Complex cyclic compounds, compositions thereof, and therapeutic methods using the same

Abstract

Provided herein is a compound having the following structure: [Chemical 1] JPEG2025517629000103.jpg44164 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof (wherein the substituents are as defined herein), a composition comprising an effective amount of the compound, and a method of inhibiting the activity of a cyclin-dependent kinase.

Description

Technical Field

[0001] This specification provides compounds that inhibit cyclin-dependent kinases, methods of using the compounds disclosed herein for the treatment of cancer, and pharmaceutical compositions containing the same.

Background Art

[0002] Human kinases are a large group of enzymes that add a phosphate group (PO 4 3-) 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, and their substrates include proteins, lipids, and nucleic acids [3. Cell Signal. 2004 Sep; 16(9): 983-9. 4. Cell. 2017 Aug 10; 170(4): 605-635.]. Dysregulation of kinases has been confirmed in many diseases including cancer, autoimmunity, neuropathy, diabetes, and cardiovascular diseases. For example, mutated kinases may become constitutively active and thus cause various cellular abnormalities, leading to cancer initiation or proliferation. The use of small molecule inhibitors to inhibit kinase activity has proven to be a successful method for treating cancer and other diseases [5. Expert Rev Anti Cancer Ther. 2018 Dec; 18(12): 1249-1270.]. So far, 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 occupies a large part of the kinase superfamily. In the case of protein targets, protein kinases can phosphorylate amino acids including serine, threonine, tyrosine, and histidine [7. Science. 2002 Dec 6;298(5600):1912-34.]. Protein kinases play a major role in the cell activation process through the antagonistic actions of kinases and phosphatases via the reversible phosphorylation and dephosphorylation of proteins, and since the phosphorylated and non-phosphorylated states of target proteins can have different activity levels, they are important components of cell signaling [8. Biochimie. 2014 Dec;107 Pt B:167-87. 9. Clin Transl Oncol. 2006 Mar;8(3):153-60.]. Different protein kinases including EGFR, BTK, ALK, JAK, PI3K, and CDK have been proven to be good targets for cancer therapeutic development.

[0004] An over-activated cell cycle is a common feature of human cancers [10. Nat Rev Cancer. 2009 Mar;9(3):153-66.]. On the other hand, cyclin is one of the most important core cell cycle regulators. There are four basic cyclin types found in humans, including G1 cyclin, G1 / S cyclin, S cyclin, and M cyclin. To advance the cell cycle, cyclins need to activate or inactivate many target proteins inside the cell. Also, these cyclins drive cell cycle events mainly by cooperating with a family of enzymes called cyclin-dependent kinases (Cdk). The Cdk kinase itself is inactive, but its binding to cyclin activates it, turning the CDK / cyclin complex into a functional holoenzyme that can modify target proteins [11. Orphanet J Rare Dis. 2020 Aug 6;15(1):203. 12. J Mol Biol. 1999 Apr 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 kinome. Of these, 21 are classified as CDKs. Among all the CDKs currently identified, CDK1, CDK2, CDK4, and CDK6 are thought to directly regulate the cell cycle mainly by phosphorylating and inactivating the RB protein and releasing the E2F transcription factor, and the E2F downstream pathway is important for regulating the initiation of DNA replication. Also, CDK4 / 6 is essential for the early onset of G1 and the G1 / S transition [13. Cell Death Differ. 1998 Feb;5(2):132-40. 14. Oncogene. 2016 Sep 15;35(37):4829-35.]. The CDK4 / 6-related pathway is generally dysregulated in many different cancer types such as breast cancer, lung cancer, and pancreatic cancer. Furthermore, there are four approved CDK4 / 6 inhibitors, including palbociclib, ribociclib, abemaciclib, and trilaciclib, which have been approved by the FDA or CDE for use either as a single agent or in combination with endocrine therapy for the treatment of HR+, Her2-breast cancer.This approach shows good efficacy clinically, but CDK4 / 6 inhibitors cause hematotoxicities such as neutropenia and leukopenia to varying degrees, which greatly limit the clinical application of CDK4 / 6 inhibitors. Also, new data showing inhibition of CDK6 / cyclin D3 may cause the blood toxicities observed clinically [15.Cell.2004 Aug 20;118(4):493-504.16.Haematologica.2021 Oct 1;106(10):2624-2632.], while 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.]. Developing CDK4-selective inhibitors may bring advantages including improved efficacy, reduced blood toxicity, and expanded clinical use in many cancers including, but not limited to, breast, lung, pancreatic, prostate, bone, liver, and endometrial cancers.

[0005] Since the protein structure of CDK4 shares very high homology with CDK4, there remains a need to develop CDK4-selective inhibitors. Most of the compounds reported so far are CDK4 / 6 dual inhibitors. Herein, the inventors report compounds with high selectivity for CDK4 over all other kinases including CDK6, which may bring better efficacy, improved toxicity profiles, and the potential to overcome resistance mechanisms.

[0006] The citation or identification of any reference in this section should not be construed as an admission that the reference is prior art to the present application.

Summary of the Invention

Means for Solving the Problems

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

Chemical

[0008] Provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopically substituted form, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0009] Provided herein is a method of 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, isotopically substituted form, stereoisomer, or prodrug thereof. In one embodiment, the CDK kinase is CDK4 kinase.

[0010] Provided herein is a method for treating or preventing CDK-responsive cancer, 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.

Best Mode for Carrying Out the Invention

[0011] Definitions As used herein, the term "CDK" refers to a cyclin-dependent kinase protein that is a member of a family of protein kinases that regulate 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 a CDK, e.g., by binding to the CDK, and (ii) reduces the expression or activity of the CDK. This term also includes naturally occurring variants of CDKs, including CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, and CDK11.

[0012] As used herein, and in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural referents and singular referents unless the context clearly indicates otherwise.

[0013] As used herein and unless otherwise specified, the terms "about" and "approximately," when used in connection with the dosage, amount, or weight percentage of a component of a composition or dosage form, mean a dosage, amount, or weight percentage recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dosage, amount, or weight percentage. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dosage, amount, or weight percentage within 30%, 20%, 15%, 10%, or 5% of the specified dosage, amount, or weight percentage.

[0014] As used herein and unless otherwise specified, the terms “about” and “approximately” are used in connection with a numerical value or values provided to characterize a particular solid form, e.g., a particular temperature or temperature range (such as those describing a melting, dehydration, desolvation, or glass transition temperature); a mass change (such as a mass change as a function of temperature or humidity); a solvent or water content (from the perspective of mass or percentage); or a peak position (such as in an analysis by IR or Raman spectroscopy or XRPD), and indicate that the value or values of the range may deviate to an extent reasonably considered by one of ordinary skill in the art, but still describe the solid form. Techniques for characterizing 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 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 the numerical value or values of the range 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 values of the range. For example, in some embodiments, the value of an XRPD peak position may vary by up to ±0.2° 2θ (or ±0.2 degrees 2θ) and still describe a particular XRPD peak.

[0015] An "alkyl" group is a saturated, partially saturated, or unsaturated straight or branched chain acyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons, and in some embodiments from 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; 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, among others. Examples of unsaturated alkyl groups include vinyl, allyl, -CH=CH(CH 3 ), -CH=C(CH 3 ) 2 , -C(CH 3 )=CH 2 , -C(CH 3 )=CH(CH 3 ), -C(CH 2 CH 3 )=CH 2 , -C≡CH, -C≡C(CH 3 ), -C≡C(CH 2 CH 3 ), -CH 2 C≡CH, -CH 2 C≡C(CH 3 ), and -CH 2 C≡C(CH 7 CH 3) Examples include, but are not limited to these. The alkyl group may be substituted or unsubstituted. When the alkyl groups described herein are said to be "substituted", they include any substituent or plurality of substituents as found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, dialkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, B(OH) 2 , or may be substituted with O(alkyl)aminocarbonyl.

[0016] The "cycloalkyl" group is a saturated, partially saturated, or unsaturated cyclic alkyl group having 3 to 10 carbon atoms with a single cyclic ring, or multiple fused rings or bridged rings, which may be optionally substituted with 1 to 3 alkyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl containing more than one ring may be fused, spiro, or bridged, or a combination thereof. Examples of 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, inter alia, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. The cycloalkyl group may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include, for example, cyclohexanol, etc.

[0017] The "aryl" group is an aromatic carbocyclic group having 6 to 14 carbon atoms with a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group has 6 to 14 carbons in the ring portion of the group, while in other embodiments, it has 6 to 12 or even 6 to 10 carbon atoms. Specific aryls include phenyl, biphenyl, naphthyl, etc. The aryl group may be substituted or unsubstituted. The term "aryl group" also includes groups containing fused rings, such as fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0018] "Heterocyclyl" is an aromatic (also called heteroaryl) or non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In some embodiments, the heterocyclyl group contains 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyl can also be attached to other groups at any ring atom (i.e., any carbon or heteroatom of the heterocyclic ring). The heterocyclyl group may be substituted or unsubstituted. Examples of heterocyclyl groups include, but are not limited to, bicyclic rings, tricyclic rings, and tetracyclic rings, as well as bridged or spirocyclic ring systems, and multiple fused rings. Heterocyclyl groups include unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidine-2,4-dione-yl) groups. The term heterocyclyl includes, for example, fused ring species that include fused aromatic and non-aromatic groups such as 1- 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. This term also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidine-2,4 - dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin - 2 - onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro - 2H - pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiynyl, dihydrodithionyl, 1,4 - dioxaspiro[4.5]decanil, homopiperazinyl, quinuclidinyl, indolyl (e.g., indolyl - 2 - onyl or isoindolin - 1 - onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or 1H - pyrrolo[2,3 - b]pyridyl), 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, benzodithiynyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (e.g., 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[4,5 - b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,groups such as 4-dihydroisoquinolin-1(2H)-onyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl, but are not limited thereto. Representative non-aromatic heterocyclyl groups do not include fused ring species containing a fused aromatic group. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decan-1-yl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono-substituted or multi-substituted, and may be 2-, 3-, 4-, 5-, or 6-substituted with various substituents such as those described below, or may be a di-substituted pyridyl or morpholinyl group, but are not limited thereto.,

[0019] A "heteroaryl" group is an aryl ring system having a heteroaromatic ring system with 1 to 4 heteroatoms as ring atoms, and the remaining atoms of the ring system are carbon atoms. In some embodiments, the heteroaryl group has 3 to 6 ring atoms in the ring portion of the group, and in other embodiments, 6 to 9 or 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 pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindoline-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), 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, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups, among others, but not limited thereto.

[0020] As used herein, a "spirocyclic ring" refers to two or more rings in which adjacent rings are joined through a single atom. The individual rings within a spirocyclic ring may be the same or different. The individual rings within a spirocyclic ring may be substituted or unsubstituted, and may have substituents different from those of the other individual rings within a set of spirocyclic rings.

[0021] The "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. The substituted cycloalkylalkyl group may be substituted in 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.

[0022] The "aralkyl" group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are as defined above. The substituted aralkyl group may be substituted in 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.

[0023] The "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as defined above. The substituted heterocyclylalkyl group may be substituted in the alkyl, heterocyclyl, or both the 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.

[0024] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0025] The "hydroxyalkyl" group is the above alkyl group substituted with one or more hydroxy groups.

[0026] An "alkoxy" or "alkoxyl" group is -O-(alkyl), where alkyl is as defined above.

[0027] An "alkoxyalkyl" group is -(alkyl)-O-(alkyl), where alkyl is as defined above.

[0028] An "amino" group is a radical of the formula: -NH 2 as defined above.

[0029] An "alkylamino" group is a radical of the formula: -NH-alkyl or -N(alkyl) 2 where each alkyl is independently as defined above.

[0030] A "carboxy" group is a radical of the formula: -C(O)OH.

[0031] An "aminocarbonyl" group is a radical of the formula: -C(O)N(R # ), -C(O)NH(R 2 ), or -C(O)NH # where each R 2 is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclic group as defined herein. # is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclic group as defined herein.

[0032] An "acylamino" group is a radical of the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ) where each alkyl and R # is independently as defined above.

[0033] A "sulfonylamino" group is a radical of the formula: -NHSO 2 (R # ) or -N(alkyl)SO 2 (R # ) where each alkyl and R# is as defined above.

[0034] The "urea" group has the formula: -N(alkyl)C(O)N(R # ) 2 , -N(alkyl)C(O)NH(R # ), -N(alkyl)C(O)NH 2 , -NHC(O)N(R # ) 2 , -NHC(O)NH(R # ), or -NH(CO)NHR # radicals, where each alkyl and R # is independently as defined above.

[0035] With the exception of alkyl groups, when the groups described herein are said to be "substituted", they may be substituted with any suitable substituent or substituents. Exemplary examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamino, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, oxo (=O), B(OH) 2, O(alkyl)aminocarbonyl, cycloalkyl which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy.

[0036] As used herein, the term “pharmaceutically acceptable salt(s)” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and inorganic bases as well as organic acids and organic bases. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to, those well known in the art, for example, Remington’s Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995). See also.

[0037] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" means one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more 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 more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. A compound can have chiral centers and can exist as a racemate, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0038] The use of such compounds in stereoisomerically pure form, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers may be synthesized asymmetrically or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0039] It should also be noted that a compound can include E isomers and Z isomers, or mixtures thereof, as well as cis isomers and trans isomers, or mixtures thereof. In certain embodiments, the compound is isolated as either the E isomer or the Z isomer. In other embodiments, the compound is a mixture of the E isomer and the Z isomer.

[0040] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric forms can vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in an aqueous solution, pyrazole can exhibit the following isomeric forms, which are called tautomers of each other:

Chemical formula

[0041] As will be readily understood by those skilled in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the present invention.

[0042] It should also be noted that a compound may contain unnatural proportions of atomic isotopes in one or more of its atoms. For example, a compound may be radiolabeled with a radioactive isotope such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N). As used herein, an "isotope molecular species" is a compound that is isotopically enriched. 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 having at least one atom with an isotopic composition other than the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled compounds and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds described herein are intended to be encompassed within the scope of the embodiments provided herein, whether radioactive or not. In some embodiments, isotope molecular species of the compounds are provided, e.g., the isotope molecular species is a compound enriched with deuterium, carbon-13, or nitrogen-15.

[0043] As used herein, "treating" means reducing, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or delaying or halting further progression or worsening of those symptoms, or reducing or eradicating the cause(s) of the disorder, disease, or condition itself. In some embodiments, "treating" means reducing, in whole or in part, a disorder, disease, or condition, or delaying or halting further progression or worsening of those symptoms. In another embodiment, "treating" means reducing, in whole or in part, a disease, disorder, or condition, or a symptom associated with the condition, where the condition is treatable or preventable by inhibition of a CDK, such as CDK4.

[0044] As used herein, "preventing" means a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, preventing a subject from acquiring the disorder, disease, or condition, or reducing the risk that a subject will acquire the disorder, disease, or condition. In one embodiment, the condition is a condition treatable or preventable by inhibition of a CDK, such as CDK4.

[0045] The term "effective amount" in relation to a compound means an amount capable of treating or preventing a disorder, disease, or condition, or a symptom thereof, disclosed herein.

[0046] The term "subject" includes animals including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs. In one embodiment, mammals are included. In another embodiment, humans are included. Compound

[0047] This embodiment can be further fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0048] Aspect 1: Provided herein is a compound of formula (I):

Chem.

[0049] In one embodiment, the compound is a compound of formula (Ia):

Chem.

[0050] In one embodiment, the compound is a compound of formula (Ib):

Chemical formula

[0051] In a preferred embodiment, R 1 is C 1-8 alkyl substituted with amino, alkylamino, or dialkylamino. Embodiment 2: Provided herein is a compound of formula (II):

Chemical formula

[0052] In one embodiment, R 2 is hydrogen, F, Cl, -CF 3 or cyclopropyl.

[0053] In one embodiment, R 2 is Cl.

[0054] In one embodiment, R 2 is hydrogen.

[0055] In one embodiment, R 2 is cyclopropyl.

[0056] In one embodiment, R 2 is F.

[0057] In one embodiment, R 2 is CF 3 .

[0058] Aspect 3: Provided herein is a compound of formula (III): [Chemical formula] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof, wherein R 3 and R 4 each independently is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl; or R 3 and R 4 together with the atom to which R 3 and R 4 are attached form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted non-aromatic heterocyclyl; n is 1, 2, or 3.

[0059] In one embodiment, R 3 and R 4 are F and n is 2.

[0060] In one embodiment, R 3 and R 4 together with the atom to which R 3 and R 4 are attached form cyclopropyl and n is 1.

[0061] In one embodiment, R 3 and R 4 together with the atom to which R 3 and R 4 are attached form cyclopropyl and n is 2.

[0062] In one embodiment, R 3 and R 4 are H and n is 1.

[0063] In one embodiment, R 3 and R 4 are H and n is 2.

[0064] Aspect 4: Provided herein is a compound of formula (IV): [Chemical formula] or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof, wherein each of R 5 and R 6 is independently hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl; or R 5 and R 6 together with the atom to which R 5 and R 6 are attached form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted non-aromatic heterocyclyl; n is 1, 2, or 3.

[0065] In one embodiment, R 5 and R 6 are H and n is 2.

[0066] In one embodiment, R 1 is methyl and R 2 is H.

[0067] In one embodiment, the compound is selected from Table 1.

[0068] Aspect 5: Provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotope-substituted form, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0069] Provided herein is a method of inhibiting the activity of cyclin-dependent kinases in a cell, the method comprising contacting the cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotope-substituted form, stereoisomer, or prodrug thereof.

[0070] In one embodiment, the cyclin-dependent kinase is CDK4.

[0071] In one embodiment, the compound is more selective for CDK4 than for CDK6.

[0072] In one embodiment, the compound is more selective for CDK4 than for CDK1, CDK2, CDK3, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, or CDK11.

[0073] 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.

[0074] In one embodiment, provided herein is a method for treating or preventing a CDK-mediated disorder, 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.

[0075] In one embodiment, provided herein is a method for treating or preventing CDK activity-responsive cancer, 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.

[0076] Method for producing a compound The compounds can be made using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, the compounds of formula (I), formula (II), formula (III), and formula (IV) can be prepared as outlined in Schemes 1-4 below, as well as in the Examples described herein. It should be noted that those skilled in the art know how to modify the procedures described in the exemplary schemes and examples to reach the desired products. General protecting groups can be used to prevent specific functional groups from undergoing unwanted reactions. Exemplary protecting groups are described in “Protective Groups in Organic Synthesis”, 4 th Edition, P.G.M. Wuts; T.W. Greene, John Wiley, 2007, and references cited therein.

[0077]

Chemical formula

[0078] As shown in Scheme 1, in some embodiments, a method for preparing a compound defined as formula (I) is provided herein. Compound 1-1 (X can be halogen, boronic acid, or boronic ester) is converted to Compound 1-3 under Chan-Lam or Ullman coupling reaction conditions (e.g., Cu(OAc)2, pyridine, dioxane, oxygen). Compound 1-3 is then converted to a compound defined as formula (I) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs 2 CO 3 , dioxane, etc.).

[0079] [Chemistry]

[0080] As shown in Scheme 2, in some embodiments, methods for preparing the compounds defined as formula (II) are provided herein. Compound 2-1 (where X can be halogen, boronic acid, or boronic 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 the compound defined as formula (II) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs 2 CO 3 , dioxane, etc.).

[0081] [Chemistry]

[0082] As shown in Scheme 3, in some embodiments, methods for preparing the compounds defined as formula (III) are provided herein. Compound 3-1 (where X can be halogen, boronic acid, or boronic 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 the compound defined as formula (III) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs 2 CO 3 , dioxane, etc.).

[0083] [Chemistry]

[0084] As shown in Scheme 4, in some embodiments, methods for preparing the compounds defined as formula (IV) are provided herein. Compound 4-1 (wherein X can be halogen, boronic acid, or boronic acid ester) is converted to Compound 4-3 under Chan-Lam or Ullman coupling reaction conditions (e.g., Cu(OAc)2, pyridine, dioxane, oxygen). Compound 4-3 is then converted to Compound 4-4 under deprotection conditions (e.g., TFA for deprotecting the Boc group when PG is Boc). Compound 4-4 is converted to the compound defined as formula (IV) under substitution or coupling reaction conditions (e.g., palladium catalyst, Cs 2 CO 3 , dioxane, etc.).

[0085] This embodiment can be further fully understood by referring to the detailed description and examples that are intended to illustrate non-limiting embodiments.

Examples

[0086] The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Unless otherwise indicated, the reactions described below are carried out in an anhydrous solvent under a positive pressure of nitrogen or argon, or using a drying tube, with a rubber septum attached to the reaction flask for the introduction of substrates and reagents by syringe, and the glassware is dried in an oven and / or by heating under vacuum. Unless otherwise specified, all reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. All solvents are redistilled before use. All anhydrous solvents are 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 Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China, and unless otherwise specified, all are eluted with petroleum ether (60 - 90 °C) / ethyl acetate (v / v) and visualized with iodine or a solution of molybdophosphoric acid in ethanol. Unless otherwise specified, all extraction solvents are dried over anhydrous Na 2 SO 4 and dried. 1 1H NMR spectra were recorded on a Bruck - 400 or Varian instrument operating at 300 MHz, 400 MHz, or 500 MHz. 1 1H - NMR spectra were recorded using CDCl 3 , CD 2 Cl 2 , CD 3 OD, D 2 O, d 6 -DMSO, d 6 -acetone, or (CD 3 ) 2 CO as the solvent, and tetramethylsilane (0.00 ppm) or residual solvent (CDCl 3 : 7.25 ppm; CD 3 OD: 3.31 ppm; D 2 O: 4.79 ppm; d 6 -DMSO: 2.50 ppm; d 6-Acetone: 2.05; (CD 3 ) 2 CO: 2.05) was obtained using. The association constants are shown 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, and br represents a broad line. LC / MS data were recorded 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 for the reagents were generated by ChemDraw® 19.1.

[0087] In the following examples, the following abbreviations are used. AcOH Acetic acid Aq. Aqueous solution BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene Brine Saturated aqueous sodium chloride solution Bn Benzyl BnBr Benzyl bromide Boc Tert-butoxycarbonyl CH 2 Cl 2 or DCM Dichloromethane CAN Cerium(IV) ammonium nitrate (Ceric ammonium nitrate) DAST Diethylaminosulfur trifluoride DMF N,N-Dimethylformamide Dppf 1,1'-Bis(diphenylphosphino)ferrocene DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DHP 3,4-Dihydro-2H-pyran DIEA or DIPEA N,N-Diisopropylethylamine DMAP 4-N,N-Dimethylaminopyridine DMB (2,4-Dimethoxyphenyl)methanamine Death Martin / DMP Death Martin Perjodinan DMF N,N-Dimethylformamide DMF-DMA N,N-Dimethylformamide Dimethyl Acetal Plum DMSO Dimethyl Sulfoxide DMEDA Dimethylethylenediamine EDCI 1-Ethyl-3-(3-dimethylpropyl)carbodiimide Hydrochloride EtOAc or EA Ethyl Acetate EtOH Ethanol Et 3 SiH Triethylsilyl Hydride Et 2 O or Ether Diethyl Ether g Gram h or hr Hour HATU O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium Hexafluorophosphate Hex Hexane HCl Hydrochloric Acid HMDS Hexamethyldisilazane HOBT 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography IBX 2-Iodoxybenzoic Acid i-PrOH Isopropyl Alcohol LCMS Liquid Chromatography-Mass Spectrometry LDA Lithium Diisopropylamide LiHMDS Lithium Bis(trimethylsilyl)amide K 2 OsO 4· H2O Potassium Osmium(VI) Acid Dihydrate mg Milligram mL Milliliter mmol Millimole MeCN Acetonitrile MeOH Methanol Min Minute ms or MS Mass Spectrum m-CPBA m-Chloroperbenzoic acid MPLC Medium Pressure Liquid Chromatography Na Sodium 2 SO Sulfur dioxide 4 Sodium sulfate NaBH(OAc) Sodium triacetoxyborohydride 3 / STAB Sodium triacetoxyborohydride NaHMDS Sodium bis(trimethylsilyl)amide NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NMO 4-Methylmorpholine N-oxide NMP N-Methylpyrrolidone PE Petroleum ether PMB (4-Methoxyphenyl)methanamine POCl Phosphorus oxychloride 3 Phosphorous oxychloride PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate PddppfCl [[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) 2 [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd Palladium 2 (dba) Tris(dibenzylideneacetone)dipalladium 3 Tris(dibenzylideneacetone)dipalladium Prep Preparative PTSA 4-Methylbenzenesulfonic acid Rt or rt Room temperature sat. Saturated SEMCl (2-(Chloromethoxy)ethyl)trimethylsilane TBSCl tert-Butyldimethylsilyl chloride TEA / Et3N Triethylamine t-BuOK Potassium tert-butoxide t-BuONa Sodium tert-butoxide T 3 P n-Propylphosphonic cyclic anhydride TMSCN Trimethylsilyl cyanide TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TLC Thin layer chromatography tBuXPhospd-G3 Methanesulfonato(2-di-t-butylphosphino-2’,4’,6’-tri-i-propyl-1,1’-biphenyl)(2’-amino-1,1’-biphenyl-2-yl)palladium(II) tBuXPhos 2-Di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl UHP Urea hydrogen peroxide Μl Microliter Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl 4CzIPN (4r,6r)-2,4,5,6-Tetra(9H-carbazol-9-yl)iso-phthalonitrile

[0088] Synthesis of compounds

[0089] 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

Chem.

[0090] Synthesis route

Chem.

[0091] Step 1: 2-Chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Chem.

[0092] 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. Then, dimethylamine hydrochloride (137 mg, 1.70 mmol), DIEA (291 mg, 2.26 mmol), and HATU (515 mg, 1.36 mmol) were added. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture 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.

[0093] 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

[0094] 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 added to a 50 mL round-bottom flask. The resulting solution was stirred at 120 °C for 1 hour. The reaction 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 (400 MHz, DMSO-d 6) δ 8.56 (s, 1H), 6.79 - 6.70 (m, 1H), 6.47 (s, 1H), 5.00 - 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.

[0095] 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

Chemical formula

[0096] Synthetic route

Chemical formula

[0097] Step 1: 2 - Chloro - N,N - dimethyl - 7-(p - tolyl)-7H - pyrrolo[2,3 - d]pyrimidine - 6 - carboxamide

Chemical formula

[0098] 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 K 2 CO3( A mixture of (246 mg, 1.785 mmol) was stirred at 90 °C for 16 h. 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 Na 2 SO 4 and concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC (PE / EA = 3:1) to give the title product (70 mg). MS (ESI, m / e) [M+H] + 315.2.

[0099] 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

[0100] 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), Cs 2 CO 3 (145 mg, 0.444 mmol), and Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (15.6 mg, 0.02 mmol) in dioxane (1 mL) was stirred at 100 °C for 16 h. 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 (300 MHz, CDCl 3) δ 8.57 (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.

[0101] 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

Chemical Structure

[0102] Synthesis Route

Chemical Structure

[0103] Step 1: 1-(4-Iodophenyl)-N,N-dimethylmethanamine

Chemical Structure

[0104] To a solution of 4-iodobenzaldehyde (1.5 g, 6.49 mmol) in DCE (10 mL) and MeOH (10 mL), dimethylamine (6.46 mL, 12.9 mmol, 2 M in THF) was added 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 H 2It was quenched with O and extracted with EtOAc. The organic layer was concentrated. The residue was purified by silica gel column (PE:EtOAc = 100:0~50:50). Thus, the title product (1.0 g) was obtained. MS (ESI, m / e) [M+H] + 261.9.

[0105] Step 2: 2-Chloro-7-(4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Chem.

[0106] Into a 40 mL vial, 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), K 2 CO 3 (528 mg, 3.83 mmol), CuI (36 mg, 0.192 mmol), and DMSO (5 mL) were added. The resulting mixture was stirred at 90 °C for 16 h. The mixture was quenched with H 2 O and extracted with EtOAc. The organic layer was concentrated. The residue was purified by preparative TLC to obtain the title product (80 mg). MS (ESI, m / e) [M+H] + 358.1.

[0107] 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

[0108] In a 20 mL vial, 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), Cs 2 CO 3 (219 mg, 0.67 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (18 mg, 0.02 mmol), and dioxane (1 mL) were added. The mixture was stirred at 90 °C overnight. The resulting mixture was concentrated. The residue was subjected to a silica gel column using DCM / MeOH (6:1) to obtain the crude product. The crude product was purified by preparative HPLC to obtain the title product (9.3 mg). 1 H NMR (300 MHz, CD 3 OD) δ 8.79 (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.

[0109] 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

Chemical Structure

[0110] Synthetic Route

Chem.

[0111] Step 1: 1-(2-Bromo-4-nitrophenyl)-N,N-dimethylmethanamine

Chem.

[0112] 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.

[0113] Step 2: 1-(2-Cyclopropyl-4-nitrophenyl)-N,N-dimethylmethanamine

Chem.

[0114] Toluene / H 2 O (30 mL / 10 mL) 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), tricyclohexylphosphane (0.65 g, 2.3 mmol), and K 3 PO 4A solution of (11.06 g, 52.1 mmol) 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.

[0115] Step 3: 3-Cyclopropyl-4-((dimethylamino)methyl)aniline

Chem.

[0116] A solution of 1-(2-Cyclopropyl-4-nitrophenyl)-N,N-dimethylmethanamine (1.3 g, 5.90 mmol) in THF (13 mL) was stirred at room temperature overnight 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.

[0117] Step 4: (3-Cyclopropyl-4-((dimethylamino)methyl)phenyl)boronic acid

Chem.

[0118] HCl (3M) / MeOH / H 2 3-Cyclopropyl-4-((dimethylamino)methyl)aniline (1.1 g, 5.8 mmol) and NaNO 2A mixture of (0.40 g, 5.8 mmol) was stirred at 0 °C for 30 minutes. To the above mixture, diboronic acid (1.55 g, 17.3 mmol) was added 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 obtain the title product (400 mg). MS (ESI, m / e) [M+H] + 220.0.

[0119] Step 5: 2-Chloro-7-(3-cyclopropyl-4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Chemical Structure

[0120] 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 for 16 hours under an oxygen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (CH 2 Cl 2 / MeOH = 10:1) to obtain the title product (80 mg). MS (ESI, m / e) [M+H] + 398.1.

[0121] 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

[0122] 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), Cs 2 CO 3 (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]dichloropalladium(II) (2-methylpyridine) (17 mg, 0.02 mmol), and (3S,4R)-4-aminooxan-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 (300 MHz, CD 3 OD) δ 8.74 (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.

[0123] 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

Chem.

[0124] Synthesis route

Chem.

[0125] Step 1: 1-(4-Bromo-2-fluorophenyl)-N,N-dimethylmethanamine

Chem.

[0126] To a 250 mL round-bottom flask, 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 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 reaction was quenched with saturated NH 4 Cl (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 Na 2 SO 4 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product (1.2 g). MS (ESI, m / e) [M+H] + 232.1.

[0127] Step 2: (4-((Dimethylamino)methyl)-3-fluorophenyl)boronic acid

Chem.

[0128] To a mixture of 1-(4-bromo-2-fluorophenyl)-N,N-dimethylmethanamine (1.0 g, 4.3 mmol) and THF (10 mL) was added n-butyllithium (5.19 mL, 12.9 mmol, 2.5 M in THF). The reaction mixture was stirred at -78 °C for 30 minutes. Then, a solution of triisopropyl borate (2.03 g, 10.77 mmol) in THF (2 mL) was added dropwise and the mixture was stirred for an additional 1 hour. The reaction was quenched with NH 4 Cl (aqueous solution) and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give the title product (300 mg). MS (ESI, m / e) [M+H] + 198.2.

[0129] Step 3: 2-Chloro-7-(4-((dimethylamino)methyl)-3-fluorophenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Chemical formula

[0130] To a 20 mL bottom flask were added (4-((dimethylamino)methyl)-3-fluorophenyl)boronic 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(II) 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 overnight under an oxygen atmosphere. The residue was purified by silica gel column chromatography to give the title product (160 mg). MS (ESI, m / e) [M+H] + 376.2.

[0131] 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

[0132] To a 10 mL round-bottom flask, 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), Cs 2 CO 3 (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 at room temperature. The resulting mixture was stirred at 100 °C overnight. The residue product was purified by reverse-phase flash to give the title product (13.7 mg). 1 H NMR (400 MHz, CD 3 OD) δ 8.74 (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.

[0133] 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

Chem.

[0134] Synthetic route

Chem.

[0135] Step 1: 1-(4-bromo-2-chlorophenyl)-N,N-dimethylmethanamine

Chem.

[0136] 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 obtain the title product (1.2 g). MS (ESI, m / e) [M+H] + 248.0.

[0137] Step 2: (3-chloro-4-((dimethylamino)methyl)phenyl)boronic acid

Chem.

[0138] A solution of 1-(4-bromo-2-chlorophenyl)-N,N-dimethylmethanamine (1.0 g, 4.0 mmol) in THF was treated with butyllithium (0.77 g, 12 mmol) at -78 °C for 1 hour, followed by dropwise addition of triisopropyl borate (1.89 g, 10.0 mmol) 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.

[0139] Step 3: 2-Chloro-7-(3-chloro-4-((dimethylamino)methyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Chemical formula

[0140] (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 a solution of 2-chloro-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (294.6 mg, 1.31 mmol) were stirred at 80 °C for 16 hours under an oxygen atmosphere. 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.

[0141] 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

[0142] 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), Cs 2 CO 3 (174.4 mg, 0.53 mmol), and a solution of (3S,4R)-4-aminooxan-3-ol (31.36 mg, 0.26 mmol) were 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 (12.3 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (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.

[0143] 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

Chemical formula

[0144] Synthetic route

Chemical formula

[0145] Step 1: 1-(4-Bromo-2-(trifluoromethyl)phenyl)-N,N-dimethylmethanamine

Chem.

[0146] To a 250 mL round-bottom flask, MeOH (60 mL), 4-bromo-1-(bromomethyl)-2-(trifluoromethyl)benzene (3.7 g, 12 mmol), and dimethylamine (11.9 mL, 23.8 mmol, 2 M in THF) were added at room temperature. The resulting mixture was stirred at room temperature for 5 h. 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.

[0147] Step 2: (4-((Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)boronic acid

Chem.

[0148] To a solution of 1-(4-bromo-2-(trifluoromethyl)phenyl)-N,N-dimethylmethanamine (1.80 g, 6.38 mmol) in THF (20 mL) in a 50 mL round-bottom flask, n-butyllithium solution (3.3 mL, 8.29 mmol, 2.5 M in hexane) was added dropwise at -78 °C. The reaction mixture was stirred for 60 min. Then, a solution of triisopropyl borate (1.9 g, 10.2 mmol) in THF (4 mL) was added dropwise and the mixture was stirred at room temperature for an additional 60 min. The reaction was quenched with MeOH (50 mL) and the mixture was concentrated under vacuum to give the 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.

[0149] Step 3: 2-Chloro-7-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Chemical Structure

[0150] To a 25 mL vial were added 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) at room temperature. The resulting mixture was stirred at 80 °C for 4 h under an oxygen atmosphere. The residue was purified by preparative TLC (PE / EA = 1:1) to afford the title product (200 mg). MS (ESI, m / e) [M+H] + 426.1.

[0151] 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

[0152] To a 10 mL sealed tube were added 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 oxalate (53.9 mg, 0.35 mmol), Pd-PEPPSI-IPentCl2-methylpyridine-o-picoline (20 mg, 0.023 mmol), and Cs 2 CO 3(229 mg, 0.72 mmol) was added 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 product (5.4 mg). 1 H NMR (300 MHz, CD 3 OD) δ 8.66 (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.

[0153] 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

Chemical formula

[0154] Synthesis route

Chemical formula

[0155] Step 1: tert - Butyl 6 - (2 - chloro - 6 - (dimethylcarbamoyl)-7H - pyrrolo[2,3 - b]pyridin - 5 - yl)-3,4 - dihydroisoquinoline - 2(1H)-carboxylate

Chemical formula

[0156] 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 with Cu(OAc) 2 (0.24 g, 1.33 mmol), pyridine (0.32 g, 4.0 mmol), and 4A MS (0.3 g) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under an oxygen atmosphere. 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 Na 2 SO 4 4. 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 product (0.1 g). MS (ESI, m / e) [M+H] + 456.1.

[0157] Step 2: 2-Chloro-N,N-dimethyl-7-(1,2,3,4-tetrahydroisoquinolin-6-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Chemical Structure

[0158] 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 dropwise TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 1:1) to give the title product (50 mg). MS (ESI, m / e) [M+H] + 356.2.

[0159] 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

Chem.

[0160] 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 h. To the above mixture was added STAB (48 mg, 0.226 mmol) portionwise 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 TCL to give the title product (13 mg). MS (ESI, m / e) [M+H] + 370.2.

[0161] 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

[0162] 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 Cs 2 CO 3(40 mg, 0.12 mmol) and Pd-PEPPSI-IPentCl2-methylpyridine (o-picoline) (3.00 mg, 0.004 mmol) were added little by little at room temperature. The resulting mixture was stirred at 100 °C for 3 hours. The residue was purified by preparative HPLC to obtain the title product (6.1 mg). 1 H NMR (400 MHz, CD 3 OD) δ 8.78 (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.

[0163] 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

Chemical formula

[0164] Synthetic route

Chemical formula

[0165] Step 1: 6-Bromo-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine

Chemical formula

[0166] 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 TiCl 4 (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 h. Then, STAB (6.95 g, 31.0 mmol) was 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 NaHCO 3 . 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.

[0167] Step 2: (5-(Dimethylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid [Chemical formula]

[0168] To a solution of 6-bromo-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine (0.80 g, 3.2 mmol) in THF (10 mL) was added dropwise n-butyllithium solution (1.64 mL, 4.12 mmol, 2.5 M in hexane) at -78 °C. The reaction mixture was stirred at -78 °C for 60 min. Then, a solution of triisopropyl borate (0.95 g, 5.1 mmol) in 2 mL of THF was added dropwise and the mixture was stirred at room temperature for an additional 1 h. The reaction was quenched with MeOH (50 mL). The combined organic phases were concentrated under vacuum and the residue was purified by reverse-phase HPLC to give the title product (0.50 g). MS (ESI, m / e) [M+H] + 220.0.

[0169] 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

Chem.

[0170] To a 25 mL vial were added 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) at room temperature. The resulting mixture was stirred at 80 °C for 4 h under an oxygen atmosphere. The residue was purified by preparative TLC to give the title product. MS (ESI, m / e) [M+H] + 398.2.

[0171] 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

[0172] To a 10 mL sealed tube were added 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-IPentCl2-methylpyridine-o-picoline (21.1 mg, 0.025 mmol), and Cs 2 CO 3(245.7 mg, 0.75 mmol) was added 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 product (4.2 mg). 1 H NMR (300 MHz, CD 3 OD) δ 8.63 (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.

[0173] 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

Chemical Structure

[0174] Synthetic Route

Chemical Structure

[0175] Step 1: 7-Bromo-1-methylene-1,2,3,4-tetrahydronaphthalene

Chemical Structure

[0176] A mixture of bromo(methyl)triphenyl-λ5-phosphane (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. To the above mixture was added 7-bromo-3,4-dihydro-2H-naphthalen-1-one (3 g, 13.33 mmol). The resulting mixture was stirred at 110 °C for an additional 15 minutes. 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 Na 2 SO 4 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title product (1.7 g).

[0177] Step 2: 7'-Bromo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]

Chemical formula

[0178] Diethylzinc (71.7 mL, 71.7 mmol) was added dropwise 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 at 0 °C. The resulting mixture was stirred at 0 °C for 3 hours. The reaction was quenched with saturated NH 4 4Cl (aqueous solution) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na 2 SO 4 2SO4. 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.

[0179] Step 3: 7'-Bromo-2',3'-dihydro-4'H-spiro[cyclopropane-1,1'-naphthalene]-4'-one

Chemical formula

[0180] 7'-Bromo-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene] (1.9 g, 8.0 mmol) in t-BuOH and KMnO 4 (1.90 g, 12.0 mmol) was added portionwise at room temperature to a stirred solution of KH 2 PO 4 (2.18 g, 16.0 mmol) and Na 2 HPO 4 (2.27 g, 16.0 mmol). The resulting mixture was stirred at room temperature for 2 h. 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 afford the title product (1.5 g). MS (ESI, m / e) [M+H] + 251.1.

[0181] Step 4: 7'-Bromo-N,N-dimethyl-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-4'-amine

Chemical formula

[0182] TiCl 4 (8 mL, 8.0 mmol) was added portionwise at 0 °C 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) in THF and dimethylamine (9.96 mL, 19.9 mmol). The resulting mixture was stirred at room temperature for 2 h. 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 an additional 2 h. The reaction was 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 anhydrous Na 2 SO 4It was dried above. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product (700 mg). MS (ESI, m / e) [M+H] + 280.2.

[0183] 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

Chemical Structure

[0184] 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 were added KOAc (385.2 mg, 3.92 mmol) and Pd(dppf)Cl 2 (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 Na 2 SO 4 above. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product (450 mg).

[0185] Step 6: (4'-(Dimethylamino)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-7'-yl)boronic acid

Chemical Structure

[0186] THF / H 2N,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 NaIO 4 (784.2 mg, 3.66 mmol) in a mixture, HCl (0.8 mL, 0.85 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was basified to pH 8 with saturated NaHCO 3 (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 Na 2 SO 4 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.

[0187] 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 [Chemical Structure]

[0188] 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, pyridine (0.18 mL, 1.4 mmol), Cu(OAc) 2(125.9 mg, 0.69 mmol), 4A MS (340 mg) were added at room temperature. The resulting mixture was stirred at 80 °C overnight under an oxygen atmosphere. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 and filtered. 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.

[0189] 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

[0190] 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 were added Cs 2 CO 3 (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]dichloropalladium(II) (2-methylpyridine) (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 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title product (17 mg). 1 1H NMR (300 MHz, CD 3 OD) δ 8.75 (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.

[0191] 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

Chemical Structure

[0192] Synthesis Route

Chemical Structure

[0193] Step 1: 7-Bromo-3,4-dihydro-2H-spiro[naphthalene-1,2'-[1,3]dithiolane]

Chemical Structure

[0194] To a 150 mL round-bottom flask, 7-bromo-3,4-dihydro-2H-naphthalen-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 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).

[0195] Step 2: 7-bromo-1,1-difluoro-1,2,3,4-tetrahydronaphthalene

Chem.

[0196] 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 reaction was stirred at -78 °C for 1 h and then at 0 °C for an additional 12 h. The reaction mixture was quenched with NaHCO 3 and extracted with DCM (3 × 25 ml). The residue was purified by silica gel column chromatography to obtain the title product (5.8 g).

[0197] Step 3: 6-bromo-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one

Chem.

[0198] To a 250 mL round-bottom flask, 7-bromo-1,1-difluoro-1,2,3,4-tetrahydronaphthalene (5.80 g, 23.5 mmol), KMnO 4 (11.1 g, 70.4 mmol), KH 2 PO 4 (12.8 g, 93.9 mmol), Na2 HPO 4 (13.3 g, 93.9 mmol), t-BuOH (60 mL), and H 2 O (36 mL) were added 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 Na 2 SO 4 and concentrated under reduced pressure after filtration. The residue was purified by silica gel column chromatography to give the title product (5.3 g).

[0199] Step 4: (E)-N-(6-Bromo-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-ylidene)-2-methylpropan-2-sulfinamide

Chem.

[0200] To a 100 mL round-bottom flask were added 6-bromo-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-one (5.3 g, 20 mmol), 2-methylpropan-2-sulfinamide (4.92 g, 40.6 mmol), titanium ethoxide (13.9 g, 60.9 mmol), and THF (60 mL) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The reaction was 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.

[0201] Step 5: N-(6-Bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-methylpropan-2-sulfinamide

Chem.

[0202] To a 60 mL round-bottom flask were added (E)-N-(6-bromo-4,4-difluoro-3,4-dihydronaphthalen-1(2H)-ylidene)-2-methylpropane-2-sulfinamide (5.30 g, 14.6 mmol), NaBH 4 (1.10 g, 29.1 mmol), and MeOH (60 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. 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.

[0203] Step 6: 6-Bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-amine

Chemical formula

[0204] To a 100 mL round-bottom flask were added N-(6-bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-methylpropane-2-sulfinamide (5.0 g, 14 mmol) and HCl (gas) in 1,4-dioxane (1.49 g, 40.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to give the title product (2.5 g). MS (ESI, m / e) [M+H] + 262.0.

[0205] Step 7: 6-Bromo-4,4-difluoro-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine

Chemical formula

[0206] To a 50 mL round-bottom flask were added 6-bromo-4,4-difluoro-1,2,3,4-tetrahydronaphthalen-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) at room temperature. The mixture was acidified to pH 8 - 10 with saturated NaHCO 3 (aqueous solution). The resulting mixture was stirred at 50 °C. To the above mixture was added STAB (5.82 g, 27.5 mmol) little by little at room temperature. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography to obtain the title product (1.2 g). MS (ESI, m / e) [M+H] + 289.9.

[0207] 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

Chemical Structure

[0208] To a 50 mL round-bottom flask were added 6-bromo-4,4-difluoro-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine (1.2 g, 4.1 mmol), bis(pinacolato)diboron (2.10 g, 8.27 mmol), Pd(dppf)Cl 2 (0.30 g, 0.41 mmol), KOAc (0.81 g, 8.3 mmol), and dioxane (15 mL) 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 obtain the title product (1 g). MS (ESI, m / e) [M+H] + 338.2.

[0209] Step 9: (5-(Dimethylamino)-8,8-difluoro-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid

Chem.

[0210] To a 50 mL round-bottom flask were added 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 (1.0 g, 2.9 mmol), sodium periodate (1.89 g, 8.83 mmol), THF (12 mL), and H 2 O (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The residue was purified by reverse-phase flash chromatography to give the title product (300 mg). MS (ESI, m / e) [M+H] + 256.1.

[0211] 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

Chem.

[0212] (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) were stirred under an oxygen atmosphere at 80 °C 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.

[0213] 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

[0214] 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), Cs 2 CO 3 (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 at 100 °C overnight. The resulting mixture was concentrated. The residue was purified by preparative HPLC to give the title product (5.4 mg). 1 H NMR (300 MHz, CD 3OD) δ 8.77 (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.

[0215] 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

Chem.

[0216] Synthetic route

Chem.

[0217] Step 1: 5-Bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine

Chem.

[0218] To a mixture of 5-bromo-2,3-dihydro-1H-inden-1-one (5.0 g, 24 mmol), THF (120 mL), and dimethylamine (59.5 mL, 119 mmol, 2 M in THF), TiCl 4(47.6 mL, 47.6 mmol, 1 M in DCM) was added at 0 - 5 °C. The resulting solution was stirred at the same temperature for 2 h. Subsequently, STAB (15.1 g, 71.4 mmol) was 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 NaHCO 3 . The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated. The residue was purified by reverse-phase HPLC to afford the title product (3.5 g). MS (ESI, m / e) [M+H] + 240.1.

[0219] Step 2: (1-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl)boronic acid

Chem.

[0220] 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-butyllithium (11.7 mL, 29.3 mmol, 2.5 M in THF) at -78 °C. The mixture was stirred at the same temperature for 1 h. 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 afford the title product (1.6 g). MS (ESI, m / e) [M+H] + 206.1.

[0221] 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

Chem.

[0222] (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), a mixture of 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 h 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.

[0223] 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

[0224] 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), Cs 2 CO 3 (764 mg, 2.34 mmol), [1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichlorido(2-methylpyridine)palladium (67 mg, 0.08 mol), and a mixture of 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 product (70 mg). 1 H NMR (300 MHz, CD 3OD) δ 8.64 (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, 1H), 2.32 (s, 6H), 2.27 - 2.10 (m, 7H), 1.66 - 2.04 (m, 2H), 1.67 - 1.52 (m, 1H), 1.16 - 0.92 (m, 4H). MS (ESI, m / e) [M+H] + 465.2.

[0225] 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

Chem.

[0226] Synthesis route

Chem.

[0227] Step 1: 6-Bromo-1-methylene-2,3-dihydro-1H-indene

Chem.

[0228] A stirred solution of 6-bromo-2,3-dihydro-1H-inden-1-one (5.0 g, 24 mmol) and bromo(methyl)triphenyl-λ5-phosphane (16.9 g, 47.4 mmol) in THF (100 mL) was added portionwise with t-BuOK (47.6 mL, 47.6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. 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 Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title product (3.7 g).

[0229] Step 2: 6'-Bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]

Chemical formula

[0230] To a stirred solution of 6-bromo-1-methylene-2,3-dihydro-1H-indene (3.6 g, 17 mmol) and ICH 2 Cl (24.2 g, 138 mmol) in DCE (122 mL) was added dropwise with ZnEt 2 (103 mL, 103.00 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated NH 4 Cl (aqueous solution). The resulting mixture was extracted with CH 2 Cl 2 (3 × 150 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title product (2.5 g).

[0231] Step 3: 6'-Bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-one

Chemical formula

[0232] t-BuOH / H 2 6'-Bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene] (2.0 g, 9.0 mmol) and KH 2 PO 4 (2.44 g, 17.9 mmol) in a stirred solution of Na 2 HPO 4 (2.55 g, 17.9 mmol) and KMnO 4 (2.12 g, 13.4 mmol) were added. 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 Na 2 SO 4 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.

[0233] (E)-N-(6'-Bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-ylidene)-2-methylpropan-2-sulfinamide

Chemical Structure

[0234] Ti(OEt) 4 (3.87 g, 17.0 mmol) was added to a stirred solution of 6'-bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-one (1.34 g, 5.65 mmol) and 2-methylpropan-2-sulfinamide (1.37 g, 11.3 mmol) in THF (20 ml). The resulting mixture was stirred at 80 °C for 4 h. The reaction was 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 Na 2 SO4 It was dried above. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product (1.24 g). MS (ESI, m / e) [M+H] + 340.0.

[0235] Step 5: N-(6'-Bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-yl)-2-methylpropan-2-sulfinamide

Chemical formula

[0236] A mixture of (E)-N-(6'-Bromospiro[cyclopropane-1,1'-indene]-3'(2'H)-ylidene)-2-methylpropan-2-sulfinamide (1.24 g, 3.64 mmol) and NaBH 4 (276 mg, 7.28 mmol) in MeOH (24 mL) was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH 4 Cl (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 Na 2 SO 4 above. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product (770 mg). MS (ESI, m / e) [M+H] + 342.0.

[0237] Step 6: 6'-Bromo-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-3'-amine

Chemical formula

[0238] 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 (4 M 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.

[0239] Step 7: 6’-Bromo-N,N-dimethyl-2’,3’-dihydrospiro[cyclopropane-1,1’-indene]-3’-amine

Chemical formula

[0240] 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) were added AcOH (10 mL) and formaldehyde (694 mg, 23.1 mmol). The resulting mixture was stirred at 50 °C for 2 hours. To the above mixture was added STAB (1.47 g, 6.93 mmol) at 50 °C. The resulting mixture was stirred at 50 °C for an additional 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 Na 2 SO 4 2SO4. 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.

[0241] 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

Chemical formula

[0242] 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) were added KOAc (287.6 mg, 2.93 mmol) and Pd(dppf)Cl 2 (107 mg, 0.14 mmol). The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 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 afford the title product (250 mg). MS (ESI, m / e) [M+H] + 314.0.

[0243] Step 9: (3'-(Dimethylamino)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-6'-yl)boronic acid

Chemical Structure

[0244] THF / H 2 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 / H MS (ESI, m / e) [M+H] +232.0.

[0245] 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

Chem.

[0246] 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 were added copper(II) acetate (86 mg, 0.47 mmol) and TEA (0.13 ml, 0.95 mmol). 4A MS was added to the above mixture. The resulting mixture was stirred at 80 °C overnight under an oxygen atmosphere. 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 2SO4. 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.

[0247] 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

[0248] 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 Cs 2 CO 3 (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]dichlorido(2-methylpyridine)palladium(II) (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). 1 H NMR (300 MHz, CD 3 OD) δ 8.62 (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), 2.38 - 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.

[0249] Assay Biochemical assay Biochemical Assays of CDK4 / Cyclin D1 and CDK6 / Cyclin D3

[0250] The 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 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, 1 mM ATP, 0.15 μM Rb(Ser780)-biotin substrate, and 0 - 10 μM of the compound. The kinase was incubated with the compound herein at room temperature for 60 minutes, and the reaction was initiated by adding ATP and the Rb(Ser780)-biotin substrate. After reacting at room temperature for 120 minutes, 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 plate was incubated at room temperature for 60 minutes, and the TR-FRET signal (excitation 337 nm, emission 665 / 620 nm) was recorded with a PHERAstar FSX plate reader (BMG Labtech). The percentage of inhibition of CDK4 / Cyclin D1 or CDK6 / Cyclin D3 kinase activity in the presence of increasing concentrations of the compound was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. The IC 50 of each compound was derived by fitting the data to a four-parameter logistic equation by Dotmatics.

[0251] Table of activities Each of the compounds in Table 1 was tested in one or more of the CDK4 biochemical assays and was found to be active therein.

[0252]

Table 1-1

Table 1-2

Table 1-3

[0253] It should be understood 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.

[0254] In the appended claims and the foregoing description of the invention, except where the context requires otherwise by express language or necessary implication, the term "comprise", or variations such as "comprises" or "comprising", are used in an inclusive sense, that is, to clearly indicate the presence of the recited features, but not to exclude the presence or addition of further features in various embodiments of the invention.

[0255] The foregoing invention has been described in some detail by way of illustration and example for the purpose of clarity of understanding, but it will be apparent to those skilled in the art that certain minor changes and modifications may be made. Accordingly, the description and examples should not be construed as limiting the scope of the invention.

[0256] Numerous references are cited and their disclosures are hereby incorporated by reference in their entirety.

Claims

1. A compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof (wherein: R ａ and R ｂ each of which is, independently, hydrogen, or a substituted or unsubstituted C １－８ alkyl; Alternatively, R ａ and R ｂ are taken together with the nitrogen to which R ａ and R ｂ is attached to form a substituted or unsubstituted non-aromatic heterocyclyl; R １ and R ２ each of which is 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 are, together with the atoms to which R １ and R ２ are attached, forming a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted non-aromatic heterocyclyl).

2. The compound is a compound of formula (Ia): 【Chemical Formula 2】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof, R ｃ and R ｄ each is, independently, hydrogen, or a substituted or unsubstituted C １－８ alkyl; Alternatively R ｃ and R ｄ are, together with the nitrogen to which R ｃ and R ｄ are attached, forming a substituted or unsubstituted non-aromatic heterocyclyl; and n is 1, 2, or 3, a compound according to claim 1.

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

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

5. R ２ is hydrogen, F, Cl, -CF ３ or cyclopropyl, the compound according to claim 4.

6. R ２ The compound according to claim 5, wherein R is Cl.

7. R ２ The compound according to claim 5, wherein R is hydrogen.

8. R ２ The compound according to claim 5, wherein R is cyclopropyl.

9. R ２ The compound according to claim 5, wherein R is F.

10. R ２ is -CF ３ The compound according to claim 5, wherein

11. The compound is a compound of formula (III): 【Chemical 5】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof, wherein, R ３ and R ４ each independently is hydrogen, halogen, substituted or unsubstituted C １－８ alkyl; or R ３ and R ４ are, together with the atom to which R ３ and R ４ is attached, forming a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted non-aromatic heterocyclyl; n is 1, 2, or 3, the compound according to claim 3.

12. R ３ and R ４ is F, and n is 2, the compound according to claim 11.

13. R ３ and R ４ wherein R ３ and R ４ together with the atom to which they are attached form a cyclopropyl, and n is 1, the compound according to claim 11.

14. R ３ and R ４ wherein R ３ and R ４ together with the atom to which they are attached form a cyclopropyl, and n is 2, the compound according to claim 11.

15. R ３ and R ４ The compound according to claim 11, wherein R and R are H and n is 1.

16. R ３ and R ４ is H and n is 2, the compound according to claim 11.

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

18. R ５ and R ６ is H and n is 2, the compound according to claim 17.

19. R １ is methyl and R ２ is H, the compound according to claim 3.

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

21. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, tautomer, isotope-substituted form, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

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

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

24. The method according to claim 22, wherein the compound is more selective for CDK4 than for CDK6.

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

26. The method according to claim 24, wherein the compound is at least 5-fold more selective for CDK4 than for CDK6.

27. The method according to claim 24, wherein the compound is at least 50-fold more selective for CDK4 than for CDK6.

28. The method according to claim 24, wherein the compound is at least 100-fold more selective for CDK4 than for CDK6.

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

30. A method for 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 according to any one of claims 1 to 20.

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