, amounts, or weight percentages within 30%, 20%, 15%, 10%, or 5% of a specified dose, amount, or weight percentage.

[0022] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in connection with a value or range of values ​​provided to characterize a particular solid form, e.g., a particular temperature or temperature range, such as describing melting, dehydration, desolvation, or glass transition temperature; a change in mass, such as a change in mass as a function of temperature or humidity; solvent or water content, e.g., in mass or percentage; or peak position, such as in analysis by, e.g., IR or Raman spectroscopy or XRPD; indicate that the value or range of values ​​may deviate to an extent that is considered reasonable by one of ordinary skill in the art while still describing the solid form. Techniques used to characterize crystalline forms and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR) and Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms "about" and "approximately" when used in this context indicate that a value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position may vary by as much as ±0.2° 2Θ (or ±0.2 degrees 2Θ) while still describing a specific XRPD peak.

[0023] An "alkyl" group is a saturated, partially saturated or unsaturated straight or branched acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbons, or in some embodiments 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH7CH3), etc. The alkyl group may be substituted or unsubstituted. When alkyl groups described herein are referred to as "substituted," they may be substituted with any one or more substituents, such as those present in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; dialkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amido; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; arylalkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0024] "Cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group with 3 to 10 carbon atoms of a monocyclic or multiple condensed or bridged rings, which can be optionally substituted by 1 to 3 alkyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, and in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6 or 3 to 7. The cycloalkyl group comprising more than one ring can be fused, spirocyclic or bridged, or a combination thereof. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or polycyclic or bridged ring structures such as 1-bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, adamantyl, etc. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. The cycloalkyl group may be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol, etc.

[0025] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a monocyclic ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl). In some embodiments, the aryl group contains 6-14 carbons, and in other embodiments, the ring portion of the aryl group contains 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. The aryl group may be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0026] "Heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl group in which one to four ring carbon atoms are independently substituted by heteroatoms from the group consisting of O, S and N. In some embodiments, the heterocyclyl group includes 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6 or 3 to 8 ring members. The heterocyclyl group may also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocyclyl group may be substituted or unsubstituted. The heterocyclyl group may include multiple fused rings, including but not limited to bicyclic, tricyclic and tetracyclic rings, and bridged or spirocyclic ring systems. The heterocyclyl group includes unsaturated, partially saturated and saturated ring systems, such as imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-diketo). The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as 1-aminotetralin and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidine.Representative examples of heterocyclyl include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithianyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, indolyl (e.g., indol-2-one or isoindol-1-one), indolinyl, isoindolyl, isoindolyl, azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d ][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzooxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[ Representative non-aromatic heterocyclic groups include, for example, 3,4-dihydroisoquinolin-1(2H)-one, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thionaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridinyl, tetrahydroimidazopyridinyl, tetrahydrotriazolopyridinyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl. Representative non-aromatic heterocyclic groups do not include fused ring species containing fused aromatic groups.Examples of non-aromatic heterocyclic groups include aziridine, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl, 2-substituted, 3-substituted, 4-substituted, 5-substituted, or 6-substituted, or disubstituted with various substituents, such as those listed below.

[0027] A "heteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, the ring portion of the group contains 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl) ), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thionaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), tetrahydroquinolyl, quinoxalinyl, and quinazolinyl.

[0028] As used herein, "spirocycle" refers to two or more rings in which adjacent rings are connected by a single atom. Each ring in a spirocycle may be the same or different. Each ring in a spirocycle may be substituted or unsubstituted and may have a substituent that is different from each other ring in a group of spirocycles.

[0029] A "cycloalkylalkyl" group is a group of the formula: -alkyl-cycloalkyl, wherein the alkyl and cycloalkyl groups are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl, and the like.

[0030] An "aralkyl" group is a group of the formula: -alkyl-aryl, wherein the alkyl and aryl groups are as defined above. Substituted aralkyl groups may be substituted at the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and fused (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl.

[0031] A "heterocyclylalkyl" group is a group of the formula: -alkyl-heterocyclyl, wherein the alkyl and heterocyclyl groups are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, heterocyclyl, or both alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0032] "Halogen" is fluorine, chlorine, bromine or iodine.

[0033] A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups.

[0034] An "alkoxy" or "alkoxyl" group is an -O-(alkyl) group wherein alkyl is as defined above.

[0035] An "alkoxyalkyl" group is a -(alkyl)-O-(alkyl) where alkyl is as defined above.

[0036] An "amino" group is a group of the formula: -NH2.

[0037] An "alkylamino" group is a group of the formula: -NH-alkyl or -N(alkyl)2 wherein each alkyl group is independently as defined above.

[0038] A "carboxy" group is a group of the formula: -C(O)OH.

[0039] An "aminocarbonyl" group is a group of the formula: -C(O)N(R # )2、-C(O)NH(R # ) or -C(O)NH2, where each R #and R is independently substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclic as defined herein.

[0040] An "acylamino" group is a group of the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ), wherein each alkyl group and R # Independently as defined above.

[0041] A "sulfonylamino" group is a group of the formula: -NHSO2(R # ) or -N(alkyl)SO2(R # ), wherein each alkyl group and R # As defined above.

[0042] A "urea" group is a group of the formula: -N(alkyl)C(O)N(R # )2, -N(alkyl)C(O)NH(R # )、-N(alkyl)C(O)NH2、-NHC(O)N(R # )2、-NHC(O)NH(R # ) or -NH(CO)NHR # , where each alkyl group and R # Independently as defined above.

[0043] When groups described herein (other than alkyl) are referred to as "substituted", they may be substituted with any suitable substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chlorine, iodine, bromine or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl , which may be a monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or a heterocyclic group, which may be a monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl); a monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0044] As used herein, the term "one or more pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases and organic acids and bases). Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, those well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton PA (1995).

[0045] Unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" as used herein means that one stereoisomer of a compound is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound with one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound with two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Compounds may have chiral centers and may appear as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

[0046] The use of stereoisomerically pure forms of such compounds and the use of mixtures of these forms are encompassed in the embodiments disclosed herein. For example, a mixture of enantiomers of a particular compound containing equal or unequal amounts can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or split using standard techniques such as chiral columns or chiral splitting agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33: 2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELEliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0047] It should also be noted that the compound may include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compound is separated into E or Z isomers. In other embodiments, the compound is a mixture of E and Z isomers.

[0048] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is located, and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0049]

[0050] It will be readily appreciated by those skilled in the art that various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present invention.

[0051] It should also be noted that a compound may contain unnatural proportions of atomic isotopes at one or more of its atoms. For example, a compound may contain an isotope such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C), or can be radiolabeled with a radioactive isotope such as deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N) isotopically enriched. As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of the atom. "Isotopically enriched" may also refer to a compound in which at least one atom contained therein has an isotopic composition different from the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents (e.g., cancer and inflammatory therapeutic agents), research reagents (e.g., combined with assay reagents) and diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of compounds as described herein (whether or not radioactive) are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, an isotopologue of a compound is provided, for example, an isotopologue is a deuterium, carbon-13, or nitrogen-15 enriched compound.

[0052] As used herein, "treating" means completely or partially alleviating a condition, disease, or disorder, or one or more symptoms associated with a condition, disease, or disorder, or slowing or stopping the further progression or worsening of those symptoms, or alleviating or eradicating the cause of the condition, disease, or disorder itself. In some embodiments, "treating" means completely or partially alleviating a condition, disease, or disorder, or slowing or stopping the further progression or worsening of those symptoms. In another embodiment, "treating" means completely or partially alleviating a condition, disease, or disorder, or symptoms associated with a disorder, wherein the disorder can be treated or prevented by inhibiting a CDK, such as CDK4.

[0053] As used herein, "prevention" means a method of completely or partially delaying and / or hindering the onset, recurrence or spread of a condition, disease or disorder; a method of preventing a subject from developing a condition, disease or disorder; or a method of reducing the risk of a subject developing a condition, disease or disorder. In one embodiment, the disorder is a disorder that can be treated or prevented by inhibiting a CDK, such as CDK4.

[0054] The term "effective amount" with respect to a compound refers to an amount capable of treating or preventing a condition, disease or disorder disclosed herein, or a symptom thereof.

[0055] The term "subject" includes animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits or guinea pigs, in one embodiment mammals, in another embodiment humans.

[0056] Compound

[0057] A more complete understanding of the embodiments of the present invention may be obtained by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0058] Aspect 1: Provided herein is a compound of formula (I):

[0059]

[0060] or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof,

[0061] in:

[0062] R a and R b are each independently hydrogen or substituted or unsubstituted C 1-8 alkyl;

[0063] or R a and R b With R a and Rb The nitrogen atoms to which they are attached together form a substituted or unsubstituted non-aromatic heterocyclic group;

[0064] R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted saturated cycloalkylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl; or

[0065] R 1 and R 2 With R 1 and R 2 The atoms to which they are attached together form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted non-aromatic heterocyclic group.

[0066] In one embodiment, the compound is a compound of formula (Ia):

[0067]

[0068] or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, R c and R d are each independently hydrogen or substituted or unsubstituted C 1-8 alkyl;

[0069] or R c and R d With R c and R d The attached nitrogens together form a substituted or unsubstituted non-aromatic heterocyclic group; and n is 1, 2 or 3.

[0070] In one embodiment, the compound is a compound of formula (Ib):

[0071]

[0072] or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof.

[0073] In a preferred embodiment, R 1 is C substituted by amino, alkylamino or dialkylamino 1-8 alkyl.

[0074] Aspect 2: Provided herein is a compound, which is a compound of formula (II):

[0075]

[0076] or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, wherein:

[0077] R 2 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted cycloalkyl.

[0078] In one embodiment, R 2 It is hydrogen, F, Cl, -CF3 or cyclopropyl.

[0079] In one embodiment, R 2 For Cl.

[0080] In some embodiments, R 2 For hydrogen.

[0081] In one embodiment, R 2 It is cyclopropyl.

[0082] In one embodiment, R 2 For F.

[0083] In one embodiment, R 2 It is -CF3.

[0084] Aspect 3: Provided herein is a compound, which is a compound of formula (III):

[0085]

[0087] or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, wherein:

[0088] R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl; or R 3 and R 4 With R 3 and R 4 The atoms to which they are attached together form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted non-aromatic heterocyclyl group; and

[0089] n is 1, 2 or 3.

[0090] In one embodiment, R 3 and R 4 is F; and n is 2.

[0091] In one embodiment, R 3 and R 4 With R 3 and R 4 The attached atoms together form a cyclopropyl group; and n is 1.

[0092] In one embodiment, R 3 and R 4 With R 3 and R 4 The attached atoms together form a cyclopropyl group; and n is 2.

[0093] In one embodiment, R 3 and R 4 is H; and n is 1.

[0094] In one embodiment, R 3 and R 4 is H; and n is 2.

[0095] Aspect 4: Provided herein is a compound of formula (IV):

[0096]

[0097] or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, wherein:

[0098] R 5 and R 6 are each independently hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl; or R 5 and R 6 With R 5 and R 6 The atoms to which they are attached together form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted non-aromatic heterocyclyl group; and

[0099] n is 1, 2 or 3.

[0100] In one embodiment, R 5 and R 6 is H; and n is 2.

[0101] In one embodiment, R 1 is methyl; and R 2 For H.

[0102] In one embodiment, the compound is selected from Table 1.

[0103] Aspect 5: Provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof and a pharmaceutically acceptable carrier, excipient or vehicle.

[0104] Provided herein is a method of inhibiting the activity of a cyclin-dependent kinase in a cell, the method comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof.

[0105] In one embodiment, the cyclin dependent kinase is CDK4.

[0106] In one embodiment, the compound is selective for CDK4 over CDK6.

[0107] In one embodiment, the compound is selective for CDK4 over CDK1, CDK2, CDK3, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, or CDK11.

[0108] In one embodiment, the compound is at least 20-fold more selective for CDK4 than for CDK6. In one embodiment, the compound is at least 50-fold more selective for CDK4 than for CDK6. In one embodiment, the compound is at least 100-fold more selective for CDK4 than for CDK6.

[0109] In one embodiment, provided herein is a method of treating or preventing a CDK-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound provided herein. In one embodiment, the CDK is CDK4.

[0110] In one embodiment, provided herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a compound provided herein. In one embodiment, the CDK is CDK4.

[0111] Methods for preparing compounds

[0112] Compounds can be prepared using conventional organic synthesis and commercially available starting materials. As an example and not limitation, compounds of formula (I), formula (II), formula (III) and formula (IV) can be prepared as outlined in Schemes 1-4 shown below and in the Examples described herein. It should be noted that one skilled in the art will know how to modify the procedures described in the illustrative schemes and Examples to obtain the desired product. Common protecting groups can be used to prevent certain functional groups from undergoing undesirable reactions. Exemplary protecting groups are described in "Protective Groups in Organic Synthesis", 4th edition, PGM Wuts; TW Greene, John Wiley, 2007, and references cited therein.

[0113] Solution 1

[0114]

[0115] As shown in Scheme 1, in some embodiments, provided herein is a method for preparing a compound as defined by formula (I). Compound 1-1 (X can be a halogen, boronic acid or boric ester) is converted to compound 1-3 under Chan-Lam or Ullman coupling reaction conditions (e.g., Cu(OAc)2, pyridine, dioxane, oxygen); then compound 1-3 is converted to a compound defined by formula (I) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs2CO3, dioxane, etc.).

[0116] Solution 2

[0117]

[0118] As shown in Scheme 2, in some embodiments, provided herein is a method for preparing a compound as defined by formula (II). Compound 2-1 (X can be a halogen, boronic acid or boric ester) is converted to compound 2-3 under Chan-Lam or Ullman coupling reaction conditions (e.g., Cu(OAc)2, pyridine, dioxane, oxygen); then compound 2-3 is converted to a compound defined by formula (II) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs2CO3, dioxane, etc.).

[0119] Solution 3

[0120]

[0121] As shown in Scheme 3, in some embodiments, provided herein is a method for preparing a compound as defined by formula (III). Compound 3-1 (X can be a halogen, boronic acid or boric ester) is converted to compound 3-3 under Chan-Lam or Ullman coupling reaction conditions (e.g., Cu(OAc)2, pyridine, dioxane, oxygen); then compound 3-3 is converted to a compound defined by formula (III) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs2CO3, dioxane, etc.).

[0122] Solution 4

[0123]

[0124] As shown in Scheme 4, in some embodiments, provided herein is a method for preparing a compound as defined by formula (IV). Compound 4-1 (X may be a halogen, boronic acid or boronic ester) is converted to compound 4-3 under Chan-Lam or Ullman coupling reaction conditions (e.g., Cu(OAc)2, pyridine, dioxane, oxygen); then compound 4-3 is converted to compound 4-4 under deprotection conditions (e.g., when PG is Boc, deprotect the Boc group with TFA); compound 4-4 is further alkylated or reductively aminized to obtain compound 4-5; compound 4-5 is converted to a compound defined by formula (IV) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs2CO3, dioxane, etc.).

[0125] A more complete understanding of the embodiments of the present invention may be obtained by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0126] Example

[0127] The following examples are intended to be exemplary only and should not be considered to be limiting in any way. Unless otherwise stated, the following reactions were all carried out in anhydrous solvents under a positive pressure of nitrogen or argon or with a drying tube; the reaction flask was equipped with a rubber septum for introducing substrates and reagents via a syringe; the glassware was oven dried and / or heat dried. Unless otherwise stated, reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. Solvents were all redistilled before use. Anhydrous solvents were all prepared according to standard methods or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin layer chromatography (TLC) are commercially available from Qingdao Ocean Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China; unless otherwise stated, all were eluted with petroleum ether (60°C to 90°C) / ethyl acetate (v / v) and developed by a solution of iodine or molybdophosphoric acid in ethanol. Unless otherwise stated, all extraction solvents were dried with anhydrous Na2SO4. Recorded on a Bruck-400 or Varian instrument operating at 300 MHz, 400 MHz, or 500 MHz 1 H NMR spectra. CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO were used as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)2CO: 2.05) was used as reference standards. 1H NMR spectra. Coupling constants are in Hertz. Peaks are reported as singlet (s), doublet (d), triplet (t), quartet (q), quintet (p), sextet (h), septet (hept), multiplet (m), or combinations thereof; br represents broad peaks. LC / MS data were recorded by using an Agilent 1100, 1200 high performance liquid chromatography-ion trap mass spectrometer (LC-MSD Trap) equipped with a diode array detector (DAD) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names except reagents are from 19.1 generated.

[0128]

[0129]

[0130]

[0131] Compound synthesis

[0132] Example 1: 7-cyclopentyl-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0133]

[0134] Synthetic route

[0135]

[0136] Step 1: 2-Chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0137]

[0138] 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (300 mg, 1.13 mmol) was placed in a 50 mL round-bottom flask and DMF (20 mL) was added. Dimethylamine hydrochloride (137 mg, 1.70 mmol), DIEA (291 mg, 2.26 mmol) and HATU (515 mg, 1.36 mmol) were then added. The resulting solution was stirred at room temperature for 2 hours. The reactant was quenched with water (30 mL) and extracted with EtOAc (25 mL * 3). The combined organic layers were washed with brine (25 mL * 3), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative TLC to give the title product (360 mg). MS (ESI, m / e) [M + H] + 293.1.

[0139] Step 2: 7-Cyclopentyl-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0140] 2-Chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (300 mg, 1.02 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (468 mg, 3.06 mmol), DIEA (329 mg, 2.55 mmol) and DMSO (5 mL) were placed in a 50 mL round-bottom flask. The resulting solution was stirred at 120 ° C for 1 hour. The reactant was quenched with water (20 mL). The resulting mixture was extracted with EA (15 mL*3). The resulting mixture was washed with brine (15 mL*3). The organic layer was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title product (57.2 mg). 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),6.79–6.70(m,1H),6.47(s,1H),5.0 0–4.93(m,1H),4.78–4.62(m,1H),3.88–3.80(m,2H),3.74(s,1H),3.62– 3.47(m,1H),3.40–3.33(m,1H),3.14–2.96(m,7H),2.41–2.26(m,2H),2. 17–2.05(m,1H),2.05–1.88(m,4H),1.72–1.56(m,2H),1.55–1.40(m,1H). MS(ESI,m / e)[M+H] + 374.0.

[0141] Example 2: 2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7-(p-tolyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0142]

[0143] Synthetic route

[0144]

[0145] Step 1: 2-Chloro-N,N-dimethyl-7-(p-tolyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0146]

[0147] A mixture of 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (200 mg, 0.893 mmol), CuI (33.8 mg, 0.178 mmol), (S)-proline (10.2 mg, 0.089 mmol) and K2CO3 (246 mg, 1.785 mmol) in DMSO (5 mL) was stirred at 90 ° C for 16 hours. The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (PE / EA=3:1) to give the title compound (70 mg). MS (ESI, m / e) [M+H] + 315.2.

[0148] Step 2: 2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7-(p-tolyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0149] A mixture of 2-chloro-N,N-dimethyl-7-(p-tolyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (70 mg, 0.222 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (51 mg, 0.333 mmol), Cs2CO3 (145 mg, 0444 mmol) and Pd-PEPPSI-IPentCl2-methylpyridine (o-methylpyridine) (15.6 mg, 0.02 mmol) in dioxane (1 mL) was stirred at 100 ° C for 16 hours. The resulting mixture was concentrated under vacuum. The crude product (10 mg) was purified by preparative HPLC to give the title product (38 mg). 1 H NMR(300MHz, CDCl3)δ8.57(s,1H),7.36–7.24(m,4H),6.70(s,1H),4.14–3.93(m,2H),3.92–3.76(m,1H),3.69–3.57 (m,1H),3.51–3.38(m,1H),3.26–3.13(m,1H),3.06–2.83(m,6H),2.44(s,3H),2.05–1.95(m,1H),1.83–1.64(m,1H). MS(ESI,m / e)[M+H] + 396.1.

[0150] Example 3: 7-(4-((dimethylamino)methyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0151]

[0152] Synthetic route

[0153]

[0154] Step 1: 1-(4-iodophenyl)-N,N-dimethylmethanamine

[0155]

[0156] To a solution of 4-iodobenzaldehyde (1.5 g, 6.49 mmol) in DCE (10 mL) and MeOH (10 mL) was added dimethylamine (6.46 mL, 12.9 mmol, 2 M in THF) at room temperature. After stirring for 3 hours, STAB (2.75 g, 13.0 mmol) was added. The resulting solution was stirred at room temperature overnight. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated. The residue was purified with a silica gel column (PE: EtOAc = 100: 0 ~ 50: 50). This produced the title product (1.0 g). MS (ESI, m / e) [M + H] + 261.9.

[0157] Step 2: 2-Chloro-7-(4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0158]

[0159] Into a 40 mL vial was placed 1-(4-iodophenyl)-N,N-dimethylmethanamine (500 mg, 1.92 mmol), 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (431 mg, 1.92 mmol), (S)-proline (22 mg, 0.192 mmol), K2CO3 (528 mg, 3.83 mmol), CuI (36 mg, 0.192 mmol) and DMSO (5 mL). The resulting mixture was stirred at 90 °C for 16 hours. The mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated. The residue was purified by preparative TLC to give the title product (80 mg). MS (ESI, m / e) [M+H] + 358.1.

[0160] Step 3: 7-(4-((dimethylamino)methyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0161] Into a 20 mL vial was placed 2-chloro-7-(4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (80 mg, 0.22 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (51.4 mg, 0.34 mmol), Cs2CO3 (219 mg, 0.67 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (18 mg, 0.02 mmol) and dioxane (1 mL). The mixture was stirred at 90 ° C overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column with DCM / MeOH (6:1) to give a crude product. The crude product was purified by preparative HPLC to give the title compound (9.3 mg). 1 H NMR(300MHz,CD3OD)δ8.79(s,1H),7.74–7.65(m,2H),7.65–7.54(m,2H),7.04(s,1H),4.89(s,2H),4.41–3.79(m,3H),3 .66–3.58(m,1H),3.39–3.35(m,1H),3.18–3.12(m,4H),3.08(s,3H),2.91(s,6H),2.07–1.98(m,1H),1.80–1.60(m,1H). MS(ESI,m / e)[M+H] + 439.2.

[0162] Example 4: 7-(3-cyclopropyl-4-((dimethylamino)methyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0163]

[0164] Synthetic route

[0165]

[0166] Step 1: 1-(2-Bromo-4-nitrophenyl)-N,N-dimethylmethanamine

[0167]

[0168] A solution of 2-bromo-1-(bromomethyl)-4-nitrobenzene (5.20 g, 17.6 mmol) and dimethylamine (1.99 g, 44.1 mmol) in MeOH (52 mL) was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (4.5 g). MS (ESI, m / e) [M+H] + 259.0.

[0169] Step 2: 1-(2-cyclopropyl-4-nitrophenyl)-N,N-dimethylmethanamine

[0170]

[0171] A solution of 1-(2-bromo-4-nitrophenyl)-N,N-dimethylmethanamine (3.0 g, 11.6 mmol), cyclopropylboronic acid (2.98 g, 34.7 mmol), Pd(OAc)2 (0.26 g, 1.2 mmol), tricyclohexylphosphine (0.65 g, 2.3 mmol) and K3PO4 (11.06 g, 52.1 mmol) in toluene / H2O (30 mL / 10 mL) was stirred at 110 °C overnight. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×20 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3×20 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give the title product (1.3 g). MS (ESI, m / e) [M+H] + 221.0.

[0172] Step 3: 3-Cyclopropyl-4-((dimethylamino)methyl)aniline

[0173]

[0174] A solution of 1-(2-cyclopropyl-4-nitrophenyl)-N,N-dimethylmethanamine (1.3 g, 5.90 mmol) in THF (13 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with THF (3×20 mL). The filtrate was concentrated under reduced pressure. The crude product (1.2 g) was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 191.1.

[0175] Step 4: (3-cyclopropyl-4-((dimethylamino)methyl)phenyl)boronic acid

[0176]

[0177] A mixture of 3-cyclopropyl-4-((dimethylamino)methyl)aniline (1.1 g, 5.8 mmol) and NaNO2 (0.40 g, 5.8 mmol) in HCl (3M) / MeOH / H2O (7 mL / 14 mL / 7 mL) was stirred at 0°C for 30 minutes. Diboric acid (1.55 g, 17.3 mmol) was added to the above mixture at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered and the filter cake was washed with MeOH (3×15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography to give the title product (400 mg). MS (ESI, m / e) [M+H] + 220.0.

[0178] Step 5: 2-Chloro-7-(3-cyclopropyl-4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0179]

[0180] A solution of (3-cyclopropyl-4-((dimethylamino)methyl)phenyl)boronic acid (350 mg, 1.60 mmol), Cu(OAc)2 (435 mg, 2.40 mmol), TEA (485 mg, 4.80 mmol) and 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (359 mg, 1.60 mmol) in 1,4-dioxane (5 mL) was stirred at 80 ° C under an oxygen atmosphere for 16 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the title product (80 mg). MS (ESI, m / e) [M+H] + 398.1.

[0181] Step 6: 7-(3-cyclopropyl-4-((dimethylamino)methyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0182] A mixture of 2-chloro-7-(3-cyclopropyl-4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (80 mg, 0.20 mmol), Cs2CO3 (196.5 mg, 0.6 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (17 mg, 0.02 mmol) and (3S,4R)-4-aminooxacyclohexane-3-ol (35.3 mg, 0.30 mmol) in 1,4-dioxane was stirred at 100 °C overnight. The resulting mixture was filtered and the filter cake was washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title product (6 mg). 1 H NMR(300MHz,CD3OD)δ8.74(s,1H),7.63–7.57(m,1H),7.38–7.30(m,1H),7.30–7.21(m,1H),6.96(s,1H),4.63(s,2H),4.02–3.78(m,3H),3.68 –3.53(m,1H),3.47–3.35(m,,1H),3.20–3.06(m,4H),2.98(s,9H),2.31 –1.98(m,2H),1.76–1.55(m,1H),1.20–1.10(m,2H),0.92–0.77(m,2H). MS(ESI,m / e)[M+H] + 479.3.

[0183] Example 5: 7-(4-((dimethylamino)methyl)-3-fluorophenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0184]

[0185] Synthetic route

[0186]

[0187] Step 1: 1-(4-Bromo-2-fluorophenyl)-N,N-dimethylmethanamine

[0188]

[0189] 4-Bromo-2-fluorobenzaldehyde (3.0 g, 15 mmol), DCE (50 mL) and dimethylamine (29.5 mL, 29.5 mmol, 1 M in THF) were added to a 250 mL round-bottom flask at room temperature. After stirring at room temperature for 1 hour, STAB (6.26 g, 29.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reactants were quenched with NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1.2 g). MS (ESI, m / e) [M+H] + 232.1.

[0190] Step 2: (4-((Dimethylamino)methyl)-3-fluorophenyl)boronic acid

[0191]

[0192] N-butyl lithium (5.19 mL, 12.9 mmol, 2.5 M in THF) was added to a mixture of 1-(4-bromo-2-fluorophenyl)-N,N-dimethylmethanamine (1.0 g, 4.3 mmol) and THF (10 mL) at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes. A solution of triisopropyl borate (2.03 g, 10.77 mmol) in THF (2 mL) was then added dropwise, and the mixture was stirred for another hour. The reactants were quenched with NH4Cl (aqueous solution), and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give the title product (300 mg). MS (ESI, m / e) [M+H] + 198.2.

[0193] Step 3: 2-Chloro-7-(4-((dimethylamino)methyl)-3-fluorophenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0194]

[0195] Into a 20 mL bottom flask were placed (4-((dimethylamino)methyl)-3-fluorophenyl)boric acid (300 mg, 1.52 mmol), 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, pyridine (602.2 mg, 7.61 mmol), copper acetate (415 mg, 2.28 mmol), dioxane (10 mL) and 4A MS (100 mg) at room temperature. The resulting mixture was stirred at 80° C. under an oxygen atmosphere overnight. The residue was purified by silica gel column chromatography to give the title product (160 mg). MS (ESI, m / e) [M+H] + 376.2.

[0196] Step 4: 7-(4-((dimethylamino)methyl)-3-fluorophenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0197] 2-Chloro-7-(4-((dimethylamino)methyl)-3-fluorophenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (150 mg, 0.39 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (70.1 mg, 0.59 mmol), Cs2CO3 (390.1 mg, 1.19 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (33.5 mg, 0.04 mmol) and dioxane (5 mL) were added to a 10 mL round-bottom flask at room temperature. The resulting mixture was stirred at 100° C. overnight. The residual product was purified by reverse phase flash to give the title product (13.7 mg). 1 H NMR(400MHz,CD3OD)δ8.74(s,1H),7.74–7.65(m,1H),7.62–7.53(m,1H),7.42–7.34(m,1H),7.02(s,1H),4.48(s,2H),3.97–3.80(m,3H) ,3.67–3.56(m,1H),3.45–3.36(m,1H),3.26(s,3H),3.17-3.09(m,1H),3.03(s,3H),2.95(s,6H),2.12–2.02(m,1H),1.73-1.60(m,1H). MS(ESI,m / e)[M+H] + 457.1.

[0198] Example 6: 7-(3-chloro-4-((dimethylamino)methyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0199]

[0200] Synthetic route

[0201]

[0202] Step 1: 1-(4-bromo-2-chlorophenyl)-N,N-dimethylmethanamine

[0203]

[0204] A solution of 4-bromo-1-(bromomethyl)-2-chlorobenzene (2.0 g, 7.0 mmol) and dimethylamine (0.63 g, 14 mmol) in MeOH was stirred at room temperature for 5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1.2 g). MS (ESI, m / e) [M+H] + 248.0.

[0205] Step 2: (3-Chloro-4-((dimethylamino)methyl)phenyl)boronic acid

[0206]

[0207] A solution of 1-(4-bromo-2-chlorophenyl)-N,N-dimethylmethanamine (1.0 g, 4.0 mmol) in THF was treated with butyl lithium (0.77 g, 12 mmol) at -78 ° C for 1 hour, and then triisopropyl borate (1.89 g, 10.0 mmol) was added dropwise at -78 ° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography to give the title product (500 mg). MS (ESI, m / e) [M+H] + 214.0.

[0208] Step 3: 2-Chloro-7-(3-chloro-4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0209]

[0210] A solution of (3-chloro-4-((dimethylamino)methyl)phenyl)boronic acid (400 mg, 1.87 mmol), Cu(OAc)2 (510.5 mg, 2.81 mmol), TEA (379.2 mg, 3.74 mmol) and 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (294.6 mg, 1.31 mmol) in 1,4-dioxane was stirred at 80 °C under oxygen for 16 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (130 mg). MS (ESI, m / e) [M+H] + 392.0.

[0211] Step 4: 7-(3-chloro-4-((dimethylamino)methyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0212] A solution of 2-chloro-7-(3-chloro-4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (70 mg, 0.18 mmol), Cs2CO3 (174.4 mg, 0.53 mmol) and (3S,4R)-4-aminooxacyclohexane-3-ol (31.36 mg, 0.26 mmol) in 1,4-dioxane was stirred overnight at 100 °C. The resulting mixture was filtered and the filter cake was washed with MeOH (3×5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (12.3 mg). 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.59–7.51(m,1H),7.32–7.24(m,1H),6.98(s,1H),6.80(s,1H),4.96–4.87(m ,1H),3.85–3.76(m,2H),3.60–3.44(m,3H),3.15–2.78(m,8H),2.23(s,6H),2.12–1.98(m,1H),1.53-1.38(m,1H). MS(ESI,m / e)[M+H] + 473.2.

[0213] Example 7: 7-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0214]

[0215] Synthetic route

[0216]

[0217] Step 1: 1-(4-Bromo-2-(trifluoromethyl)phenyl)-N,N-dimethylmethanamine

[0218]

[0219] MeOH (60 mL), 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene (3.7 g, 12 mmol) and dimethylamine (11.9 mL, 23.8 mmol, 2M in THF) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 5 hours. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC to give the title product (2.0 g). MS (ESI, m / e) [M+H] + 282.0.

[0220] Step 2: (4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)boronic acid

[0221]

[0222] In a 50 mL round-bottom flask, to a solution of 1-(4-bromo-2-(trifluoromethyl)phenyl)-N,N-dimethylmethanamine (1.80 g, 6.38 mmol) in THF (20 mL) was added dropwise a solution of n-butyllithium (3.3 mL, 8.29 mmol, 2.5 M in hexanes) at -78 °C. The reaction mixture was stirred for 60 minutes. A solution of triisopropyl borate (1.9 g, 10.2 mmol) in THF (4 mL) was then added dropwise, and the mixture was stirred at room temperature for another 60 minutes. The reactants were quenched with MeOH (50 mL) and the mixture was concentrated in vacuo to give a crude product (4.0 g). The residue was purified by reverse phase HPLC to give the title product (0.80 g). MS (ESI, m / e) [M+H] + 248.0.

[0223] Step 3: 2-Chloro-7-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0224]

[0225] Dioxane (4 mL), (4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)boronic acid (0.5 g, 2.02 mmol), 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (450 mg, 2.02 mmol), TEA (0.61 g, 6.1 mmol) and Cu(OAc)2 (0.56 g, 3.03 mmol) were added to a 25 mL vial at room temperature. The resulting mixture was stirred at 80 °C under an oxygen atmosphere for 4 hours. The residue was purified by preparative TLC (PE / EA=1:1) to give the title compound (200 mg). MS (ESI, m / e) [M+H] + 426.1.

[0226] Step 4: 7-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0227] Dioxane (4 mL), 2-chloro-7-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.23 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (53.9 mg, 0.35 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine-o-methylpyridine (20 mg, 0.023 mmol) and Cs2CO3 (229 mg, 0.72 mmol) were added to a 10 mL sealed tube at room temperature. The resulting mixture was stirred at 100°C overnight. The crude product (30 mg) was purified by preparative HPLC to give the title compound (5.4 mg). 1H NMR(300MHz,CD3OD)δ8.66(s,1H),7.95–7.83(m,2H),7.63–7.56(m,1H),6.88(s,1H),3.95–3.83(m,3H),3.67(s, 2H),3.64–3.50(m,1H),3.48–3.40(m,1H),3.15–2.95(m,7H),2.31(s,6H),2.19–2.13(m,1H),1.85–1.63(m,1H). MS(ESI,m / e)[M+H] + 507.4.

[0228] Example 8: 2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0229]

[0230] Synthetic route

[0231]

[0232] Step 1: tert-Butyl 6-(2-chloro-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0233]

[0234] To a stirred solution of 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (0.56 g, 2.00 mmol) and (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (0.30 g, 1.34 mmol) in 1,4-dioxane (9 mL) was added Cu(OAc)2 (0.24 g, 1.33 mmol), pyridine (0.32 g, 4.0 mmol) and 4AMS (0.3 g) at room temperature. The resulting mixture was stirred at 80 °C under an oxygen atmosphere for 4 hours. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1:1) to give the title compound (0.1 g). MS (ESI, m / e) [M+H] + 456.1.

[0235] Step 2: 2-Chloro-N,N-dimethyl-7-(1,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0236]

[0237] To a solution of tert-butyl 6-(2-chloro-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 0.22 mmol) in DCM (2 mL) was added TFA (1 ml) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1:1) to give the title compound (50 mg). MS (ESI, m / e) [M+H] + 356.2.

[0238] Step 3: 2-Chloro-N,N-dimethyl-7-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0239]

[0240] To a solution of 2-chloro-N,N-dimethyl-7-(1,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.14 mmol) in DCE (4 mL) was added formaldehyde (34 mg, 40 wt% in water) dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. STAB (48 mg, 0.226 mmol) was added portionwise to the above mixture at 0°C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title product (13 mg). MS (ESI, m / e) [M+H] + 370.2.

[0241] Step 4: 2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0242] To a stirred solution of 2-chloro-N,N-dimethyl-7-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (13 mg, 0.04 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (6.00 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was added Cs2CO3 (40 mg, 0.12 mmol) and Pd-PEPPSI-IPentCl2-methylpyridine (o-methylpyridine) (3.00 mg, 0.004 mmol) portionwise at room temperature. The resulting mixture was stirred at 100° C. for 3 hours. The residue was purified by preparative HPLC to give the title compound (6.1 mg). 1 H NMR(400MHz,CD3OD)δ8.78(s,1H),7.54–7.45(m,1H),7.44–7.33(m,2H),7.00(s,1H),4.80–4.37(m,2H) ,4.01–3.63(m,5H),3.41(m,1H),3.24–3.13(m,7H),3.00(s,3H),2.11–2.03(m,1H),1.81–1.64(m,1H). MS(ESI,m / e)[M+H] + 451.2.

[0243] Example 9: 7-(5-(dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0244]

[0245] Synthetic route

[0246]

[0247] Step 1: 6-Bromo-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine

[0248]

[0249] To a mixture of 6-bromo-3,4-dihydronaphthalen-1(2H)-one (2.3 g, 10 mmol), THF (30 mL) and dimethylamine (28.8 ml, 51.8 mmol, 2 M in THF) was added TiCl4 (21.2 mL, 21.2 mmol, 1 M in DCM) at 0-5 °C. The resulting solution was stirred at the same temperature for 2 hours. STAB (6.95 g, 31.0 mmol) was then added at 0 °C and the resulting mixture was stirred at room temperature. The mixture was quenched by adding 100 mL of water and the pH was adjusted to 8 with NaHCO3. The resulting mixture was extracted with EtOAc and the combined organic phases were concentrated. The residue was purified by reverse phase HPLC to give the title product (1.1 g). MS (ESI, m / e) [M+H] + 254.3.

[0250] Step 2: (5-(Dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid

[0251]

[0252] To a solution of 6-bromo-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-1-amine (0.80 g, 3.2 mmol) in THF (10 mL) was added n-butyl lithium solution (1.64 mL, 4.12 mmol, 2.5 M in hexane) dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 60 minutes. A solution of triisopropyl borate (0.95 g, 5.1 mmol) in 2 mL THF was then added dropwise, and the mixture was stirred at room temperature for another 1 hour. The reactant was quenched with MeOH (50 mL). The combined organic phases were concentrated in vacuo, and the residue was purified by reverse phase HPLC to give the title compound (0.50 g). MS (ESI, m / e) [M + H] + 220.0.

[0253] Step 3: 2-Chloro-7-(5-(dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0254]

[0255] Dioxane (4 mL), (5-(dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (0.50 g, 2.3 mmol), 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (0.51 g, 2.3 mmol), TEA (0.69 g, 6.8 mmol) and Cu(OAc)2 (0.62 g, 3.4 mmol) were added to a 10 mL vial at room temperature. The resulting mixture was stirred at 80 °C under an oxygen atmosphere for 4 hours. The residue was purified by preparative TLC to give the title product. MS (ESI, m / e) [M+H] + 398.2.

[0256] Step 4: 7-(5-(Dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0257] Dioxane (4 mL), 2-chloro-7-(5-(dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.25 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (38.5 mg, 0.25 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine o-methylpyridine (21.1 mg, 0.025 mmol) and Cs2CO3 (245.7 mg, 0.75 mmol) were added to a 10 mL sealed tube at room temperature. The resulting mixture was stirred at 100° C. overnight. The solvent was removed and the crude product was purified by preparative HPLC to give the title compound (4.2 mg). 1 H NMR(300MHz,CD3OD)δ8.63(s,1H),7.68–7.60(m,1H),7.24–7.13(m,2H),6.78(s,1H),3.94–3.80(m,4H),3.61–3.52 (m,1H),3.48–3.37(m,1H),3.19–3.12(m,1H),3.03–2.92(m,6H),2.89–2.74(m,2H),2.30(s,6H),2.22–1.55(m,6H). MS(ESI,m / e)[M+H] + 479.4.

[0258] Example 10: 7-(4'-(dimethylamino)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0259]

[0260] Synthetic route

[0261]

[0262] Step 1: 7-Bromo-1-methylene-1,2,3,4-tetrahydronaphthalene

[0263]

[0264] A mixture of bromo(methyl)triphenyl-λ5-phosphine (4.86 g, 13.6 mmol) and t-BuOK (2.30 g, 20.5 mmol) in toluene was stirred at 110 ° C for 40 minutes. 7-bromo-3,4-dihydro-2H-naphthalene-1-one (3 g, 13.33 mmol) was added to the above mixture. The resulting mixture was stirred at 110 ° C for 15 minutes. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1.7 g).

[0265] Step 2: 7'-Bromo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]

[0266]

[0267] To a stirred solution of 7-bromo-1-methylene-1,2,3,4-tetrahydronaphthalene (2.0 g, 9.0 mmol) and chloroiodomethane (6.48 mL, 89.6 mmol) in DCE was added diethylzinc (71.7 mL, 71.7 mmol) portionwise at 0 ° C. The resulting mixture was stirred at 0 ° C for 3 hours. At 0 ° C, the reactant was quenched with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.9 g) was used directly in the next step without further purification.

[0268] Step 3: 7'-Bromo-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one

[0269]

[0270] To a stirred solution of 7'-bromo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene] (1.9 g, 8.0 mmol) and KMnO4 (1.90 g, 12.0 mmol) in t-BuOH was added portionwise KH2PO4 (2.18 g, 16.0 mmol) and Na2HPO4 (2.27 g, 16.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was washed with 200 mL of brine. The residue was purified by silica gel column chromatography to give the title product (1.5 g). MS (ESI, m / e) [M+H] + 251.1.

[0271] Step 4: 7'-Bromo-N,N-dimethyl-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-amine

[0272]

[0273] To a stirred solution of 7'-bromo-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one (1.0 g, 4.0 mmol) and dimethylamine (9.96 mL, 19.9 mmol) in THF was added TiCl4 (8 mL, 8.0 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. STAB (1.69 g, 7.96 mmol) was added to the above mixture at room temperature. The resulting mixture was stirred at room temperature for another 2 hours. The reactants were quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (700 mg). MS (ESI, m / e) [M+H] + 280.2.

[0274] Step 5: N,N-dimethyl-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-amine

[0275]

[0276] To a mixture of 7'-bromo-N,N-dimethyl-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-amine (550 mg, 1.96 mmol) and bis(pinacolato)diboron (747.6 mg, 2.94 mmol) in dioxane was added KOAc (385.2 mg, 3.92 mmol) and Pd(dppf)Cl2 (143.6 mg, 0.19 mmol) at room temperature. The resulting mixture was stirred at 80 ° C overnight. The resulting mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (450 mg).

[0277] Step 6: (4'-(Dimethylamino)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl)boronic acid

[0278]

[0279] To a mixture of N,N-dimethyl-7'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-amine (400 mg, 1.22 mmol) and NaIO4 (784.2 mg, 3.66 mmol) in THF / H2O was added HCl (0.8 mL, 0.85 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (200 mg). MS (ESI, m / e) [M+H] + 246.3.

[0280] Step 7: 2-Chloro-7-(4'-(dimethylamino)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0281]

[0282] To a mixture of (4'-(dimethylamino)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl)boronic acid (170 mg, 0.69 mmol) and 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (202.5 mg, 0.90 mmol) in 1,4-dioxane was added pyridine (0.18 mL, 1.4 mmol) and Cu(OAc)2 (125.9 mg, 0.69 mmol), 4A MS (340 mg) at room temperature. The resulting mixture was stirred at 80 °C under an oxygen atmosphere overnight. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (60 mg). MS (ESI, m / e) [M+H] + 424.0.

[0283] Step 8: 7-(4'-(dimethylamino)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0284] To a stirred solution of 2-chloro-7-(4'-(dimethylamino)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (55 mg, 0.13 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (29.8 mg, 0.19 mmol) in 1,4-dioxane was added CsCO (126.8 mg, 0.39 mmol) and [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (10.9 mg, 0.01 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (17 mg). 1HNMR(300MHz,CD3OD)δ8.75(s,1H),7.63–7.56(m,1H),7.42–7.34(m,1H),7 .09–6.94(m,2H),4.01–3.79(m,3H),3.71–3.54(m,1H),3.44–3.34(m,2H),3 .21–3.07(m,4H),3.07–2.93(m,6H),2.93–2.72(m,3H),2.44–2.30(m,2H), 2.15–1.98(m,1H),1.98–1.83(m,2H),1.81–1.60(m,1H),1.22–0.95(m,4H). MS (ESI, m / e) [M+H] + 505.3.

[0285] Example 11: 7-(5-(dimethylamino)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0286]

[0287] Synthetic route

[0288]

[0289] Step 1: 7-Bromo-3,4-dihydro-2H-spiro[naphthalene-1,2'-[1,3]dithiolane]

[0290]

[0291] 7-bromo-3,4-dihydro-2H-naphthalene-1-one (11 g, 49 mmol), 1,2-ethanedithiol (9.2 g, 98 mmol), PTSA (0.84 g, 4.9 mmol) and toluene (150 mL) were added to a 150 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product (13 g).

[0292] Step 2: 7-Bromo-1,1-difluoro-1,2,3,4-tetrahydronaphthalene

[0293]

[0294] A mixture of NIS (38.8 g, 173 mmol) and DCM (30 mL) was cooled to -78 °C. HF-pyridine (34.2 g, 345 mmol) was added, followed by 7-bromo-3,4-dihydro-2H-spiro[naphthalene-1,2'-[1,3]dithiolane] (13 g, 43.15 mmol). The reactants were stirred at -78 °C for 1 hour, and then stirred at 0 °C for another 12 hours. The reaction mixture was quenched with NaHCO3 and extracted with DCM (3*25 mL). The residue was purified by silica gel column chromatography to give the title product (5.8 g).

[0295] Step 3: 6-Bromo-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one

[0296]

[0297] 7-Bromo-1,1-difluoro-1,2,3,4-tetrahydronaphthalene (5.80 g, 23.5 mmol), KMnO4 (11.1 g, 70.4 mmol), KH2PO4 (12.8 g, 93.9 mmol), Na2HPO4 (13.3 g, 93.9 mmol), t-BuOH (60 mL) and H2O (36 mL) were added to a 250 mL round-bottom flask at room temperature. The mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (5.3 g).

[0298] Step 4: (E)-N-(6-Bromo-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-ylidene)-2-methylpropane-2-sulfenamide

[0299]

[0300] 6-Bromo-4,4-difluoro-3,4-dihydronaphthalene-1(2H)-one (5.3 g, 20 mmol), 2-methylpropane-2-sulfinamide (4.92 g, 40.6 mmol), titanium ethoxide (13.9 g, 60.9 mmol) and THF (60 mL) were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at 80 ° C for 3 hours. The reactants were quenched with water (10 mL) at room temperature. The solvent was removed and the residue was purified by silica gel column chromatography to give the title product (5.3 g). MS (ESI, m / e) [M+H] + 364.0.

[0301] Step 5: N-(6-bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-methylpropane-2-sulfenamide

[0302]

[0303] To a 60 mL round-bottom flask was added (E)-N-(6-bromo-4,4-difluoro-3,4-dihydronaphthalene-1(2H)-ylidene)-2-methylpropane-2-sulfenamide (5.30 g, 14.6 mmol), NaBH4 (1.10 g, 29.1 mmol) and MeOH (60 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (5.0 g). MS (ESI, m / e) [M+H] + 366.0.

[0304] Step 6: 6-Bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-amine

[0305]

[0306] N-(6-bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-methylpropane-2-sulfinamide (5.0 g, 14 mmol) and 1,4-dioxane (1.49 g, 40.9 mmol) containing HCl (gas) were added to a 100 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give the title product (2.5 g). MS (ESI, m / e) [M+H] + 262.0.

[0307] Step 7: 6-Bromo-4,4-difluoro-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine

[0308]

[0309] 6-bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalene-1-amine (2.4 g, 9.2 mmol), NaOAc (0.75 g, 9.2 mmol), AcOH (2.75 g, 45.8 mmol), formaldehyde (2.75 g, 91.6 mmol) and DCE (30 mL) were added to a 50 mL round-bottom flask at room temperature. The mixture was acidified to pH 8-10 with saturated NaHCO3 (aqueous solution). The resulting mixture was stirred at 50 ° C. STAB (5.82 g, 27.5 mmol) was added portionwise to the above mixture at room temperature. The resulting mixture was stirred at room temperature for another 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to obtain the title product (1.2 g). MS (ESI, m / e) [M+H] + 289.9.

[0310] Step 8: 4,4-difluoro-N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

[0311]

[0312] 6-Bromo-4,4-difluoro-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-1-amine (1.2 g, 4.1 mmol), bis(pinacolato)diboron (2.10 g, 8.27 mmol), Pd(dppf)Cl2 (0.30 g, 0.41 mmol), KOAc (0.81 g, 8.3 mmol) and dioxane (15 mL) were added to a 50 mL round-bottom flask at room temperature. The reaction mixture was stirred at 80 ° C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1 g). MS (ESI, m / e) [M+H] + 338.2.

[0313] Step 9: (5-(Dimethylamino)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid

[0314]

[0315] 4,4-difluoro-N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (1.0 g, 2.9 mmol), sodium periodate (1.89 g, 8.83 mmol), THF (12 mL) and H2O (3 mL) were added to a 50 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The residue was purified by reverse flash chromatography to give the title product (300 mg). MS (ESI, m / e) [M+H] + 256.1.

[0316] Step 10: 2-Chloro-7-(5-(dimethylamino)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0317]

[0318] A mixture of (5-(dimethylamino)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (300 mg, 1.17 mmol), 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (176 mg, 0.78 mmol), triethylamine (238 mg, 2.35 mmol), Cu(OAc)2 (214 mg, 1.17 mmol), dioxane (5 mL) and 4A MS (100 mg) was stirred at 80 °C under an oxygen atmosphere overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC to give the title product (52 mg). MS (ESI, m / e) [M+H] + 434.0.

[0319] Step 11: 7-(5-(Dimethylamino)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0320] A mixture of 2-chloro-7-(5-(dimethylamino)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.23 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (53 mg, 0.34 mmol), Cs2CO3 (17.5 mg, 0.23 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (19.3 mg, 0.02 mmol) and dioxane (5 mL) was stirred overnight at 100° C. The resulting mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (5.4 mg). 1 H NMR (300MHz, CD3OD) δ8.77(s,1H),8.13–8.01(m,1H),7.86–7.77(m,1H),7.76–7.64(m,1H),7.05(s,1H),5.08–4.97(m,1H),4.01–3.80( m,3H),3.73–3.54(m,1H),3.44–3.34(m,1H),3.24(s,3H),3.15–2.80(m,10H),2.68–2.36(m,4H),2.13–2.02(m,1H),1.74-1.58(m,1H). MS(ESI,m / e)[M+H] + 515.1.

[0321] Example 12: 7-(1-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0322]

[0323] Synthetic route

[0324]

[0325] Step 1: 5-Bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine

[0326]

[0327] To a mixture of 5-bromo-2,3-dihydro-1H-inden-1-one (5.0 g, 24 mmol), THF (120 mL), dimethylamine (59.5 mL, 119 mmol, 2 M in THF) was added TiCl4 (47.6 mL, 47.6 mmol, 1 M in DCM) at 0-5°C. The resulting solution was stirred at the same temperature for 2 hours. STAB (15.1 g, 71.4 mmol) was subsequently added at 0°C. The resulting solution was stirred at room temperature overnight. The mixture was quenched by adding water (100 mL) and the pH was adjusted to 8 with NaHCO3. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified by reverse phase HPLC to give the title product (3.5 g). MS (ESI, m / e) [M+H] + 240.1.

[0328] Step 2: (1-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl)boronic acid

[0329]

[0330] To a mixture of 5-bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine (3.50 g, 14.6 mmol) in THF (40 mL) was added n-butyl lithium (11.7 mL, 29.3 mmol, 2.5 M in THF) at -78 ° C. The mixture was stirred at the same temperature for 1 hour. Then, triisopropyl borate (44 g, 23 mmol) was added at -78 ° C. The resulting solution was stirred at room temperature overnight. The mixture was quenched with MeOH (20 mL) at 0 ° C. The resulting mixture was concentrated. The residue was purified by reverse phase HPLC to give the title product (1.6 g). MS (ESI, m / e) [M + H] + 206.1.

[0331] Step 3: 2-Chloro-7-(1-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0332]

[0333] A mixture of (1-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)boronic acid (1.5 g, 7.3 mmol), TEA (2.22 g, 22.0 mmol), copper acetate (1.99 g, 10.9 mmol), dioxane (15 mL) and 4A MS (1.5 g), 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1.64 g, 7.3 mmol) was stirred at 80 °C for 2 hours under an oxygen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC to give the title product (300 mg). MS (ESI, m / e) [M+H] + 384.0.

[0334] Step 4: 7-(1-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0335] A mixture of 2-chloro-7-(1-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (300 mg, 0.78 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (179 mg, 1.17 mmol), Cs2CO3 (764 mg, 2.34 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (67 mg, 0.08 mmol) and dioxane (5 mL) was stirred at 90° C. overnight. The resulting mixture was concentrated. The residue was purified by silica gel column to give the title compound (70 mg). 1 H NMR(300MHz,CD3OD)δ8.64(s,1H),7.55–7.47(m,1H),7.40–7.33(m,1H),7.29–7.20(m,1H),6.79(s,1H),4.53–4.40(m,1H),3 .99–3.72(m,3H),3.60–3.52(m.1H),3.45–3.36(m,1H),3.19–2.81(m,9H),2.32(s,6H),2.27–2.10(m,3H),1.66–1.52(m,1H). MS(ESI,m / e)[M+H] + 465.2.

[0336] Example 13: 7-(3'-(dimethylamino)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-6'-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0337]

[0338] Synthetic route

[0339]

[0340] Step 1: 6-Bromo-1-methylene-2,3-dihydro-1H-indene

[0341]

[0342] To a stirred solution of 6-bromo-2,3-dihydro-1H-indene-1-one (5.0 g, 24 mmol) and bromo(methyl)triphenyl-λ5-phosphine (16.9 g, 47.4 mmol) in THF (100 ml) was added t-BuOK (47.6 mL, 47.6 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (3.7 g).

[0343] Step 2: 6'-Bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]

[0344]

[0345] To a stirred solution of 6-bromo-1-methylene-2,3-dihydro-1H-indene (3.6 g, 17 mmol) and ICH2Cl (24.2 g, 138 mmol) in DCE (122 mL) was added ZnEt2 (103 mL, 103.00 mmol) dropwise at 0 ° C. The mixture was stirred at room temperature for 3 hours. The reactant was quenched with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (2.5 g).

[0346] Step 3: 6'-bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-one

[0347]

[0348] To a stirred solution of 6'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (2.0 g, 9.0 mmol) and KH2PO4 (2.44 g, 17.9 mmol) in t-BuOH / H2O (20 mL / 10 mL) was added Na2HPO4 (2.55 g, 17.9 mmol) and KMnO4 (2.12 g, 13.4 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1.2 g). MS (ESI, m / e) [M+H] + 236.9.

[0349] Step 4: (E)-N-(6'-bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-ylidene)-2-methylpropane-2-sulfenamide

[0350]

[0351] To a stirred solution of 6'-bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-one (1.34 g, 5.65 mmol) and 2-methylpropane-2-sulfinamide (1.37 g, 11.3 mmol) in THF (20 ml) was added Ti(OEt)4 (3.87 g, 17.0 mmol). The resulting mixture was stirred at 80 °C for 4 hours. The reactants were quenched with water. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1.24 g). MS (ESI, m / e) [M+H] + 340.0.

[0352] Step 5: N-(6'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-yl)-2-methylpropane-2-sulfenamide

[0353]

[0354] A mixture of (E)-N-(6'-bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-ylidene)-2-methylpropane-2-sulfinamide (1.24 g, 3.64 mmol) and NaBH4 (276 mg, 7.28 mmol) in MeOH (24 mL) was stirred at room temperature for 2 hours. The reactant was quenched with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (770 mg). MS (ESI, m / e) [M+H] + 342.0.

[0355] Step 6: 6'-Bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-amine

[0356]

[0357] A solution of N-(6'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-yl)-2-methylpropane-2-sulfinamide (770 mg, 2.24 mmol) and HCl (4M in 1,4-dioxane) (1.7 mL, 6.74 mmol) in 1,4-dioxane (11.5 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0358] Step 7: 6'-Bromo-N,N-dimethyl-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-amine

[0359]

[0360] To a mixture of 6'-bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-amine (550 mg, 2.31 mmol) and NaOAc (189 mg, 2.31 mmol) in DCE (25 mL) was added AcOH (10 mL) and formaldehyde (694 mg, 23.1 mmol). The resulting mixture was stirred at 50 ° C for 2 hours. STAB (1.47 g, 6.93 mmol) was added to the above mixture at 50 ° C. The resulting mixture was stirred at 50 ° C for another 2 hours. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (390 mg). MS (ESI, m / e) [M+H] +266.0.

[0361] Step 8: N,N-dimethyl-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-amine

[0362]

[0363] To a mixture of 6'-bromo-N,N-dimethyl-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-amine (390 mg, 1.46 mmol) and bis(pinacolato)diboron (556 mg, 2.19 mmol) in 1,4-dioxane (6 mL) was added KOAc (287.6 mg, 2.93 mmol) and Pd(dppf)Cl2 (107 mg, 0.14 mmol). The resulting mixture was stirred at 80 °C for 2 hours. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title product (250 mg). MS (ESI, m / e) [M+H] + 314.0.

[0364] Step 9: (3'-(Dimethylamino)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-6'-yl)boronic acid

[0365]

[0366] To a mixture of N,N-dimethyl-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-amine (250 mg, 0.79 mmol) and sodium periodate (512 mg, 2.34 mmol) in THF / H2O (4 mL / 1 mL) was added HCl (1 M, 0.56 mL, 0.55 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title product (110 mg). MS (ESI, m / e) [M+H] + 232.0.

[0367] Step 10: 2-Chloro-7-(3'-(dimethylamino)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-6'-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0368]

[0369] To a stirred solution of (3'-(dimethylamino)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-6'-yl)boronic acid (110 mg, 0.47 mmol) and 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (132 mg, 0.58 mmol) in ACN was added copper acetate (86 mg, 0.47 mmol) and TEA (0.13 ml, 0.95 mmol). To the above mixture was added 4A MS. The resulting mixture was stirred at 80 °C under an oxygen atmosphere overnight. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title product (70 mg). MS (ESI, m / e) [M+H] + 410.0.

[0370] Step 11: 7-(3'-(dimethylamino)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-6'-yl)-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

[0371] To a mixture of 2-chloro-7-(3'-(dimethylamino)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-6'-yl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (104 mg, 0.25 mmol) and (3S,4R)-4-aminooxan-3-ol hydrochloride (58 mg, 0.38 mmol) in 1,4-dioxane (2.4 mL) was added CsCO (247.6 mg, 0.76 mmol) and [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (21.3 mg, 0.03 mmol). The resulting mixture was stirred at 100° C. overnight. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (60 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title product (10.9 mg). 1HNMR(300MHz,CD3OD)δ8.62(s,1H),7.50–7.43(m,1H),7.23–7.18(m,1H) ,6.87–6.81(m,1H),6.77(s,1H),4.62–4.51(m,1H),3.97–3.77(m,3H),3 .61–3.48(m,1H),3.47–3.35(m,1H),3.19–3.08(m,1H),2.93(s,6H),2.3 8–2.22(m,7H),2.21–2.04(m,2H),1.67–1.51(m,1H),1.16–0.92(m,4H). MS(ESI,m / e)[M+H] + 491.3.

[0372] Determination

[0373] Biochemical assays

[0374] CDK4 / cyclin D1 and CDK6 / cyclin D3 biochemical assays

[0375] Compounds disclosed herein were tested for inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinases in an assay based on the time-resolved fluorescence resonance energy transfer (TR-FRET) method. The assay was performed in a 384-well low-volume black plate in a reaction mixture containing CDK4 / cyclin D1 or CDK6 / cyclin D3, 1 mM ATP, 0.15 μM Rb (Ser780)-biotin substrate and 0-10 μM compound in a buffer containing 50 mM HEPES pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 50 mM MgCl2, 1 mM DTT and 0.005% Tween-20. The kinase was incubated with the compound at room temperature for 60 minutes and the reaction was initiated by adding ATP and Rb (Ser780)-biotin substrate. After 120 min of reaction at room temperature, an equal volume of stop / detection solution was added according to the manufacturer's instructions (Cisbio Bioassays). The stop / detection solution contained streptavidin-XL665 and anti-pRb(Ser780) mAb-Eu cryptate in detection buffer (Cisbio Bioassays). The plates were incubated for 60 min at room temperature and TR-FRET signals (ex337 nm, em665 nm / 620 nm) were recorded on a PHERAstarFSX microplate reader (BMG Labtech). The percentage inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinase activity in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. The data were fitted to a four-parameter logistic equation by Dotmatics to obtain the IC for each compound. 50 .

[0376] Active Table

[0377] Each compound in Table 1 was tested in one or more CDK4 biochemical assays and found to be active therein.

[0378] Table 1.

[0379]

[0380]

[0381]

[0382] It will be appreciated that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

[0383] In the following claims and in the foregoing description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises / comprising" are used in an inclusive sense, i.e. specifying the presence of the stated features in various embodiments of the invention rather than excluding the presence of additional features or the addition of additional features.

[0384] Although the foregoing invention has been described in some detail by way of illustration and example for the purpose of clear understanding, it is obvious to those skilled in the art that some minor changes and modifications will be implemented. Therefore, the description and examples should not be construed as limiting the scope of the invention.

[0385] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, in: R a and R b are each independently hydrogen or substituted or unsubstituted C 1-8 alkyl; or R a and R b With R a and R b The attached nitrogens together form a substituted or unsubstituted non-aromatic heterocyclic group; R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted saturated cycloalkylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl; or R 1 and R 2 With R 1 and R 2 The atoms to which they are attached together form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted non-aromatic heterocyclic group.

2. The compound according to claim 1, wherein the compound is a compound of formula (Ia): or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, R c and R d are each independently hydrogen or substituted or unsubstituted C 1-8 alkyl; or R c and R d With R c and R d The attached nitrogens together form a substituted or unsubstituted non-aromatic heterocyclic group; and n is 1, 2 or 3.

3. The compound according to claim 1, wherein the compound is a compound of formula (Ib): or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof.

4. The compound according to claim 3, wherein the compound is a compound of formula (II): or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, in: R 2 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted cycloalkyl.

5. The compound as claimed in claim 4, wherein R 2 It is hydrogen, F, Cl, -CF3 or cyclopropyl.

6. The compound as claimed in claim 5, wherein R 2 It is -Cl.

7. The compound as claimed in claim 5, wherein R 2 For hydrogen.

8. The compound of claim 5, wherein R 2 It is cyclopropyl.

9. The compound of claim 5, wherein R 2 For F.

10. The compound of claim 5, wherein R 2 It is -CF3.

11. The compound according to claim 3, wherein the compound is a compound of formula (III): or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, in: R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl; or R 3 and R 4 With R 3 and R 4 The atoms to which they are attached together form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted non-aromatic heterocyclyl group; and n is 1, 2 or 3.

12. The compound of claim 11, wherein R 3 and R 4 is F; and n is 2.

13. The compound of claim 11, wherein R 3 and R 4 With R 3 and R 4 The attached atoms together form a cyclopropyl group; and n is 1.

14. The compound of claim 11, wherein R 3 and R 4 With R 3 and R 4 The attached atoms together form a cyclopropyl group; and n is 2.

15. The compound of claim 11, wherein R 3 and R 4 is H; and n is 1.

16. The compound of claim 11, wherein R 3 and R 4 is H; and n is 2.

17. The compound according to claim 3, wherein the compound is a compound of formula (IV): or a pharmaceutically acceptable salt, tautomer, stereoisomer or enantiomer thereof, in: R 5 and R 6 are each independently hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl; or R 5 and R 6 With R 5 and R 6 The atoms to which they are attached together form a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted non-aromatic heterocyclyl group; and n is 1, 2 or 3.

18. The compound of claim 17, wherein R 5 and R 6 is H; and n is 2.

19. The compound of claim 3, wherein R 1 is methyl; and R 2 For H.

20. The compound of any one of claims 1 to 19, wherein the compound is selected from Table 1.

21. A pharmaceutical composition comprising an effective amount of a compound as described in any one of claims 1 to 20, or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

22. A method for inhibiting the activity of a cyclin-dependent kinase in a cell, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof.

23. The method of claim 22, wherein the cyclin-dependent kinase is CDK4.

24. The method of claim 22, wherein the compound is selective for CDK4 over CDK6.

25. The method of claim 24, wherein the compound is selective for CDK4 over CDK1, CDK2, CDK3, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, or CDK11.

26. The method of claim 24, wherein the compound is at least 5-fold selective for CDK4 over CDK6.

27. The method of claim 24, wherein the compound is at least 50-fold selective for CDK4 over CDK6.

28. The method of claim 24, wherein the compound is at least 100-fold selective for CDK4 over CDK6.

29. A method of treating or preventing a CDK4-mediated disorder, the method comprising administering to a subject in need thereof an effective amount of a compound as claimed in any one of claims 1 to 20.

30. A method of treating or preventing a cancer responsive to CDK4 activity, the method comprising administering to a subject in need thereof an effective amount of a compound as claimed in any one of claims 1 to 20.

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