WO2023049691A1 - Inhibiteurs de cdk7 et méthodes de traitement du cancer - Google Patents

Inhibiteurs de cdk7 et méthodes de traitement du cancer Download PDF

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WO2023049691A1
WO2023049691A1 PCT/US2022/076690 US2022076690W WO2023049691A1 WO 2023049691 A1 WO2023049691 A1 WO 2023049691A1 US 2022076690 W US2022076690 W US 2022076690W WO 2023049691 A1 WO2023049691 A1 WO 2023049691A1
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compound
pharmaceutically acceptable
acceptable salt
alkyl
substituted
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PCT/US2022/076690
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Junhu Zhang
Wanlong Jiang
Sunny Abraham
Kevin Duane BUNKER
Peter Qinhua HUANG
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Zeno Management, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide

Definitions

  • CDK7 INHIBITORS AND METHODS OF TREATING CANCER INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Serial No. 63/261,546, filed September 23, 2021, which is hereby incorporated herein by reference in its entirety. BACKGROUND Field [0002] The present application relates generally to compounds that are CDK7 inhibitors and methods of using them to treat conditions characterized by excessive cellular proliferation, such as cancer and tumors. Description [0003] Cyclin-dependent kinase 7 (CDK7) is a protein in the cyclin-dependent protein kinase (CDK) family.
  • CDK7 is also involved in the regulation of transcription as a component of transcription factor TFIIH. See Sava, G.P. et al, “CDK7 Inhibitors as Anticancer Drugs,” Cancer and Metastasis Reviews (2020) 39:805-823. [0004] A number of compounds of varying chemical structure that inhibit CDK7 have been evaluated for their ability to treat cancer and/or tumors.
  • Table 1 illustrates several selective CDK7 inhibitors that have progressed to Phase I/II clinical trials involving patients with advanced solid malignancies:
  • C S CDK7 Inhibitor Structure [0005] The clinical advances of multiple compounds represent milestones in the development of CDK7 inhibitors. However, there remains a need for improved compounds that inhibit the activity of CDK7.
  • SUMMARY [0006] Various embodiments provide compounds of the Formula (I) and methods of using them.
  • An embodiment provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR 5a , or NR 5a R 5b ; R 3 is substituted or unsubstituted C3-C8 cycloalkyl or C3-C8 heterocyclyl, wherein the substituted C3-C8 cycloalkyl or C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 ; R 4 is halogen, CN, alkyl, cycloalkyl, -NR 7 R 8 , OR 6 , -CO2R 6 , or -C
  • FIG. 1 illustrates a general synthetic scheme for preparing compounds of the Formula (I). [0012] FIG.
  • FIG. 2 illustrates a reaction scheme for making 7-bromo-3-(2,5- dichloropyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (Intermediate 2).
  • FIG. 3 illustrates a reaction scheme for making 3-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile (Intermediate 5).
  • FIG. 3 illustrates a reaction scheme for making 3-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indole-6-carbonitrile (Intermediate 5).
  • FIG. 4 illustrates a reaction scheme for making 3-(2-(((3S,6S)-6- Methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(1-oxidophospholan-1- yl)-1H-indole-6-carbonitrile (Example 1).
  • FIG. 5 illustrates a reaction scheme for making 3-(5-Chloro-2-(((3S,6S)-6- methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxidophospholan-1-yl)-1H-indole-6- carbonitrile (Example 8).
  • FIG. 5 illustrates a reaction scheme for making 3-(5-Chloro-2-(((3S,6S)-6- methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1-oxidophospholan-1-yl)-1H-indole
  • FIG. 6 illustrates a reaction scheme for making N-(3,5-dimethylisoxazol-4- yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrrolo[2,3-b]pyridine-6-carboxamide (Example 18). [0017] FIG.
  • CDKs Cyclin-dependent kinases
  • CDK7 binds to cyclin H and MATI to form a trimeric cyclin-activating kinase (CAK) that performs its function by phosphorylating other CDKs involved in cell-cycle control. These complexes control specific transitions between two subsequent phases in the cell cycle.
  • CDK7 is implicated in both temporal control of the cell cycle and transcriptional activity.
  • CDK7 is implicated in the transcriptional initiation process by phosphorylation of Rbp1 subunit of RNA Polymerase II (RNAPII). Uncontrolled cell proliferation and deregulated transcription is a cancer hallmark.
  • Targeting CDK7 selectively may offer an advantage by simultaneously inhibiting active transcription and cell-cycle progression.
  • CDK7 is a promising target for the treatment of cancer, in particular aggressive and hard to-treat cancers.
  • Definitions [0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0020] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents.
  • the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sul
  • Ca to Cb in which “a” and “b” are integers refer to the number of carbon atoms in a group.
  • the indicated group can contain from “a” to “b”, inclusive, carbon atoms.
  • a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.
  • R groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle.
  • R a and R b of an NR a R b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:
  • alkyl refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain.
  • Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
  • Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
  • the alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • An alkyl group may be substituted or unsubstituted.
  • alkylene refers to a bivalent fully saturated straight chain aliphatic hydrocarbon group.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene and octylene.
  • An alkylene group may be represented by , followed by the number of carbon atoms, followed by a “*”. For example, to represent ethylene.
  • the alkylene group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated).
  • the alkylene group may also be a medium size alkyl having 1 to 12 carbon atoms.
  • the alkylene group could also be a lower alkyl having 1 to 4 carbon atoms.
  • An alkylene group may be substituted or unsubstituted.
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a C 3-6 monocyclic cycloalkyl group (e.g., [0025]
  • alkenyl used herein refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2- butenyl and the like.
  • An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • the term “fused” refers to two rings which have two atoms and one bond in common.
  • the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
  • the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
  • a cycloalkyl group may be unsubstituted or substituted.
  • mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.
  • cycloalkenyl refers to a mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic (such as bicyclic) aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group or a C6 aryl group.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic or multicyclic (such as bicyclic) aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • the number of atoms in the ring(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms.
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3- oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine
  • a heteroaryl group may be substituted or unsubstituted.
  • Those skilled in the art understand that the partial circle in the fused “A” ring of the following moiety indicates that the “A” ring is aromatic: [0032] For example, when any one or more of Q1, Q2 and Q3 is nitrogen, the above moiety is a heteroaryl group. Similarly, when Q 1 , Q 2 and Q 3 are all carbon, the above moiety is an aryl group.
  • heterocyclyl or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • the term “fused” refers to two rings which have two atoms and one bond in common.
  • the term “bridged heterocyclyl” or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non- adjacent atoms.
  • the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge.
  • Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
  • five carbon atoms and one heteroatom four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom.
  • heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
  • heterocyclyl or heteroalicyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3- dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3- dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, triox
  • spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2- oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.
  • aralkyl and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted.
  • heteroarylkyl and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted.
  • heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted.
  • Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).
  • hydroxy refers to a –OH group.
  • alkoxy refers to the Formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • a non- limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n- butoxy, iso-butoxy
  • acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0040] A “cyano” group refers to a “-CN” group.
  • halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-amido may be substituted or unsubstituted.
  • S-sulfonamido refers to a “-SO 2 N(R A R B )” group in which R A and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-sulfonamido may be substituted or unsubstituted.
  • An O-carboxy may be substituted or unsubstituted.
  • a “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a sulfenyl may be substituted or unsubstituted.
  • a sulfinyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.
  • a sulfonyl may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri- haloalkyl and polyhaloalkyl).
  • haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2- fluoroisobutoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • a “mono-substituted amine” group refers to a “-NHR A ” group in which R A can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • the R A may be substituted or unsubstituted.
  • a mono-substituted amine group can include, for example, a mono-alkylamine group, a mono-C 1 -C 6 alkylamine group, a mono- arylamine group, a mono-C6-C10 arylamine group and the like.
  • Examples of mono-substituted amine groups include, but are not limited to, ⁇ NH(methyl), ⁇ NH(phenyl) and the like.
  • a “di-substituted amine” group refers to a “-NR A R B ” group in which R A and RB can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • R A and R B can independently be substituted or unsubstituted.
  • a di-substituted amine group can include, for example, a di-alkylamine group, a di-C1-C6 alkylamine group, a di-arylamine group, a di-C6-C10 arylamine group and the like.
  • di-substituted amine groups include, but are not limited to, ⁇ N(methyl) 2 , ⁇ N(phenyl)(methyl), ⁇ N(ethyl)(methyl) and the like.
  • “mono-substituted amine(alkyl)” group refers to a mono-substituted amine as provided herein connected, as a substituent, via a lower alkylene group.
  • a mono-substituted amine(alkyl) may be substituted or unsubstituted.
  • a mono-substituted amine(alkyl) group can include, for example, a mono-alkylamine(alkyl) group, a mono-C1-C6 alkylamine(C1-C6 alkyl) group, a mono-arylamine(alkyl group), a mono- C6-C10 arylamine(C1-C6 alkyl) group and the like.
  • Examples of mono-substituted amine(alkyl) groups include, but are not limited to, ⁇ CH 2 NH(methyl), ⁇ CH 2 NH(phenyl), ⁇ CH2CH2NH(methyl), ⁇ CH2CH2NH(phenyl) and the like.
  • di-substituted amine(alkyl) refers to a di-substituted amine as provided herein connected, as a substituent, via a lower alkylene group.
  • a di-substituted amine(alkyl) may be substituted or unsubstituted.
  • a di-substituted amine(alkyl) group can include, for example, a dialkylamine(alkyl) group, a di-C1-C6 alkylamine(C1-C6 alkyl) group, a di-arylamine(alkyl) group, a di-C6-C10 arylamine(C1-C6 alkyl) group and the like.
  • di-substituted amine(alkyl)groups include, but are not limited to, ⁇ CH2N(methyl)2, ⁇ CH2N(phenyl)(methyl), ⁇ NCH2(ethyl)(methyl), ⁇ CH2CH2N(methyl)2, ⁇ CH2CH2N(phenyl)(methyl), ⁇ NCH2CH2(ethyl)(methyl) and the like.
  • substituents e.g. haloalkyl
  • substituents there may be one or more substituents present.
  • “haloalkyl” may include one or more of the same or different halogens.
  • C1-C3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • the term “radical” can be used interchangeably with the term “group.”
  • pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate).
  • Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2- oxopentanedioic or naphthalenesulfonic acid.
  • an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as di
  • CDK7 inhibition refers to inhibiting the activity or function of a CDK7 protein.
  • CDK7 inhibitor refers to an agent (including small molecules and proteins) that inhibits the function of CDK7 protein.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • the compounds described herein can be labeled isotopically.
  • each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like.
  • the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. [0072] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. [0073] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting.
  • the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like;
  • the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps;
  • the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment.
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • R 1 and R 2 in Formula (I) can each independently be hydrogen, halogen, CN, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, NHR 5a , or NR 5a R 5b .
  • at least one of R 1 and R 2 is hydrogen.
  • at least one of R 1 and R 2 is halogen.
  • at least one of R 1 and R 2 is CN.
  • at least one of R 1 and R 2 is alkyl, e.g., C 1-3 alkyl.
  • at least one of R 1 and R 2 is alkoxy, e.g., C1-3 alkoxy.
  • At least one of R 1 and R 2 is haloalkyl, e.g., C1-3 haloalkyl. In another embodiment, at least one of R 1 and R 2 is hydroxyalkyl, e.g., C1-3 hydroxyalkyl. In another embodiment, at least one of R 1 and R 2 is cycloalkyl, e.g., C 3-6 cycloalkyl. In another embodiment, at least one of R 1 and R 2 is NHR 5a . In another embodiment, at least one of R 1 and R 2 is NR 5a R 5b . In another embodiment, at least one of R 1 and R 2 is hydrogen, chloro, fluoro, methyl, hydroxyethyl, or trifluoromethyl.
  • R 3 in Formula (I) can be a substituted or unsubstituted C 3 -C 8 cycloalkyl or C3-C8 heterocyclyl.
  • the substituted C3-C8 cycloalkyl or C3-C8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 .
  • R 3 is substituted C3-C8 cycloalkyl.
  • R 3 is unsubstituted C3-C8 cycloalkyl.
  • R 3 is substituted C3-C8 heterocyclyl. In an embodiment, R 3 is unsubstituted C3- C 8 heterocyclyl. In an embodiment, R 3 is piperidinyl, methylpiperidinyl, dimethylpiperidinyl, difluoropiperidinyl, pyrrolidinyl, (N-ethylamino)cyclobutyl, (N-ethylamino)cyclopentyl, azaspirooctyl, azaspirononyl, or oxaazaspirodecyl.
  • R 4 in Formula (I) can be halogen, CN, alkyl, cycloalkyl, -NR 7 R 8 , OR 6 , - CO 2 R 6 , or -C(O)-NR 7 R 8 .
  • R 4 is halogen.
  • R 4 is CN.
  • R 4 is alkyl, e.g., C1-3 alkyl.
  • R 4 is cycloalkyl, e.g., C1-3 cycloalkyl.
  • R 4 is -NR 7 R 8 .
  • R 4 is OR 6 .
  • R 4 is -CO2R 6 .
  • R 4 is -C(O)-NR 7 R 8 .
  • R 7 and R 8 of R 4 are each independently unsubstituted alkyl, e.g., C1-3 alkyl.
  • the R 7 and R 8 of R 4 along with the N to which they are connected, are taken together to form an unsubstituted or substituted C3-C8 heterocyclyl.
  • R 4 is CN, N,N- dimethylamido, N,N-diethylamido, [0079]
  • Each R 5a , R 5b , and R 6 in Formula (I) can independently be hydrogen, alkyl, haloalkyl, or cycloalkyl.
  • At least one of R 5a , R 5b , and R 6 is hydrogen. In an embodiment, at least one of R 5a , R 5b , and R 6 is alkyl, e.g., C1-3 alkyl. In an embodiment, at least one of R 5a , R 5b , and R 6 is haloalkyl, e.g., C1-3 haloalkyl. In an embodiment, at least one of R 5a , R 5b , and R 6 is cycloalkyl, e.g., C 3-6 cycloalkyl.
  • R 7 and R 8 in Formula (I) can each independently be hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.
  • the substituted alkyl or substituted cycloalkyl is substituted by 1-3 independently selected from halogen, OR 6 , CN, alkyl, NHR 5a , or NR 5a R 5b .
  • R 7 and R 8 in Formula (I), along with the N to which they are connected, are taken together to form an unsubstituted or substituted C 3 -C 8 heterocyclyl.
  • the substituted C 3 -C 8 heterocyclyl is substituted by one or more groups independently selected from halogen, alkyl (e.g., C1-3 alkyl), alkoxy (e.g., C1-3 alkoxy), haloalkyl (e.g., C1-3 haloalkyl), cycloalkyl (e.g., C3-6 cycloalkyl), heterocyclyl, NHR 5a , NR 5a R 5b , or OR 6 .
  • alkyl e.g., C1-3 alkyl
  • alkoxy e.g., C1-3 alkoxy
  • haloalkyl e.g., C1-3 haloalkyl
  • cycloalkyl e.g., C3-6 cycloalkyl
  • heterocyclyl e.g., NHR 5a , NR 5a R 5b , or OR 6 .
  • At least one of R 7 and R 8 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C 1-3 alkyl), or substituted or unsubstituted cycloalkyl (e.g., C3-6 cycloalkyl). In an embodiment, at least one of R 7 and R 8 is hydrogen. In an embodiment, at least one of R 7 and R 8 is substituted alkyl. In an embodiment, at least one of R 7 and R 8 is unsubstituted alkyl (e.g., C 1-3 alkyl). In an embodiment, at least one of R 7 and R 8 is substituted cycloalkyl (e.g., substituted C3-6 cycloalkyl).
  • R 7 and R 8 is unsubstituted cycloalkyl (e.g., C3-6 cycloalkyl).
  • R 7 and R 8 in Formula (I), along with the N to which they are connected, are taken together to form an unsubstituted C3-C8 heterocyclyl.
  • R 7 and R 8 in Formula (I), along with the N to which they are connected, are taken together to form a substituted C 3 -C 8 heterocyclyl.
  • X in Formula (I) can be N or CR 9 ;
  • Q1 can be C or N;
  • Q2 can be CH or N; and
  • Q3 can be CH, N, or NH.
  • R 9 in Formula (I) can be hydrogen , , or .
  • R 9 is hydrogen.
  • R 9 is .
  • I 9 n an embodiment, R is In an embodim 9 9 ent, R is .
  • R is Each n in Formula (I) can independently be 0, 1, 2, 3, or 4.
  • n in R 9 is 1. In another embodiment, n in R 9 is 2. [0083]
  • Each R 10 in Formula (I) can independently be hydrogen, alkyl (e.g., C1-3 alkyl), haloalkyl (e.g., C 1-3 haloalkyl), or cycloalkyl (e.g., C 3-6 cycloalkyl). In an embodiment,
  • each R 10 is C 1-3 alkyl. In various embodiments of Formula (I), when each R 10 is independently methyl or ethyl, Formula (I) is not .
  • Y and Z in Formula (I) can each independently be N or CH. In an embodiment, at least one of Y and Z is N. In an embodiment, at least one of Y and Z is CH.
  • the compound of Formula (I) has a chemical structure as described in any one of Tables 2-6 and/or the examples below. Synthesis [0086] Compounds of the Formula (I), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein, including the Examples provided below.
  • compounds of the Formula (I) are prepared in accordance with the general scheme illustrated in FIG 1.
  • Compounds of the Formulae A and B can undergo an AlCl3 induced heteroarylation reaction or metal-catalyzed coupling reaction followed by installation of R 9 on X or full decoration of R 4 .
  • L represents a suitable leaving group which is replaced by R 3 amine via aromatic nucleophilic substitution or Buchwald amination. Removal of the protecting group via a hydrogenolysis reaction or acidic hydrolysis provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Any preliminary reaction steps required to form starting compounds or other precursors, can be carried out by those skilled in the art.
  • FIG. 1 See FIG.
  • compositions [0087] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • composition refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
  • an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • stabilizers such as anti-oxidants and metal-chelating agents are excipients.
  • the pharmaceutical composition comprises an anti-oxidant and/or a metal- chelating agent.
  • a “diluent” is a type of excipient.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
  • a compound, salt and/or composition can be administered orally.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for treatment of an indicated condition.
  • Some embodiments described herein relate to a method for treating a cancer or a tumor described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer or tumor described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer or a tumor described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer or a tumor described herein.
  • Some embodiments described herein relate to a method for inhibiting replication of a malignant growth or a tumor described herein that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting replication of a malignant growth or a tumor described herein.
  • the use can include contacting the growth or the tumor with the medicament.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting replication of a malignant growth or a tumor described herein.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein.
  • the use can include contacting the malignant growth or a tumor described herein with the medicament.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for contacting a malignant growth or a tumor described herein, wherein the malignant growth or tumor is due to a cancer described herein.
  • suitable malignant growths, cancers and tumors include, but are not limited to: urothelial cancer, uterine cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, gastric cancer, hepatobiliary cancer, pancreatic cancer, cervical cancers, prostate cancer, haemotological cancers, sarcomas, skin cancer, or gliomas.
  • a “subject” refers to an animal that is the object of treatment, observation or experiment.
  • “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • the subject can be human.
  • the subject can be a child and/or an infant, for example, a child or infant with a fever.
  • the subject can be an adult.
  • the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition.
  • treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • therapeutically effective amount and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated.
  • a therapeutically effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated.
  • an effective amount of a compound is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor.
  • a therapeutically effective amount is that amount that alleviates or eliminates cough, shortness of breath and/or pain.
  • an effective amount, or a therapeutically effective amount of a CDK7 inhibitor is the amount which results in the reduction in CDK7 protein activity. Methods for measuring reductions in CDK7 activity are known to those skilled in the art and can be determined by the analysis of CDK7 binding, e.g., as illustrated in the Examples below.
  • the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive diseases or conditions.
  • a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg.
  • a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day, or any amount in between.
  • the compound may be administered in unit dosage form; for example, containing 1 to 500 mg, 10 to 100 mg, 5 to 50 mg or any amount in between, of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed.
  • effective dosage levels that is the dosage levels necessary to achieve the desired result
  • useful dosages of a compound of Formula (I), or pharmaceutically acceptable salts thereof can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine) [0110]
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data.
  • Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. [0111] It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration.
  • the severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods.
  • the dose and perhaps dose frequency will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line.
  • a cell line such as a mammalian, and preferably human, cell line.
  • the results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • FIG. 1 illustrates a synthetic scheme for making compounds of the Formula (I). Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
  • Intermediate 1 7-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile 1
  • Intermediate 1 was synthesized according to a published procedure (WO 2020/093006).
  • reaction mixture was stirred at 0 °C for 3 h. After consumption of starting material by TLC, the reaction mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layer was separated, dried over Na 2 SO 4 and evaporated.
  • the crude material was purified by silica-gel (100-200) column chromatography using 30-40% EtOAc in pet-ether as an eluent to afford 7-bromo-3-(2-chloro-5-nitropyrimidin- 4-yl)-1-((2 (trimethylsilyl)ethoxy)methyl)-1H-indole-6-carbonitrile (2.50 g, 4.91 mmol, 66% yield).
  • the reaction mixture was heated at 150 °C in a microwave for 1h. After consumption of starting material by monitoring TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The crude compound was purified by silica gel (100-200) column chromatography using 50-60% EtOAc as a mobile phase in pet-ether to afford Benzyl (2S,5S)-5-((4-(6-cyano-7-(1-oxidophospholan-1-yl)-1H-indol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-2-methyl-piperidine-1-carboxylate (85 mg, for 3 batches, 0.13 mmol, 27% yield) as a pale-yellow sticky liquid.
  • Example 8 3-(5-Chloro-2-(((3S,6S)-6-methylpiperidin-3-yl)amino)pyrimidin-4-yl)-7-(1- oxidophospholan-1-yl)-1H-indole-6-carbonitrile (FIG. 5) [0134] To a stirred solution of benzyl (2S,5S)-5-amino-2-methylpiperidine-1- carboxylate HCl salt (0.689 g, 2.42 mmol) in 1,4-dioxane (12 mL) was added DIPEA (2.10 mL, 12.1 mmol), followed by adding Intermediate 2 (1.21 g, 2.42 mmol) and stirred at 120 °C for 16 h.
  • Example 28 N-(3,5-dimethylisoxazol-4-yl)-3-(2-(((3S,6S)-6-methylpiperidin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carboxamide (FIG. 7) [0151] To a stirred solution of 1H-indole-6-carboxylic acid (two batches, 2 x 5.00 g, 2 x 31.0 mmol) in DMF (60 mL) were added DIPEA (2 x 16.2 mL, 93.0 mmol) and HATU (2 x 14.1 g, 37.2 mmol).
  • reaction mixture was stirred for 10 min, then added 3,5- dimethylisoxazol-4-amine (2 x 3.48 g, 31.0 mmol).
  • the reaction mixture was stirred at rt for 16 h.
  • the reaction mixture was quenched with ice water (250 mL) and extracted with ethyl acetate (2x 100 mL), solvent was evaporated to get crude compound.
  • the combined crude compound was purified by silica gel (100-200) column chromatography using 70-80% EtOAc in pet-ether to afford N-(3,5-dimethylisoxazol- 4-yl)-1H-indole-6-carboxamide (10.0 g, 39.2 mmol, 63% yield).
  • Prep-HPLC method Column/dimensions: X-BRIDGE-C18 (19*250*5um); Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: CAN; Gradient (Time/%B): 0/35, 3/35, 15/75, 18/75, 18.1/100, 20/100, 20.1/35, 22/35; Flow rate: 17ml/min. Solubility: WATER+THF+ACN.
  • Prep-HPLC Method Column/dimensions: X –bridge PHENYL ((19*250*5 ⁇ m); Mobile phase A: 10mM ABC in water; Mobile phase B: Acetonitrile; Gradient (Time/%B): 0.01/20, 1/20, 10/40, 17/40, 17.1/100, 21/100, 21.1/20, 23/20; Flow rate: 18 ml/min; Solubility: Acetonitrile + THF+WATER.
  • reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2 x 15 mL). The combined organic layer was separated, dried over Na2SO4, filtered and evaporated. Crude was purified by silica gel (100-200) column chromatography using 50-70% EtOAc in pet-ether to afford tert-butyl (S)-3-((4-(6-cyano-7-(1,1-dioxidoisothiazolidin-2-yl)-1H-indol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (113 mg, 0.186 mmol, 69% yield).
  • Example A CDK7 enzymatic inhibition activity was evaluated at Reaction Biology Corporation using the “HotSpot” assay platform as published in the literature (Anastassiadis T. et al., Nat Biotechnol. 2011, 29(11):1039-45). The data is provided in Table 7. [0164] The effect of the CDK7 inhibitor to inhibit the growth of MCF7 and OVCAR3 cells was evaluated through the 6 day-time period of viability assay (Table 7). Briefly, the candidate cell lines were plated in 96 well plate at the following density of cells respectively, 3000-3500 cells/well for MCF7, 3000 cells/well for OVCAR-3.
  • DMSO solvent without compound served as a control.
  • cells were analyzed for the viability using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat# G7570). All viability assays were performed in duplicate, and Luminescence was read using an Envision (Perkin Elmer, USA). Nonliner regression and sigmoidal dose-response curves are used to calculate EC50 with Graphpad Prism software.

Abstract

L'invention concerne des composés de formule (I) et des sels pharmaceutiquement actifs de ceux-ci, les variables dans la formule (I) étant décrites dans la description. De tels composés et sels sont des inhibiteurs de CDK7 qui sont utiles pour traiter des états pathologiques caractérisés par une prolifération cellulaire excessive, tels que le cancer et les tumeurs.
PCT/US2022/076690 2021-09-23 2022-09-20 Inhibiteurs de cdk7 et méthodes de traitement du cancer WO2023049691A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089913A1 (fr) * 2003-04-11 2004-10-21 Novartis Ag Derives de 2-aminopyrimidine et leur application en medecine
WO2006038001A1 (fr) * 2004-10-06 2006-04-13 Celltech R & D Limited Derives d’aminopyrimidine en tant qu’inhibiteurs de la jnk
WO2018013867A1 (fr) * 2016-07-13 2018-01-18 Marineau Jason J Inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
WO2019143730A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
WO2020093011A1 (fr) * 2018-11-01 2020-05-07 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089913A1 (fr) * 2003-04-11 2004-10-21 Novartis Ag Derives de 2-aminopyrimidine et leur application en medecine
WO2006038001A1 (fr) * 2004-10-06 2006-04-13 Celltech R & D Limited Derives d’aminopyrimidine en tant qu’inhibiteurs de la jnk
WO2018013867A1 (fr) * 2016-07-13 2018-01-18 Marineau Jason J Inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
WO2019143730A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
WO2020093011A1 (fr) * 2018-11-01 2020-05-07 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)

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