WO2022236257A1 - Composés hétérocycliques utilisés comme inhibiteurs de kinase - Google Patents

Composés hétérocycliques utilisés comme inhibiteurs de kinase Download PDF

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WO2022236257A1
WO2022236257A1 PCT/US2022/072067 US2022072067W WO2022236257A1 WO 2022236257 A1 WO2022236257 A1 WO 2022236257A1 US 2022072067 W US2022072067 W US 2022072067W WO 2022236257 A1 WO2022236257 A1 WO 2022236257A1
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compound
alkylene
pharmaceutically acceptable
tautomer
stereoisomer
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PCT/US2022/072067
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English (en)
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Son Minh Pham
Jayakanth Kankanala
Jeremy D. Pettigrew
Chris P. Miller
Brahmam PUJALA
Bhawana BHATT
Varun Kumar
Anjan Kumar NAYAK
Amit Shivraj SHETE
Sanjeev SONI
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Nuvation Bio Inc.
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Publication of WO2022236257A1 publication Critical patent/WO2022236257A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the cell cycle is a period between the successive divisions of a cell. During this period, the contents of the cell must be accurately replicated.
  • the processes that permit the cell to divide are very precisely controlled by a multitude of enzymatic reactions amongst which the protein kinase-triggered protein phosphorylation plays a major role.
  • there are four main stages/phases of cell cycle namely the Gap-1 (G1) phase, Synthesis (S) phase, Gap-2 (G2) and Mitosis (M) phases.
  • An extended phase of Gap-1 phase is coined as Gap-0 (G0) phase or Resting phase (Cancers 2014, 6, 2224-2242).
  • CDK Cyclin- dependent kinases
  • CDK1, CDK2, CDK4 and CDK6 are generally considered cell cycle CDK, whereas CDK7, CDK8, CDK9 and CDK11 are mainly involved in transcription regulation (Genome Biol 2014;15(6):122, Nat Cell Biol 2009;11(11):1275-6).
  • CDK5 is the prototype of atypical CDK: it is activated by the non-cyclin proteins p35 (or CdkSRi) and p39 (or Cdk5R2) and has unique post-mitotic functions in neuronal biology, angiogenesis and cell differentiation.
  • Proliferative signals induce the transition front the GO or GI phases into S phase through the activation of the structurally related CDK4 and CDK6 [Development, 2013 ; 140 ( 15): 3079-93, Biochem Pharmacol 2012;84(8):985-93, Nature 2014;510(7505):393-6].
  • the binding of cyclin D to CDK4 and to CDK6 promotes the phosphorylation of the transcriptional repressor retinoblastoma protein (RBI).
  • CDK hyperactivity is often observed in cancer, reflecting their prominent role in cell cycle and transcription regulation.
  • cancer cells the process of cell division becomes unregulated, resulting in uncontrolled growth that leads to the development of a tumor.
  • a number of mechanisms contribute to the dysregulation of the cell cycle in malignant cells, including the amplification and hyperactivity of CDK4/6, or their genomic instability, which might cause CDK4/6 to become oncogenic drivers of cell replication. Usurping these mechanisms, cancer cells can continue to replicate by triggering the G! to S phase transition. This process appears to be facilitated by a shortening of the Gl phase.
  • CDK4/6 antagonizes intrinsic tumor suppression mechanisms including cell senescence and apoptosis, which further augments the growth of a tumor.
  • Cancer cells also upregu!ate other CDK and cyclins and decrease suppressive mechanisms such as intrinsic CDK inhibitors and tumor suppressor proteins. The o verall effect of this type of cell cycle dysregulation is malignant cell proliferation and the development of cancer (Clinical Breast Cancer, 2016, 1526-8209).
  • CDK inhibitors have been reported (such as in W02Q11101409 and WO2011101417) or clinically developed. Flavopiridol and R-Roscovitine (Seliciclib), were tiie first generation of pan-CDK inhibitors with anti-tumor activity attributed to down- regulation of CDK9-mediated anti-apoptotic proteins, especially Mcl-1. Recently, a new generation of CDK inhibitors have been developed, advanced to clinical trials, and approved for certain types of cancer.
  • CDK4/6 inhibitors Compounds for the treatment of hyper-proliferative diseases preferably have at least one advantageous property selected from selectivity , potency, stability', pharmacodynamic properties and safely ' profile.
  • a novel class of CDK4/6 inhibitors is provided herein.
  • pro vided is a compound of Formula (J): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Yy Q 1 , Q 2 , Q 3 , Z, R 1 , R 2 , R 3 , R 4 , 1, m, and n are as detailed herein.
  • a method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effecti ve amount of a compound as detailed herein.
  • a method of modulating CDK4/6 in an individual comprising administering to the individual a compound detailed herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a method of modulating CDK4/6 and one or more of CDK1, CDK2, and CDK9 in an individual comprising administering to the individual a compound detailed herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • kits comprising a compound detailed herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of tiie foregoing, are also provided. Kits may optionally include instructions for use, such as instructions for use in any of the methods detailed herein, for example, for use in tire treatment of cancer. A compound as detailed herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is also provided for the manufacture of a medicament for the treatment of cancer. DETAILED DESCRIPTION
  • the term “about” refers to a variati on of ⁇ 1%, ⁇ 3%. ⁇ 5%, or ⁇ 10% of the value specified.
  • “about 50” can in some embodiments includes a range of from 45 to 55.
  • the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range.
  • the term “about” is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.
  • the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and includes reference to one or more compounds and equivalents thereof known to those skilled in the art.
  • Alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (Ci-20 alkyl or C1-C2 0 alkyl), 1 to 8 carbon atoms (Ci-8 alkyl or Ci-Cs alkyl), 1 to 6 carbon atoms (Ci-6 alkyl or Ci-Ce alkyl), or 1 to 4 carbon atoms (Ci -4 alkyl or C1-C4 alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-hutyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CHrbCHs), sec-butyl (i.e.
  • -CH(CH3)CH2CH3) iso-butyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. ⁇ ( (il l ⁇ ) ).
  • propyl includes n-propyl (i.e. -(CPT ⁇ CEl ⁇ ) and isopropyl (i.e. - (T hil l ⁇ ) ⁇ .
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
  • a residue is substituted with more than one halogen, it may be referred to by- using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).
  • the alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations.
  • Particular alkenyl groups are those having 2 to 20 carbon atoms (C2-20 alkenyl or C2-C20 alkenyl), having 2 to 8 carbon atoms (C2-8 alkenyl or Cr-Cs alkenyl), having 2 to 6 carbon atoms (C2-6 alkenyl or C2-C6 alkenyl), or having 2 to 4 carbon atoms (C2-4 alkenyl or C2-C4 alkenyl).
  • alkenyl examples include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyi, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2- methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
  • groups such as ethenyl (or vinyl), prop-l-enyi, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2- methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
  • Alkylene refers to the same residues as alkyl, but having bivalency. Particular aikylene groups are those having 1 to 6 carbon atoms (Ci-6 aikylene or Ci-Ce aikylene), 1 to 5 carbon atoms (Ci-j aikylene or C1-C5 aikylene), 1 to 4 carbon atoms (Ci *4 aikylene or C1-C4 aikylene) or 1 to 3 carbon atoms (Ci-3 aikylene or C1-C3 aikylene).
  • aikylene examples include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene ( ⁇ CH2.CH2CH2-), butylene (-CH2CH2CH2CH2-), and the like.
  • Alkoxy refers to the group “-O-alkyl”. Examples of alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec- butoxy, npentoxy, n-hexoxy and 1,2-dimethylbutoxy.
  • Alkynyl refers to an unsaturated linear or branched hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e. , having at least one moiety of the formula CoC).
  • Particular alkynyl groups are those having 2 to 20 carbon atoms (C2-20 alkynyl or C2-C20 alkynyl), having 2 to 8 carbon atoms (C2-8 alkynyl or C2-Cs alkynyl), having 2 to 6 carbon atoms (C2-6 alkynyl or Ci-Ce alkynyl), or having 2 to 4 carbon atoms ( €2-4 alkynyl or C2-C4 alkynyl).
  • alkynyl examples include, but are not limited to, groups such as ethynyi (or acetylenyl), prop-l-ynyl, prop-2 -ynyl (or propargyl), but-l-ynyi, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
  • Aryl refers to and includes polyunsaturated aromatic hydrocarbon groups.
  • Aryl may contain additional fused rings (e.g., from 1 to 3 rings).
  • the aryl group contains from 6 to 14 annular carbon atoms (“Gs-Cw aryl”),.
  • Gs-Cw aryl annular carbon atoms
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ting system is heterocyclyl.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems, bubble term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • cycloalkyl has from 3 to 20 ring carbon atoms (C.3-20 cycloalkyl or C3-C20 cycloalkyl), 3 to 12 ring carbon atoms (C3-12 cycloalkyl or C3-Ct2 cycloalkyl), 3 to 10 ring carbon atoms ( €3-10 cycloalkyl or C3-C10 cycloalkyl), 3 to 8 ring carbon atoms (C3-8 cycloalkyl or C3-C8 cycloalkyl), or 3 to 6 ring carbon atoms (C3-6 cycloalkyl or C3-C6 cycloalkyl).
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkyl is intended to encompass any non-aromatic cyclic alkyl ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • Halo or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and iodo.
  • Heteroaryl refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms, 3 to 12 ring carbon atoms, or 3 to 8 carbon ring atoms, and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2.
  • heteroaryl includes 5- to 12- membered, 5- to 10- membered ring systems, 5- to 7- membered ring systems, or 5- to 6- membered ring systems, each independently having 1 to 4 ring heteroatoms, I to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or I ring heteroatom independently selected from nitrogen, oxygen and sulfur.
  • Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings).
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • Heterocyclyl refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bi cyclic heterocyclic groups, such as bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups.
  • Any nonaromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • the term h eterocyclyl is intended to encompass any non -aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms, 2 to 12 ring carbon atoms, 2 to 10 ring carbon atoms, 2 to 8 ring carbon atoms, 3 to 12 ring carbon atoms, 3 to 8 ring carbon atoms, or 3 to 6 ring carbon atoms; and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, I to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.
  • heteroaryl includes 3- to 12- membered, 5- to 10- membered ring systems, 5- to 7- membered ring systems, or 5- to 6- membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • the term “hi cyclic heterocyclic” encompasses fused- heterocyclyl groups.
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g,, 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different, provided that the group’s normal valence is not exceeded, in one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has tour substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.
  • CDK4/6 refers to both CDK4 and CDK6.
  • inhibitors of CDK4/6 inhibit both CDK4 and CDK6.
  • a '‘pharmaceutically acceptable earner” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals, in reference to cancers or other unwanted cell proliferation
  • beneficial or desired results include shrinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of tumor; and/or relieving to some extent one or more of the symptoms associated with the cancer, in some embodiments, beneficial or desired results include preventing or delaying occurrence and
  • “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer).
  • Hus delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.
  • an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the seventy of, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation, in some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence.
  • an effective amount can be administered in one or more administrations, in the case of cancer, the effective amount of the drag or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • An effective dosage can be administered in one or more administrations.
  • an effective dosage of compound or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drag, compound, or pharmaceutical composition. Thus, an ‘ ‘ effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • the term “individual” is a mammal, including humans.
  • An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate, in some embodiments, the individual is human.
  • the individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden.
  • the individual is at an early stage of a proliferative disease (such as cancer).
  • the individual is at an advanced stage of a proliferative disease (such as an advanced cancer).
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive ingredient Guide prepared by the U.8. Food and Drug administration.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base e.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the iike.
  • Further examples of pharmaceutically acceptable salts include those listed in Berge et ah, Pharmaceutical Salts, J. Pliarm. Sci. 1977 Jan;66(l): 1-19.
  • Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the disclosure in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • excipient means an inert or inactive substance that may ⁇ be used in tire production of a drug or pharmaceutical, such as a tablet containing a compound of the disclosure as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the disclosure as an active ingredient.
  • Various substances may be embraced by tiie term excipient, including without limitation any substance used as a binder, disintegrant, coatmg, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • Q 1 is O orNH
  • Q 3 is C, n ix or N; indicates a partially saturated or fully saturated ring; , wherein
  • A is C3-Ce cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or Ce aryl, each of which is optionally substituted w ith one or more R 3 ;
  • L is a bend, NR 10 SO 2 -;
  • B is hydrogen, Cj-Ce cyeioaikyl, 3- to 7-membered heterocyclyl, 5- to 7- membered heteroaryl, or Ce and, each of which is optionally substituted with one or more R 6 ;
  • C is Cj-Ce cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or Ce aryl, each of which is optionally substituted with one or more R 5 , wherein C is fused to D;
  • D is Ce-Ce cycloalkyl, 3- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or Ce aryl, each of which is optionally substituted w ith one or more R 6 ;
  • R 1 is hydrogen, Ci-Ce alkyl, Ci-Ce alkenyl, C2-C6 alkynyl, Ci-Csalkoxy, C3- Ci2 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce- Ci4 aryl, -(Ci-Cj alkylene)(C3-C12 cycloalkyl), -(C 1 -C 3 alkylene)(3- to 12-membered heterocyclyl), -C(0)R 10 , -(C 1 -C 3 alkylene)(5- to lG-membered heteroaryl) or -(C 1 -C 3 alkylene)(C 6 -C 14 and), wherein R ; is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR 13 , -NR 13 R 14 , -C(0)R 1J , -CN, (A
  • each R 10 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -(C 1 - C 3 alkylene)(C 3 -C 6 cycloalkyl ⁇ , C 6 -C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6- membered heteroeyclyl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR 15 , -NR 5ri R 16 , and Ci-Ce alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR 15 , -NR 5ri R 16 , and Ci-Ce alkyl optionally substituted with one or more substituents selected from the group consisting of hal
  • R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, Ci-Ce cycloalkyl, -(Ci- C3 alkylene)(C:i-C6 cycloalkyl), Ce-Ci4 aryl, 5- to 6-membered heteroaryl or 3- to 6- membered heteroeyclyl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR 15 , -N R 15 R 16 , and Ci-Ce alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, and oxo, or R 11 and R 12 are taken together with the atom to which they attached to form a 3- to 6- membered heteroeyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, and Ci-Ce alkyl optionally substituted with one
  • R 13 and R 14 are each independently hydrogen or Ci-Ce alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, -OR 15 , -NR !5 R l6 , and oxo, or R 13 and R 14 are taken together with the atom to which they attached to form a 3- to 6- membered heteroeyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, and Ci-Ce alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, and oxo; and
  • R 15 and R 16 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 - C 6 alkynyl, wherein the Ci-Ce alkyl, Ci-Ce alkenyl, and C 2 -C 6 alkynyl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, and oxo, or R !;) and R 16 are taken together with the atom to which they attached to form a 3- to 6- membered heterocydyi optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, and Ci-Ce alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, and oxo;
  • / is 0, 1, or 2; m, p and q are each independently 0, 1, 2 or 3, provided that at least one of m and 1 is not 0; and n is 0, 1, 2, 3 or 4.
  • a compound of Formula provides a compound of Formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q ! , Q 2 , Q 3 , A, B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , 1, in, n, p, and q are as detailed herein for Formula (J).
  • Q 2 is NR 1 . In some embodiments, Q 2 is CUR 1 .
  • Q 3 is CH?.. In some embodiments, Q 3 is N.
  • a compound of Formula (J) is of Formula (J-l), (1-1), or (TI-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of tine foregoing.
  • a compound of Formula (J) is of Formula (J-2), (1-2), or (11-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a compound of Formula (J) is of Formula (J-3), (1-3), or (P-3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of tiie foregoing.
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 aikynyl, Ci-Csalkoxy, C 3 ⁇
  • R 1 is hydrogen, Ci-Ce alky], C 3 -C 6 cycloalkyl, 3- to 12- membered heterocyclyl, 5- to 10-membered heteroaryd, Ce-Ci4 aryl, -C(O)R 10 , -(C 1 - C 3 alkyiene)(C 3 -C 6 cycloalkyl), -(C 1 -C 3 alkylene)(3- to 12-membered heterocyclyl), -(C 1 - C 3 alkylene)(5- to 10-membered heteroaryl) or -(C;-Cj alkylene)(C 6 -C 14 aryl), each of which is unsubstituted .
  • R 1 is CI-CG alkyl, Cti-Ce alkenyl, CI-CG aikynyl, C 1 - Csalkoxy, C 3 -C 6 cycloalkyl, 3- to 12-rnernbered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, -(C 1 -C 3 aikylene)(C 3 -C 6 cycloalkyl), -C(O)R t0 , or -(C 1 -C 3 aikylene)(C 6 -C 14 ary1 ⁇ ]), each of which independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR 13 , -NR 13 R 14 , -C(0)R 13 , -CN, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkyl optionally substituted with one or more substituent
  • R 1 is Cr-Ce alkyl, Ce-Ce alkenyl, Ci-Cs alkynyl, Ci-Csalkoxy, C 3 -C 6 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-Cir aryl, or -C(0)R l °, each of which independently optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, -OR 13 , -NR 13 R 14 , -C(())R 13 , -CN, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of oxo, -OH or halogen.
  • R 1 is hydrogen, C 1 -C 6 alkyl, -C(O)R 10 , -(C 1 -C 3 alkylene)(C 3 - C 6 cycloalkyl), -(C 1 -C 3 alkylene)(5- to 10-membered heteroaryl), or C 3 -C 6 cycloalkyl, each of which is optionally substituted with halogen, oxo, -NH 2 .
  • R 1 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl or cyelopropyl-methyl.
  • R 1 is isopropyl, in some embodiments, R 1 is C 1 -C 6 alkyl. In some embodiments, R 1 is C 2 -C 6 alkyl.
  • R 1 is selected from the group consisting of
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. in some embodiments, n is 3. In some emboidments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, I, 2, or 3. In some emboidments, n is 1, 2, or 3.
  • each R-' is independently Ci-Ce alkyl, oxo, -C(Q)R 10 , or -CN.
  • each R 2 is independently Ci-Ce alkyl, oxo, or halogen, in some embodiments, each R 2 is oxo.
  • each R 2 is independently -NR ⁇ R 12 .
  • each R 2 is -CN.
  • each R 2 is independently -C(0)R 10 .
  • R 2 is -C(Q)R 10 , wherein R 10 is Ci-Ce alkyl such as methyl, in some embodiments, R 2 is -C(0)NR 11 R 12 . In some embodiments, R 2 is halogen, such as iluoro. In some embodiments, R 2 is Ci-Ce alkyl, such methyl. In some embodiments, R 2 is H. In some embodiments, each R 2 is independently oxo or Ci-Ce alkyl such as methyl. In some embodiments, each R 2 is independently oxo or Ci-Ce alkyl such as methyl: and n is 1 or 2. In some embodiments, each R 2 is independently oxo or Ci-Ce alkyl such as methyl; and n is i.
  • each R 2 is independently oxo or Ci-Ce alkyl such as methyl; and n is 2. in some embodiments, R 2 is Ci-Ce alkyl such as methyl. In some embodiments, R 2 is Ci-Ce alkyl such as methyl; and n is 1. In some embodiments, each R 2 is independently -C(0)R 10 , wherein R 10 is Ci-Ce alkyl such as methyl. In some embodiments, each R 2 is independently -C(O)R !0 , wherein R 10 is Ci-Ce alkyl such as methyl; and n is 1 . In some embodiments, each R 2 is oxo; and n is 1 or 2.
  • each R 2 is oxo; and n is 1. In some embodiments, each R 2 is oxo; and n is 2. in some embodiments, each R 2 is independently oxo or -CN. In some embodiments, each R 2 is independently oxo or -CN; and n is 2. In some embodiments, R 2 is independently methyl, oxo, - ⁇ 2(0)O3 ⁇ 4, or -CN. In some embodiments, n is 1; and R 2 is oxo. In some embodiments, n is 0 or 1; and R 2 is oxo.
  • At least two R 2 are taken together with the atom or atoms to which they are attached to form Cb-Cs cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl or Cb aryl, each of which is independently optionally substituted with one or more subsituents selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, and - OH. in some embodiments, at least one R 2 is taken together with R !
  • Cb-Gs cycloalkyl 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl or Ce aryl, each of which is independently optionally substituted with one or more subsituents selected from the group consisting of Ci-Ce alkyl, C i-Ce haloalkyl, halogen, and - OH.
  • [Q055] in some embodiments of a compound of Formula (J) or any related formula where applicable, is / is 0. In some embodiments, / is 1 or 2. In some embodiments, / is 1. In some embodiments, / is 2.
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2. in some embodiments, in is 0 or I. In some embodiments, m is 0, 1, or 2.
  • each R 3 is independently Cb-Gs alkyl, C3-C6 cycloalkyl, Cb-Gs haloalkyl, Ci-Ce aikoxy, Ci-Ce haloalkoxy, halogen, or -OH.
  • each R 3 is independently Ci-Ce alkyl, Gs-Ce cycloalkyl, Ci-Ce haloalkyl, Ci-Ce aikoxy, Ci-Cehaloalkoxy or halogen, in some embodiments, each R 3 is independently fluoro, chloro, methyl, trifiuoromethyl, trifluorom ethoxy, methoxy, and cyclopropyl. In some embodiments, R 3 is halogen .
  • each R 4 is independently Ci-Ce alkyl, C3-C& cycloalkyl, Ci-Cehaloalkyl, Ci-Cs alkoxy, Ci-Ce haloalkoxy, halogen, or -OH.
  • each R 4 is independently Ci-Cs alkyl, Ci-Ce cycloalkyl, Ci-Cehaloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy or halogen, in some embodiments, each R 4 is independently fluoro, chloro, methyl, tritluoromethyl, trifluoromethoxy, methoxy, and cyclopropyl. In some embodiments, R 4 is halogen.
  • A is Cb-Ce cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryi or C & and, each of which is unsubstituted.
  • A is Cs-Ce cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl or Ce aryl, each of which is optionally substituted with one or more R 3 .
  • A is Ce aryl optionally substituted with one or more R 5 .
  • A is phenyl optionally substituted with one or more R 5 .
  • A is 5- to 7-membered heteroaryl optionally substituted with one or more R 3 .
  • A is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl or imidazolyl, each of which is optionally substituted with one or more R 5 .
  • A is 4- to 7-membered heterocyclyl optionally substituted with one or more R 3 .
  • A is piperidinyl, pyrrolidinyl, azetidinyl, dihydropyridine, or pyridone, each of optionally substituted with one or more R 5 .
  • A is C3- Ce eycloalkyl optionally substituted with one or more R 5 .
  • A is cyclohexyl or cyclopentyl, each of which is optionally substituted with one or more R 3 .
  • A is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, imidazolyl, piperidinyl, pyrrolidinyl, azetidinyl, pyridone, cyclohexyl, or cyclopentyl, each of which is unsubstituted ,
  • A is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, imidazolyl, piperidinyl, pyrrolidinyl, azetidinyl, dihydropyridine, pyridone, cyclohexyl, or cydopentyl, each of which is optionally substituted with one or more R 5 .
  • B is hydrogen, Cb-Ce eycloalkyl, 3- to 7-membered heterocyclyl, 5- to 7- membered heteroaryl, or Ce aryl, each of which is optionally substituted with one or more R b .
  • B is Cb-Ce eycloalkyl, 3- to 7-membered heterocyclyl, 5- to 7- membered heteroary l, or Ce aryl, each of which is unsubstituted.
  • B is hydrogen.
  • B is 3- to 7-membered heterocyclyl optionally substituted with one or more R 6 .
  • B is diazepanyi, azepanyi, piperazinyi, piperidmyl, pyrroiidinyl or azetidinyl, each of which is optionally substituted with one or more R 6 .
  • B is 5- to 7 ⁇ membered heteroaryl optionally substituted with one or more R 6
  • B is imidazolyl or pyrazolyi, each of which is optionally substituted with one or more R 6 .
  • B is phenyl optionally substituted with one or more R 6 .
  • B is Ci-Ce cycloaikyl optionally substituted with one or more R 6 .
  • B is cyclopentyl, cyelohexyi, or cycioheptyl, each of which is optionally substituted with one or more R 6 .
  • B is hydrogen, diazepanyi, azepanyi, piperazinyi, piperidinyl, pyrroiidinyl, azetidinyl, imidazolyl, pyrazolyi, phenyl, cyclopentyl, cyelohexyi, or cycioheptyl, each of which is unsubstituted.
  • B is hydrogen, diazepanyi, azepanyi, piperazinyi, piperidinyl, pyrroiidinyl, azetidinyl, imidazolyl, pyrazolyi, phenyl, cyclopentyl, cyelohexyi, or cycioheptyl, each of which is optionally substituted with one or more R 6 .
  • L is abend, -CH2-, -NH-, -0-, -S-, -S(0)2-, -CO-, -NCH3-, -S(0)2NH-,or - NHS(Q)2-.
  • L is a bond, -CHi-, -NH-, - 0-, or-S-.
  • L is a bond, in some embodiments, L is -CH2-.
  • L is -NH-.
  • L is -S-.
  • L is -0-.
  • L is -8(0)2-, In some embodiments, L is -C(O)-, In some embodiments, L is -NCHj-. In some embodiments, L is -NH8(0)2-. In some embodiments, L is -CR l l R i2 -. in some embodiments, L is -NR !t' -. In some embodiments, L is -NR !0 S(Q)2-. In some embodiments, L is -SlQbNR 10 -. in some embodiments, L is -S(0)2NH-. In some embodiments, L is - NHS(0)2-. In some embodiments, L is a bond or -CH2-.
  • ⁇ is 0, 1, or 2; and t' is 0 or 1. In some embodiments, which is
  • R 6 is methyl and q is 1. in some embodiments, which is some embodiments, t is 0. In some embodiments, t is 1. in some embodiments, t is 2. In some embodiments, t’ is 0. In some embodiments, f is 1. In some embodiments, t is 1 and f is I.
  • D is fused with C to form a 7- to 12- membered bicyclic ring having at least one aromatic ring, wherein C and D are optionally substituted with one or more R 5 and R 6 .
  • D is fused with C to form a 7- to 12- membered bicyclic ring having at least one aromatic ring and at least one heteroatom selected from the group consisting of N, O, and S, wherein C and D are optionally substituted with with one or more R 3 and R b .
  • D is fused with C to form a 7- to 12- membered bicyciic ring having at least one aromatic ring and at least one nitrogen atom, wherein C and D are optionally substituted with with one or more R 5 and R 6 .
  • D is fused with C to form a 7- to 12- membered bicyciic ring having at least one aromatic ring and at least one nitrogen atom, wherein C and D are optionally substituted with with one or more R 3 and R 6 .
  • Z is
  • R 7 is hydrogen, Ci-Cs alkyl, Cs-Cs cycloalky l, -C(Q)R 10 , each of which (except hydrogen) is optionally substituted by halogen, oxo, -OR 13 , -NR i3 R 14 , ⁇ C(0)R 13 ,
  • R 7 is hydrogen, methyl, ethyl, isopropyl, cyclopropyl, -( ' ⁇ OK I I ' M K i lo or -CH2CH2OH.
  • p is 0. In some embodiments, p is 0 or 1. In some embodiments, p is 0, I, or 2.
  • each R 5 is independently Ci-Ce alkyl, halogen, oxo, -CN, -OR 10 , -NR U R 12 , -C(0)R 10 , -C(0)NR l l R i2 , CJ-CS cycloalkyl, 3- to 12-membered heterocyelyl, -(Ci- C3 alkylene)OR 10 , -(Ci-Cs alkylene)NR 1] R 12 , -(Ci-Cs alkylene)C(0)R 10 , -(Ci- C3 alkylene)(C3-C6 cycloalkyl), -(C1-C3 alkylene)(3- to 12-membered heterocyclyl), each of which is optionally substituted by halogen, oxo, -OR i3 , -NR 13 R 14 , ⁇ C(Q)R
  • each R 5 is independently -CN, halogen, methoxy, oxo, trifluoromethoxy, - NH(CH 3 ), -N(CH3) 2 , -(CH2)NH(CH 3 ), -(CH 2 )NH 2 , -(CH2)N(CH3) 2 , -C(0)NH2, -
  • each R 5 is independently -CN, halogen, metlioxy, oxo, trifluoromethoxy, -NH(Cft), -
  • q is 0. In some embodiments, q is 0 or 1. In some embodiments, q is 0, 1, or 2.
  • each R 6 is independently Ci-Ce alkyl, halogen, oxo, -CN, -NR ⁇ R 1 ⁇ , -C(O)R i0 , C 3 - Ce cycloalkyl, 3- to 12-membered heterocyclyl, -(Ci-C 3 alkylene)OR !0 , -(Ci- C 3 alkylene)NR n R 12 , each of which is optionally substituted by halogen, oxo, -OR 13 , -NR i3 R 14 , -C(0)R 13 , -CN, -(C]-C 3 alkylene)()R 13 , -(C 1 -C 3 alkylene)NR 13 R 14 , -(Ci- C3 alkylene)C(0)R 13 , C 3 -Cs cycloalkyl, or Ci-Ce alkyl optionally substitute
  • each R 6 is independently ethyl, methyl, isopropyl, pyrrolidinyl, -M(CHI)2, -CH2OH, oxo, - C(0)CH2NHCH3, -CH2CH2OH, difluoroethyi, -( ⁇ . ⁇ N(( ⁇ :) ⁇ -OH, or -C(0)CH 2 0H.
  • each R 6 is independently ethyl, methyl, isopropyl, pyrrolidinyl, cyclopropyl, methoxy, -N(CH3)2, -NHCH3, -CH2OH, oxo, -C(0)CH2NHCH3, -CH2CH2OH, difluoroethyi,
  • Z is selected from the group consisting of:
  • Z is j 0071 j
  • Z is selected from the group consisting of:
  • R 1 any specific value of R 1 detailed herein for a compound of Formula (J) as well as all related formulae may be combined with any other specific value for one or more of the variables Q 1 , Q-', Z, R 2 , R 3 , R 4 , /, rn, and n the same as if each and every combination were specifically and individually listed.
  • salts of compounds referred to herein such as pharmaceutically acceptable salts.
  • the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers thereof or other forms of the compounds described. It is understood that individual enantiomers and diastereomers are provided herein and their corresponding structures can be readily determined.
  • a compound as detailed herein may in one aspect be in a purified fonn and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a composition of substantially pure compound or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity.
  • compositions of substantially pure compound or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein the composition contains or no more than 3%, 2%, 1% or 0.5% impurity.
  • salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
  • the present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described.
  • the structure or name is intended to embrace ail possible stereoisomers of a compound depicted.
  • Ail forms of the compounds are also embraced by the invention, such as crystalline or non- crystalline forms of the compounds.
  • Compositions comprising a compound of the invention are also intended, such as a composition of substan tially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.
  • Hie invention also intends isotopically-labeled and/or isotopically-enriehed forms of compounds described herein.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, J H, n C, 13 C, 14 C 1J N, !3 Q, 17 0, 32 P, J5 S, 18 F, 36 C1.
  • Certain isotope labeled compounds e.g. 3 H and 14 C
  • Incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
  • isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically- labeled reagents in place of the corresponding non-labeled reagent.
  • the disclosure also includes any or all metabolites of any of the compounds described.
  • the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
  • Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided.
  • the container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
  • the compounds detailed herein are orally bioavailable.
  • the compounds may also be formulated for parenteral ⁇ e.g,, intravenous) administration.
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below), in the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein .
  • diastereomerie derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound.
  • the diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered, in another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystaliization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates and/or polymorphs of a compound provided herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are also contemplated.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcohoiates are formed when the solvent is alcohol.
  • compounds disclosed herein may be synthesized according to the schemes shown below.
  • compositions of any of the compounds detailed herein are embraced by this disclosure.
  • the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a stereoisomer or tautomer thereof, or a pharmaceutically accep table salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is in substantially pure form.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • a compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g,, intramuscular, subcutaneous or intravenous), topical or transdermai delivery torn: .
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g, intramuscular, subcutaneous or intravenous
  • topical or transdermai delivery torn e.g., topical or transdermai delivery torn: .
  • a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
  • One or several compounds described herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various fomis.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g. , m Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000), which is incorporated herein by reference.
  • Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules m a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poiy-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts tor the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, can be formulated as a 10 mg tablet.
  • compositions comprising a compound provided herein are also described.
  • the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of any formula provided herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening pusposes and/or for conducting quality control assays.
  • the methods comprise administration of a compound detailed herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, as a monotherapy.
  • a method of treating a disease in an individual comprising administering an effective amount of a compound disclosed herein or a variation thereof, to the individual.
  • a method of treating a proliferative disease in an individual comprising administering an effective amount of a compound disclosed herein to tiie individual.
  • a method of treating ameer in an individual comprising administering an effecti ve amount of a compound disclosed herein to the individual.
  • the compound is administered to the individual according to a dosage and/or method of administration described herein.
  • the cancer in the individual has one or more mutations or amplification or overexpression of the genes encoding cyciins or of the genes encoding the CDK or loss of endogenous INK4 inhibitors by gene deletion, mutation, or promoter hypermethylation, or other genetic events leading to overactivity of one or more of CDK 1, CDK2, CDK4, CDK6 and CDK9.
  • the cancer in the individual has one or more mutations or amplification or ov erexpression of the genes encoding cyciins or of the genes encoding the CDK or loss of endogenous INK4 inhibitors by gene deletion, mutation, or promoter hypermethylation, or other genetic events leading to overactivity of CDK4/6 and one or more of CDK1 , CDK2, and CDK9.
  • a method of treating a cancer in an individual comprising (a) selecting the individual for treatment based on (i) the presence of phosphorylation of the retinoblastoma (Rh) protein in the cancer, or (ii) presence of mutations or amplification or overexpression of CDK4 or CDK6 in the cancer, and administering an effective amount of a compound disclosed herein to the individual.
  • the cancer is assayed for the expression of pliosphoryiated Rh.
  • the cancer is assayed for the expression of CDK4 or CDK6.
  • the CDK4 or CDK6 gene of the cancer is sequenced to detect the one or more mutations or amplifications.
  • the CDK4 or CDK6 gene is sequenced by biopsying the cancer and sequencing the CDK4 or CDK6 gene from the biopsied cancer.
  • the CDK4 or CDK6 gene is sequenced by sequencing circulating-tumor DNA (ctDNA) from the individual.
  • a compound disclosed herein is used to treat an individual having a proliferative disease, such as cancer as described herein.
  • the individual is at risk of developing a proliferative disease, such as cancer.
  • the individual is determined to be at risk of developing cancer based upon one or more risk factors.
  • the risk factor is a family history and/or gene associated with cancer.
  • a compound disclosed herein is believed to be effective for treating a variety of diseases and disorders.
  • a compound disclosed herein may be used to treat a proliferative disease, such as cancer.
  • the cancer is a solid tumor.
  • the cancer is any of adult and pediatric oncology, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell carcinoma, particularly of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute noniymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer of the adrenal cortex, ACTH-producing tumors, lung cancer, including small cell carcinoma and nonsmall cell cancers, breast
  • the cancer is defined by a molecular characteristic.
  • the cancer is an estrogen receptor-posistive breast cancer.
  • the breast cancer is triple negative breast cancer.
  • the cancer is a KKAS-mutant non-small cell lung cancer.
  • the cancer is mantle cell lymphoma defined by a translocation involving CCND! resulting in cyclin D i overexpression.
  • the compounds and compositions described herein cause Gi-S cell cycle arrest In a cell (such as a cancer cell).
  • the cancer cell is a cancer cell from any of the cancer types described herein.
  • arrested cells enter a state of apoptosis.
  • arrested cells enter a state of senescence.
  • provided herein is a method of causing Gi-S checkpoint arrest in a cell comprising administering an effective amount of a compound disclosed herein to tire cell.
  • the Gi-S cell cycle arrest occurs in about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more of cells in a cell population. In some embodiments, the Gi-S cell cycle arrest occurs in up to about 9914, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 85%, or up to about 80% of cells in the cell population.
  • a method of inducing senescence in a cell comprising administering an effective amount of a compound disclosed herein to the cell.
  • senescence is induced in about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more of cells in a cell population.
  • senescence is induced in up to about 99%, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 85%, or up to about 80% of cells in the cell population.
  • a method of inducing apoptosis in a cell comprising administering an effective amount of a compound disclosed herein to the cell.
  • apoptosis is induced in about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 85% or more, about 90% or more, about 95%) or more, about 96'% or more, about 97% or more, about 98% or more, or about 99% or more of cells in a cell population. In some embodiments, apoptosis is induced in up to about 99%, up to about 98%, up to about 97 %, up to about 96%, up to about 95%, up to about 90%, up to about 85%, or up to about 80%) of cells in the cell population.
  • CDK4 or CDK6 is inhibited by about 10% or more, about 20% > or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70%o or more, about 75% or more, about 80% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more, in some embodiments, CDK4 or CDK6is inhibited up to about 99%, up to about 98% > , up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 85%, up to about 80%), up to about 70%, or up to about 60%.
  • the activity of CDK4 or CDK6 is measured according to a kinase
  • a method of inhibiting one or more of CDK1, CDK2, CDK4, CDK6, and CDK9 in a ceil comprising administering an effective amount of a compound disclosed herein to the cell .
  • one or more of CDKL CDK2, CDK4, CDK6, and CDK9 is inhibited by about 10% or more, about 20% or more, about 30%) or more, about 40% or more, about 50% or more, about 60% or more, about 70% ) or more, about 15% or more, about 80% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.
  • one or more of CDK1, CDK2, CDK4, CDK6, and CDK9 is inhibited up to about 99%, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 85%, up to about 80%, up to about 70%, or up to about 60% ) .
  • the activity of one or more of CDK1, CDK2, CDK4, CDK6, and CDK9 is measured according to a kinase assay.
  • a method of inhibiting CDK4 or CDK6 comprising contacting CDK4 or CDK6 with an effective amount of a compound disclosed herein or a variation thereof.
  • a compound disclosed herein binds to CDK4 or CDK6 with an ICso of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM, or less than 0.5 nM.
  • a compound disclosed herein binds to CDK4 or CDK6 with an ICso between 0.1 nM and 1 nM, between 1 nM and 5 nM, between 5 nM and 10 nM, between 10 nM and 50 nM, between 50 nM and 100 nM, beween 100 nM and 200 nM, between 200 nM and 300 nM, between 300 nM and 400 nM, betwee 400 nM and 500 nM, between 500 nM and 600 nM, between 600 nM and 700 nM, between 700 nM and 800 nM, between 800 nM and 900 nM, or between 900 nM and 1 mM.
  • the ICso is measured according to a kinase assay.
  • the ICso is measured according to a cell proliferation assay.
  • provided herein is a method of inhibiting one or more of
  • CDKI, CDK2, CDK4, CDK6, and CDK9 comprising contacting one or more of CDK1 , CDK2, CDK4, CDK6, and CDK9 with an effective amount of a compound disclosed herein or a variation thereof, in some embodiments, a compound disclosed herein binds to one or more of CDKI, CDK2, CDK4, CDK6, and CDK9 with an ICso of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM.
  • a compound disclosed herein hinds to one or more of CDKI, CDK2, CDK4, CDK6, and CDK9 with an ICso between 0.1 nM and 1 nM, between 1 nM and 5 nM, between 5 nM and 10 nM, between 10 nM and 50 nM, between 50 nM and 100 nM, beween 100 nM and 200 nM, between 200 nM and 300 nM, between 300 nM and 400 nM, betwee 400 nM and 500 nM, between 500 nM and 600 nM, between 600 nM and 700 nM, between 700 nM and 800 nM, between 800 nM and 900 nM, or between 900 nM and 1 mM.
  • the ICso is measured according to a kinase assay, in some embodiments, the ICso is measured
  • provided herein is a method of modulating CDK4/6 in an individual, comprising administering to the individual a compound disclosed herein or a variation thereof. In some embodiments, provided herein is a method of modulating CDK4 and CDK 6 in an individual, comprising administering to the indi vidual a compound disclosed herein or a variation thereof. In some embodiments, provided herein is a method of modulating CDK4/6 and one or more of CDK1, CDK2, and CDK9 in an individual, comprising administering to the a compound disclosed herein or a variation thereof.
  • provided herein is a method of modulating CDK4 and CDK 6 and one or more of CDK1, CDK2, and CDK9 in an individual, comprising administering to the individual a compound disclosed herein or a variation thereof, in some embodiments, a compound disclosed herein binds to one or more of CDK4/6 with an ICso of less than 1 mM, less than 900 nM, less than 800 n ⁇ l.
  • nM less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM, or less than 0.5 nM.
  • a compound disclosed herein binds to one or more of CDK4 and CDK6 with an IC50 of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM, or less than 0.5 nM.
  • a compound disclosed herein binds to one or more of CDKl, CDK2, CDK4, CDK6, and CDK9 with an ICso between 0.1 nM and 1 nM, between 1 nM and 5 nM, between 5 nM and 10 nM, between 10 nM and 50 nM, between 50 nM and 100 nM, beween 100 nM and 200 nM, between 200 nM and 300 nM, between 300 nM and 400 nM, betwee 400 nM and 500 nM, between 500 nM and 600 nM, between 600 nM and 700 nM, between 700 nM and 800 nM, between 800 nM and 900 nM, or between 900 nM and 1 mM.
  • the ICso is measured according to a kinase assay. In some embodiments, the ICso is measured according to a cell proliferation assay.
  • a compound disclosed herein may enhance the antitumour immunity by increasing the functional capacity of tumour ceils to present antigen or by reducing the immunosuppressive Tiieg population by suppressing their proliferation.
  • a method of inhibiting the proliferation of a cell comprising contacting the cell with an effective amount of a compound disclosed herein or a variation thereof.
  • a compound disclosed herein is effective in inhibiting the proliferation of the cell with an ECso of less than 5 mM, less than 2 mM, less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, or less than 50 nM.
  • a compound disclosed herein is effective in inhibiting the proliferation of the cell with an ECso between 10 nM and 20 nM, between 20 nM and 50 nM, between 50 nM and 100 nM, between 100 nM and 500 nM, between 500 nM and I mM, beween 1 mM and 2 mM, or between 2 mM and 5 mM.
  • the ECso is measured according to a ceil proliferation assay.
  • a compound disclosed herein may affect the immune system. Accordingly, a compound disclosed herein may be used in combination with other anticancer agents or immunotherapies.
  • a method of treating a disease in an individual comprising administering an effective amount of a compound disclosed herein and an additional therapeutic agent to the individual, in some embodiments, the additional therapeutic agent is a cancer immunotherapy agent or an endocrine therapy agent or a chemotherapeutic agent.
  • tire disease is a proliferative disease such as cancer.
  • the additional therapeutic agent is a cancer immunotherapy agent.
  • the additional therapeutic agent is an immunostimulatory agent, in some embodiments, the additional therapeutic agent targets a checkpoint protein (for example an immune checkpoint inhibitor), in some embodiments, the additional therapeutic agent is effecti ve to stimulate, enhance or improve an immune response against a tumor.
  • a checkpoint protein for example an immune checkpoint inhibitor
  • a combination therapy for the treatment of a disease such as cancer.
  • a method of treating a disease in an individual comprising administering an effective amount of a compound disclosed herein in combination with a radiation therapy.
  • tire endocrine therapy is antiestrogen therapy.
  • the endocrine therapy is a selective estrogen receptor degrader (SERD, such as fuivestrant).
  • SESD selective estrogen receptor degrader
  • the endocrine therapy is an aromatase inhibitor (such as letrozole).
  • tire combination of a CDK4/6 inhibitor and endocrine therapy causes enhancement of Gl-S cell-cycle arrest.
  • the combination of a CDK4/6 inhibitor and endocrine therapy causes enhanced entry into a senescent state.
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the endocrine therapy agent, in some embodiments, a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the endocrine therapy agent.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a second chemotherapeutic agent.
  • the chemotherapeutic agent is another kinase inhibitor.
  • a compound disclosed herein is administered prior to, after, or simultaneously coadministered with the second chemotherapeutic agent.
  • a compound disclosed herein is administered I or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the second chemotherapeutic agent.
  • chemotherapeutic agents that can be used in combination with a compound disclosed herein include DNA-targeted agents, a DNA alkylating agent (such as cyclophosphamide, meelilorethamine, chlorambucil, melphalan, daearbazine, or nitrosoureas), a topoisomerase inhibitor (such as a Topoisomerase I inhibitor (e.g., irinotecan or topotecan) or a Topoisomerase II inhibitor (e.g., etoposide or teniposide)), an anthracycline (such as daunorubiein, doxorubicin, epimbicin, idarubicin, mitoxantrone, or vairubicin), a histone deacetylase inhibitor (such as vorinostat or romidepsin), a bromodomain inhibitor, other epigenetic inhibitors, ataxane (such as paclitaxe), a topo
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a kinase inhibitor (such as bortezomih, erlotinib, gefitinib, imatinib, vemurafenih, vismodegib, or ibrutinib).
  • a compound disclosed herein is administered prior to, after, or simultaneously eo-administered with the kinase inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the kinase inhibitor.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a DNA damaging agent.
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the DNA damaging agent, in some embodiments, a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the DNA damaging agent.
  • a method of treating a di sease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a DNA alkylating agent (such as cyclophosphamide, mechlorethamme, chlorambucil, meiphalan, dacarbazme, or nitrosoureas).
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the DNA alkylating agent.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the DNA alkylating agent.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount ofatopoisomera.se inhibitor (such as a Topoisomerase I inhibitor (e.g., irinotecan or topotecan) or a Topoisomerase II inhibitor (e.g., etoposide or temposide)).
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the topoisomerase inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the topoisomerase inhibitor,
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of an anthracycline (such as daunonibicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or vaimbiein).
  • an anthracycline such as daunonibicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or vaimbiein.
  • a compound disclosed herein is administered prior to, after, or simultaneously co-admimstered with the anthracycline.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the anthracyciine.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effecti ve amount of a histone deacetylase inhibitor (such as vorinostat or romidepsin).
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the histone deacetylase inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 2.4 or more hours, or 48 or more hours) prior to or after the histone deacetylase inhibitor.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a taxane (such as paclitaxel or docetaxel).
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the taxane.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the taxane.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a nucleotide analog or precursor analog (such as azacitidine, azathioprine, capecitabine, cytarabme, doxifluridine, 5-fhiorouracil, gemcitabme, hydroxyurea, mereaptopurme, methotrexate, ortioguanine).
  • a nucleotide analog or precursor analog such as azacitidine, azathioprine, capecitabine, cytarabme, doxifluridine, 5-fhiorouracil, gemcitabme, hydroxyurea, mereaptopurme, methotrexate, ortioguanine.
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the nucleotide analog or precursor analog.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the nucleotide analog or precursor analog.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a platinum-based chemotherapeutic agent (such as eisp!atin, earhoplatin, or oxaliplatin).
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the platinum -based chemotherapeutic agent.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the platinum-based chemotherapeutic agent.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of pemetrexed.
  • Formula (I a compound disclosed herein is administered prior to, after, or simultaneously eo-admmistered with the pemetrexed.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the pemetrexed.
  • a method of treating a disease in an individual comprising (a) administering an effective amount a compound disclosed herein and (b) administering an effective amount of a Bruton’s tyrosine kinase (BTK) inhibitor.
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the BTK inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the BTK inhibitor.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (h) administering an effective amount of a PI3K or Akt inhibitor.
  • a compound disclosed herein is administered prior to, after, or simultaneously eo-administered with the PI3K or Akt inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the PI3K or Akt inhibitor.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a DNA damage repair (DDR) pathway inhibitor, in some embodiments, a compound disclosed herein is administered prior to, after, or simultaneously eo-administered with the DDR pathway inhibitor. In some embodiments, a compound disclosed herein is administered I or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the DDR pathway inhibitor.
  • DDR DNA damage repair
  • inhibitors of the DDR pathway include poly(ADP ⁇ ribose) polymerase (PAR?) inhibitors (such as olaparib, rueaparib, niraparib, or talazoparib), ataxia telangiectasia mutated (ATM) protein inhibitors, ataxia telangiectasia and Rad3 -related (ATR) protein inhibitors, checkpoint kinase 1 (Chkl) inhibitors, or combinations thereof.
  • PAR poly(ADP ⁇ ribose) polymerase
  • ATM telangiectasia mutated
  • ATR ataxia telangiectasia and Rad3 -related protein inhibitors
  • Chkl checkpoint kinase 1
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a PARP inhibitor (such as olaparib, rueaparib, niraparib, or talazoparib).
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the PARP inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12. or more hours, 24 or more hours, or 48 or snore hours) prior to or after the PARP inhibitor.
  • a method of treating a disease in an indiv idual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of an ATM protein inhibitor.
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the ATM protein inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the ATM protein inhibitor.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of an ATR protein inhibitor.
  • a compound disclosed herein is administered prior to, after, or simultaneously co-administered with the ATR protein inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the ATR protein inhibitor.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of an Chkl inhibitor, in some embodiments, a compound disclosed herein is administered prior to, after, or simultaneously co-admmistered with the Chkl inhibitor. In some embodiments, a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the Chkl inhibitor.
  • a method of treating a disease in an individual comprising (a) administering an effective amount of a compound disclosed herein and (b) administering an effective amount of a further CDK4/6 inhibitor.
  • a compound disclosed herein is administered prior to, after, or simultaneously eo-administered with the further CDK4/6 inhibitor.
  • a compound disclosed herein is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after tire further CDK4/6 inhibitor.
  • a combination therapy in which a compound disclosed herein is coadministered (which may be separately or simultaneously) with one or more additional agents that are effective in stimulating immune responses to thereby further enhance, stimulate or upreguiate immune responses in a subject.
  • a method for stimulating an immune response in a subject comprising administering to the subject a compound disclosed herein and one or more immunostimulatory antibodies, such as an anti -PD- 1 antibody, an anti-PD-Ll antibody and/or an anti-CTLA-4 antibody, such that an immune response is stimulated in the subject, for example to inhibit tumor growth, in one embodiment, the subject is administered a compound disclosed herein and an anti-PD-1 antibody.
  • the subject is administered a compound disclosed herein and an anti-PD-Ll antibody.
  • the subject is administered a compound disclosed herein and an anti-CTLA-4 antibody.
  • the immunostimulatory antibody e.g.. anti-PD-1, anti-PD-Ll and/or anti-CTLA-4 antibody
  • the immunostimulatory antibody is a human antibody.
  • the immunostimulatory antibody can be, for example, a chimeric or humanized antibody (e.g., prepared from a mouse anti-PD-1, anti-PD-Ll and/or anti-CTLA-4 antibody).
  • the present disclosure provides a method for treating a proliferative disease (e.g., cancer), comprising administering a compound disclosed herein and an anti-PD-I antibody to a subject, in further embodiments, a compound disclosed herein is administered at a subtherapeutic dose, the anti-PD-1 antibody is administered at a subtherapeutic dose, or both are administered at a subtherapeutic dose.
  • a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimuiatory agent comprising a compound disclosed herein and a subtherapeutic dose of anti-PD-1 antibody to a subject, in certain embodiments, the subject is human.
  • the anti-PD- 1 antibody is a human sequence monoclonal antibody.
  • the present invention provides a method for treating a hyperproliferative disease (e.g., cancer), comprising administering a compound disclosed herein and an anti-PD-Ll antibody to a subject.
  • a compound disclosed herein is administered at a subtherapeutic dose
  • the anti-PD-Ll antibody is administered at a subtherapeutic dose
  • the present invention provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimuiatory agent, comprising administering a compound disclosed herein and a subtherapeutic dose of anti-PD- Ll antibody to a subject.
  • the subject is human.
  • the anti-PD-Ll antibody is a human sequence monoclonal antibody.
  • the combination of therapeutic agents discussed herein can be administered concurrently as a single composition in a pharmaceutically acceptable carrier, or concurrently as separate compositions each in a pharmaceutically acceptable carrier.
  • the combination of therapeutic agents can be administered sequentially.
  • an anti-CTLA-4 antibody and a compound disclosed herein can be administered sequentially, such as anti-CTLA-4 antibody being administered first and a compound disclosed herein second, or a compound disclosed herein being administered first and anti-CTLA-4 antibody second.
  • an anti-PD-1 antibody and a compound disclosed herein can be administered sequentially, such as anti-PD-1 antibody being administered first and a compound disclosed herein second, or a compound disclosed herein being administered first and anti-PD-1 antibody second.
  • an anti-PD-Ll antibody and a compound disclosed herein can be administered sequentially, such as anti-PD-Ll antibody being administered first and a compound disclosed herein second, a compound disclosed herein being administered first and anti-PD-Ll antibody second.
  • the order of the sequential administration can be reversed or kept in the same order at each time point of administration, sequential administrations can he combined with concurrent administrations, or any combination thereof.
  • the combination of a compound disclosed herein can be further combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • a compound disclosed herein can also be further combined with standard cancer treatments.
  • a compound disclosed herein can be effectively combined with chemotherapeutic regimens, in these instances, it is possible to reduce the dose of other chemotherapeutic reagent administered with the combination of the instant disclosure.
  • Other combination therapies with a compound disclosed herein include radiation, surgery, or hormone deprivation.
  • Angiogenesis inhibitors am also be combined with a compound disclosed herein. Inhibition of angiogenesis leads to tumor cell death, which can be a source of tumor antigen fed into host antigen presentation pathways.
  • a compound disclosed herein can be used in conjunction with anti-neoplastic antibodies.
  • treatment with an anti-cancer antibody or an anti-cancer antibody conjugated to a toxin can lead to cancer cell death (e.g., tumor cells) which w'ould potentiate an immune response mediated by CTLA-4, PD-1, PD-L1 or a compound disclosed herein
  • a treatment of a hyperproliferative disease e.g., a cancer tumor
  • Other antibodies that can be used to activate host immune responsiveness can be further used in combination with a compound disclosed herein.
  • a compound disclosed herein can be combined with an anti-CD73 therapy, such as an anti-CD73 antibody.
  • the dose of a compound administered to an individual may v ary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated.
  • the amount of the compound or salt thereof is a therapeutically effective amount.
  • the effective amount of the compound may in one aspect be a dose of between about 0,01 and about 100 mg/kg.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery', the phannacokinetics of the agent, the seventy and course of the disease to be treated, the subject’s health status, condition, and weight.
  • An exemplar ⁇ ' dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient.
  • a compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desi red period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g. , about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a 'drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • a 'drug holiday e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more.
  • the compounds pro vided herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdennai.
  • a compound provided herein can be administered frequently at low doses, known as 'metronomic therapy,' or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs.
  • Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles.
  • Metronomic therapy or maintenance therapy can comprise intra-turnorai administration of a compound provided herein.
  • the invention provides a method of treating cancer in an individual by parenteraliy administering to the indi vidual (e.g., a human) an effecti ve amount of a compound or salt thereof.
  • the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous.
  • the route of administration is oral.
  • the route of administration is transdermal.
  • compositions including pharmaceutical compositions as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein.
  • the composition comprises a pharmaceutical formulation which is present in a unit dosage fonn.
  • articles of manufacture comprising a compound of the disclosure or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, composition, and unit dosages described herein in suitable packaging for use in the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • kits for carrying out the methods of the invention which comprises one or more compounds described herein or a composition comprising a compound described herein.
  • the kits may employ any 7 of the compounds disclosed herein.
  • the kit employs a compound described herein or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of cancer.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
  • kits may be in unit dosage forms, bulk packages (e.g, multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful tor a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions tor use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • Step-1 Preparation of Methyl 3-(4-Bromo-2-fluoro-6- nitrophenoxy)propanoate: To a stirred solution of TPP (6.66 g, 25.42 mmol, 1.2 eq) in THF (50 mL), was added DIAD (5.1 mL, 25.42 mmol, 1.2 eq) dropwise at 0 °C and the mixture was warmed to RT followed by the addition of 4-bromo-2-fluoro-6-nitrophenol (5 g, 21.18 mmol, 1 eq) and methyl 3-bydroxypropanoate (2.6 g, 25,42 mmol, 1.2 eq).
  • Step ⁇ 3 Preparation of 7-Bromo-9-fluoro-5-isopropyl-2,3- dihydrobenzo[£][l,4]oxazepin-4(5/?) ⁇ one: To a stirred solution of 7-bromo-9-fluoro-2, 3- dihydrobenzo[h][l,4]oxazepm-4(5//)-one (3 mg, 11.58 mmol, 1 eq) in DMF (30 mL) was added NaH (60% in mineral oil) (927 mg, 23.16 mmol, 2.0 eq) at 0 °C and the mixture was allowed to stir at same temperature 30 min followed by the addition of 2-iodopropane (2.3 mL, 23.16 mmol, 2 eq).
  • Step-5 Preparation of 9-FIuoro-5-isopropyl-7-(4,4,5,5-tetramethyI-l,3,2- dioxaborolan-2-yl)-2,3,4,5-tetrahydrobenzo[£
  • Step-6 Preparation of 7-(2-Chloro-5-fluoropyrimidin-4-yl)-9-fhioro-5- isopropyl-2,3,4,5-tetrahydrobenzo[A] [l,4]oxazepane: To a stirred solution of 9 ⁇ fluoro ⁇ 5- isopropyi-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,4,5- tetrahydrobenzo [6] [ 1 ,4]oxazepine (300 mg, 0.89 mmol, 1 eq) m THF: water (2:1, 6 mL) were added 2,4-dichloro-5-fluoropyrimidme (165 mg, 0.98 mmol, 1.1 eq), potassium carbonate (307 mg, 2.22 mmol, 2.5 eq) and Pd(PPhj)4 (41 mg, 0.035 mmol, 0.04 eq
  • Step-7 Preparation of 5-Fluoro-4-(9-fluoro-5-isopropyl-2,3,4,5- tetrahydrobenzo[A][l ,4] oxazepin-7-yl)-/V-(5-(l-methylpiperidm-4-yl)pyridm-2- yl)pyrimidin-2-amme: To a solution of 7-(2-cbloro-5-fluoropyrimidin-4-yl)-9-fluoro-5- isopropyl-2,3,4,5-tetrahydrobenzo[6][l,4]oxazepine (100 mg, 0.29 mmol, 1 eq) in dioxane (5 mL) were added 5-(l-methylpiperidin-4-yl)pyridin-2-amine (62 mg, 0.32 mmol, 1.1 eq) and cesium carbonate (142 mg, 0.43 mmol, 1,5 eq) and the mixture was degas
  • Example S-2 Preparation of 9-Fluoro-7-(5-fluoro-2-(5-(J-methylpiperidin-4-yl)pyridin-2- ylamino)pynrnidin-4-yl)-5-isopropyl-2, 3-dihydrobenzofb ][1, 4 Joxa ⁇ epin-4(5H)-one (Compound 82)
  • Step-1 Preparation of 9-FIuoro-5-isopropyl-7-(4,4,5,5-tetramethyl-l,3,2- d s o x a h o r o 1 a n - 2 ⁇ y I ⁇ - 2 ,3 - d i h y drohenzo[/?jj !,4j o % az e p i n - 4 ( 5 H) -one: To a stirred solution of 7-bromo ⁇ 9 ⁇ fluoro-5-isopropyl ⁇ 2,3 ⁇ dihydrobenzo[A][i ,4]oxazepm-4(5i7)-one (400 mg, 1 .32 mmol, 1 eq) in dioxane (5mL) was added 4,4,4',4',5,5,5',5'-oetamethyl-2,2'-bi(l,3,2- dioxaborolane
  • Step-2 Preparation of 7-(2-ChIoro-5-fIuoropyrimidin-4-y!)-9-fluoro-5- isopropyl-2,3-dihydrobenzo[/>][l,4]oxazepm-4(5i/)-one: To a stirred solution of 9-fluoro- 5-isopropy!-7-(4,4,5,5-tetramethyi-L3,2-dioxaboro ⁇ an-2-yl)-2,3- dibydrobenzo[£][l,4]oxazepin-4(J/7)-one (350 mg, 1 .002 mmol, 1 eq) in THF: water (2: 1 , 6 mL) was added 2,4-dichloro-5-fluoropyrimidine (184 mg, 1.103 mmol, 1.1 eq), potassium carbonate (346 mg, 2.5 mmol, 2.5 eq) and Pd(PPh3)4 (46 mg, 0,04 m
  • reaction mixture was allowed to stir at 70 °C for 4h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted wit ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound which was purified by CombiFlash Chromatography to obtain the title compound (300 mg, 84.7%). LCMS: 354 [M+H] + .
  • Step-3 Preparation of 9-Fli!oro-7-(5-fluoro-2-i5-(l-methyipiper!din-4- y!pyridm-2-ylammo)pyrimidm-4-yl)-5-isopropyl-2,3-dihydrobenzo[A][l,4]oxa2;epin- 4(5iT)-one: To a solution of 7-(2-chloro-5-fluoropyrimidin-4-yl)-9-fluoro-5-isopropyl-2,3- dihydrobenzo[.6][l,4]oxazepiii-4(5/7)-one (100 mg, 0.28 mmol, 1 eq) in dioxane (5 mL), was added 5-(l-methylpiperidin-4-yl)pyridin-2-amiiie (60 mg, 0.31 mmol, 1.1 eq) and cesium carbonate (138.5 mg
  • reaction mixture was purged with nitrogen gas for 10 min., followed by the addition of palladium acetate (1.2 mg, 0.005 mmol, 0.02 eq) and BINAP (7.0 mg, 0.011 mmol, 0.04 eq).
  • the resultant reaction mixture was allowed to stir at 100 °C for 6h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL).
  • ICJO values of compounds against CDK4 and CDK6 are determined by luminescence using retinoblastoma as substrate.
  • Kinase assays are performed in kinase buffer (#PV6135, invitrogen, Life Technologies Grand Island, NY) where total reaction volume is 30 pL/well in 96-well half area white plates (#3693, Costar).
  • 25xtest compounds at specific concentrations (e.g., final concentration range: 0.1 nM - 200 iiM) is mixed with 10 pL oG2.5 kinase (5 nM, CDK4 #PR8064A and CDK6 #PR8422B,
  • Readings are taken at 15 min and 45 min incubation after detection reagent is added in a Synergy Neo Plate reader (Bio ' Tek, Winooski, VT) at single excitation of 340 nm and Dual emission at 495 nm and 520 nm respectively.
  • the following equations are used in die CDK4 and CDK6 assay data analysis. Percent inhibition (100 -% activity) is fitted to the ‘‘four-parameter logistic model” in XLfit for determination of ICso values.
  • Equation 3 Percent Inhibition ⁇ 00*(%Conversion each data point/% Conversion Enzyme)
  • ICso values of compounds against CDK1 are determined by Z'- LYTF,TM These screening assays are performed at Invitrogen Life Technologies (Grand Island, NY) on a low volume NBS, black 384-well plate (#4514, Coming).
  • 0.1 pL of 100 c test compound in 100% OMSO (at specific solutions) is mixed with 2.4 pL of Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 niM MgCb, 1 mM EGTA), 5 mE of 2x Kinase (3.5 - 46.4 ng CDK1 /cyclin B)/Peptide (2 mM Ser/Thr 18), and 2,5 mE of 4xATP solution (34 mM).
  • Kinase Buffer 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 niM MgCb, 1 mM EGTA
  • 5 mE of 2x Kinase 3.5 - 46.4 ng CDK1 /cyclin B)/Peptide (2 mM Ser/Thr 18
  • 2,5 mE of 4xATP solution 34 mM
  • Development Reagent Solution (5 pL of 1: 1024 dilution) is added to the plates followed with another 30-second plate shake, and the plates are further incubated at room temperature for one hour. The plates are read on fluorescence plate reader with Dual emission at 445 nm and 520 nm.
  • ICso values of compounds against CDK2 are determined by Z' ⁇ LYTETM. These screening assays are performed at invitrogen Life Technologies (Grand island, NY) on a low volume NBS, black 384-well plate (#4514, Coming).
  • 0.1 pL of 100 c test compound in 100% DMSQ (at specific solutions) is mixed with 2.4 pL of Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRU-35, 10 niM MgCk, 1 mM EGTA), 5 pL of 2.x Kinase (1,22 - 10.3 ng CDK2/cyclin AV ' Peptide (2 mM Ser/Thr 12), and 2.5 pL of 4xATP solution (31 pM). The plates are shaken for 30 seconds, and incubated for 60 minutes at room temperature.
  • Kinase Buffer 50 mM HEPES pH 7.5, 0.01% BRU-35, 10 niM MgCk, 1 mM EGTA
  • 5 pL of 2.x Kinase (1,22 - 10.3 ng CDK2/cyclin AV ' Peptide (2 mM Ser/Thr 12
  • 4xATP solution 31 pM
  • Development Reagent Solution (5 pL of 1: 1024 dilution) is added to the plates followed with another 30-second plate shake and the plates are further incubated at room temperature for one hour. The plates are read on fluorescence plate reader with Dual emission at 445 nm and 520 nm.
  • ICso values of compounds against CDK5 are determined by Z'-LYTETM. These screening assays are performed at invitrogen Life Technologies (Grand Island, NY) on a low volume NBS, black 384-well plate (#4514, Coming).
  • 0.1 pL of 100 x test compound in 100% DMSO (at specific solutions) is mixed with 2.4 pL of Kinase Buffer (50 mM HEPES pH 7,5, 0,01% BRIJ-35, 10 mM MgCb, 1 mM EGTA), 5 pL of 2* Kinase (0.18 - 2 ng CDK5/p25)/Peptide (2 pM Ser/Thr 12), and 2,5 pL of 4xATP solution (17 pM).
  • Kinase Buffer 50 mM HEPES pH 7,5, 0,01% BRIJ-35, 10 mM MgCb, 1 mM EGTA
  • 5 pL of 2* Kinase (0.18 - 2 ng CDK5/p25)/Peptide (2 pM Ser/Thr 12
  • 2,5 pL of 4xATP solution 17.
  • Development Reagent Solution (5 pL of 1:4096 dilution) is added to the plates followed with another 30- second plate shake and die plates are further incubated at room temperature tor one hour. Hie plates are read on fluorescence plate reader with Dual emission at 445 nm and 520 nm.
  • ICso values of compounds against CDK7 are determined by AdaptaTM Assay at Invitrogen Life Technologies (Grand Island, NY) where total reaction volume is 10 pL/well in low volume, white 384-well plate (#4512, Coming).
  • Detection Mix prepared in TR-FRET Dilution Buffer; the Detection mix consists of EDTA (30 mM), Eu-anti-ADP antibody (6 nM) and ADP tracer, and contains the ECeo concentration of tracer for 5-150 pM ATP) is added to the plates followed with another 30-second plate shake and centrifugation for 1 min at 1000xg, and the plates are further incubated at room temperature for one hour. The plates are read on fluorescence plate reader with Dual emission at 615 nm and 665 mn.
  • the following equations are used for AdaptaTM Assay Data Analysis.
  • the ATP/ADP standard curve is fit to model number 205 (sigmoidal dose-response model) in XLfit.
  • the dose response curve is also curve fit to model number 205.
  • ICJO values of compounds against CDK2 are determined by LanthaScreenTM Eu Kinase Binding Assay at Invitrogen Life Technologies (Grand Island, NY) where total reaction volume is 16 iiL/well in low volume, white 384-well plates (#784207, Greiner).
  • 0.16 pL of 100 c test compound in 100% DMSQ (at specific solutions) is mixed with 3.84 pL of Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 niM MgCk, 1 mM EGTA), 8.0 pL of 2 Kinase (2.5 nM)/Antibody (Eu-anti-GST, 2 nM) Mixture and 4.0 pL of 4 - Tracer (Tracer 236, 100 nM). The plates are shaken for 30 seconds, and incubated for 60 minutes at room temperature. The plates are read on fluorescence plate reader with Dual emission at 615 nm and 665 nm.
  • Kinase Buffer 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 niM MgCk, 1 mM EGTA
  • ICJO values of compounds against CDK9 are determined by LanthaScreenTM Eu Kinase Binding Assay at Invitrogen Life Technologies (Grand Island, NY) where total reaction volume is 16 pL/well m low volume, white 384-well plates (#784207, Greiner).
  • 0.16 pL of 100 - test compound in 100% OMSO is mixed with 3.84 pL of Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCb, 1 mM EGTA), 8,0 pL of 2x Kinase (5 nM)/ Antibody (Eu-anti-His, 2 nM) Mixture and 4,0 mE of 4 x Tracer (Tracer 236, 100 nM).
  • the plates are shaken for 30 seconds, and incubated for 60 minutes at room temperature.
  • the plates are read on fluorescence plate reader with Dual emission at 615 nm and 665 nm.
  • ICso values of compounds against FMS kinase are determined by LanthaScreenTM Eu Kinase Binding Assay at Invitrogen (Life Technologies Grand Island, NY) where total reaction volume is 10 m L in low-volume 384-well plates (#4511, Coming). Serially diluted compounds (3 -fold) are incubated with kinase (1.25 iiM) for 10 min, following which a mixture of ATP (10 mM) (#AI852, Sigma, St-Louis, MO) and fluoreseent-PolyGT substrate (200 nM) (#PV3610, invitrogen, Life Technologies Grand Island, NY) is added and incubated in dark at room temperature for 1H.
  • ICso values of compounds against the PI3K5 kinase are determined by an assay performed by Reaction Biology Corporation (Malvern, PA). Briefly, this assay is conducted in buffer (Tris-HCl 40 mM (pH7.5), Orthovanadate 3 mM, MgCk 20 mM, DTT 2 mM, CHAPS 0.05%, DMSO 1%). R ⁇ 3K5 kinase is added to the reaction solution and mixed gently.
  • test compounds in 100% DMSO are mixed with the kinase reaction mixture to achieve the final compounds at pre-defmed concentrations (e.g., range - 0.5 nM to 100 mM) by Acoustic technology (Echo550; nanoliter range).
  • concentrations e.g., range - 0.5 nM to 100 mM
  • ATP is added into the reaction mixture to initiate the reaction followed by a 30-min incubation at 30 C.
  • the plates are incubated for 40 min.
  • the Detection Mixture is added, and the plate is incubated for an additional 30 min.
  • luminescence is measured.
  • the luminescence is converted into mM ADP production based on ADP standard curves.
  • the nonlinear regression to obtain the standard curve and ICso values is performed using GraphPad Prism (GraphPad Software, Inc., San Diego, CA).
  • ICso values of compounds against CDK12 are determined by KmaseProfilerTM radiometric protein kinase assay at Eurofins Pharma Discovery (Dundee, UK). Compounds are prepared to 5 Ox final assay concentration in 100% DMSO. This working stock of the compound is added to the assay well as the first component in each reaction.
  • CDK12/Cyclin K is diluted in buffer (20 mM TRIS, 0.2 mM EDTA, 0.1% b- mereaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg/m] BSA) prior to addition to the reaction mix.
  • CDK12/Cyc!in K is incubated with 20 mM Tris/HC!
  • Example B2 Determination of potency of compounds in cancer cell proliferation assay as a single agent.
  • test compounds were studied in two breast cancer cell lines of different subtype.
  • the cancer cells (Table below) are harvested during the logarithmic growth period and counted. Cell concentrations are adjusted to the appropriate number with respective medium and 90 pL cell suspensions are added to 96-well plates. After cells are seeded, the plates are shaken gently to distribute ceils evenly and incubated at 37 °C, 5% CO?, on day 1.
  • Ceils are treated with test compounds at 7 to 9 concentrations within a desired concentration range (e.g. 1.1 nM - 10 mM) on day 2 by series diluting the test compound stock solution (10 mM in DM80) with culture medium. Treatment duration was 144H (with a medium change at 72.H) for both MCF-7 and DU4475 cells. Cell viability is assessed by Cell Titer-Glo® as recommended by Promega (Cat. No.: G7572), or by resazurin assay (Sigma Aldrich, Cat. No.: R7017) post treatment.
  • a desired concentration range e.g. 1.1 nM - 10 mM
  • Ceil viability data are plotted using GraphPad Prism (GraphPad Software, Inc.,
  • test compounds are studied in additional cell lines of various histotypes, such as A549 lung adenocarcinoma, HCT-116 colorectal carcinoma, ZR-75-30 breast ductal carcinoma, Hs ⁇ 578T breast epithelia carcinoma and BT-549 breast ductal carcinoma cells.
  • the cancer cells are harvested during the logarithmic growth period and counted. Cell concentrations are adjusted to the appropriate number with suitable medium, and 90 pL cell suspensions are added to 96-well plates.
  • Cells are treated with test compounds at typically 7-9 concentrations within a desired concentration range (e.g. 1.5 nM - 10 mM) on day 2 by series diluting the test compound stock solution (10 niM in DM8Q) with culture medium.
  • Cell viability 7 is assessed by Cell Titer-Glo® as recommended by Promega (Cat. No.: G7572, Promega) typically 48-144H post-treatment, with a medium change as necessary.
  • Cell viability data are plotted using GraphPad Prism (GraphPad Software, Inc., San Diego, CA). in addition, a nonlinear regression model with a sigmoidal dose response and variable slope within GraphPad Prism is used to calculate the IC50 value of individual test compounds.
  • Additional test compounds are studied in the same and/or other cancer cell lines using similar proliferation methods with possible variations in cell seeding densities and/or incubation durations.
  • the cell cycle phase distribution post treatment of lest compounds is studied using flow cytometer using DAPI staining.
  • Cellular senescence is evaluated after continuously treating cells for a long time (e.g., 14 days) followed by staining cells lines for Senescence associated-P-galactosidase (8AbOAI,).

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Abstract

L'invention concerne des composés hétérocycliques utilisés comme inhibiteurs de CDK4 ou de CDK6 ou d'autres CDK. Ces composés peuvent être utilisés comme agents thérapeutiques pour le traitement de maladies et peuvent trouver une application particulière en oncologie.
PCT/US2022/072067 2021-05-03 2022-05-02 Composés hétérocycliques utilisés comme inhibiteurs de kinase WO2022236257A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180072704A1 (en) * 2015-04-29 2018-03-15 Guangdong Zhongsheng Pharmaceutical Co., Ltd Fused-Ring Or Tricyclic Aryl Pyrimidine Compound Used As Kinase Inhibitor
US20190248774A1 (en) * 2018-02-15 2019-08-15 GiraFpharma LLC Heterocyclic compounds as kinase inhibitors
WO2021030623A1 (fr) * 2019-08-14 2021-02-18 Nuvation Bio Inc. Composés hétérocycliques en tant qu'inhibiteurs de kinase
WO2022113003A1 (fr) * 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180072704A1 (en) * 2015-04-29 2018-03-15 Guangdong Zhongsheng Pharmaceutical Co., Ltd Fused-Ring Or Tricyclic Aryl Pyrimidine Compound Used As Kinase Inhibitor
US20190248774A1 (en) * 2018-02-15 2019-08-15 GiraFpharma LLC Heterocyclic compounds as kinase inhibitors
WO2021030623A1 (fr) * 2019-08-14 2021-02-18 Nuvation Bio Inc. Composés hétérocycliques en tant qu'inhibiteurs de kinase
WO2022113003A1 (fr) * 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem ANONYMOUS : "Substance record for 369563483", XP093004631 *
DATABASE PubChem ANONYMOUS : "Substance Record for 427566837", XP093004630 *

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