Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• This disclosure relates generally to therapeutics which play a crucial role in the control of the cell cycle and more particularly, compounds that inhibit eye! in -dependent kinases (CDK).
• CDK -dependent kinases
• the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the trea tment of diseases associated with these pathway
• 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 ceil 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 ceil cycle namely the Gap-1 (Gl ) phase, Synthesis (S) phase, Gap-2 (G2) and Mitosis (M) phases.
• An extended phase of Gap- 1 phase is coined as Gap-0 (GO) phase or Resting phase (Cancers 2014, 6, 2224-2242)
• CDK Cycim-dependeni kinases
• CDK5 is the prototype of atypical CDK: it is activated by the non-cyclm proteins p35 (or CdkSRl ) and p39 (or Cdk5R2) and has unique post-mitotic functions in neuronal biology, angiogenesis and cell differentiation.
• Proliferative signals induce the transition from the GO or Gl phases into S phase through the activation of the structurally related CDK4 and CDK6 [Development, 2013:140 (15): 3079-93, Biochern Pharmacol 2012;84(8):985 ⁇ 93. Nature 2014:510(7505):393--61.
• the binding of cychn D to CDK4 and to CDK6 promotes the phosphorylation of the transcriptional repressor retinoblastoma protein (RBI).
• CDK hyperactivity is often observed m cancer reflecting their prominent role in ceil cycle and transcription regulation in cancer cells, the process of ceil division becomes unregulated, resulting in uncontrolled growth that leads to the development of a tumor.
• a number of mecha sms contribute to the dysreguiation 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 Gl to S phase transition. This process appears to be facilitated by 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 mechamsms such as intrinsic CDK inhibitors and tumor suppressor proteins. The overall effect of this type of cell cycle dysreguiation is malignant cell proliferation and the development of cancer (Clinical Breast Cancer 2016, 1526-8209).
• WO201110141 or clinically developed.
• F!avopirido! and R-Roscovitine were the first generation of pan-CDK inhibitors with anti-tumor activity attributed to down-regulation of CDK9-mediated anti-apoptohc proteins, especially Mcl-1.
• a new generation of CDK inhibitors have been developed, advanced to clinical trials and approved for certain types of cancer. Dinaciciib, a selective inhibitor of CDK 1, CDK2, CDK 5, and CDK9, was directed towards refractory chronic lymphocytic leukemia while palbociclib was tested against advanced estrogen receptor (ER)-positive breast cancer as a selective inhibitor of CDK4 and CDK6.
• ER estrogen receptor
• CDK4/6 inhibitors has led to a renewed enthusiasm for manipulating the cyclin D1 -CDK4/6 axis in cancer treatment.
• CDK4/6 inhibitors There are three FDA-approved CDK4/6 inhibitors presently:
• CDK4/6 inhibitors for the treatment of hyper-proliferative diseases preferably have at least one advantageous property selected from selectivity, potency, stability, pharmacodynamic properties and safety profile.
• a novel class of CDK4/6 inhibitors is provided herein.
• the compound of Formula (I) or a salt thereof is of Formula (I- A) as detailed herein.
• a method of treating cancer m an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound as detailed herein, such as a compound of any one of Formula (J), Formula (I ), Formula (II), (I-A), (I-B1 ) to (F-B12).
• a compound as detailed herein such as a compound of any one of Formula (J), Formula (I ), Formula (II), (I-A), (I-B1 ) to (F-B12).
• the methods comprise administration of a compound detailed herein, or a salt thereof as a monotherapy.
• kits comprising a compound detailed herein, or a salt thereof, are also provided. Kits may optionally include instructions for use, such as instructions for use m any of the methods detailed herein, for example, for use in the treatment of cancer. A compound as detailed herein, or a salt thereof, is also provided for the manufacture of a medicament for the treatment of cancer.
• FIG 1 shows the body weight changes of the mice m the different groups of a pharmacological study of test compound in a MC-38 mouse model.
• FIG 2 shows the relative change of body weights (%) of the mice m the different groups of a pharmacological study of test compound i n a MC-38 mouse model.
• FIG. 3 A and FIG. 3B show tumor growth curves of fee mice in the different groups of a pharmacological study of test compound in a MC-38 mouse model
• FIGS. 4A-4D show individual tumor growth curves of the mice m fee different groups of a pharmacological study of test compound i n a MC-38 mouse model.
• FIG. 5 shows tumor growth inhibition curves of the mice in the different groups of a pharmacological study of test compound in a MC-38 mouse model.
• FIG. 6 shows time-io-end point Kap!an-Meier survival curves of the mice m the different groups of a pharmacological study of test compound in a MC-38 mouse model.
• Alkyl refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e. , Ci-Cio means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a“ - C o alkyl”).
• alkyl groups are those having 1 to 8 carbon atoms (a ' Ck-Ck alkyl”), 3 to 8 carbon atoms (a fofoCg alkyl”), 1 to 6 carbon atoms (a "‘CyC , alkyl”), 1 to 5 carbon atoms (a“CfeCi alkyl”), or 1 to 4 carbon atoms (a“Cr-Cfe alkyl”).
• alkyl examples include, but are not limited to, groups such as methyl ethyl, n-propyl, isopropyl n-butyl, t-but l isobutyl sec ⁇ butyl homologs and isomers of, for example n -pentyl, n-hexyl, n-heptyl, n-oetyl, and the like.
• the alkenyl group may be in“cis” or “trans” configurations, or alternatively in ⁇ ” or“Z” configurations.
• alkenyl groups are those having 2 to 20 carbon atoms (a“CW alkenyl”), having 2 to 8 carbon atoms (a‘TfoCl alkenyl”), having 2 to 6 carbon atoms (a‘"C -Cs alkenyl”), or having 2 to 4 carbon atoms (a“CV Cfi alkenyl”).
• alkenyl include, but are not limited to, groups such as etheny!
• Alkylene refers to the same residues as alkyl, but having bivaiency. Particular aiky!ene groups are those having 1 to 6 carbon atoms (a“C -Q, alkylene”), 1 to 5 carbon atoms (a“CfoCs alkylene”), 1 to 4 carbon atoms (a ' (l ⁇ i.fi alkylene”) or 1 to 3 carbon atoms (a“Cfi-Cfi alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (- €3 ⁇ 4-). ethylene (- ( ' I I t 1 1 ; ⁇ . propylene (-CH 2 CH 2 CH 2 -), butylene
• Alkynyl refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e. , having at least one moiety of the formula CoC) and having the number of carbon atoms designated foe. means two to ten carbon atoms).
• Particular alkynyl groups are those having 2 to 20 carbon atoms (a“(VCfio aikynyf”), having 2 to 8 carbon atoms (a“( C* alkynyl”) having 2 to 6 carbon atoms (a“Crlfi alkynyl”), or having 2 to 4 carbon atoms (a“(V C.i alkynyl”).
• alkynyl examples include, but are not limited to, groups such as ethynyl (or aeetylenyl), prop-1 -ynyl, prop-2-ynyi (or propargy! but-l-ynyl, but-2-ynyl, but-3-ynyl homologs and isomers thereon and the like.
• Aryl refers to and includes polyunsaturated aromatic hydrocarbon groups.
• Aryl may contain additional fused tings (e.g., from 1 to 3 rings), including additionally fused aryl heteroary!, cycloalkyl, and/or heterocyclyi rings.
• foe aryl group contains from 6 to 14 annular carbon atoms. Examples of ary l groups include, but are not limited to, phenyl, naphthyl, biphenyl and the like.
• Carbonyl refers to the group ( O.
• Cyc!oa!kyr refers to and includes cyclic univalent hydrocarbon structures winch may be fully saturated, mono ⁇ or polyunsaturated but which are non-aromatic, having the number of carbon atoms designated (e.g., C i-Cio means one to ten carbons) Cycioalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantly, but excludes ami groups. A cycioalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof A preferred cycioalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms.
• a more preferred cycioalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C- -C 3 ⁇ 4 cycioalkyl").
• cycioalkyl include, but are not limited to, cyclopropyl, cyclobutyi, cyclopentyl, cyclohexyl, 1 -cydohexeny!, 3-cyciohexenyl, cycloheptyl, norbornyl, and the like.
• Halo or“halogen” refers to elements of the Group 17 senes having atomic number 9 to 85.
• Preferred halo groups include fiuoro, ch!oro, bromo and iodo. Where 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, e.g., dihaioaryi, diha!oa!kyi, trihaloaryl etc.
• aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups which may be but are not necessarily the same halo; thus 4-diloro-3-fluorophenyl is within the scope of dihaioaryi.
• An alkyl group in which each hydrogen is replaced with a halo group is referred to as a
• perhaloalkyl A preferred perhaloaikyl group is tnfluoroalkyl ( ⁇ CF ).
• perhaloa!koxy refers to an alkoxy group in which a halogen takes the place of each 1 1 in the hydrocarbon making up the alkyl moiety of the alkoxy group.
• An example of a perhaloalkoxy group is trif!uoromethoxy (-OCIA).
• Heteroaryl refers to and includes unsaiurated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatermzed
• a heteioaryl group can be attached to the rema inder of the molecule a t an annular carbon or at an annular heteroaiom.
• Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocycly! rings.
• heteroaryl groups include, bat are not limited to, pyridy!, pyrirmdyl, thiophenyl, furany!, thiazoiyl, pyrazoiyl, oxazolyl, isooxazolyl, mndazolyl, qumolyl, isoquinolyl, benzimidazolyl, benzpyrazolyi, benzotriazolyl, indole, benzothiazyi, benzoxazolyl, benzisoxazoiyi, imidaxopyndmy! and the like.
• Heterocycle or“heterocycly G refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatermzed.
• a heterocycly! group may have a single ring or multiple condensed rings, but excludes heteroaryl groups
• a heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof In fused ring systems, one or more of the fused rings can be aryl or heteroaryl Examples of heterocycly!
• groups include, but are not limited to, tetrahydropyrany!, dihydropyranyl, pipendiny!, piperazinyt, pyrrolidinyl, thiazobnyl, thiazo!idinyl, tetrahydrofuranyl,
• Oxo refers to the moiety O
• Optionally substituted unless otherwise specified means that 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 winch the substituents may be the same of different, provided that the group’s normal valence is not exceeded.
• an optionally substituted group has one substituent.
• an optionally substituted group has two substituents.
• an optionally substituted group has three substituents.
• an optionally substituted group has four substituents.
• 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 substituent
• CDK4/6 refers to both CDK4 and CDK6.
• inhibitors of CDK4/6 inhibit both CDK4 and CDK6.
• A“pharmaceutically acceptable carrier” 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.
• 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
• beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation.
• “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This 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 severity of or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of foe disease, its complications and intermediate pathological phenotypes presenting during development of foe disease.
• beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease increasing the quality of lift; of those suffering from the disease decreasing the dose of oilier 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.
• 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 ease of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (hi) inhibit, retard, slow to some extent and preferably stop cancer ceil infiltration into peripheral organs: (iv) inhibit (i.e. , slow to some extent and preferably stop) tumor metastasis: (v) inhibit tumor growdi, (vi) prevent or delay occurrence and/or recurrence of tumor, and/or (vb) relieve to some extent one or more of the symptoms associated with the cance
• An effective dosage can be administered in one or more administrations.
• an effective dosage of compound or a salt thereof, or pharmaceutical composition is an amount sufficient 10 accomplish prophylactic or therapeutic treatment either directly or indirectly. Ii 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 drug, compound, or pharmaceutical composition.
• 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 effecti e amount it) in conjunction with one or more other agents a desirable result may be or i achieved.
• the term“individual” is a mammal, including humans.
• An individual includes, but is not limbed to, human hov me horse, feline canine, rodent, or primate
• 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).
• Reference to“about’ a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to“about X” includes description of“X”.
• A is (X-C & cycloalkyl, 4- to 7-membered heterocyeiyl, 5 to 7-membered heteroaryh or (A, aryl, each of which is optionally substituted with Rf
• B is hydrogen, C C 6 cycloalkyl, ' ⁇ ⁇ to 7-membered heterocyeiyl, 5- to 7 membered heteroaryl, aiyl, each of which is optionally substituted with Rf
• C is (f -Cf cycloalkyl, 5- to 7-membered heterocyeiyl, 5- to 7-membered heteroaryl, or (f aryl, each of which is optionally substituted with Rf wherein C is fused to D;
• D is (f ⁇ (f, cycloalkyl, 3- to 7-membered heterocyeiyl, 5- to 7-membered heteroaryh or Cf aryl, each of which is optionally substituted with Rf
• each X and Y are independently N or CH, provided that at least one of X and Y is N:
• R * is hydrogen, Ck-Ck alkyl, Cz- , alkenyl, (3 ⁇ 4-Ck alkynyl, Ck-Cg aikoxy, Ck-Ck cycloalkyl, 3- to 12- em bered heterocyclyl, 5- io 10-metnhered heteroaryl.
• R l is Cg-Ck alkyl, (k-(k alkenyl, ( ' ⁇ ().
• alkynyl (h-Cs aikoxy, Ck-Ck cycioalkyl, 3- to 12-metnhered heterocyclyl, 5- to 10-membered heteroaryl, C -Cir aryl, -(Ck-Ck alkylene)((k-Ck cycioalkyl), -C(0)R ! k or -(Ck-Cg a!kylene)((k- Cfe aryl), wherein R ⁇ is independently optionally substituted by halogen, oxo, -OR ' -C(0)R l k -CN, Ck-Cg cycioalkyl, or (k-(k alky! optionally substituted by oxo, -Oil or halogen;
• each R is independently Cj-C alkyl, oxo, -NR l l R li , -CN, -C(0)R :iJ , -C(0)NR : : R’ z or halogen, wherein any two R groups are independently attached to same carbon or two different carbons;
• each of R ' and R is independently Cj-Ck alkyl, CVCk cycioalkyl, (k-(k haloa!kyi, CYC. ⁇ . alkoxy, (k-Ck ha!oa!koxy, halogen or -OH;
• each R ' is independently (k-Ck alkyl, .. alkenyl, CYCk alkynyl, halogen, oxo, -CN, -OR i 0 , -SR 10 , -NR J J R 12 , -C(0)R°, -C(0)NR 5 i R i 2 , ⁇ OPO ⁇ U Y k -NR i0 C(O)R n ,
• each k ' is independently oxo or R . or any two R ': groups, when bound to the same carbon atom, are taken together with the carbon to which they are attached to form a Cb- C , cycioaikyl;
• R 7 ts independently hydrogen, Crib, alkyl, C .y O. ⁇ . alkenyl, Cb-Ck alkynyl, Cb-Cb, cycioaikyl, 3- to 6-membered heterocyclyl, -ORti -NR n R° -NR i0 C(O)Rfo -NR i0 C(O)NR ii R 12 , - S( O) : . -NR 30 S(O ⁇ ?
• each R is independently optionally substituted by halogen, oxo, -OR 13 , ⁇ N R : RN -C(0)R 13 , -CN, ⁇
• Rb ' is independently hydrogen, Cb -Cb alkyl, C 3 -C 0 cycioaikyl, -(Cj-C 3 alkylene)(C 3 -C 6 cycioaikyl), Cb-Cb-; aryl, 5- to 6-membered heteroaryi or 3 ⁇ to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, -OR : b -Nlfo ' R 1 , or Cb-Cb alkyl optionally substituted by halogen, -OH or oxo;
• RN and II are each independently hydrogen, Cb-Cb alkyl, Cb-Cb eyeloalkyl,
• R ! ! and R ' are taken together with the ato to winch they attached to form a 3- to 6- membered heterocyclyl optionally substituted by halogen, oxo, or f b -C 1, alkyl optionally substituted by halogen,
• R’ ' and R : ' are taken together with the atom to which they attached to form a 3- to 6- non: tiered heterocyclyl optionally substituted by halogen, oxo or CyCb alkyl optionally substituted by halogen or oxo; and R ⁇ ' and K ' " are each independently hydrogen, (CCA alkyl optionally substituted by halogen or oxo, ( C; alkenyl optionally substituted by halogen or oxo, or (VC; alkynyi optionally substituted by halogen or oxo;
• K : r and R : ' are taken together with the atom to which they attached to form a 3 - to 6- membered heterocydyl optionally substituted by halogen, oxo or Grid alkyl optionally substituted by oxo or halogen;
• 1, nr, p and q are each independently 0, 1, 2 or 3, provided that at least one of m and I is not 0;
• n 0, 1, 2, 3 or 4.
• L is a bond, Qfo, NH O. S, or S0 2
• B is hydrogen, (VC. cycloalkyl, 3- to 7-rnembered heterocydyl, 5- to 7- membered heteroaiyh or Cfo aryl, each of winch is optionally substituted with K
• C is (VC. cycloalkyl, 5- to 7-rnembered heterocydyl, 5- to 7-membered heteroaryl or C 6 aryl, each of which is optionally substituted with K wherein C is fused to D; and D is CX-CX cycloalkyl, 3 ⁇ to 7-membersd heterocyclyl, 5- to 7- mem bered heteroaryl, or CX aryl, each of which is optionally substituted with R
• each X and Y are independently N or ( 1 1. provided that at least one of X and Y is N,
• R is hydrogen.
• k is independently optionally substituted by halogen, oxo, -OR 1 1 -NRYR'l -CX O sR -CM, ( , -( X cycloalkyl, or (X-CX alkyl optionally substituted by oxo, -OH or halogen, provided that when Z is
• R ' is (X-CX alkyl, CX-CX alkenyl (X-CX alkynyl, (X -C alkoxy, (X-(X cycloalkyl 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, CX-CX,* aryl, -(CX -CX a ll lono K CX-CX cycloalkyl ), ( ' 0)11 : l or -(CX-iX alk iene)(CX- aryl), wherein R; is independently optionally substituted by halogen, oxo, -OR 1 2 - ⁇ R : dX 1 -C(0)R J l -CM, (X-Cg cycloalkyl, or CX -CX alkyl optionally substituted by oxo, -OH or halogen; each R 2 is independently CX-CX alkyl, oxo
• each of k and R 4 is independently (X-(X alkyl, CX-CX cycloalkyl, CX -CX haloalkyl, CX-CX alkoxy, CX-CX ha!oalkoxy, halogen or -OH;
• each R is independently Cj-CX alkyl, CX-CX alkenyl, CX-CX alkynyl, halogen, oxo, -CM, -OR 10 , -SR i 0 , -NR n R 12 , -( ' (O nXX -CiOlNR ⁇ R 12 , -0C(0)NR 5 i R J 2 , -NR 10 C(O)R u ,
• each ti is independently optionally substituted by halogen, oxo, -OR - (b alkylsne)NRh’R : b - ⁇ Ci-Cb alky!ene)C(0)R‘ ⁇ C 3 -(b cycloaikyl, or C -CV, alkyl optionally substituted by oxo -OH or halogen,
• each R° is independently oxo or R or any two R° groups, when bound to the same carbon atom, are taken together with the carbon to which they are attached to form a Cw
• R 7 is independently hydrogen, Crib alkyl, C .y -C. ⁇ . alkenyl, Cg-C alkynyl, C C cycloaikyl, 3-- to 6-membered heterocyciyi, -C(Q)R J b ⁇ ( (0 ⁇ R : ! R !
• R l °, (id -id alkylene)NR 1 S(O) 2 R u , -(CrC- 3 alkylene)S(0) 2 NR' 'R / , ⁇ (CrCd alkyleneXCb-Cb cydoalkyl), or -(CrC 3 alkylene)(3- to 6-membered heterocyciyi), wherein each R' is independently optionally substituted by halogen, oxo, ⁇ OR n , - R fobb -C(0)R i 3 , -CN, did- id alkyieneiOR 13 , - ⁇ C -C 3 aikylene)NR3 ⁇ 4 i4 , - ⁇ C - alkyl ene)C(0)R b Cy-Cg cydoalkyl , or C C 6 alkyl optionally substituted by oxo, -OH or halogen;
• id is independently hydrogen, C ; ⁇ ( . alkyl, ( -, ⁇ ( . ⁇ . cycloalkyl, ⁇ (( ; ⁇ ( ⁇ . alkyleneXCrCb cycloaikyl), Cy-Cfo aryl, 5- to 6-rnembered heteroaryl or 3-- 10 6-membered heterocyciyi each of winch is independently optionally substituted by halogen, oxo, -CN, -Old -NR ⁇ fo or . ⁇ alkyl optionally substituted by halogen, -OH or oxo,
• R " and K ' are each independently hydrogen, . ⁇ alkyl, ⁇ . cycloaikyl, -(( ; - Cb alkylene)(C3-C6 cycloaikyl), (b-Cy aryl 5- 10 6-membered heteroaryl or 3- to 6-mernbered heterocyciyi each of which is independently optionally substituted by halogen oxo, -CN, -OR d -NR 3 5 R 16 or ( fob alkyl optionally substituted by halogen, -OH or oxo;
• id and id are taken together with the atom to which they atached to form a 3- to 6- membered heterocyciyi optionally substituted by halogen oxo, or C -Cd alkyl optionally substituted by halogen;
• Id and R'’ are each independently hydrogen or C -Cd alkyl, wherein the Ch-Cg alkyl of K and R ’ are optionally substituted by halogen, -O ' 1 -NR’tidti or oxo;
• R 1 ' and i ⁇ are taken together with the atom to which they attached to form a 3- to 6- membered heterocyciyi optionally substituted by halogen, oxo or Cd ⁇ ( " . ⁇ . alkyl optionally substituted by halogen or oxo; and R ' ' and R ' ' are each independently hydrogen, ( ; ⁇ ( 1 alkyl optionally substituted by halogen or oxo, (fo-Ck alkenyl optionally substituted by halogen or oxo, or CfoCA alkynyi optionally substituted by halogen or oxo;
• R : r and R : ' are taken together with the atom to which they attached to form a 3 - to 6- membered heterocyclyl optionally substituted by halogen, oxo or ( ' : ⁇ ( . ⁇ . alkyl optionally substituted by oxo or halogen;
• 1, nr, p and q are each independently 0, 1, 2 or 3;
• X, Y. A, B, L, R ⁇ R . k . R “ , K ' . R L m, n, p and q are as detailed herein for Formula (J ).
• A is CfoCy cycloaikyl, 4- to 7 membered heteroeyclyl, 5- to 7-membered heteroaryl or C ( , aryl, each of which is unsubstituted.
• A is CYC & cycloalkyl, 4- to 7-membered heteroeyclyl, 5 to 7-membered heteroary! or C . ⁇ .
• A is C 6 aryl optionally further substituted with R
• A is phenyl optionally substituted with R ' .
• A is 5- ⁇ to 7-membered heteroary!
• A is selected from the group consisting of pyridine, pyrimidine, pyrazolyl, ihiazolyl, oxazolyl, isooxazolyl or imidazolyl, each of which is optionally substituted with Ry
• A is 4- to 7-membered heteroeyclyl, optionally further substituted with R
• A is piperidmyi, pyrrolidmyl, azetidmyi, dihydropyridme, or pyndone, each of optionally substituted with R .
• A is CfoCV, cycloalkyl substituted with Ry In some embodiments A is cyclohexyl or cyclopentyl, each of optionally substituted with Ry In some embodiments of a compound of Formula 0 ), A is phenyl, pyridine, pyrimidine, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, imidazolyl, piperidinyl, pyrrolidinyb azetidinyi, pyridone, cyclohexyl, or cyclopentyl, each of which is unsubstituted.
• A is phenyl, pyridine, pyrimidine, pyrazolyl, dnazolyl, oxazolyl, isooxazolyl, mudazo!yi, piperidinyl, pyrrolidinyl, azetidmyl, dihydropyridine, pyridone, cyciohexyl, or cyclopentyl, each of which is optionally substituted with R .
• B is hydrogen, CO
• B is C Ce cyeloaikyi, ' ⁇ to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or C 3 ⁇ 4 aryl, each of which is unsubstituted.
• B is hydrogen.
• B is 3- to 7- membered heterocyclyl optionally substituted with R u .
• B is diazepanyi, azepanyl, piperazinyl, piperidinyl, pyrrolidinyl or azetidinyl, each of which is optionally substituted with R7
• B is 5- to 7- membered heteroaryl optionally substituted with R”
• B is imidazolyl or pyrazolyl .
• B is phenyl optionally substitu ted wi th R7
• B is cyeloaikyi optionally substituted with R”.
• B is eyciopentyl. cyciohexyl, or cyeloheptyl, each of which is optionally substituted with R” In some embodiments of a compound of Formula (I).
• B is hydrogen, diazepanyi, azepanyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, imidazolyl, pyrazolyl, phenyl, cyclopentyl, cyciohexyl, or cyeloheptyl, each of which is unsubstituted
• B is hydrogen, diazepanyi.
• azepanyl piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, imidazolyl, pyrazolyl, phenyl, eyciopentyl, cyciohexyl, or cyeloheptyl, each of which is optionally
• L is a bond, 4 1 1 -. -NH-, - ⁇ ) ⁇ . - S-, -SO ?. -, -CO-, -NCHv-, -Si3 ⁇ 4NH-,of -NHSO -
• L is a bond, -O F- ⁇ , -Nil- ⁇ , - () , or -S-.
• L is a bond.
• L is ⁇ ( 1 1 ⁇
• L is -Nil ⁇ -.
• L is -S-.
• L is -0-.
• L is -SO- ⁇ . In some embodiments, L is -CO-. In some embodiments, L is - ⁇ ( 1 1 ⁇ In some embodiments, L is -NHSO -. In some embodiments L is -f n : : R : ⁇ In some embodimetns, L i -NRt'Y In some embodimeins, L is X R SO ⁇ In some embodimetns, L is -SO ⁇ R : ' ⁇ In some embodiments, L is -SCFNFF
• D is fused with C to form a 7- 12 membered bicyclic rmg having at least one aromatic ring, wherein C and D are optionally substituted with R; s and R".
• D is fused with C to form a 7-12 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 R and Rf
• D is fused with C to form a 7-12 membered bicyclic r g having at least one aromatic rmg and at least one nitrogen atom, wherein C and D are optionally substituted with R and R7
• D is fused with C to form a 7-12 membered bicyclic r g ha ving at least one aromatic rmg and at least one nitrogen atom, wherein C and D are optionally substituted with R and R”
• X, Y, Rf R:f R’, R " . k . 1C K . 1, m, n, p, and q are as described herein for Formula 0 ⁇ and t and f are each independently 0 1 2, or 3.
• t is 0. In some embodiments, t is 0 or 1 In some embodiments, t is 0, 1, or 2. In some embodiments, f is 0. In some embodiments, f is 0 or 1. In some embodiments, f is 0, I , or 2.
• k is hydrogen, Cr-(Y alkyl, (b- ⁇ ( .. cycloalkyl, ( ⁇ 0)R each of which (except hydrogen) is optionally substituted by halogen, oxo, -OR i3 , YR foFF -C(G)R 13 , -CN, ⁇ ( ; ⁇ ( alkylene)OIl ! 5 , -(C r C 3 alkylene)NR3 ⁇ 4 ;4 , ⁇ (>
• R is hydrogen, methyl, ethyl isopropyl, cyclopropyl, ⁇ ( (OKI CO 101 K or --CIFCFbOFI.
• R is hydrogen, Ci-Cf, alkyl, C 2 ⁇ C 6 alkenyl, C alkynyi, C -Cg alkoxy, Cf-Cf cycloalkyl, 3-- to 12-membered heterocyclyl, 5- to 10-membered heteroaryi, Cf-Cfo aryl, -C(0)R 1,J , -(Cj- (F alkylsneXCF-Ck cycloalkyl), -((h-CF alkylene)(3- io 12-membered heterocyciyl), -ICi- CF a!kylene)(5- io lO-membered heteroaryl) or -(CF-CF alkylene)((VCi4 aryl), each of which is optionally substituted by halogen, oxo, --OR 1 ', ⁇ ( ' ; () ; NR J J R i ⁇ , - ⁇ R !
• Ci4 aryl each of which is unsubstituted in some embodiments of a compound of Formula (J), Formula (I), or Formula (II),
• R is CF-Ck alkyl, Cg-Cg alkenyl, O .y Ck alkynyi, Ck-Cg a!koxy, CF- C 3 ⁇ 4 cycloalkyl, 3- to 12-membered heterocyciyl, 5- to 1 0-membered heteroatyl, C . ⁇ . ⁇ ( aryl, ⁇ (Cy (F aiky!eneXCF-Ck cyeloaikyl), -C(0)R l F or -(CrC-g alkylene)(C6-Cj4 aryl), wherein R; is independently optionally substituted by halogen, oxo, -OR 1 ' , -NR ⁇ RtF -C(0)R J , -CN, CF-Cg cye
• R 1 is CF-Ck alkyl, CF-Ck alkenyl, CF- (k aikyny!, CF-Cg aikoxy, Ck-Ck cyeloaikyl, 3- to 12-membered heterocyciyl, 5- to 10-membered heteroatyl, ( . ⁇ . ⁇ ( aryl, or -Ci())R i , wherein IN is independently optionally substituted by halogen, oxo, -CN, C 3 -C 3 cyeloaikyl, or CF-Ck alkyl optionally substituted by oxo, -OH or halogen.
• k ' is hydrogen, CF-Ck alkyl, -C(())R F'F, -(CF-Cg a!kyleneXCF-Ck cyeloaikyl).
• R ' is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyk cyclohexyl or cyclopropyl-methyl.
• RF is isopropyl.
• R ! is CF-Ck alkyl.
• RF i selected from the group consisting of
• R l is selected from the proup consisting; of
• n is 0. In some embodiments, n is 0 or 1. In some embodiments, n is 0 1 or 2. In some embodiments, n is 0 1 , 2, or 3.
• each IF is independently C -Ce alkyl oxo, -NR 1 : R : l --CN, or halogen.
• each K is independently O.-Cs alkyl, oxo, or halogen.
• IF is oxo.
• Ef is -Nl E f In some embodiments of a compound of Formula (I), Formula (I), or Formula (II), E is -CN.
• K is -C(0 ⁇ IFl In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), K is halogen, such as flu or o. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II). 11 is -Ce alkyl, preferably methyl or dimethyl attached to the same carbon.
• groups ol ! ⁇ are oxo and methyl, independently attached to two different carbons
• groups of R are oxo and dimethyl, each independently attached to two different carbons.
• groups of Kf are oxo and -CN, each independently attached to two different carbons.
• groups of R are oxo and ⁇ ⁇ R : : M : each
• groups of it are oxo and -C(G)R i ' J , each
• rn is 0 In some embodiments, rn is 0 or 1. In some embodiments, rn is 0. 1 , or 2 In some embodiments, m is 0, 1 , 2, or 3 In some embodiments, m is 0, 1, 2, or 3, provided that at least one of m and 1 is not 0
• each R:’ is independently Ch-CR alkyl, CV( . ⁇ . cycloalkyl, (VCg haloalkyh CrCfe alkoxy, C ; ⁇ C,. haloalkoxy, halogen, or -Oi .
• each R:’ is independently CVC 6 alkyl, C 3 - CuCs haloalkoxy or halogen.
• each k is independently fluoro, chloro, methyl, tnfluoromeihy! triiluoromethoxy, methoxy, and cyclopropyl
• R ' is halogen
• 1 is 0. In some embodiments, I is 0 or 1. In some embodiments, 1 is 0, 1 , or 2. In some embodiments. 1 is 0, 1 , 2, or 3 In some embodiments, 1 is 0, 1 , 2, or 3, provided that when Z is
• oxo then at least one of m and 1 is not 0. In some embodiments, 1 is 0, 1, 2 , or 3, provided that at least one of m and 1 is not 0.
• each R ' " is independently CVCR alkyl, CR- CR cycloaikyl, (R-Ck haloalkyl, V-Ck a iko . CR -CR haloalkoxy or halogen.
• each R " is independently fluoro, chloro, methyl, tnf!uoromeihy!, trifluoromethoxy, methoxy, or cyclopropyl.
• IR is halogen.
• each Rf and R “ is independently CR-CR alkyl, CR-CR cycloaikyl (R-(R haloalkyl, CR-CR alkoxy, CR -CR baloalkoxy, halogen, or -OH and 1 and m are independently 0, 1 , 2 or 3.
• each Rf and R “ is independently CR-CR alkyl, CR-CR cycloaikyl (R-(R haloalkyl, CR-CR alkoxy, CR -CR baloalkoxy, halogen, or -OH and 1 and m are independently 0, 1 , 2 or 3.
• each Rf and R “ is independently CR-CR alkyl, CR-CR cycloaikyl (R-(R haloalkyl, CR-CR alkoxy, CR -CR baloalkoxy, halogen, or -OH and 1 and m are independently 0, 1 , 2 or 3.
• R ' and R 4 is independently CR -CR alkyl, (R-(R cycloaikyl, CR-CR haloalkyl, (R-CR alkoxy, CR -CR baloalkoxy, halogen, or -OH and 1 and are independently 0, 1 , 2 or 3, provided that when Z is
• R:’ and IF is independently CR Ck alkyl, ⁇ k ⁇ (k cycloaikyl CR-CR haloalkyl, CR-CR alkoxy, CR-CR baloalkoxy, halogen, or -OH and 1 and rn are independently 0, 1 , 2 or 3, provided that at least one of m and 1 is not 0.
• R ' and R 4 are halogen.
• Rf is F and Rf is Cl.
• Rf is Cl and R 4 is F
• both Rf and Rf are F [0068] in some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH; Y is N; and R and R ' are independently Cr-CY alkyl, CYCf cycloalkyl, CVCf, haioalkyl, CrC fj aikoxy, (YCff haloalkoxy, halogen or -OH.
• X is N; Y is CH; and
• R J and R 4 are independently hydrogen, Cr V, alkyl, (YC. ⁇ . cycioalkyi, (YCY haloalkyi, (YC ⁇ . alkoxy, CrC 6 haloalkoxy, halogen or -OH.
• X is N;
• Y is N; and
• Rf and IX are independently hydrogen, (YC.. alkyl, (YC. ⁇ . cycloalkyl, (YCY haloalkyi, C Ck alkoxy, C CY ha!oalkoxy, halogen or -OH.
• X is CH; Y is N; R is F; and R '4 is F.
• X is CH; Y is N; R is F; and R '4 is F.
• Formula (I), or Formula (II) X is N; Y is CH; K ' is F; and R " is F.
• X is N, Y is N; R J is Cl; and R " is F.
• X is N; Y is N, Ef is F; and R “ is Cl In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH: Y is N; E; is Cl; and R '4 is F In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is CH; Y is N: R ' is F; and R " is Cl In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; R is Cl; and R 4 is F In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; R is F; and R " is Cl In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), X is N; Y is CH; R is F; and R " is Cl In some embodiments of a compound of Formula (J), Formula (I), or Formula
• X is CH; Y is N; R is F and R 4 is F, and each k is independently hydrogen, Ci-Cf alkyl, oxo.
• X is N; Y is CH; Rf is F and R 4 is F; and each R is independently hydrogen, C -C f , alkyl, oxo. --NR ! ! R lz , -CN, -C(0)R l ⁇ ⁇ C(O)NR”R : or halogen.
• X is N, Y is N; K is F and R is F, and each R" is independently hydrogen, (Y(Y alkyl, oxo -NRXRY
• X is N; Y is N; IN is F; R is F, and each R" is independently F, wherein each F is attached to same carbon or two different carbons.
• X is N; Y is N: IX is F, R 4 is F; and each
• R is independently CYC ' s alkyl, preferably methyl, each methyl attached to same carbon or two different carbon.
• X is N; Y is N; R is F; IX is F; each k is oxo or methyl, each of winch is attached to two different carbons.
• X is N; Y is N; R is F; IX is F; and each R 2 is oxo or F, winch are attached to two different carbons.
• X is N; Y is N; R 3 is F; R 4 is F; IX is oxo.
• X is N; Y is N; K ' is F; k : is F; each R is independently hydrogen.
• X is N; Y is N; each R J and R 4 is independently Cj-Q, alkyl, CYC. ⁇ cycioalky!, CrCs haloalkyi, CY C hko.w CYCf haloa!koxy, halogen, or -OH; each IX is independently hydrogen, Cj-Q, alkyl, oxo, -Nl MX .
• any two R:" groups are independently attached to same carbon or two different carbon, and R ; is hydrogen, C C 3 ⁇ 4 alkyl, CYCs alkenyl, CYCr aikynyi, CrCg aikoxy, ( " ; ⁇ ( " . ⁇ . cycioalkyl, 3- to 12-membered heterocyelyl, 5 ⁇ to 10- membered heteroaryl , CY ' .Y ami, -C(0)R 11 ', -(CYCF al Y !ene)((h-(f. cycioalkyl), ⁇ (( ' ; ⁇
• X is CH, Y is N; each k and k " is independently Ci ⁇ C 6 alkyl, CYC's ey chalky I, C ' : haiouikvi
• Ci-CX alkoxy, CYCs haloalkoxy, halogen, or -OH each IX is independently hydrogen, ( ' ; ⁇ ( . ⁇ . alkyl, oxo, -NR : : RY -CN, ⁇ C(0)RX', -( (OY ' ! ⁇ ' or halogen, any two R groups are independently attached to same carbon or two different carbon; IX is Cs-Cfe alkyl CY
• each of winch is optionally substituted by halogen, oxo, -OR 1 ' ’ -C(O) NR’ ⁇ R' , -NR ⁇ R' 4 , -C(0)R 1 ' ,
• X is N; Y is CH; each R 3 and R 4 is independently (Y-CY alkyl, G ⁇ ( ), cycloalkyl.
• each k is independently hydrogen, CYiY alkyl, oxo, or halogen, any two K groups are independently attached to same carbon or two different carbon: R 1 :s C C ⁇ alkyl, CY
• C -C 3 ⁇ 4 cycloalkyl, or CYCk alkyl optionally substituted by oxo, -OH or halogen.
• X is N; Y is N; each and R 4 is independently F; each R is independently hydrogen, CYCY alkyl, oxo, - ⁇ R : : R : . -CN, -C(0)R ;' c -C(Q)NR l 3 ⁇ 4N or halogen, any two k groups are independently attached to same carbon or two different carbon; R 1 is hydrogen, CYC), lkyl ( ' ⁇ ( ' ⁇ .
• X is N; Y is N; each R and R is independently F; each R is independently hydrogen, CY-CY alkyl, oxo, -CN, -C(0)R l Y -C(0)NR“R‘ or halogen, any two R groups are independently attached to same carbon or two different carbon; R 1 is CYCY alkyl, cycloalkyl, 3- to 12- membered heterocyclyl, -(( ; ⁇ ( .
• alkyleneXCY-CY cycloalkyl -(CYC 3 alkylene)(3- 10 12- mem bered heterocyclyl), or -(C -CY a!ky!eneXCYCY aryl ) each of which is optionally substituted by halogen, oxo, -OR i3 ’-C(0 NR% 3 Y --NR 13 R i4 , -CtOjR 13 , -CN, C 3 -C 8 cycloalkyl. or Cr-(Y alkyl optionally substituted by oxo, -OH or halogen.
• X is N: Y is N; each R ' and R 4 is independently F; each IN is independently hydrogen or Y ⁇ ( ' . ⁇ . alkyl, any two R" groups are independently attached to same carbon or two different carbon.
• IX is Ci-C ft alkyl, (3 ⁇ 4 (3 ⁇ 4 cycloalkyl, 3- to 12-tnembered heterocyclyl, -(CrCX alkyleneKCh-CR cycioalkyl), - ⁇ Cr-CR aikylene)(3- to 12-membered heterocyclyl), or -(Ci-CR aik iene)(CR ⁇
• X is N; Y is N; each R3 and R is independently F; each R is independently hydrogen or C -CR alkyl, any two IX groups are independently attached to same carbon or two different carbon;
• R J is (R-CR alkyl, (R-Ce cycioalkyl, -(CrCR alkyieneXCR-CR cycioalkyl) or -(Ci-CR alkylene)((R- Cj aryl), each of which is optionally substituted by halogen, oxo, -OR -C(O) N R ' R .
• X is N; Y i N; each R ' and IX is independently F; each IX is independently hydrogen or CR-C . ⁇ . alkyl, any two R groups are independently attached to same carbon or two different carbon;
• R ! is C C o alkyl, (VO ⁇ cycioalkyl or -(CR-CR alkyiene)(C-rC 6 cycioalkyl), each of which is optionally substituted by halogen, oxo, ⁇ O ⁇ C -NR )J R 1'* or CR-CR alkyl optionally substituted by oxo, -OH or halogen.
• X is N; Y is N; each " and ' is independently F; each R" is independently hydrogen, R 4 is CR CR alkyl or CRCR cycioalkyl, wherein R !
• X is N; Y is N; each R :' and R ' is independently F; each IX is independently hydrogen; IX is CR-CR alkyl, wherein R is independently optionally substituted by halogen, oxo, -O!X -MX ' R : ! o CR-CR alkyl optionally substituted by oxo, -OH or halogen.
• X is N; Y is N; each R ' and !XMs independently F, each R" is independently hydrogen; ' is selected from the group consisting of
• X is N; Y is N; each Rf and R ' is independently F; each FT is independently hydrogen; R J is selected from the group consisting
• X is N; Y is N; each R; and 1C is independently F; each R" is independently hydrogen; R 5 is (VO. aim f
• p is 0. In some embodiments of a compound of Formula (I), Formula (I), or Formula (II), p is 0 or 1. In some embodiments of a compound of Formula (J), Formula (I), or Formula (II), p is 0, I, or
• each R ' is independently (VCy alkyl, halogen, oxo, ⁇ CN, -OR n ', NR ! ! R y -C(0)R ;,! ,
• each R ⁇ is independently -CN, halogen, methoxy, oxo, trifluoromethoxy, -NH(CH 3 ), -N(CH 3 ) 2 , (CFFINHtCFF), ⁇ (CH 2 )NH 2 ,
• each k is independently -CN, halogen, methoxy, oxo, trifluoromethoxy, - NH(CIR), -NiCtR -(CH 2 )NH(C3 ⁇ 4), -(CH 2 )NH 2 , -(CH 2 )N(C3 ⁇ 4) 2 , -C(0)N3 ⁇ 4, -C(Q)N(CH ? ⁇ 2 , methyl, ethyl, isopropyl, n-propyl, cyclopropyl, -
• q is 0 In some embodiments of a compound of Formula (J) Formula (I), or Formula (II), q is 0 or 1 In some embodiments of a compound of Formula (J), Formula (I) or Formula 01 ), q is 0 1 , or
• each R" is independently ( ' ⁇ ( ' . ⁇ . alkyl, halogen, oxo, -CN, -NR , , R , ⁇ C(0)R :iJ , (Vi .. cycloalkyl, 3-- to 12-membered heterocyc!yi, ⁇ ( ' ⁇ ( ' , alkyleneiOR 1 '’, o ( ' ⁇ ⁇ ( ' , ah- ⁇ ooo ⁇ k : : u : . each of which is optionally substituted by halogen, oxo, --OR 1 ' , -NRARA -C(0)R ⁇
• each RAs independently ethyl, methyl, isopropyl, pyrrolidinyl, -N(C3 ⁇ 4) 2 , ⁇ ( 1 1 Oi !
• each IA is independently ethyl, methyl, isopropyl, pyrrolidinyl, cyclopropyl, methoxy, ⁇ N; ( ' P I ⁇ ⁇ NP( l b.
• A, L and B together with Kf and R° are selected from the group consisting of:
• a and B together with R” and R ' are selected from the group consisting of
• C-D are selected from the srouo consisting of
• each description of C-D may be combined with each description of X, Y lib R ⁇ R ' . k ' . R " . 1, m n n and o the same as if each and every combination were specmcaiiv ana mamcmairv ustect
• salts of compounds referred to herein such as pharmaceutically acceptable sails.
• the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers 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 m one aspect be m a purified form and compositions comprising a compound m purified forms are detailed herein.
• Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
• a composition containing a compound as detailed herein or a salt thereof 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 salt thereof
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity.
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0 5% impurity
• the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, die N-oxides are also provided and described.
• tautomeric forms may be present for any of the compounds described herein, each and every' tautomeric form is i ntended even though only one or some of the tautomeric forms may be explicitly depicted.
• the tautomeric forms specifically depicted may or may not be the predominant forms m solution or when used according to the methods described herein
• compositions comprising a compound of the invention are also intended, such as a composition of substantially 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-race ic mixture.
• the invention also intends isotopicaliy-kbeled and/or isotopically-enriched 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 isotopioal!y-dabeied compound of the formula (I) or variations thereof described herein, where a traction 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 ⁇ I . ⁇ , , !
• isotope labeled compounds e.g. “ H and l ) are useful in compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deu terium ( ⁇ ) 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-iabeled 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-iabeled reagents in place of the corresponding non-iabeied reagent.
• the invention 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, ⁇ . v. bag, and the like.
• the compounds detailed herein are orally bioavai!abie.
• 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 form
• 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).
• the symbols when used m the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
• enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
• diastereomeric 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.
• a racemate may be separated using chiral High Performance Liquid
• Solvates and/or polymorphs of a compound provided herein or a salt thereof are also contemplated.
• Solvates contain either stoichiometric or non-stoichiometnc amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol
• Polymorphs include the different crystal packing arrangements of the same elemental composition of compound Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystaliization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate
• compounds of the Formula (I) or (II) may be syn thesized according to Scheme I .
• A, B. C, D, L, X, Y; Rl Rl R . R°; p and q are as described for Formula (J), Formula (I), or Formula (II). Particular examples are provided in the Example Section 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 salt thereof 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 salt thereof are provided, such as compositions of substantially pure compounds.
• a composition containing a compound as detailed herein or a salt thereof 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.
• present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier in another variation, 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 form
• 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 elix
• One or several compounds described herein or a salt thereof can be used m the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with pharmaceutically acceptable carrier, such as those mentioned above.
• a formulation such as a pharmaceutical formulation
• pharmaceutically acceptable carrier such as those mentioned above.
• the carrier may be in various forms.
• the carrier may be in various forms.
• compositions may contain preservatives, solubilizers, stabilizers, re-wetting agents, emu!gators, 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 ma be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g; , in Remington b Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 U 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 in a hard or in soft shell, emulsions or suspensions.
• examples of carriers which may be used for the preparation of such compositions are lactose, corn starch or its derivatives, tale stearate or its salts, etc.
• Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
• pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emuigators, sweeteners dyes, adjusters, and salts for 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 salt thereof 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 earner 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 provide herein or a salt thereof 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 purposes and/or for conducting quality control assays.
• the methods comprise administration of a compound detailed herein, or a salt thereof, as a monotherapy.
• a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (J), Formula (I), Formula (11), (F A). (I-Bl) to (I-B 12), (T-C 1 ) - (I-C23) or any embodiment, variation or aspect thereof
• a compound of Formula (J). (collectively, a compound of Formula (J).
• a method of treating a proliferative disease in an individual comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (I-Bl 2). (FC! - (F C23), or a pharmaceutically acceptable salt thereof to the individual.
• Also provided herein is method of treating cancer in an individual comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2) (FC! ) - (FC23)or a pharmaceutically acceptable salt thereof to the individual.
• the compound is administered to the individual according to a dosage and/or method of
• 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
• 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 GNK4 inhibitors by gene deletion, mutation, or promoter hypermethyiation, or other genetic events leading to overactivity of CDK4/6 and one or more of CDK! , 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 (RhJ protein in the cancer, or (il) presence of mutations or amplification or overexpression of CDK4 or CDK6 in the cancer, and administering an effective amount of the compound of Formula (J), Formula (i), Formula (II), (I- A). (FBI) to (FBI 2), (F Cl ) - (FC23), or a pharmaceutically acceptable salt thereof, to the Individual
• the cancer is assayed for the expression of phosphorylated Kb.
• the cancer is assayed for the expression of CDK4 or CDK6 In some embodiments,
• the CDK4 or CDK6 gene of the cancer is sequenced to detect the one or more imitations or amplifications.
• the CDK4 or CDK6 gene is sequenced by biopsymg the cancer and sequencing the CDK 4 or CDK6 gene Bom the biopsied cancer.
• the CDK4 or CDK6 gene is sequenced by sequencing circulating- tumor DNA (ctDNA) from the individual.
• a compound of Formula (J), Formula (1), Formula (II) (I- A), (KB1) to (KB12), (I -Cl ) - (I-C23) or a salt thereof 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.
• the present compounds or salts thereof are believed to be effective for treating a variety of diseases and disorders.
• the present compositions 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 non lymphocytic leukemia, chrome 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 nonsrnal!
• breast cancer including small cell carcinoma and ductal carcinoma
• gastrointestinal cancers including stomach cancer, colon cancer colorectal cancer, polyps associated with colorectal neoplasia, pancreatic cancer, liver cancer, urological cancers, including bladder cancer including primary superficial bladder tumors, invasive transitional eell carcinoma of the bladder, and muscle-invasive bladder cancer, prostate cancer, malignancies of the female genital tract, including ovarian carcinoma, primary peritoneal epithelial neoplasms, cervical carcinoma, uterine endometrial cancers, vaginal cancer, cancer of the vulva, uterme cancer and solid tumors in tbe ovarian follicle, malignancies of the male genital tract, including testicular cancer and penile cancer, kidney cancer, including renal cell carcinoma, brain cancer including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers, including osteomas and osteosarcom
• the cancer is defined by a molecular characteristic in some embodiments, the cancer is an estrogen receptor-posistive breast cancer. In some embodiments, the breast cancer is triple negative breast cancer In some embodiments, the cancer is a KRAS- mutant non-small cell lung cancer. In some embodiments, the cancer is mantle cell lymphoma defined by a translocation involving CCND1 resulting in cyclic Di overexpression.
• the compounds and compositions described herein cause G -S cell cycle arrest in a cell (such as a cancer cell) in some embodiments, the cancer cell is a cancer cell from any of the cancer types described herein.
• arrested cells enter a state of apoptosis.
• arrested ceils enter a state of senescence
• a method of causing GrS checkpoint arrest in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), ( FA) (FBI) to (I-B12).
• the G .-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
• the (11: S cell cycle arrest occurs 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 io about 80% of cells in the cell population.
• a method of inducing senescence in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FB12). (FCi ) - (FC23)or a pharmaceutically acceptable sail thereof, to the cell.
• senescence is induced in about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 8091; 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 ceil 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 m the cell population.
• apoptosis in some embodiments, provided herein is a method of inducing apoptosis in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (I- A), (i-Bl) to (1-B 12), (I-Cl ) - (I-C23)) or a pharmaceutically acceptable salt thereof, to the cell in some embodiments 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 ceil population.
• 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
• a method of inhibiting CDK4 or CDK6 in a cell comprising administering an effective amount of the compound of Formula (J), Formul (I), Formula (II), ( FA) (ffBl) to (I-BI2). (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof, to the cell.
• 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% 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.
• CDK4 or CDK6 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 CDK4 or CDK6 is measured according to a kinase assay
• a method of inhibiting one or more of CDKi CDK2, CDK4, CDK6, and CDK9 in a cell comprising administering an effective amount of the compound of Formula (J), Formula (I), Formula (II), (I -A), (I-B1 ) to (I-B12), (I-Cl) -- (I- C23) or a pharmaceutically acceptable salt thereof to the cell.
• one or more of CDKI, 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 75% or more, about 80% or more, about 907b or more about 95% or more, about 967b or more, about 977b or more, about 987b or more, or about 99% or more.
• one or more of CDK1 , CDK2, CDK4, CDK6, and CDK9 is inhibited up to about 997b, up to about 98%, up to about 97%, up to about 96%, up to about 95%, up to about 90%, up to about 857b, up to about 807b, up to about 707b, or up to about 607b
• the activity of one or more of CDKl, CDK2, CDK4, CDK6, and CDK9 is measured according to a kinase assay.
• a method of inhibiting DK4 or DK6 comprising contacting CDK4 or CDK6 with an effective amount of the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof in some embodiments, the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FB12), (FCi) - (FC23)or pharmaceutically acceptable salt thereof binds to CDK4 or CDK6 with an Kffo of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM.
• the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCI) - (FC23)or a pharmaceutically acceptable salt thereof binds to CDK4 or CDK6 with an IC50 between 0.1 nM and 1 nM, between 1 nM and 5 nM.
• the ICM is measured according to a kinase assay hi some embodiments, the IC50 is measured according to a cell proliferation assay
• a method of inhibiting one or more of CDKl comprising contacting one or more of CDKl , CDK2, CDK4, CDK6, and CDK9 with an effective amount of the compound of Formula (J), Formula (I) Formula (II), (FA), (FBI ) 1° (FBI 2), (FCI ) - (FC23) or a pharmaceutically acceptable salt thereof
• the compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FC I ) - (I-C23) or a pharmaceutically acceptable salt thereof binds to one or more of CDK1 , CDK2, CDK4, CDK6.
• the pharmaceutically acceptable salt thereof binds to one or more of CDK1, CDK2, CDK4, CDK6, and CDK9 with an IC 3 ⁇ 4 o between 0.1 nM and 1 nM, between I 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 IC50 is measured according to a kinase assay
• the KM is measured according to a cell proliferation assay.
• provided herein is a method of modulating CDK4/6 in an individual, composing administering to the individual a compound of Formula (J).
• a method of modulating CDK4 and CDK 6 in an individual comprising administering to the individual a compound of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (I-Cl ) - (FC23) or a
• provided herein is a method of modulating CDK4/6 and one or more of CDK! , CDK2, and CDK9 in an individual, comprising administering to the individual a compound detailed herein, or a salt thereof
• pharmaceutically acceptable salt thereof binds to one or more of CDK4/6 with an KM of less than 1 uM, 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.
• the compound of Formula (j), Formula (I), Formula (31), (FA), (FBI) to (FBI 2), (I-Cl) - (F C23) or a pharmaceutically acceptable salt thereof binds to one or more of CDK4 and CDK6 with an ICfe of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nVl 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.
• the compound of Formula (J), Formula (I), Formula (11), (I- A), (I-Bl) to (I- B12), ( 1-C 1 ) - (l-C23)or a pharmaceutically acceptable salt thereof binds to one or more of CDK1 , CDK2, CDK4, CDK6, and CDK9 with an IO 3 ⁇ 4 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
• tire compound or a salt thereof may enhance tire antitumour immunity by increasing the functional capacity of tumour cells to present antigen or by reducing the immunosuppressive population by suppressing their proliferation.
• provided herein is a method of inhibiting the proliferation of cell, comprising contacting the cell with an effective amount of the compound of Formula (J), Formula (I), Formula (II), (I-A), (FBI) to (I-B12), (I-CI) - (I-C23) or a pharmaceutically acceptable salt thereof In some embodiments, the compound of Formula (J).
• Formula (I), Formula (II), (IA-) , (I-Bl) to (I-RI 2), (I--C1 ) - (I-C23) or a pharmaceutically acceptable salt thereof is effective in inhibiting the proliferation of the cell with an E(3 ⁇ 4o 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.
• the compound of Formula (J), Formula (I), Formula (II), (I-A), (I-Bi) to (I-RI2), (I-CI) - (I-C23) or a pharmaceutically acceptable salt is effective in inhibiting the proliferation of the cell with an ECtio 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 1 mM, beween 1 mM and 2 mM, or between 2 mM and 5 mM.
• the EC50 is measured according to a cell proliferation assay.
• the presently disclosed compounds or a salt thereof may affect the immune system. Accordingly, the present compounds or a salt thereof may he used in combination with other anti-cancer agents or immunotherapies.
• a method of treating a disease m an individual comprising administering an effective amount of a compound of Formula (J), Formula (I), Formula (II), (I- A), (BBi) to (FBI 2), (I-CI) - (I-C23), or any embodiment, variation or aspect thereof (collectively, a compound of Formula (J), Formula (I), Formula (II), ( ⁇ - ⁇ ), (FBI ) to (BBI 2), (BC1) - (BC23) or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent to the individual.
• the second therapeutic agent is a cancer immunotherapy agent or an endocrine therapy agent or a chemotherapeutic agent
• the disease is a cancer immunotherapy agent or an endocrine therapy agent or a chemotherapeutic
• the additional therapeutic agent is a cancer immunotherapy agent.
• the additional therapeutic agent is an mimunostimulatory agent.
• the additional therapeutic agent targets a checkpoint protein (for example an immune checkpoint inhibitor).
• the additional therapeutic agent is effective to stimulate, enhance or improve an immune response against a tumor.
• a combination therapy for the treatment of a di ease such as cancer.
• a method of treating a di ease in an individual comprising administering an effective amount of Formul (J), Formula (I), Formula (IT), (BA), (BBi) to (BB12), (I-CI ) - (BC23), or any embodiment, variation or aspect thereof (collectively a compound of Formula (J), Formula ( ⁇ ), Formula (II), (IA-) , (I-Bl ) to (I-B12) (B Cl ) - (BC23), or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, in combination with a radiation therapy.
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (I- A), (BBI) to (BBI 2), (I -Cl) - (I-C23)or any embodiment, variation or aspect thereof
• the endocrine therapy is antiestrogen therapy.
• the endocrine therapy is a selective estrogen receptor degrader (SERB, such as fu!vestrant).
• the endocrine therapy is an aromaiase inhibitor (such as letrozole).
• the 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 canses enhanced entry into a senescent state.
• Formula (J), Formula (I), Formula (II), (FA), (I-Bl) to (FB12), (I-Cl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co administered with the endocrine therapy agent.
• T-C 1 ) - (I-C23) or a pharmaceutically acceptable salt thereof 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 endocrine therapy agent.
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (I- A), (FBI) to (FB12), (FC1) - (FC23), or any embodiment, variation or aspect thereof
• the chemotherapeutic agent is another kinase inhibitor in some embodiments, Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCI) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admini tered with the second chemotherape tic agent.
• Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI ) - (I-C23) or a pharmaceutically acceptable salt thereof 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 second chemotherapeutic agent.
• chemotherapeutic agents that can be used in combination with Formula (J), Formula (I), Formula til ), (FA), (FBI) to (FBI 2), (FCI) - (I-C23) or a pharmaceutically acceptable salt thereof include DNA-targeted agents, a DMA alkylating agent (such as cyclophosphamide, mechloretha me, chlorambucil, melphalan, dacarbazine, 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 anihracyciine (such as
• daunorubicin doxorubicin, epirubiein, idarubicin, mitoxantrone, or valrubicin
• a histone deaceiyiase inhibitor such as vormostat or romidepsin
• a bromodomain inhibitor other epigenetic inhibitors
• a taxane such as paciitaxel or docetaxei
• a kinase inhibitor such as bortezomib, eriotinib, gefitinib.
• imatunb vemurafenib, vismodegib, ibrutinib
• an anti- angiogenic inhibitor such as azacitidine, azathioprrne, capecitabme, cytarabine, doxiflundine, 5-fluorouracil, gemcitabme, hydroxyurea
• nucleotide analog or precursor analog such as azacitidine, azathioprrne, capecitabme, cytarabine, doxiflundine, 5-fluorouracil, gemcitabme, hydroxyurea
• a method of treating a disease in an individual composing (a) administering an effective amount of Formula (J), Formula (I).
• Formula (FBI) to (FBI 2), (I-Cl ) - (FC23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of a kinase inhibitor (such as bortezomib, eriotinib, gefitinib, imatimb, vemurafenib, vismodegib, or ibrutinib).
• a kinase inhibitor such as bortezomib, eriotinib, gefitinib, imatimb, vemurafenib, vismodegib, or ibrutinib.
• Formula (J), Formula (I), Formula (II), (I-A), (FBI) to (FBI 2), (I-Cl ) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co administered with the kinase inhibitor In some embodiments.
• Fomm!a (J), Formula (I), Formula (II) (I-A), (FBI) to (FBI 2), (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof 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 Formula (J), Formula (I), Formula (II), (F A), (I-Bl ) to (FBI 2) (I-Cl ) - (I-C23), or any embodiment, variation or aspect thereof
• Formula (J), Formula (I), Formula (H), (I-A), (F Bl) to (FBI 2), (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co-admmistsred wife the DM A damaging agent.
• Formula (J), Formula (I) Formula ( ⁇ ), (FA), (FBI ) to (FB12), (I-Cl ) - (FC23) or a pharmaceutically acceptable salt thereof 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) poor to or after the DNA damaging agent
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (/), Formula (I), Formula (II), (F A), (FBI ) to (I-Bl 2), (FCI) - (FC23)), or any embodiment, variation or aspect thereof
• a DM A alkylating agent such as cyclophosphamide, mechiorethamine, chlorambucil, meipha!an, dacarbazme, or nitrosoureas.
• Formula (I), Formula (I), Formula (II), (I- A), (I-Bl ⁇ to (FB12), (DO) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the DNA alkylating agent.
• Formul (J), Formula (I), Formula (II), (DA), (FBI) to (FBI 2), (DO) - (DC23) or a pharmaceutically acceptable salt thereof 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 Formula (I), Formula (I), Formul (II), (I- A) (I-Bl ) to (I-Bl 2), (DC! ) - (FC23), or any embodiment, variation or aspect thereof
• Formula (J) Formula (I), Formula (II), (FA) (I-Bl) to (I-Bl 2), (DC! ) - (FC23)) or a pharmaceutically acceptable salt thereof and (b) administering an effective amount of a topoisomerase inhibitor (such as a Topoisomerase I inhibitor (e.g. , irinotecan or topotecan) or a Topoisomerase II inhibitor (e.g. eioposide or temposide)).
• a topoisomerase inhibitor such as a Topoisomerase I inhibitor (e.g. , irinotecan or topotecan) or a Topoisomerase II inhibitor (e.g. eioposide or temposide)
• Formula (J), Formula (I), Formula (II), (FA) , (FBI) to (I-Bl 2), (FCi ) - (DC23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co-administered with the topoisomerase inhibitor.
• Formula (J), Formula (I), Formula (II), (FA), (I- Bl) to (FB12), (FCI ) - (DC23) or a pharmaceutically acceptable salt thereof 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 [0149]
• a method of treating a disease m an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula 01 ), (F A), (FBI) to (FBI 2), (FCl ⁇ -- (FC23), or any embodiment variation or aspect thereof
• Formula (J) Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCl ⁇ -- (FC23)) or a pharmaceutically acceptable salt thereof and (b) admi nistering an effective amount of an anthracycline (such as daunorubicm, doxorubicin, epirubicm, idarubicm, mitoxantrone, or valrubicm).
• an anthracycline such as daunorubicm, doxorubicin, epirubicm, idarubicm, mitoxantrone, or valrubicm.
• Formula (J), Formula (I), Formula (II), (FA), (FBI) to (F B12), (FCl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the anthracycline.
• Formula (J), Formula (I), Formula (II), (IA ⁇ ) , (FBI) to (FBI 2), (FCl ) - (FC23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, B or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) prior to or after the anthracycline.
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (F A), (FBI) to (FBI 2), (FCl) - (FC23), or any embodiment, variation or aspect thereof
• a histone deacety!ase inhibitor such as vorinostat or romidepsin
• Formula 1 or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-adrmnisiercd with the histone deacety!ase inhibitor.
• Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCl ) - (FC23) or a pharmaceutically acceptable salt thereof 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 instone deacetylase inhibitor.
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (B ), (F A), (FBI) to (FBI 2), (I -Cl) - (FC23), or any embodiment, variation or aspect thereof
• a taxane such as pac!itaxel or docetaxe!
• Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (I -Cl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admimstered with the taxane. In some embodiments.
• Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (I-Cl) - (F C23) or a pharmaceutically acceptable salt thereof 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 Formula (J), Formula (I), Formula (II), (F A), (FB1 ) to (FBI 2), (FC1) - (FC23), or any embodiment, variation or aspect thereof
• a nucleotide analog or precursor analog such as azacitidine, azathioprine, eapecitabme, cytarabine, doxiflurid e, 5-fluorouracif gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or tioguanine.
• Formula (J), Formula (I), Formula (II), (F A), (FBI) to (FBI 2), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously coadministered with the nucleotide analog or precursor analog.
• Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FB12), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof 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 platinum ⁇ based chemotherapeutic agent such as cisplaiin, carbopiatm or oxahp!aiin.
• Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (I-Cl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co administered with the platinum-based chemotherapeutic agent.
• Formula (J), Formula (I), Formula (11), (I-A), (I-Bl) to (I-B12), (l-Cl ⁇ - (I-C23) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hoars, 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 Formula (J), Formula (I), Formula (11), (I- A). (I-Bl) to (I-Bl 2), (I-Cl j - (I-C23), or any embodiment variation or aspect thereof
• Formula (J), Formula (1), Formula (II), (I-A), (I-Bl) to (I- B12), (I-C! - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the pemetrexed.
• Formula (J). Formula (I), Formula (II), (I-A).
• I-Bl to (I-Bl 2), (1-0 ) - (I-C23) or a pharmaceutically acceptable salt thereof 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 pemetrexed.
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J).
• BTK Bruton’s tyrosine kinase
• Formula (J), Formula (I), Formula (II), (IA-), (I-Bl ) to (I-Bl 2), (I-Cl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior io, after, or simultaneously co-administered with the BTK inhibitor.
• Formula (J), Formula (I), Formula (IT), (I-A), (I-Bl) to (I-RI2), (I-Cl ) - (I--C23) or a pharmaceutically acceptable salt thereof 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 Formula (J), Formula (I), Formula (II), (I- A). (I-Bl) to (I-B12), (I -Cl) - (FC23) or any embodiment, variation or aspect thereof
• Formula (J), Formula (I), Formula (II), (FA), (I- B1 ) to (I-Bl 2), (FCl) - (I-C23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administerecl with the PI3K or Akt inhibitor in some embodiments, Formula (J), Formula (I), Formula (11), (i-A), (I-Bl) to (I-B12), (FCl) - (1-C23) or a pharmaceutically acceptable salt thereof 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.
• ⁇ 01S7 there is provide a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J).
• (I-Bl) to (I-Bl 2), (FCl ) - (I-C23)) or any embodiment, variation or aspect thereof
• Formula (J) Formula (I), Formul (II), (I-A). (I-Bl) to (I-Bl 2), (FCl ) - (FC23)) or pharmaceutically acceptable salt thereof, and (b) administering an effeetive amount of a DNA damage repair (DDR) pathway inhibitor.
• DDR DNA damage repair
• Formula (J), Formula (I), Formula (II), (IA-) , (I-Bl) to (I-Bl 2), (FCl) - (FC23)or pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admmi stored with the DDR pathway inhibitor in some embodiments, Formula (J), Formula (I), Formula (II), (IA-) , (I-Bi) to (I- B12), (FCl ) - (I ⁇ C23)or a pharmaceutically acceptable salt thereof 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 h urs) prior to or after the DDR pathway inhibi or Examples of inhibitors of the DDR pathway include poly(ADP-ribose) polymerase (PARP) inhibitors (such as olaparib, rucaparib, niraparib, or taiazoparib), ataxia tel
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (II), (I- A), (I-Bl ) to (FBI 2) (FCl ) - (I-C23), or any embodiment, variation or aspect thereof
• a PARP inhibitor such as oiaparib, rueaparib, niraparib, or ialazoparib.
• Formula (J), Formula (I), Formula (II), (FA), (I-Bi) to (i B12), (I-Cl) -- (I-C23) or a pharmaceutically acceptable salt thereof 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 PARP inhibitor.
• a method of treating a disease in an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula (11), (I- A), (FBI ) to (FBI 2), (i-CI j - (I-C23)), or any embodiment, variation or aspect thereof
• Formula (J) Formula (I), Formula (II), (FA), (FBI ) to (I-Bl 2), (I-Cl ) - (I-C23)) or pharmaceutically acceptable salt thereof and (b) administering an effective amount of an ATM protein inhibitor
• Formula (J), Formula (I), Formula (II) In some embodiments, Formula (J), Formula (I), Formula (II).
• Formula (FA), (F Bl) to (I-R12), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-administered with the ATM protein inhibitor
• Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (I-B12), (FC1) - (FC23) or a pharmaceutically acceptable salt thereof 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 Formula (J).
• Formula (J) Formula (I), Formula (II), (FA), (I-Bl) to (I-Bi 2), (I-Cl ) - (FC23)) or a pharmaceutically aecep table salt thereof and (b) admini tering an effective amount of an ATR protein inhibitor.
• Formula (J), Formula (I), Formula (II), ( A) (F Bl) to (FBI 2), (I-Cl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to after, or simultaneously co-adrmissered with the ATR protein inhibitor.
• Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (I-B12), (I-Cl ) - (FC23) or a pharmaceutically acceptable salt thereof 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 alter the ATR protein inhibitor.
• a method of treating a disease m an individual comprising (a) administering an effective amount of Formula (J), Formula (I), Formula 01 ), (I- A), (FBI) to (I- ⁇ BI2), (FCl ) - (FC23), or any embodiment, variation or aspect thereof
• Formula (J), Formula (I), Formula (II), (FA), (I-Bl ) to (I-B12), (FCl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admimsierecl with the Chkl inhibitor.
• Formula (J), Formula (I), Formula (II), (FA), (I-Bl ) to (I-B12), (FCl) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously co-admimsierecl with the Chkl inhibitor.
• pharmaceutically acceptable salt thereof 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 Formula (J), Formula (I), Formul (II), (I- A), (FBI) to (FBI 2), (FCl ) - (FC23)), or any embodiment, variation or aspect thereof
• Formula (I), Formula (II), (FA) (FBI) to (FBI 2), (FCl ) - (FC23) or a pharmaceutically acceptable salt thereof is administered prior to, after, or simultaneously Co-administered with the further CDK4/6 inhibitor.
• Formula (J), Formula (I), Formula (II), (IA-) , (FBI ) to (FBI 2), (FCl) - (FC23) or a pharmaceutically acceptable salt thereof 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 further CDK4/6 inhibitor
• a combination therapy which a compound of Formula (J), Formula (I), Formula (II ) (I-A), (FBI) to (FBI 2), (FCl ) - ⁇ (F-C23), or a salt thereof 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 upregulaie immune responses in a subject.
• a method for stimulating an unmune response in a subject comprising administering to tbe subject a compound of Formula (J), Formula (1), Formula ⁇ II), (I-A), (FBI) to (FBI 2), (FC1 ) - (FC23), or a salt thereof and one or more immunostimuiatory 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 m the subject, for example to inhibit tumor growth.
• a compound of Formula (J) Formula (1), Formula ⁇ II), (I-A), (FBI) to (FBI 2), (FC1 ) - (FC23), or a salt thereof and one or more immunostimuiatory 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 m the subject, for example to inhibit tumor growth.
• the subject is administered a compound of formula Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI) - (FC23) or a salt thereof and an anti-PD-1 antibody.
• the subject is administered a compound of Formula (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI) - (FC23), or a salt thereof and an anti-PD-Ll antibody.
• the subject is administered a compound of Formula (J), Formula (I), Formul (II), (I-A), (FBI) to (FB12), (F Cl) - (FC23) or a salt thereof and an anti-CTLA-4 antibody
• the immunostimuiatory antibody e.g., anti-PD-1, anti-PD-L! and/or ami-CTLA-4 antibody
• the immunostimuiatory antibody is a human antibody.
• the immunostimuiatory antibody can be, for example, a chimeric or humanized antibody (e g., prepared from a mouse anti-PD-1 , anti-PD-Ll and/or ami-CTLA-4 antibody).
• the present disclosure provides a method for treating a proliferative disease (e.g , cancer), comprising administering a compound of Formul (J), Formula (I), Formula (II), (FA), (FBI) to (FBI 2), (FCI) - (FC23), or a salt thereof and an anti- PD-i antibody to a subject.
• a proliferative disease e.g , cancer
• a compound of Formul (J), Formula (I), Formula (FA), (FBI) to (FBI 2), (FCI) - (FC23), or a salt thereof and an anti- PD-i antibody e.g , cancer
• Formula (II), ( A), (FBI ) to (FBI 2), (FCI) - (FC23) or a salt thereof is administered at a subtherapeutic dose
• the anti- PD- 1 antibody is administered ai a subtherapeutic dose
• both are administered at a subtherapeutic dose
• the present disclosure provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimuiatory agent, comprising administering a compoun of Formula (J), Formula (I), Formula (II), (FA), (FBI ) to (FBI 2), (FCI ) - (I-C23 ), or a salt thereof and a subtherapeutic dose of anti-PD-1 antibody to a subject
• the subject is human.
• the anti-PD-I 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 of Formula (J) Formula (I), Formula (II), (I -A), (I-Bl ) to (FBI 2), (I-Ci) - (I-C23), or a salt thereof and an anti- PD-Ll antibody to a subject.
• a compound of Formula (J), Formula (I), Formula (II), (I- A), (FB 1 ) to (I-B 12), (I-CI ) - (I-C23) or a salt thereof is administered at a subtherapeutic dose, the anti-PD-Ll antibody is administered at a subtherapeutie dose, or both are 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 imniunostimulatory agent, comprising administering a compound of Formula (J), Formula (I), Formul (II), (I- A). (I-B!) to (I-B!
• 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 earner, or concurrently as separate compositions each in pharmaceutically acceptable carrier. In another embodiment the combination of therapeutic agents can be administered sequentially.
• an ami-CTLA-4 antibody and a compound of Formula (J), Formul (I), Formula (II), (FA), (FBI ) to (FBI 2), (FC1 ) - (I-C23), or a salt thereof can be administered sequentially, such as anti-CTLA-4 antibody being administered first and a compound of Formula (J), Formula (I), Formula (II), (I-A), (I-B 1 ) to (FBI 2), (I-CI) - (I-C23), or a salt thereof second, or a compound of Formula (J), Formula (I), Formula (II), (I-A), (FBI ) to (FBI 2), (FC1 ) - (I-C23), or a salt thereof being administered first and anti-CTLA-4 antibody second.
• an anti-PD-l antibody and a compound of Formula (I), Formula (I), Formula (II), (I-A), (I-B I ) to (I-B12), (I -Cl ) - (FC23), or a salt thereof can be administered sequentially, such as anti-PD-l antibody being administered first and a compound of Formula (J), Formula (I) Formula (II), (I- A) (I-B 1 ) to (I-B 12) (FC 1 ) - (I-C23), or a salt thereof second, or a compound of Formula (I) Formula (I), Formula (II), (I-A) (FBI ) to (I-B 12), (I-CI ) - (I-C23), or a salt thereof being administered first and anti-PD-l antibody second.
• Ci) - (I-C23), or a salt thereof can be administered sequentially, such as anti-PD-Ll antibody being administered first and a compound of Formula (I) Formula (I), Formula (II). (I -A) (I-Bl ) to 0-B12) (F-Cl ) - (I-C23), or a salt thereof second, or a compound of Formula (I) Formula (I), Formula (II), (I- A), (I-Bl) to (I-B 12), (I-Cl) - (I-C23), or a salt thereof being administered first and anti-PD-Ll antibody second.
• immunogenic agent such as cancerous ceils, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
• a compound of Formula (I), Formula (I), Formula (II), (I--A), (I-Bl) to (I-B 12), (I- C! ) - (I-C23), or a salt thereof can also be further combined with standard cancer treatments.
• Angiogenesis inhibitors can also be combined with a compound of Formula (J), Formula (I), Formula (II), (I-A), (I-Bl ) to (I-Bl 2), (I-Cl) - (I-C23), or a salt thereof.
• Inhibition of angiogenesis leads to tumor cel l death, which can be a source of tumor antigen fed into host antigen presentation pathways.
• a compound of Formula (J), Formula (I), Formula (II), (I-A), (I- B 1 ) to (I-B 12), (I-Cl ) - (I-C23)), or a salt thereof can be used in conjunction with anti -neopla tic 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) winch would potentiate an immune response mediated by CTLA-4, PD-1 , PD F!
• a treatment of a hyperproliferative disease can include an anti -cancer antibody in combination with a compound of Formula (J), Formula (I), Formula (II), (I- A).
• Other antibodies that can be used to activate host immune responsiveness can be further used in combination with a compound of Formula (J), Formula (I), Formula (31), (I- A), fi-Bl j to (I-B12), (I-Cl) - (1-C23) or a salt thereof.
• a compound of Formula (J), Formula (1), Formula (II), (I- A), (I-Bl) to (I-B12), (i-Cl) - (I-C23), or a salt thereof can be combined with an anti-CD73 therapy such as an anti-CD73 antibody.
• the compound of Formula (J), Formula (1), Formula (11), (I- A), (1-B 1 ) to (1-BI 2), (i-C 1 ) - (I-C23), or a salt thereof is administered in combination with another CDK4 or CDK6 inhibitor or other CDK inhibitor.
• the dose of a compound administered to an individual may vary 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 m 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 pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject ' s health status, condition, and weight
• An exemplary dose is m the range of about from about 0 7 rng to 7 g daily, or about 7 rng to 350 rng 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 salt thereof 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 desired 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 in one variation, 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)
• 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
• the compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and iransdermai.
• a compound provided herein can be administered frequently at lo 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 eycles
• Metronomic therapy or maintenance therapy can comprise intra-turn oral admini tration of a compound provided herein
• the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g , a human) an effective amount of a compound or salt thereof
• the route of administration is intra venous, intra-arterial, intramuscular or subcutaneous.
• the route of administration is oral.
• the route of administration is iransdermal.
• 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 form.
• articles of manufacture comprising a compound of foe disclosure or a salt thereof composition, and unit dosages described herein m suitable packaging for use in the methods described herein.
• suitable packaging is known m 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 of the compounds disclosed herein in one variation, the kit employs a compound described herein or a salt thereof
• 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
• kits may be in unit dosage forms, bulk packages (e.gi, 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 for 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 for use and be packaged in quantities sufficient for storage and use pharmacies ( .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 in vention.
• the instructions included with the kit generally include information as to the components and their administration to an individual.
• Example- 1 Synthesis of 5-jluoro ⁇ 4 ⁇ (8 ⁇ jluoro ⁇ 4 ⁇ isopropyl ⁇ 3, 4-dihydro-2H-henzo[bj[ 7, 4/oxazin-
• Step-1 Synthesis of 6-bromo-8-fluoro-4-isopropyi-2H-beo*o[h] [1 ,4]oxazm-
• Step-2 Synthesis of 6-bromo-8-t1uoro-4-isopropyl-3, 4-dihydro-2B- henzojb j [I,4]oxazine: To a stirred solution of 6-bromo--8--iluoro-4--isopropyi--2H- benzo[b][ l,4]oxazm-3(4H)-one (1400 mg, 4.87 mmol, 1 equiv) in THF (14 L), was added BIT.DMS (9 7 mL, 7.66 mmol, 4 equiv) drop wise at 0 °C. The reaction mixture was heated to 80 °C for 16 h.
• Step-3 Synthesis of 84I >rO 44sopropyl4H4,AA4>4etrame hyT4,3fo ⁇
• reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 ml, x 2) Organic layer was washed with brine (100 mL), dried over anhydrous NafoCft and concentrated under reduced pressure to obtain 8-ftuoro-4- isopropyl-6 ⁇ (4,4,5,5Aetiameth i-l ,3,2-dioxaborolan-2-yi)--3,4-dihydiO 2H-benzo[b][l,4]oxazine ( 1000 mg, 69%) as a dark brown viscous compound.
• Step-4 Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yI)-8-fluoro-4-isopropyl-3, 4-d «hyclro-2H-ben*o[b] [l,4]oxa2me: To a stirred solution of 2, 4-dichlofo-5-fluofopyrimidine
• reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 mL x 2), organic layer was washed with water ( 100 mL) and brine solution (100 ml,). The organic layer dried over anhydrous NafoCL and concentrated under reduced pressure to obtain crude compound, which was purified by normal phase combi-flash to obtain 6-(2-chloro ⁇ 5 ⁇ fluoropyrimidin-4-yi)-8-fluoro-4-isopropyi-3, 4-dihydro- 2H ⁇ benzo[b][l,4]ox:azine (800 mg,
• Step-5 Synthesis of tert-butyl 4-(6-(5-fluoro-4-(8-fluoro-4-isopropyl-3, 4- dihydro-2H-benzo(b]jl,4
• Step-6 Synthesis of 5 ⁇ flm>ro-4-(8 ⁇ fluoro-4 ⁇ isopropyl-3, 4-dihydro-2M- benzo[b][l,4]oxaz «n-6-yl)-N-(5-(piperaz «n-1-yl)pyridin-2-yi)pyrimidin-2-aniine: Tert-butyl 4-(6-(5-fiuoro-4-(8-fiuoro-4-isopropyl-3, 4-dihydro-2H-benzo[bj[ I,4]oxazin--6--yl)pynmidin-2- yiammo)pyridiw3-yi)piperazme-4-carboxyiate (190 mg 0.335 mmol, 1 equiv) was taken in 1.25 M HCI in ethanol (5 L) and the resultant reaction mixture was stirred at RT for 16 h.
• Example-2 Synthesis qf 8dluoro-6-(5dluoro-2-(5-(piperazin-l-yl)pyridin-2-ylammo)pyrimidin ⁇ 4 ⁇ yl) ⁇ 4-isopropyl-2H-benso[b jl ,4]oca ⁇ h-3(4H)-ohb (Compound 2):
• Step-2 Synthesis of 8-fluoro-4-isopropyi-6-(4,4,5,5-tetramethyl- J ,3,2- dioxaboro!an-2-yl) ⁇ 2H ⁇ beBzo[b]
• oxazin-3(4H)-one To a stirred solution of 6-bromo-8- fluoro-4tisopropyl-2H-benzofb]f l,4]oxazin-3(4H)-one (1000 mg, 3.48 mmol, 1 equiv) and 4,4,5,5 tetramet!iyl-2-(4,4,5,5-tetramethyl l ,3,2-dioxaborolan-2-yl)-1 ,3,2-diOxaborolane (1062 mg, 4 18 mmol, 1.2 equiv) in Dioxane was added Potassium acetate (1023 mg, 10.44 mmol, 3 equiv).
• Step-3 Synthesis of 6-(2-ch1oro-5-fluoropyrimidin-4-yI)-8-fluoro-4-isopropy1- 2H-benzo[b] [ 1 ,4]oxazin-3(4H)-one: To a stirred solution of 2, 4-dichloro- 5 ⁇ fluoropyriraid ine
• reaction mixture was heated to 80 °C for 4 h. 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 EtOAc (100 ml, x 2) Organic layer was washed with water (100 ml,) and brine solution (100 ml,).
• Step-4 Synthesis of tert-butyl 4-(6-(5-flworo-4-(8-flworo-4-«sopropyI-3-oxo-3,4- dihydro-2H-benz ⁇ [b][i,4]oxazi «-6-yI)pyrhmdin-2-yIaMmo)pyrHiin-3-yl)piperazme-J- carhoxyiate: To a solution of 6-(2-chloro-5-fiuoropyrimidin-4-yi)-8-fluoro ⁇ 4-isopropyi-2H- benzol b 1 jd ,4joxazm--3(4H)-one (240 mg, 0.707 mmol, 1 equiv) m Dioxane (10 inL), was added ten-butyl 4-(6-ammopyndm-3-yl)piperazme-l-carboxyiaie (21 7 mg, 0.7
• Step-5 Synthesis of 8-fluoro-6-(5-fluoro-2-(5-(piperazia-l-yl)pyridiii-2- yIamin0)pyrimidin ⁇ 4 ⁇ yI)-4-is0propyl-2H ⁇ ben3 ⁇ 4o[bj[l » 4]oxazin-3(4H) ⁇ one: Tert-buty!
• Example-3 Synthesis of 5 ⁇ jluoro-4-(8-jluoro-3, 4-dihydro-2H ⁇ benzo/bjfl, 4/oxazin-6-ylJ ⁇ N-(5 (piperazin- 1 -yl)pyridin-2 ⁇ yl)pyritnidm ⁇ 2-amine (Compound 3):
• Step-1 Synthesis of 6- ⁇ 2-chloro-5-flaoropyrimidin-4-yl)-8-fl «oro-3,4-dihy ro- 2H-benzo[b] [l,4]oxazine: To a stirred solution of 2, 4 ⁇ dichloro-5-fiuoropyrimidine (4000 mg, 24.09 mmol, 1 equiv), 8 ⁇ iluoro-6 ⁇ (4,4,5,5-tetrameiliyl-l ,3,2-dioxahorolan-2-yi)-3,4-dihydro-2H- benzo[b][l ,4]oxazine (6722 mg, 24 09 mmol 1 equiv), Potassium carbonate (6649 mg, 48.18 rnmol, 2 equiv), FdtPPfng (1391 mg, 1 2 mmol 0.05 equiv) in THF: Water (1 : 1,40 mL)
• reaction mixture was heated to 80 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, the reaction mixture was diluted with water ( 100 mL) and extracted wit EtOAc (150 mL * 3). Organic layer was washed with water (150 mL), brine solution (I 50 mL).
• reaction mixture was aerated with nitrogen gas for 30 m., followed by the addition of palladium acetate (3.1 mg, 0.014 mmol, 0.02 equiv) and BINAP (18 mg, 0 028 mmol, 0.04 equiv) again purged nitrogen for 5 min
• the resultant reaction mixture was heated to 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, tin: reaction mixture was diluted with water (25 mL) and extracted with EtOAc (50 mL x 3). Organic layer was washed with water (50 mL) and brine solution (50 l,).
• Step-3 Synthesis of 5-fl «oro-4-(8-fl «oro-3, 4-dihydro-2H-ben*o b][l,4)oxa2 «n-6- yl)-N ⁇ (5 ⁇ (piperazm-l-yl)pyridin-2-yl)pyrimidin-2-amine: Tert-butyl 4-(6-(5-fluoro-4-(8- fluoro-3.4-dihydro-2H-benzo[bl[1 ,4]oxazm-6-yl)pyrimidin-2-ylamino)pyridin ⁇ 3-yl)piperazine-l- carboxy!ate (90 mg, 0 133 mmol, 1 equiv) was taken in 1 .25M HC1 in ethanol (5 mL) and the resultant reaction mixture was stirred at RT for 16 h.
• Example-4 Synthesis ofN-(5-((4-ethylpiperami-l-yl) methyl) pynchn-2-yI) ⁇ 5 ⁇ fluoro ⁇ 4 ⁇ (8 ⁇ fluoro ⁇ 4-isopropyl-3, 4-dihydro-2H-henzo[b J[J 4)oxazm-6-yt)pynmidin-2 ⁇ mine (Compound 4):
• Step-1 Synthesis of 6-bromo-8 ⁇ fluoro-4 ⁇ isopropyi-2H ⁇ bea*o[b] [l,4]oxa*in ⁇ 3(4H)-oiie: To a stirred solution of 6 bromo--8--fkioro--21T-benzoib][l,4]oxazin- 3(4H)--one (7 0 g, 28 56 mmol, 1 equiv) in DMF (70 ml,), was added NaH (60%) (2.282 g, 57.12 mmol .
• Step-2 Synthesis of 6-bromo-8-fluoro-4-isopropyl 3, 4-dihydro ⁇ 2Il- benzo[b] [l,4]oxazrae: To a stirred solution of 6-bromo-8-fluoro-4-isopropyl-2H- benzofb] [ 1 ,4] oxazi n-3 (4H)-one (1400 mg, 4.87 mmol, 1 equiv) in THF (14 ml,), was drop wise added B!3 ⁇ 4 DMS (9.7 ml,, 7.66 mmol, 4 equiv) at 0 C The reaction mixture was heated to 80 °C for 16 h.
• Step-3 Synthesis of 8-fluoro-4-isopropyi-6-(4,4,5,5-tetramethyi- J ,3,2- dioxaboro!an-2-yl) ⁇ 3,4-ilihydro-2H ⁇ beiizo(b]
• reaction mixture was healed to 100 °C for 4 h 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 EtOAc (100 ml, c 2), organic layer was washed with brine (1 00 ml,). Tire organic layer dried over anhydrous Na ⁇ SCL and concentrated under reduced pressure to obtain 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyj-l ,3,2-dioxaborolan-2-yI)-3,4-dihydro-2H- benzo[b][l,4]oxazine ( 1000 mg, 69%) as a dark brown viscous compound.
• Step-4 Synthesis of 6-(2-chloro-5-flaoropyrimidin-4-yI)-8-fl «oro-4-isopropyl-3,
• Step-5 Synthesis of N-(5-((4-ethyIpiperazm-l -yl) methyl) pyridin-2-yl)-5-tluoro- 4-(8-flooro-4-isopropyi-3,4-dihyclro-2H-benzofb][l 5 4)oxazin-6-yt)pyrimidin-2-amine: To a solution of 6-(2-chloro-5-fluoropyrmiidin-4-yl)-8 ⁇ fluoro-4-isopropyl-3, 4-dihydro ⁇ 2H- benzo[b][l ,4]oxazine (200 mg, 0.676 mmol, 1 equiv) in Dioxane (10 mL), was added 5 ⁇ ((4 ⁇ ethylpiperazin-l-yi)methyl)pyndin-2-amine (149 mg, 1.015 m o
• reaction mixture was aerated with nitrogen gas for 30 m ., followed by the addition of palladium acetate (3 mg, 0.012 mmol, 0.02 equiv) and BINAP (15.3 mg, 0 024 mmol, 0.04 equiv) again purge nitrogen for 5 in The resultant reaction mixture was heated to 100 °C for 16 h. Progress of the reaction was monitored hy TLC and LCMS. After completion of the reaction , the reaction mixture was diluted with water (25 ml) extracted with EtOAc (100 ml), organic layer was dried over anhydrous Na ⁇ SCft and
• Step-1 Synthesis of 6-bromo-8-fluoro-4-isopropyi-2H-ben*o[h] [1 ,4]oxa*in-
• Step-2 Synthesis of 6-bromo-8-fluoro-4-isopropyl-3 3 ⁇ 4 4 ⁇ dihydro-2H- benxo[b] [lL4]oxaxfee: To a stirred solution of 6-bromo ⁇ 8 ⁇ iluoro ⁇ 4 ⁇ isopropyl ⁇ 2H- benzo[b][l ,4]oxazin-3(4H) ⁇ one (1400 mg, 4.87 mmol, 1 equiv) in THF (14 ml,), was drop wise added B1L.DMS (9 7 ml,, 7.66 mmol, 4 equiv) at 0 C The reaction mixture was heated to 80 °C for 16 h Progress of the reaction was monitored by TLC and LCMS.
• Step-3 Synthesis of 8-!1 «oro-4-isopropyl-6-(4, 4,5, 5-tetraniethyI-1,3,2- dioxaboroIan-2-yl)-3,4-dihydro-2H-benzo[b][l,4]oxaz «nei
• 6-bromo-8- fl uoro-4-i sopropy 1 -3 4-dihydro-2H-benzo[b][l ,4]oxazine (1200 mg, 4 39 mmol.
• reaction mixture was heated to 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction the reaction mixture was diluted with water (30 niL) and extracted with EtOAc (100 ml, 2). organic layer was washed with brine ( 100 mL). The organic layer dried over anhydrous Na SCft and concentrated under reduced pressure to obtain 8-fliK>rG-4-isopropyl-6-(4,4,5,5-tetrainethyLl,3,2-diox:aborolan-2-yi)-3,4 ⁇ dihydro ⁇ 2H- benzo[b][! ,4]oxazme ( 1000 mg, 69%) as a dark brown viscous compound.
• Step-4 Synthesis of 6-(2-chIoro-5-fltioropyrimidm-4-yl)-8-t1uoro-4-isopropyI-3, 4-dihydro-2H-benzo[b]
• Step-5 Synthesis of tert-butyi 4-(2-((5 ⁇ flaoro-4-(8 ⁇ flaoro-4 ⁇ isopropyi-3,4 ⁇ dihydro-2II-benzo[b][i,4]oxazm-6-yl ⁇ pyrimidin-2-yl)amino)pyr «dm-4-yi)piperazine ⁇ l ⁇ carhoxylate: To a solution of 6-(2-chlorO 5--fiuoropyrimidin-4-y!)-8-fluoro-4-isopropyft3, 4- dihydro-2H--benzo
• Step-6 Synthesis of S-t1uoro-4-(8-t1uoro-4-isopropyI-3, 4-dfliydro-2H-benzo[b] [l, 4]oxazin-6-yl) ⁇ -(4-(piperazin-l-yl)pyridm-2-yl)pyrimiilIn-2-arame: Tert- butyl 4-(2-((5- fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[bl[l ,4]oxazm-6-yl)pyrimidin ⁇ 2 ⁇ yl)ammo)pyndin-4-yl)piperazine ⁇ l ⁇ carboxyiate (140 mg, 0.246 mmol, 1 equiv) was taken in 1 .25M HC1 in ethanol (5 i,) and the resultant reaction mixture was stirred at RT for 16 h.
• Example-6 Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyi-3, 4-dihydro-2H-benzo[bj /!/, 4/oxazin- 6-yl)-N-(4-(4-methylpiperazin-l-yl)phenyi)pynmidin-2-amine (Compound 6):
• Step-2 Synthesis of 6-bromo-8-fluoro-4-isopropyl-3 3 ⁇ 4 4 ⁇ dihydro-2H- bemzo[b] [L4]oxazlne: To a stirred solution of 6-bromo ⁇ 8 ⁇ iluoro ⁇ 4 ⁇ isopropyl ⁇ 2H- benzo[b][!
• Step-3 Synthesis of 8-f1 «oro-4-isopr »py1-6-(4, 4,5, 5-tetramelhyI-1,3,2- dioxaboroIan-2-yl)-3,4-dihydro-2H-benzo[b][l,4]oxaz «nei
• 6-bromo-8- fl uoro-4-i sopropy 1 -3 4-dihydro--2!:I-benzo[b][ l ,4]oxazine (1200 mg, 4 39 mmol.
• Step-5 Synthesis of 5-f! uoro ⁇ 4 ⁇ (8-f! uoro-4-lsopropyl-3, 4-dihydro-2H ⁇ benz ⁇ [b][l,4]oxaziR-6-yI) ⁇ N-(4-(4-raethyipiperaziR-l-yI)phenyi)pyrimidin-2-asnine: To a solution of 6-(2-chloro-5-fluoropynrnidm-4-yl)-8-fluoro-4-isopropyl-3, 4-dihydro-2H ⁇ benzo[b][! ,4]oxazine (150 mg, 0 461 mmol.
• Example -7 Synthesis of E(6-(2-((5-((4-ethyIpipen ⁇ zirmEy!)meihyIjryndm-2-yIjammo)-5- fliioropyriffiidin 4 yl) ⁇ 8fliioro ⁇ 2, 3aEh)Ero-4H-Eenzofb I f 1 E Joxaz -EyUethan- Eone
• Step-2 Synthesis of l-(6-(2-chIoro-5-fiuoropyrimidm-4-yl)-8-fluoro-2 i 3-d «hyclro-
• reaction mixture was allowed to stir at RT for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted wit EtOAc (50 mL > ⁇ 3), organic layer was washed with NaHCQ- (!
• Step-3 Synthesis of l-(6-(2-((5 ⁇ ((4 ⁇ ethylpiperazia-l-yi)methyi)pyridia-2- yl)amino)-5-fluoropyrimidin-4-yl)-8-f!uoro-2,3-dihydro-4H-benzo(bJ [l,4]oxa*in-4-yl)ethan-
• Step-1 Synthesis of (6-(2-chIoro-5-fiuoropyrimidin-4-yl)-8-fluoro-2 dihydro- 4H-benzo[b] [l,4]oxa*in-4-yl)(cyclopropyl)inethanone: To a stirred solution of 6-(2-ehloro-5- iluoropymmdin-4-yl)-8-fluoro-3,4-dihydro-2H-benzo[b](l,4]oxazine (300 mg, 1.06 mmol, 1 equiv) in DCM (10 mL), was added tnethyl amine (0.37ml. 2,65 mmol, 2 5 equiv) ai 0 °C.
• Step-2 Synthesis of cydopropyi(6-(2-((5-((4-ethyipipera2in-I-yi)methyl)pyridin- 2-yl)ammo)-5-fluoropyrimidm-4-yl)-8-!1uoro-2 i 3-d «hyclro-4H-ben*o!b]
• [l,4]oxa2iii-4- yi)metbanone To a solution of (6-(2-chloro-5-fluoropyrmiidin ⁇ 4-yl) ⁇ 8 ⁇ fluoro-2,3-dihydro-4H- benzo[b][ l,4]oxazin-4-yl)(cyciopropyl)methanone (200 mg, 0.676 mmol, 1 equiv) in Dioxane (10 mL), was added 5-((4-ethylpiperazin- 1 -yl )
• reaction mixture was aerated with nitrogen gas for 30 min followed by the addition of palladium acetate (6.8 g, 0.030 mmol, 0.05 equiv) and BINAP (19.12 mg, 0.030 mmol, 0.05 equiv).
• the resultant reaction mixture was stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS.
• reaction mixture was diluted with water (50 niL) and extracted wit EtOAc (50 mL x 2), organic layer was washed with Na!ICCti (100 ml), brine solution (50 ml, x 3) and dried over anhydrous NafoCfo Concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase combi-flash chromatography to obtain cycloprGpyl(6-(2-((5-((4 ⁇ ethylpiperazin-l -yl)methyi)pyridin ⁇ 2 ⁇ yl)ammo) ⁇ 5 ⁇
• Step- 1 Synthesis of tert- butyl (4-(6-(2-((5-((4-ethylpiperazin-l- yl)methyl)pyridm-2-yl)amino)-5-fliioropyrimid «n-4-yl)-8-tluoro-2 3-dfliydro-4H- benzojb j [1,4] oxaz «B-4-yl)cyciohexyl)carbamate: To a solution of 4-(4-((tert- butoxyearbonyl)amino)cyciohexyl)-6 ⁇ (2 ⁇ chloro-5-fluoiOpyrimidin-4-yi)-8-fluoro-2H- benzo[b] [l ,4]oxazm-4-ium (100 mg, 0.31 mmol, 1 equiv) in dioxane (4 mL), was added 5-((4-(4-(2-
• reaction mixture was stirred at 100 °C for 16 h. Reaction was monitored by 1 ( ' MS. After completion of reaction, reaction mass was diluted with water (5 mL) and extracted with EtOAc (3x1 OmL). Organic layer was passed through the anhydrous NafoCfi, filtered and concentrated the organic layer under reduced pressure to afford 200 mg crude desired product.
• Step-2 Synthesis of 4-(4-(4-amiaocyclohexyl)-8 ⁇ fluoro-3 > 4-dihydro-2H ⁇ benzo[b]jI,4ioxaz «B-6-yl)-N-(S-((4-ethy!pipei in-l-yl)methyl)pyridin-2-yl) ⁇ 5”
• Example- 10 Synthesis of 5-fluoro-4-(8-fluoro-4-isopropyI-3,-l ⁇ dihydro ⁇ 2H-be ofhJfJ4joxazm- 6-yl) ⁇ M-(5-(3-methylpiperazin-l-yi)pyndm-2-yi)pyrimidin-2-amine (Compound 10):
• reaction mass was degassed by the purging nitrogen for 10 min After 10 min.
• BINAP 7 mg, 0 0123 mmol, 0 04 equiv
• PdiOAcfo 1. mg, 0.0062 mmol, 0 02 equiv
• Resultant reaction mixture was stirred at 100 °C for 28 h Reaction was monitored by LCMS. After completion of reaction, reaction mass was diluted with water (5 niL) and extracted with EtOAc (3 x !O L).
• Step-2 Synthesis of S-fluorG-d ⁇ S-fluoro-d-isopropyl-Syi-dihydro-lil- benzofblll ⁇ joxazm-d-ylJ-N ⁇ S ⁇ S-methylpipeimm-l-yljpyridin-l-j ⁇ pyrimidm-l-amiiie: To a solution of tert-butyi 4-(6-((5-fiuoro-4-(8-fiuoro-4-isopropyl-3,4-dihydro-2 ⁇ -j- benzolb][l, 4 joxazin-6-yi)pyrimidin-2-y!amino)pyridin-3-yj) 2-meihyj piperazine- 1 -carboxylate
• Step-1 Synthesis of tert-butyl 4- ⁇ 3-fluoro-4- ⁇ 5-fluoro-4- ⁇ 8-fluoro-4-isopropyI- 3,4 ⁇ d «hydro-2H-beRzo[b][l,4]oxazm-6-yi)pyr «nMdm-2-yl ⁇ afnmo)phenyl)p «pera2:ine-l- carboxylafe: To a solution of 6-(2-chloro-5-fIi oropyrimidin-4-yl)-8-f3uoro-4-isopropyl-3 4- dihydro-ZH-benzo[b] [ 1 ,4]oxazine (100 mg, 0 31 mmo!, 1 equiv) m dioxane (4 ml ,), was tert- butyl 4-(4-ainino-3-fiuorophenyl)piperazine-l-carboxylate (101 mg 0.
• reaction mass was degassed by the purging nitrogen for 1 0 min. After 10 min, BINAP (7 7 mg, 0.0123 mol, 0.04 equiv), and Pd(OAc) 2 (1.4 mg, 0.0062 mmol, 0.02 equiv) were added, followed by nitrogen purging for 10 min. Resultant reaction mixture was stirred at 100 °C for 24 h. Reaction was monitored by LCMS. After completion of reaction, reaction mass was diluted with water
• Step-2 Synthesis of S-t1uoro-N-(2-(luoro-4-(piperazui-l-yl)phenyI)-4-(8-fl «oro-4- isopropyl-3,4-dihydro-2H-ben2o b] [l,4]oxa2m-6-yl)pyrimidui-2-amine: To a solution of tert- butyi 4-(3 ⁇ fluoro-4-((5 ⁇ fluoro-4-(8 ⁇ fluoro-4 ⁇ isopropyl-3,4-dihydiO-2H ⁇ benzo[b][l,4]ox;azin-6- yl)pyrimidin ⁇ 2 ⁇ yl)amino)phenyl)piperazme ⁇ l ⁇ carboxylate ("5 mg) in 1.25M ethanolic HC!
• Example- 12 Synthesis of5 ⁇ fiuoro-N-(3 ⁇ fiuoro-4-(pipefxmn-l ⁇ yl)phenyl)-4-(8-flnoro-4- isoprapyl ⁇ 5, 4 ⁇ diiiydro ⁇ 2H ⁇ henzo[h( jp4]oxazin ⁇ 6 ⁇ yi)pyrimidln ⁇ 2 ⁇ mnine hydrochloride
• Step-1 Synthesis of tert-but l 4-(2-fl «oro-4-((5-fluoro-4-(8-fluoro-4-isopropyl- 3,4-dihydro-2H-ben3 ⁇ 4o[b][l,4
• reaction mass was degassed by the purging nitrogen for 10 min. After 10 m , BINAP (6.5 mg, 0.0123 mmol, 0.04 equiv), and Pd(OAc) 2 (1.4 mg, 0.0062 m ol, 0 02 equiv) were added, followed by nitrogen purging for 10 min. Resultant reaction mixture was stirred at 100 °C for 16 h Reaction was monitored by LCMS. After completion of reaction, reaction mass was diluted with water (5 mL) and extracted with EtOAc ( 10 mL x 3). Organic layer was passed through the anhydrous Na SCti, filtered and concentrated the organic layer under reduced pressure io afford 200 g crude desired product.
• Step- 1 Synthesis of tert- butyl 6-((5-fluoro-4-(8-fl «oro-4-isopropyI-3,4-dihydro-
• Hie reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (3 mg, 0.01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol. 0.04 equiv).
• Hie resultant reaction mixture was allowed to stir at 100 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with EtOAc (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-2 Synthesis ofN ⁇ (5 ⁇ fluoro-4 ⁇ (8-fluoro-4 ⁇ isopropyi-3,4 " dihydro-2H- benzo[b]il » 4]oxa3 ⁇ 4in-6-yi)pyrimidin-2-yl)- 2 ⁇ ,4-tetrahydroisoquinolin-6-ainine: A solution of ten-butyl 6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,d-dihydro-2H-benzo[b][1 ,4]oxazim6- yl)pyrimidm ⁇ 2-yl)ammo) ⁇ 3,4-dihydroisoqumoline-2(1 H)-carboxyIate (90 mg, 0.11 mmol, 1 equi v) in 1 25 M HC!
• Example-14 SyrUhesis of 5 ⁇ fluoro ⁇ N ⁇ (3 ⁇ fluoro ⁇ 4 ⁇ (4 ⁇ meth ⁇ 4piperazin ⁇ I ⁇ yi) phenyl)-4-(8-fiisoro-4- isopropyl ⁇ 3, 4-dihydro-2H-henso[bJ[J 4] oxazin-6-yl) pyrimidin-2-amine (Compound 14):
• Step-1 Synthesis of tert-butyi 4-(2-fl «oro-4-((5-flluoro-4-(8-fliuoro-4-isopiOpyi- 3,4-d «hydiO-2H-henzo[b][l,4!oxazia-6-yi)pyrimidm-2-yl)ammo)phenyl)piperaziiie-l- carboxylate: To a solution of 6-(2-chloro-5-fiuoropyrimidin-4-yI)-8-fluoro-4-isopropyI-3,4 ⁇ dihydro-2H-benzo[b] [ 1 ,4]oxazine (300 mg, 0 92 mmol, 1 equiv) in dioxane (10 ml,), was added tert-butyi 4 ⁇ (4-ammo-2-f]uoropheny ⁇ )pipera ine-i-carhoxylate (
• Step-2 ; Synthesis of 5 ⁇ flm>ro-N-(3-fluor ⁇ -4-(pipera3 ⁇ 4m ⁇ l ⁇ yl) pi iyI) ⁇ 4 ⁇ (8 ⁇ fl «oro ⁇
• Step-3 Synthesis of 5-fl «oro-N-(3-tluoro-4-(4-methylpipera*m-l-yI) phenyI)-4- (S-fluoro-4-isopropyl-3, 4-dihydro-2H-benzo
• Step-1 Synthesis of tert-butyi 5-((5-fluoro-4-(S-flaoro-4-isopropyi-3,4- ihydro- 2H-benzofb1 (l,4]oxazin-6-yl)pyriraidin-2-yI)amino ⁇ -3,4-dihy roisoquinoline-2 ⁇ lH)- carhoxyiate: To a solution of 6-(2-chloro-5--fluoropynmidln-4-yl)-8-iIuoro-4-isopropy 1-3,4- dihydro-2H-benzo[b]p ,4]oxazine (200 mg, 0.61 mmol, 1 equiv) in dioxane (10 mL), was added ten-butyl 5 ⁇ amino-3,4-dihydrGiscqmnohne-2(1 H)-carbcxylate (168 mg, 0.67 mmol, 1 1 1
• reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (3 mg, 0.01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol, 0.04 equiv).
• Hie resultant reaction mixture was allowed to stir at 100 °C for 16 h Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with EtOAc (100 mL). Organic layer was -washed with -water (50 mL) and brine solution (50 mL).
• Step-2 Synthesis of N-(S-flnoro-4-(8-flnoro-4-isopropyi 3,4-dihydro-2H
• Step-1 Synthesis of tert-butyl 7-((5-fluoro-4-(S-flaoro-4-isopropyi-3,4- ihydro- 2H-benzo[b1 (l,4]oxazin-6-yl)pyriraidin-2-yI)amino ⁇ -3,4-dihy roisoquinoline-2 ⁇ lH)- carboxylate: To a solution of 6-(2-diloro-5-fluoropyrimidin-4 -yl)-8-fluoro-4-isopropyl-3 > 4- dihydro ⁇ 2H--benzo[b][l,4]oxazme (200 mg 0.61 mmol, 1 equiv) n dioxane (10 mL) was added tert-butyl 7-ammo ⁇ 3,4--dibydroisoquinoime--2(l H) ⁇ carboxylaie (1 68 mg, 0 67 mmol, 1.1
• reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (3 rng, 0.01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol, 0.04 equiv).
• the resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with EtOAc (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-2 Synthesis of N-(5-fluoro-4-(8-fluoro-4-isopropyi-3,4-dihydro-2H- henzojbj [1 ,4]oxa2:in-0-yl)pyrimidin-2-yl)-i,2,3,4-tetrahydroisGq «iinolin-7-amme: A solution of tert-butyl 7-ii5-fiuoro-4-(8-fluoro-4-isoprop l-3,4-dihydro-2B-benzo[b][l ,4]oxazm-6- yl)pyrimidin-2-yi)amino)-3,4-dihydroisoqiiinoline-2 ⁇ lH)-carboxylaie (90 mg, 04 1 mmol 1 equiv) in 1 25 M HC1 in ethanol (5 nil,) was allowed to stir for 1 h at 50 °C.
• Example-! 7 Synthesis of S ⁇ fluoro ⁇ N ⁇ (3 ⁇ fluoro ⁇ 4 ⁇ (4 ⁇ isopropylpiperazm ⁇ 1-yi) phenyl)-4-(8- fluoro ⁇ 4 ⁇ isopropyl ⁇ 3,4 ⁇ dihydro-2H ⁇ benzo[b][l,4]oxa ⁇ in-6-yi)pyrifnidin-2-amine (Compound 17):
• Step-1 Synthesis of 5-fluoro-lN-(3-fluoro-4-(4-isopropylpiperazin-l-yi) pfaenyl)- 4-(S-fl «oro-4-isopropyi-3,4-dihydro-2H-benzo[b] [l » 4joxazin-6-yi)pyrimidin-2-araine: To a stirred solution of 5-f1uoro ⁇ N-(3-fluoro-4-(piperazin-l-yl)phenyI)-4-(8-fiuoro-4-isopropyl-3,4 - dihydro-2H-benzo[b] 1 > 4]oxazin-6-yi)pyrimidin-2-arnine (30 mg.
• reaction mixture was diluted with wa er (25 ml-) and extracted with EtOAc (50 mL x 2). Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Example- 18 Synthesis of 5-fluoro-N-(3-fluoro-4-(pipendm ⁇ 4 ⁇ yl) phenyl) ⁇ 4 ⁇ (8-fiuoro ⁇ 4 ⁇ isopropyl-3, 4 ⁇ dihydro ⁇ 2H ⁇ bemofb][l, 4] oxazin-6-yI) pyrimidm-2-amine (Compound 18):
• Step-1 Synthesis of tert-butyl 4- ⁇ 2-fluoro-4- ⁇ 5-fluoro-4- ⁇ 8-fluoro-4-isopropyI- 3,4-dihydro-2H-ben2:o[b][l » 4joxazm-6-yi)pyrimidin-2-yi ⁇ araino)pheny!piperidine-l- carboxylaie:To a solution of 6-(2-ch!oro-5- ⁇ 1uoropyrimidin-4-yl) ⁇ 8 ⁇ iluoro-4-isopropyl ⁇ 3,4- dihydro-ZH-benzo[b] [ 1 ,4]oxazine (150 mg.
• Example- ⁇ 9 Synthe is ofN-(5-fluoro-4-(8-fluoro-4-isopropyi-5, 4-dihydro ⁇ 2H- benza[h]fl, 4]oxazin-6-yl)pyrimidin-2 ⁇ yr) ⁇ 2 ⁇ isopropyl ⁇ lJ2, 3,4 ⁇ tetrahydraisoqumolin ⁇ 7 ⁇ amine (Compound 19):
• Step-1 Synthesis of tert-butyl 7- ⁇ 5-fluoro-4-(8-fluoro-4-«sopropyI-3,4-dihydro ⁇ 2H-benzo[b] [l,4]oxa*in-6-yl)pyrimidiH 2-yl)amino)-3,4 ⁇ dihydro «soquinoline-2(iH)- carboxylate: To a solution of 6-(2-chloro-5-fluoropyrimidm-4-yl)-8-fluoro-4-isopropyl-3,4- dihydro-ZH-benzo[b][l ,4]oxazine (200 mg, 0.61 mmol, 1 equiv) m dioxane (10 mL), was added tert-butyl 7-amino-3,4-dihydroisoquinoiine-2(lH)-carboxylate ( 168 mg, 0.67 mmol, 14 equiv) and
• the reaction mixture was degassed with mtrogen gas for 30 min., followed by the addition of palladium acetate (3 mg, 0.01 mmol, 0 02 equiv) and BIMAP (15 mg, 0 02 mmol 0 04 equiv)
• the resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 no . ⁇ . Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-2 Synthesis of M-(S-fluoro-4-(8 ⁇ fluoro-4-isopropyI ⁇ 3,4 iBhydro-2H ⁇ benzo[b][l,4]oxazin-6 ⁇ y!pyri idm-2-yl)-l ⁇ 3,4-tetrahydro «soquinolin ⁇ 7 ⁇ amme: A solution of tert-butyl 7 ⁇ ((5-fluoro ⁇ 4-(8- ⁇ 1uoro ⁇ 4 -isopropyl ⁇ 3,4-dihydro-2H ⁇ benzo[h][1 ,4]oxazm-6- yi)pyrimidm 2 yj ⁇ ammo ⁇ 3,4-dihydroisoquino!ine-2i!H) ⁇ carboxykte (40 mg, 0.07 mmol, 1 equiv) in 1.25 Mi HCi in ethanol (5 mL) was allowed to stir for 1 h at 50 °C.
• Step-3 Synthesis of N-(5-fluoro-4-(8 ⁇ iIuoro-4-isopropyl ⁇ 3,4-dihydro-2H ⁇ benzo[b][I,4]oxazin-6-y!pyrimidin-2-yI)-2-isopropy!-l » 2 ⁇ L4-tetrahydroisoquinoIia-7- amine: To a stirred solution of N-fS-fiuoro-d-iB-fiuoro- -isopropyj-S ⁇ -dihydro-dH- benzolbjl l joxazm-e-ynpyrimidin-ti-yl)- ⁇ ] ,2,3,4-tetraliydroisoqumolim7-amine (50 mg, 0 1 mmol, 1 equiv) in DCE (5 mL), was added Acetone (0.02 mL, O.dmmol, 3 equiv), acetic acid
• reaction mixture was cooled to 0 °C. NaCNB!iL (19 mg, 0.3 mmol, 3 equiv) was added to above mixture and raise the temperature to RT The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS After completion of the reaction the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2).
• Example-20 Synthe is ofN ⁇ (5 ⁇ fluoro ⁇ 4 ⁇ (8 ⁇ fluoro ⁇ 4 ⁇ isopropyi ⁇ 5, 4 ⁇ dihydro ⁇ 2H ⁇
• Step-1 Synthesis of tert-buty! S-((5-fll «oro-4-(8-fliuoro-4-isopropyl-3,4-dihytlro- 2H ⁇ benzo ⁇ b
• Step-2 Synthesis of N -( S-t1uoro-4-( 8-fluoro-4-isopropyl-3,4-dihy dro-2H- benzo j b j ( 1 ,4) oxazin-6 ⁇ yl)pyri idin ⁇ 2-yl)-l,2,3,4-tetrahydroisoqumolin ⁇ 5-amiBe: A solution of tert-butyi 5 ⁇ ((5-fli3oro ⁇ 4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[bl[l ,4]oxazin-6- yl)pyrknidm-2-yi)ammo ⁇ -3,4 ⁇ dihydroisoquinoline ⁇ 2(lH)-earbox:ylate (50 mg, 0.09 mmol, 1 equiv) in 1.25 Mi HC1 in ethanol (5 L) was allowed to stir for lb at 50
• Step-3 Synthesis of N-(5-fluoro-4-(8 ⁇ fluoro-4-isopropyl ⁇ 3,4-dihydro-2H ⁇ benzo[b][i,4]oxazin-6-yI)pyrimidin-2-yI)-2-isopropy!-l » 2 ⁇ L4-tetrahydroisoquinoIm-5-amin:
• Example-21 Synthesis of 5 ⁇ ((5 ⁇ fluoro ⁇ 4 ⁇ (8 ⁇ fluoro ⁇ 4 ⁇ isopropyi ⁇ 3, 4-dihydro-2H ⁇ henzo[b] [ l, 4/ oxazin ⁇ 6 ⁇ yi) pynmidm ⁇ 2 ⁇ yl) amino) ⁇ 2 ⁇ (piperazin ⁇ l ⁇ yi) henzonitrile (Compound 21):
• Step-1 Synthesis of tert-butyi 4-(2-cyaao-4-((5-fluoro-4-(8-fluoro-4-isopropyl- 3,4-dihydiO-2H-henzo[b][l,4!oxazia-6-yi)pyrimidm-2-yl)ammo)phenyl)piperazme-l- carboxylate: To a solution of 6 ⁇ (2-chloro-5-fiuoropyrimidin-4-yI)-8-fluoro-4-isopropyI-3,4 ⁇ dibydro-2H-benzo[b] [ 1 ,4]oxazine (150 mg, 0 46 mmol, 1 equiv) m dioxane (10 ml..), was added tert-butyi 4-(4 ⁇ amino-2-cyanophenyI)piperazine-l-carboxylate (1 68 mg, 0 67 mmol,
• reaction mixture was degassed with nitrogen gas for 30 min. , followed by the addition of palladium acetate (2 g, 0.009 mmol, 0 02 equiv) and BINAP (12 mg, 0 018 mmol 0.04 equiv).
• the resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL) Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-2 Synthesis of 5-((5-fl «oro-4-(8-fluoro-4-isopropyi-3, 4-dihydro-2H- benzo[b][l, 4] oxazin ⁇ 6 ⁇ yi) pyrimidm-2-yl) amino)-2 ⁇ (piperazm-l-yl) benzonitriie:A solution of tert-butyl 4 ⁇ (2 ⁇ cyano-4-((5-fluoro-4-(8-fluorG-4-isopropyl-3,4-dihydro-2H- benzo[b][l,4]oxazin-6-yl)pynmidin ⁇ 2-yl)amino)phenyl)piperazine ⁇ I ⁇ carboxyiate (100 mg, 0.16 mmol, 1 equiv) m 1.25 M HC1 m ethanol (5 niL) was allowed to stir for 1 h at 50 °C.
• Step-1 Synthesis of tert-butyl 6 ⁇ ((5 ⁇ flu ⁇ ro ⁇ 4-(8 ⁇ flu ⁇ ro ⁇ 4-isopr ⁇ pyl-3,4-dihydro- 2M-benzo[b [l,4]oxazM ⁇ 6 ⁇ yI)pyrira «din-2-yl)asmn ⁇ )-3,4-dihydrois ⁇ i
• reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (3 mg, 0 01 mmol, 0.02 equiv) and BINAP (15 mg, 0.02 mmol, 0.04 equiv).
• the resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-2 Synthesis of M-(5-fluoro-4-(8 ⁇ fluoro-4-isopropyI ⁇ 3,4 dihydro-2H ⁇ benzo[b][2,4]oxazin ⁇ 0 ⁇ yI)pyrimidin-2 ⁇ yI)-1 ⁇ 4-tetrahydr0is ⁇ qu noHn ⁇ 6 ⁇ amme: A solution of tert-butyl 6-((5-fluoro-4-(8-fluoro-4-isopropyb3,4-dihydro-2H-benzo[b)(l ,4]oxazm-6- yl)pyrimidm-2-yl)ammo)-3,4-dihydroisoquinoline-2(lH)-carboxy!ate (30 mg, 0.05 mmol, I equiv) in 1.25 Mi HO in ethanol (5 mL) was allowed to stir for 1 h at 50 °C Progress of the reaction was monitored by LCMS.
• Step-3 Synthesis of N ⁇ S-fluoro- ⁇ S-fluoro- ⁇ isopropyl-Syt-dihydro-ZB- benzolb joxaziR-e- pyrimidin- -yl ⁇ Z-isopropyl-LZ ⁇ yi-teirahydroisoiimnolin- - mine: To a stirred solution of N-(5-f3uoro-4-(8-f3uoro-4-isopropyl-3,4-dihydro-2H- benzolbl] !
• Step-1 Synthesis of tert-butyl 4-(5-((5-fluoro-4-(8-fluoro-4-isopropyI-3,4- dihydro-2H-benzoib][l,4]oxazin ⁇ 0 ⁇ yI)pyrimidin-2-yl)amino)pyridin-2 ⁇ yI)p perazme-l- carboxylaie:To a solution of 6-(2-ch!oro-5-f!uoropyrimidin ⁇ 4 ⁇ yl) ⁇ 8 ⁇ fTuoro-4-isopropyl-3,4- dihydro-ZH-benzo[b] [ 1 ,4]oxazine (100 mg, 0 3 mmol, 1 equiv) in dioxane (10 ml,), was added tert-butyl 4-(5-aminopyridin ⁇ 2 ⁇ yl)piperazine-I-earboxylate (94 mg.
• reaction mixture was degassed with nitrogen gas for 30 mm., followed by the addition of palladium acetate (3 mg, 0.009 mmol, 0 02 equiv) and BINAP (12 mg, 0.018 mmol, 0.04 equiv).
• the resultant reaction mixture was allowed to stir at 100 °C for 16 b Progress of the reaction was monitored by TLC and LCMS After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-2 Synthesis of 5-fluoro-N ⁇ (3 ⁇ fluoro-4 ⁇ (piperidin ⁇ 4 ⁇ y!) pfaenyl) ⁇ 4 ⁇ (8 ⁇ fluoro- 4-isopropyI-3, 4-dlhydro-2H-benzo[b] [1, 4] oxazm-6-yi) pyrimidiR ⁇ 2 ⁇ amine: A solution of tert-butyl 4-(2-fluoro-4-((5-fluoro-4-(8-fluoro-4-isopropyh3,4-diliydro-2H-benzo[b][1 ,4]oxazm- 6-yl)pyrimidin-2-yl)amino)phenyl)piperidme-l-carboxylate (200 mg, 0.34 mmol, 1 equiv) 1 25 M HCI m ethanol (5 ml,) was allowed to stir for ih at 50°C.
• Step-3 Synthesis of 5-fl oro-N-(3-fiuoro-4-(l-methylpiperidin-4-yI) phenyi) ⁇ 4 ⁇ (8-flMoro-4- «sopr pyI-3, 4-dihydro-2H- benzo [b] [1,4] oxazin-6-y I )pyr ⁇ midin-2-amine: To a stirred solution of 5-iluoro-N (3--fluoro-4-(piperidin-4--y! phenyl)-4-(8-f!uoro-4-isopropyl-3, 4- dihydro-2H-benzof b] 1 whenever 4] oxazin-6-yl)pyrimidin-2-amine (100 mg, 0.2 mmol, I equiv) m DCE (5 mL), was added Formaldehyde (40% in water) (0.02 mL, 0.61 mmol, 3 equiv), acetic acid (0.05 oxazin
• reaction mixture was allowed to stir at RT for Ih
• the reaction mixture was cooled to 0°C NaCNBI-L (38 mg, 061 mmol, 3 equiv) was added to above mixture and raise the temperature to RT
• the reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50 mL x 2) Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-3 Synthesis of N ⁇ (4 ⁇ (4 ⁇ (dimethylammo) p «peridin-l ⁇ yl)-3-fluoropheayl)-5- fluoro-4-(8-fluoro-4- «sopiOpy!-3, 4-dihydro-2H-benzo[h]jl,4[oxazm-6-yl)pyrimitlln ⁇ 2” amine: To a solution of 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-3,4-dihydro- 2H ⁇ benzo[b][l ,4]oxazine (100 mg, 0.3 mmol, 1 equiv) in dioxane (10 mL), was added l-(4- amino-2-tluorophenyI)-N, N-dimethylpiperidin-4-amine (78 mg, 0 33 mmol, 1 1 equiv) and ces
• reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol. 0 04 equiv)
• the resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LCMS.
• Step-1 Synthesis 4-(2-f! uoro-4-nitrophenyl) morpholine:
• Step- 1 Synthesis of " 1 -(2-fluoro-4- «tropheayi) piperidm-4-o «e:
• Step-2 Synthesis l ⁇ (2 ⁇ fluoro-4 ⁇ aitrophenyl)-4-(pyiTolidm-l-yl) piperidine:
• Step-4 Synthesis 5-fluoro-N-(3 ⁇ fiuoro-4-(4 ⁇ (pyrrolidm-l-yl) piperidin-l-yi) phenyi)-6-(8-fluoro-4-isopropyl-3, 4-dihydro-2H-henzo f b) [
• Step-1 Synthesis tert-butyl 4-(2,3-difluoro-4-((5 ⁇ fluoro-4-(8 ⁇ fluor0-4 ⁇ isopropyl-
• reaction mixture was degassed with nitrogen gas for 30 min , followed by the addition of palladium acetate (2 mg, 0.006 mmol, 0.02 equiv) and BINAP (8 mg, 0 012 mmol. 0 04 equiv)
• the resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of foe reaction was monitored by TLC and LG MS After completion of the reaction, diluted with water (30 ml ,) and extracted with ethyl acetate ( 100 niL). Organic layer was washed with water (50 l,) and brine solution (50 ml,).
• Step-2 Synthesis of N-(2, 3-dif1uoro-4-(pipera*m-l-yI) phenyI)-5-fluoro-4-(8- fluoro-4-isopropyI-3, 4-dihydro-2H- benzo [b] [ 1,4] oxazm-6-y l)py ri idin-2-amme: A solution of obtain tert-butyl 4-(2,3-difiuoro-4-((5-fiuoro-4-(8-fluoro-4-isopropyl-3,4-dihydro- 2H-benzo[b][l,4]oxazin ⁇ 6-yl)pyritnidin-2-yl)anuno)phenyl)piperazine-] -carboxyiate (90 mg, 0.14 mmol, 1 equiv) in 1.25 M HCI in ethanol (5 mL) was allowed to stir tor In at 50°C
• Step- 1 Synthesis tert-butyl 4-(2-inethoxy-4-mtrophenyl) piperazine- J- carhoxyiate:
• Step-2 Synthesis of tert-buty! 4-(4-amiiio-2-methoxypfaenyl) piperazine-1- carboxyiate:
• Step-3 Synthesis of tert-buty! 4-(4-((5-fluoro-4-(8-fluoro-4-isopropyI-3,4- dihydro-2H-benzoib][i,4]oxazin-6-yI)pyrimidin-2-yI)amino)-2-imethoxyphenyI)pipera3 ⁇ 4 j ne- l-carboxylate:
• reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 rng, 0 006 rnmo!, 0.02 equiv) and BINAP (8 mg, 0.012 m ol, 0.04 equiv).
• the resultant reaction mixture was allowed to s ir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL).
• Step-4 Synthesis of 5-fluoro-4-(S-iluoro-4-isopropyl-3, 4-dihydro-2H- benzo[b][l,4]os:azi «-6-yi) ⁇ N-(3-methoxy-4-(pipei in-l-yl)pheayl)pyri idin-2-amiae;
• Step-l Synthesis of 6-(2, 5-dichloropyri idio-4-yi)-8-flaoro-4-isopropyl-3, 4- dihyd ro-2H- benxo j b
• Step-2 Synthesis tert-butyl 4-(4-((5-chioro-4-(8-fiuoro-4-isopropyl-3, 4-dihydro-
• reaction mixture was degassed with nitrogen gas for 30 min., followed by the addition of palladium acetate (2 rng, 0 006 mol, 0.02 equiv) and BINAP (8 mg. 0.012 mmol, 0.04 equiv).
• the resultant reaction mixture was allowed to stir at 100 °C for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (30 mi,) and extracted with ethyl acetate (100 ml,) Organic layer was washed with water (50 ml,) and brine solution (50 ml,).
• Step-3 Synthesis of 5-chloro-N-(3-fluoro-4-(piperazin-l-yi) pheny l)-4-( 8-fluoro- 4-isopropyI-3 > 4-dihy dro-2H-benzo b] [ 1 ,4] oxazin-6-y 1 ipyrini idm-2-amine:
• Example-31 Synthesis ofN ⁇ (2,5-difluoro ⁇ 4 ⁇ (piperazin ⁇ I-ylJpheriyl)-5 ⁇ fluoro-4-(8 ⁇ fluoro-4 ⁇ isoprop ⁇ 4 ⁇ 3, 4-dihydro-2H ⁇ benzofbffI > 4]oxazin ⁇ 6 ⁇ ylJpyrimidin ⁇ 2 ⁇ amine (Compound 31):
• Step-1 Synthesis of tert-butyi 4-(2,5-dif!uoro-4-nitrophenyI)piperaz.ine ⁇ l ⁇ carboxylate:
• Step-3 Synthesis of tert-butyl 4-(2,5-difluoro-4-((5-fluoro-4-(S ⁇ fluoro-4- isopropyI-3,4-dihydro-2H-benzo[b] [l,4]oxazin-6-yI)pyrimidin-2- yI)amino)phenyi)piperaz;ine-l-earboxylaie::
• Step-4 Synthesis of N- ⁇ S-difiuoro ⁇ ipiperazin-l-yl pfaenyO-S-fluoro ⁇ iS- fluoro ⁇ isopropyl-Syi-dihydro ⁇ II-benzojblJlyijoxazin-fi'-yOpyrimidin-l-amme:
• Example-32 Synthesis of 5-ftiioro-N-(3-jhioro-4-(piperazin- l-yl) phenyl)-4 ⁇ (8-jhioro-4- isopropyl-2-methyl-3,4-dihydro-2H-benzo[b [J4]oxazm ⁇ 6 ⁇ yl)pyrimidin ⁇ 2 ⁇ amine (Compound 32):
• Step-1 Synthesis of 2-araino-4-hromo-6-fl «orophenoi :
• reaction mass concentrated the reaction poured on tee-cold water (500 rnL) and was basified by 3N NaOH solution up to pH 10 and was extracted with ethyl acetate (350 ml, x 3), orga c layer was washed with water (150 ml, ⁇ and brine solution (150 ml, ⁇ .
• Organic layer dried over anhydrous sodium sulphate and concerttrated under reduced pressure to afford 2-ammo-4-bromo-6-iluorophenol (1 1 g ⁇ .
• Step-2 Synthesis of 4 ⁇ bromo-2-fiuoro-6-(i$epropyIaniim>)phem>I:
• Step-3 Synthesis of 6-bromo-8 ⁇ fluoro-4 ⁇ isopropyi-2- ethyi-2H- ben*o[b] [l,4]oxa*in-3(4H)-onet
• Step-4 Synthesis of 6-bromo-8-f!uoro-4-isopropyI-2-methyI-3,4-dihydro-2H- henzo [b] [ 1,4] oxazin e:
• Step-5 Synthesis of 8-fl «oro-4-isopropyl-2-methyl-6-(4,4,5,5-tetramethy!-l,3,2- dioxaboroian-2-yI)-3,4-dihydro-2H-henzo ⁇ b] [1 ,4]oxazi»e: To a stirred solution of 6-brorao-8- fluoro-4-isopropyl-2-rnethyl-3 4-dihydro-2H-benzo bl ] ,4]oxazine (200 mg, 0 7 mmol, 1 equiv) in dioxane (4 niL), was added 4,4,5,5-tetfainethyl-2-(4,4,5,5-tetramethyi ⁇ ] ,3,2-dioxaborolan-2- yl)-l,3.2-dioxaborolane 094 mg, 0 76 mmol, 1.1 equiv) and potassium
• Step-6 Synthesis of 6-(2-chloro-5-fluoropyrimidm-4-yl) ⁇ 8-fluoro-4 ⁇ isopropyi-2- methyl-3,4-dihydro-2H-benzo[b]jl,4[oxazme:
• reaction mixture was heated to 80 f for 4 h. 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, c 2), organic layer was washed with water (100 mL) and brine solution (100 mL).
• Step-7 Synthesis of iert-bidyl 4-(2-fluoro-4-((5-fluoro 4-(8-fluoro-4-isopropyi-2- raethyl-3,4-dihydro-2H-ben*o[b][l,4]oxazin-6-yl)pyr «midin-2-yl)amino)phenyl)pipera*me- l ⁇ carboxylate: To a solution of 6-(2-chioro-5-fiuoropyriinidin-4-yi)-8-fluofo-4-isopropyi-2-methyi-3, 4-dihydro-

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