Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • 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
  • 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
  • C07D471/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems

Definitions

• the invention is concerned with compounds and pharmaceutical compositions that degrade the proto-oncogene tyrosine-protein kinase receptor (RET), which may be either wild type RET or a mutant form of RET, via the ubiquitin proteasome pathway (UPP), methods of treating diseases and disorders associated with said RET protein and pathway using said compounds and pharmaceutical compositions, and methods of synthesizing said compounds and compositions.
• RET proto-oncogene tyrosine-protein kinase receptor
• UPP ubiquitin proteasome pathway
• the UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and the secretory pathway, the response to stress and extracellular modulators, ribosome biogenesis and viral infection.
• Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins.
• Cereblon forms part of an E3 ubiquitin ligase complex which interacts with damaged DNA binding protein 1, forming an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (known as RBX1) where it functions as a substrate receptor to select proteins for ubiquitination.
• the binding of lenalidomide to cereblon facilitates Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and degradation by the proteasome (see Lu, G. et al.
• RET germline missense and somatic mutations cause medullary thyroid cancer (MTC) and neuroendocrine tumors, whereas RET fusion proteins, overexpression, and copy number gains are present in a broad spectrum of additional cancers such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, lung adenocarcinomas, and breast cancer.
• additional cancers such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, lung adenocarcinomas, and breast cancer.
• a first aspect of the instant disclosure is generally directed to compounds of Formula I and pharmaceutically acceptable salts, solvates, isomers, enantiomers, and Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, tautomers described herein that include a Targeting Ligand that binds to RET, an E3 Ligase binding portion (typically via a cereblon subunit), and a Linker that covalently links the Targeting Ligand to the E3 Ligase binding portion.
• R1 is –OCH2CH3, –OCH3, –OCF3, –OCH2CH2OH, –OCH2CH2F, 1-methylpyrazol-4-yl, or halogen
• a 1 is independently aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 2 ; wherein R 2 is independently halogen, OH, C 1 -C 3 alkyl, or C1-C3 alkoxy
• B is a moiety that is capable of binding a E3 ligase
• L 4 is independently –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –C(O)
• Another aspect of the disclosure relates to a method of treating RET-mediated disorders and diseases in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or Formula II.
• Another aspect of the disclosure is directed to a method of modulating a RET protein. The method involves administering to a patient in need thereof an effective amount of a compound of Formula I or Formula II.
• the method of treating RET mediated disorders and diseases in a subject includes modulating RET protein in the subject.
• Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula I or Formula II and a pharmaceutically acceptable carrier.
• the pharmaceutically acceptable carrier can further include an excipient, diluent, or surfactant.
• the present invention also provides methods for the treatment of diseases or disorders by degrading RET the using the instant compounds of Formula I or Formula II and pharmaceutically acceptable composition of the compounds of Formula I or Formula II.
• the present invention also provides compounds of Formula I or Formula II that bind and inhibit to E3 ligase and further degrade the RET protein.
• the present technology also has the advantage of being able to be used for a number of different types of diseases, including disorder mediated by RET fusion proteins, overexpression, or copy number gains, such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, acute myeloid leukemia (AML), chronic myelomonocytic leukemia, lung adenocarcinomas, lung cancer, non-small cell lung cancer (NSCLC), nonsyndromic paraganglioma, breast cancer, nonhereditary (sporadic) cancers, colorectal, or a hematologic malignancy.
• diseases including disorder mediated by RET fusion proteins, overexpression, or copy number gains, such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, acute myeloid leukemia (AML), chronic myelomonocytic leukemia, lung adenocarcinomas, lung cancer, non-small cell lung cancer (NSCLC), nonsyndro
• the present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders and diseases in which RET is implicated, such as inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an RET- related disease in a subject that has been determined to carry a germline or somatic mutation in RET.
• disorders and diseases in which RET in which RET is implicated, such as inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease,
• Alkyl refers to optionally substituted, straight and branched chain aliphatic groups having from 1 to 30 carbon atoms.
• C1, C2, C3, C4, C5 or C6 alkyl” or “C1-C6 alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups.
• C1-C6 alkyl is intends to include C1, C2, C3, C4, C5 and C6 alkyl groups.
• alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n- pentyl, i-pentyl, or n-hexyl.
• a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
• heteroalkyl as used herein contemplates an alkyl with one or more heteroatoms.
• optionally substituted alkyl refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
• substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
• alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
• alkenyl includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
• a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain).
• C2-C6 includes alkenyl groups containing two to six carbon atoms.
• C3-C6 includes alkenyl groups containing three to six carbon atoms.
• optionally substituted alkenyl refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
• substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulf
• alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
• alkynyl includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups.
• a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain).
• C2-C6 includes alkynyl groups containing two to six carbon atoms.
• C3-C6 includes alkynyl groups containing three to six carbon atoms.
• C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups.
• C2-C6 alkenylene linker is intended to include C2, C3, C4, C5 and C6 alkenylene linker groups.
• optionally substituted alkynyl refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
• substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
• optionally substituted moieties include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
• substituted heterocycloalkyl Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.
• cyano refers to a nitrile radical (e.g., —CN).
• cycloalkyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8).
• cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
• cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
• polycyclic cycloalkyl only one of the rings in the cycloalkyl needs to be non- aromatic.
• heterocycloalkyl refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise.
• heteroatoms such as O, N, S, P, or Se
• heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-
• heterocycloalkyl In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7- tetrahydrobenzo[c]isoxazolyl).
• optionally substituted heterocycloalkyl refers to unsubstituted heterocycloalkyl having designated substituents replacing one or more hydrogen atoms on one or more carbon or heteroatom.
• substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
• aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
• the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, -halogen.
• the substituents can themselves be optionally substituted.
• the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring
• Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.
• heteroaryl means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C.
• Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B.
• Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, or B.
• the aromatic radical is optionally substituted independently with one or more substituents described herein.
• substituents described herein include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl,
• the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo.
• a fully unsaturated aromatic ring e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is
• a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein.
• exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-11H-isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyr
• the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino
• Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).
• a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring.
• substituent When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula.
• halo refers to fluoro, chloro, bromo and iodo.
• haloalkyl or haloalkoxyl refers to an alkyl or alkoxyl substituted with one or more halogen atoms.
• optionally substituted haloalkyl refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
• substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
• alkoxy or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.
• alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
• substituted alkoxy groups include halogenated alkoxy groups.
• the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, s
• halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.
• substituted means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound.
• a substituent is oxo or keto (i.e., ⁇ O)
• 2 hydrogen atoms on the atom are replaced.
• Keto substituents are not present on aromatic moieties.
• Ring double bonds as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C ⁇ C, C ⁇ N or N ⁇ N).
• “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a RM, and formulation into an efficacious therapeutic agent. [0043] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.
• compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
• methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
• the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
• synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used.
• any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models. [0049] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein.
• any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition.
• the treatment includes treatment of human or non-human animals including rodents and other disease models.
• the term “subject” is interchangeable with the term “subject in need thereof”, both of which refer to a subject having a disease or having an increased risk of developing the disease.
• a “subject” includes a mammal.
• the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
• the mammal is a human.
• a subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
• a subject in need thereof can also be one who is suffering from a Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, disease or disorder disclosed herein.
• a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
• a subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment).
• references to “treating” or “treatment” include the alleviation of established symptoms of a condition.
• “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
• a compound of the present disclosure can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
• the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
• one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques.
• compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
• the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
• the pharmaceutical composition is in bulk or in unit dosage form.
• the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
• the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
• active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
• the dosage will also depend on the route of administration.
• routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
• Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
• the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non- toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
• a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
• routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration.
• Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, gly
• the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
• the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
• a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
• a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
• the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
• compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
• suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
• the composition must be sterile and should be fluid to the extent that easy syringeability exists.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
• isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
• Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
• Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation.
• dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
• methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
• Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier.
• Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day.
• An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression.
• the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
• the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
• compositions include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
• the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
• a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
• an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
• the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.
• references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.
• the compounds, or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally.
• One skilled in the art will recognise the advantages of certain routes of administration.
• the dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated, the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
• An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
• An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition.
• Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co, Easton, Pa. (1995).
• the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
• suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, or organic solutions.
• the compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
• All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure.
• the present disclosure provides, inter alia, compounds of Formula and pharmaceutically acceptable salts, solvates, hydrates, isomers or tautomers thereof, wherein A, B, L1, L2, R1, X1, X2, and n are described herein as set forth in the disclosure.
• the disclosure relates to compounds of Formula I(a): wherein Het A is 4- to 6-membered heterocycloalky.
• the compounds of the disclosure are of Formula I(b): wherein Het A is 4- to 6-membered heterocycloalky.
• the compounds of the disclosure are of Formula I(c): I(c) wherein Het A is 4- to 6-membered heterocycloalky.
• the compounds of the disclosure are of Formula I(d): wherein Het A is 4- to 6-membered heterocycloalky.
• the compounds of the disclosure are of Formula I(e): wherein Het A is 4- to 6-membered heterocycloalky.
• the compounds of the disclosure are of Formula I(f): Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, wherein Het A is 4- to 6-membered heterocycloalky.
• the compounds of the disclosure are of Formula I(g): [0093] In other embodiments, the compounds of the disclosure are of Formula I(h): [0094] In other embodiments, the compounds of the disclosure are of Formula II: II. [0095] In some embodiments of the compounds of the disclosure, R 1 is halogen, – OCH2CH3, –OCF3, –OCH2CH2OH, or –OCH2CH2F. In some embodiments, R1 may be halogen, –OCH 2 CH 3 , –OCF 3 , or –OCH 2 CH 2 OH. In some embodiments, R 1 may be halogen, –OCH 2 CH 3 , or –OCF 3 .
• R 1 may be halogen or –OCH 2 CH 3 . In some embodiments, R1 is halogen. In some embodiments, R1 is –OCH2CH3. In some embodiments, R 1 is –OCF 3 . In some embodiments, R 1 is –OCH 2 CH 2 OH. In some embodiments, R 1 is –OCH 3 . In some embodiments, R 1 is 1-methyl-pyrazol-4-yl. [0096] In certain embodiments of the compounds of the disclosure, A is H, OH, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heteroaryl.
• A is OH, C1-C6 alkyl, C3- C 8 cycloalkyl, or aryl. In other embodiments, A is OH, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl. In other embodiments, A is OH or C1-C6 alkyl. In other embodiments, A is OH. In other embodiments, A is C1-C6 alkyl. In other embodiments, A is C3-C8 cycloalkyl. In other embodiments, A is aryl. In other embodiments, A is heteroaryl. In other embodiments, A is C 1 -C 6 alkyl optionally substituted with one or more R 2 .
• A is C 3 -C 8 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, cycloalkyl optionally substituted with one or more R2.
• A is aryl optionally substituted with one or more R2.
• A is heteroaryl optionally substituted with one or more R 2 .
• A1 is aryl, or heteroaryl.
• A is aryl optionally substituted with one or more R2.
• A is heteroaryl optionally substituted with one or more R 2 .
• R 2 is halogen, OH, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
• R2 is halogen.
• R2 is OH.
• R2 is C1-C3 alkyl.
• R2 is C1-C3 alkoxy.
• A is H.
• L 1 is a bond, –C 1 -C 3 alkylenyl–, –NHCO–, –CONH–, –O–, or –NH–.
• L1 may be –C1-C3 alkylenyl–, –NHCO–, –CONH–, or –O–. In further embodiments, L1 may be –C1-C3 alkylenyl–, –NHCO–, or –CONH–. In further embodiments, L 1 may be –C 1 -C 3 alkylenyl– or –NHCO–. In further embodiments, L1 may be –C1-C3 alkylenyl–. Yet in further embodiments, L1 may be –NHCO–. Yet in further embodiments, L1 may be –CONH–. Yet, in further embodiments, L 1 may be –O–.
• L 1 may be —NH–. Yet, in further embodiments, L 1 may be a bond.
• L2 is independently – (CH2)p–(4- to 12-heterocycloalkyl)–Y1–C(O)–Y2–.
• L 2 is –(CH 2 ) p –(4- to 12-heterocycloalkyl)–C(O)–Y 1 –Y 2 –.
• L2 is –(CH2)p–(4- to 12-heterocycloalkyl)–C(O)–Y1–C(O)- Y2–.
• L 2 is –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –Y 2 –.
• L2 is –(OCH2CH2)p–(4- to 12-heterocycloalkyl)–Y2–.
• L2 is –(CH2OCH2C(O))p–(4- to 12-heterocycloalkyl)–Y2– .
• L 2 is –(CH 2 OCH 2 C(O)NH) p –Y 2 –.
• L2 is –(CH2)p–(4- to 12-heterocycloalkyl)–Y1– (CH2CH2O)p–C(O)–Y2–.
• L 2 is –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 – (CH2CH2O)p–Y2–.
• L2 is –(CH2)p–(4- to 12-heterocycloalkyl)–Y1– (OCH 2 CH 2 ) p –Y 2 –.
• L2 is –(CH2)p–(4- to 12-heterocycloalkyl)–Y1– (OCH2CH2)p–C(O)–(OCH2CH2)p–Y2–.
• L 2 is –(CH 2 OCH 2 ) p –(heteroaryl)–Y 2 –.
• L2 is –NHC(O)–(4- to 12-heterocycloalkyl)–Y1-C(O)– Y2–.
• L 2 is –NHC(O)–(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 - C(O)–Y 2 –.
• L2 is –NHC(O)–(CH2)p–(4- to 12-heterocycloalkyl)–Y2–.
• L2 is –C(O)NH–Y1–Y2–.
• L 2 is –(CH 2 ) p –NH–Y 1 –Y 2 –.
• L2 is –C(O)NH–(CH2CH2O)p–Y2–.
• L2 is –(CH2OCH2)p–NR3C(O)–(CH2CH2O)p–Y2–.
• L 2 is –(CH 2 ) p –NR 3 C(O)–(CH 2 CH 2 O) p –Y 2 –.
• L2 is –(CH2OCH2CH2)p–(4- to 12-heterocycloalkyl)–Y1– C(O)–(CH2CH2O)p–Y2–.
• L 2 is –(CH 2 OCH 2 ) p –C(O)NH–(CH 2 CH 2 O) p –Y 2 –.
• L 3 is a bond, –C 1-8 alkylenyl, 4- to 12-membered heterocycloalkyl, –C3-C10 cycloalkyl, or –(4- to 8-membered heterocycloalkyl)–(CH2)m–.
• L3 is a bond.
• L3 is –C1-8 alkylenyl.
• L 3 is 4- to 8-membered heterocycloalkyl.
• L 3 is –C 3 -C 10 cycloalkyl. In some embodiments, L3 is –(4- to 8-membered heterocycloalkyl)–(CH2)m–. [00104] In certain embodiments of the compounds of the disclosure, L4 is –(CH2)p–(4- to 12-heterocycloalkyl)–Y 1 –C(O)–Y 2 –. [0119] In certain embodiments of the compounds of the disclosure, L4 is –(CH2)p–(4- to 12-heterocycloalkyl)–C(O)–Y1–Y2–.
• L 4 is –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –Y 2 –.
• R3 is –H or – C1-C3 alkyl.
• R3 is –H.
• R3 is –C1-C3 alkyl.
• Y1 is a bond, –C1-8 alkylenyl, 4- to 12- membered heterocycloalkyl, or –C3-C10 cycloalkyl.
• Y1 is a single bond. In other embodiments, Y 1 is C 1-8 alkylenyl. In other embodiments, Y 1 is 4- to 12- membered heterocycloalkyl. In other embodiments, Y1 is –C3-C10 cycloalkyl. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0123] In further embodiments of the compounds of the disclosure, Y2 may be a single bond. [0124] In a further embodiment of the disclosure, Y 2 is –C 1 -C 3 alkyl–. [0125] In yet another embodiment of the disclosure, Y2 is –(CH2)m–O–.
• Y2 is –O–(CH2)m–(4- to 6-membered heterocycloalkyl)–. [0127] In other embodiments of the disclosure, Y 2 is –(CH 2 ) m –O–(CH 2 ) m –NH–. [0128] In other embodiments of the disclosure, Y2 is –(CH2)m–NH–. [0129] In other embodiments of the disclosure, Y2 is –(CH2)m–NHC(O)–(CH2)mO–. [0130] In certain embodiments of the disclosure, Y 2 is –(CH 2 ) m –C(O)NH–(CH 2 ) m –.
• Y2 is –(CH2)m–C3-C10 cycloalkyl–. [0132] In certain embodiments of the disclosure, Y2 is –(CH2)m–aryl–. [0133] In certain embodiments of the disclosure, Y 2 is –(CH 2 ) m –heteroaryl–. [0134] In certain embodiments of the disclosure, Y2 is –(CH2)m–(4- to 6-membered heterocycloalkyl)–. [0135] In certain embodiments of the disclosure, Y 2 is –(CH 2 ) m –(4- to 6-membered heterocycloalkyl)–C(O)–.
• Y2 is –(CH2)m–(4- to 6-membered heterocycloalkyl)–C(O)–(CH2)m–.
• Y 2 is –(CH 2 ) m –(4- to 6-membered heterocycloalkyl)–C(O)–(CH2)m–O–.
• Y2 is –(CH2)m–C3-C10 cycloalkyl– C(O)NH–.
• Y2 is –(CH2)m–(4- to 6-membered heterocycloalkyl)–O–.
• X 1 is CH or N. In some embodiments, X 1 is CH. In some embodiments, X 1 is N.
• X2 is CH or N. In some embodiments, X2 is CH. In some embodiments, X2 is N.
• X 7 is O, S, NH, or a bond. In some embodiments, X7 is O. In some embodiments, X7 is S. In some embodiments, X7 is NH. In some embodiments, X7 is a bond.
• m is at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.
• m Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, is independently 0.
• m is independently 1.
• m is independently 2.
• m is independently 3.
• m is independently 4.
• m is independently 5.
• m is independently 6.
• m is independently 7.
• m is independently 8.
• m is independently 9.
• m is independently 10.
• m is independently 11.
• n is, independently at each occurrence, 0, 1, or 2. In yet other embodiments, n is 0 or 1. In yet other embodiments, n is 0 or 2. In yet other embodiments, n is 1 or 2. In yet other embodiments, n is 0. In yet other embodiments, n is 1. In yet other embodiments, n is 2. [0145] In further embodiments of the disclosure, p is, independently at each occurrence, 0, 1, 2, or 3. In yet other embodiments, p is 1 or 2.
• B represents a moiety that is capable of binding a E3 ligase.
• the E3 ligase binding portion B is of the structure: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, [0147] In other embodiments, the E3 ligase binding portion B is of the structure: , [0148] In other embodiments, E3 ligase binding portion B is cereblon subunit. In further embodiments, the cereblon subunit may be of the general structure: wherein X 3 , X 4 , X 5 , and X 6 are independently N or CH.
• the cereblon subunit may be of the general structure: Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, wherein X3, X4, X5, and X6 are independently N or CH.
• suitable compounds of the disclosure include: N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazine
• suitable compounds of the disclosure include: 6 ⁇ [1 ⁇ (3 ⁇ 4 ⁇ [2 ⁇ (2,6 ⁇ dioxopiperidin ⁇ 3 ⁇ yl) ⁇ 1 ⁇ oxo ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ isoindol ⁇ 5 ⁇ yl]piperazin ⁇ 1 ⁇ yl ⁇ propanoyl)piperidin ⁇ 4 ⁇ yl]methoxy ⁇ 4 ⁇ 6 ⁇ [(1R,5S) ⁇ 6 ⁇ [(6 ⁇ methoxypyridin ⁇ 3 ⁇ yl)methyl] ⁇ 3,6 ⁇ diazabicyclo[3.1.1]heptan ⁇ 3 ⁇ yl]pyridin ⁇ 3 ⁇ yl ⁇ pyrazolo[1,5 ⁇ a]pyridine ⁇ 3 ⁇ carbonitrile; 6 ⁇ [1 ⁇ (7 ⁇ 4 ⁇ [2 ⁇ (2,6 ⁇ dioxopiperidin ⁇ 3 ⁇ yl) ⁇ 1 ⁇ oxo ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ isoindol ⁇ 5 ⁇ yl]piperazin ⁇ 1 ⁇
• the compound is a pharmaceutically acceptable salt of any one of the compounds described herein.
• the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.
• the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
• the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
• the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
• the compound is an isotopic derivative of any one of the compounds described in Table 1.
• the isotopic derivative can be prepared using any of a variety of art-recognised techniques.
• the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• the isotopic derivative is a deuterium labeled compound.
• the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
• isotopic derivative refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled.
• an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I).
• the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S.
• the isotopic derivative is a deuterium labeled compound (i.e., being enriched Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, with 2 H with regard to one or more atoms thereof).
• the compound is a 18 F labeled compound.
• the compound is a 123 I labeled compound, a 124 I labeled compound, a 125 I labeled compound, a 129 I labeled compound, a 131 I labeled compound, a 135 I labeled compound, or any combination thereof.
• the compound is a 33 S labeled compound, a 34 S labeled compound, a 35 S labeled compound, a 36 S labeled compound, or any combination thereof.
• the 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and/or 36 S labeled compound can be prepared using any of a variety of art-recognised techniques.
• the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18 F, 125 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and/or 36 S labeled reagent for a non-isotope labeled reagent.
• a compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 S atom(s) is within the scope of the invention.
• substitution with isotope may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half- life or reduced dosage requirements.
• isotope e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and/or 36 S
• isotope e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and/or 36 S
• a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
• an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
• the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers.
• racemic mixture A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
• chiral center refers to a carbon atom bonded to four nonidentical substituents.
• chiral isomer means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre.
• Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre.
• the substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413. Cahn and Ingold, J. Chem Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).
• the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules. [0171] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers.
• tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism.
• keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
• Ring-chain tautomerism arises as a result of the aldehyde group (—CHO) in a sugar chain molecule reacting with one of the hydroxy groups (—OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
• —CHO aldehyde group
• —OH hydroxy groups
• stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
• enantiomers When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof.
• a mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
• the compounds of this disclosure may possess one or more asymmetric centres, such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, and mixtures, racemic or otherwise, thereof.
• a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.
• Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
• the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt.
• a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
• Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion.
• the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
• the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
• Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
• Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
• solvate means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.
• the solvent is water the solvate formed is a hydrate, and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.
• the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
• an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
• the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.
• certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms.
• a suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.
• Figure US11319319-20220503-C00141 The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, compound of the disclosure.
• a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
• a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached
• prodrugs include derivatives containing in vivo cleavable alkyl or acyl substitutents at the ester or amide group in any one of the Formulae disclosed herein.
• the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof.
• the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.
• a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
• Various forms of prodrug have been described, for example in the following documents a) Methods in Enzymology, Vol 42, p.309-396, edited by K.
• a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
• An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
• Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, phosphoramidic cyclic esters).
• ester forming groups for a hydroxy group include C1-C10, alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N—(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
• Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ⁇ - acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
• a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1—(C4 alkyl)2-amine such as dimethylamine, N- ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2- methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
• an amine such as ammonia
• a C1-4alkylamine such as methylamine
• a (C1—(C4 alkyl)2-amine such as dimethylamine, N- ethyl-N-methylamine or diethylamine
• a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
• Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
• Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4 alkyl)piperazin-1-ylmethyl.
• the in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).
• Methods of Use [0193]
• a compound described herein can be used in an effective amount to treat a patient, typically a human, in need thereof, who have a disorder mediated by RET which can be a wild-type RET or mutant RET as described generally herein.
• compound of the present invention degrades an additional protein, for example an aurora kinase or VEGFR2.
• a compound of the present invention degrades RET and aurora A kinase (AURKA).
• Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating or preventing cancer in a patient in need thereof; wherein there is a need of RET inhibition for the treatment or prevention of cancer.
• the method comprises administering an effective amount of the active compound or its salt as described herein, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of agents, to a patient in need thereof.
• the present invention provides a method of treating any of the disorders described herein, in a patient in need thereof.
• the patient is administered an additional therapeutic agent.
• the compound as described herein, and the additional therapeutic agent are administered simultaneously or sequentially.
• the application provides a method of preventing any of the disorders described herein, in a patient in need thereof.
• the patient is a human.
• Another aspect of the present invention provides a method of treating or preventing a proliferative disease.
• the method comprises administering an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof and optionally a pharmaceutically acceptable carrier to a patient in need thereof.
• the disease is mediated by RET, for example, RET plays a role in the initiation or development of the disease.
• the RET mediated disorder is a benign growth, metastasis, neoplasm, tumor, solid tumor, rhabdoid tumor, carcinoma, leukemia, cancer, abnormal cellular proliferation, an amyloid-based proteinopathy, a proteinopathy, fibrotic disorder, inflammation, arthritis, pulmonary disorders, or immune disorders.
• the RET mediated disorder is a cancer that has metastasized, for example a cancer that has metastasized to the brain.
• the RET mediated disorder is a cancer that has metastasized to the brain, lungs bone, liver, peritoneum, adrenal gland, skin, or muscle.
• a compound of the present invention penetrates the blood brain barrier and can be used for the treatment of a CNS involved cancer or a cancer that has metastasized to the brain.
• the disease or disorder is cancer or a proliferation disease.
• the RET mediated disorder is an abnormal cell proliferation, including, but not limited to, a tumor or cancer, or a myelo- or lymphoproliferative disorder such as B- or T-cell lymphomas, multiple myeloma, Waldenstrom’s macroglobulinemia, Wiskott- Aldrich syndrome, or a post-transplant lymphoproliferative disorder.
• a myelo- or lymphoproliferative disorder such as B- or T-cell lymphomas, multiple myeloma, Waldenstrom’s macroglobulinemia, Wiskott- Aldrich syndrome, or a post-transplant lymphoproliferative disorder.
• the hematological cancer is acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy-cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, B
• Solid tumors that can be treated with the compounds described herein include, but are not limited to lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancers including inflammatory breast cancer, ER-positive breast cancer including tamoxifen resistant ER-positive breast cancer, and triple negative breast cancer, colon cancers, midline carcinomas, liver cancers, renal cancers, prostate cancers including castrate resistant prostate cancer (CRPC), brain cancers including gliomas, glioblastomas, neuroblastoma, and medulloblastoma including MYC-amplified medulloblastoma, colorectal cancers, Wilm’s tumor, Ewing’s sarcoma, rhabdomyosarcomas, ependymomas, head and neck cancers, melanomas, squamous cell carcinomas, ovarian Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PC
• the disease or disorder is sarcoma of the bones, muscles, tendons, cartilage, nerves, fat, or blood vessels. [0210] In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma.
• the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi’s sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, Pleomorphic sarcoma, chondrosarcoma, Ewing’s sarcoma, reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.
• the disease or disorder is multiple myeloma.
• the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyiarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn’s disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, autoimmune disease, graft vs.
• COPD chronic obstructive pulmonary disease
• cancer leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, disorders, central nervous system
• the pharmaceutical composition comprising the compound as described herein and the additional therapeutic agent are administered simultaneously or sequentially.
• the disease or disorder is cancer.
• the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, solid tumors, hematological cancers or solid cancers.
• said method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically-mediated diseases.
• said condition is selected from a proliferative disorder.
• the RET mediated disorder is an immune disorder, including but not limited to, autoimmune disorders such as Addison disease, Celiac disease, dermatomyositis, Graves disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes.
• autoimmune disorders such as Addison disease, Celiac disease, dermatomyositis, Graves disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes.
• Such diseases include, but are not limited to, a proliferative or hyperproliferative disease.
• proliferative and hyperproliferative diseases include, without limitation, cancer.
• the term “cancer” includes, but is not limited to, the following cancers: breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin’s, hair
• cancer includes, but is not limited to, the following cancers: myeloma, lymphoma, or a cancer selected from gastric, renal, or and Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, the following cancers: head and neck, oropharangeal, non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, and pulmonary.
• NSCLC non-small cell lung cancer
• cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like.
• cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T- cell lymphomas, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin’s lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma.
• CCL cutaneous T-cell lymphomas
• myelodisplastic syndrome childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms’ tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as head and neck cancers, such as oral, laryngeal, nasopharyngeal and esophageal, genitourinary cancers, such as prostate, bladder, renal, uterine, ovarian, testicular, lung cancer, such as small-cell and non-small cell, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin’s syndrome, such as medulloblastoma or meningioma, and liver cancer.
• childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms’ tumor, bone tumors, and soft-tissue sarcomas
• common solid tumors of adults
• Additional exemplary forms of cancer include, but are not limited to, cancer of skeletal or smooth muscle, stomach cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.
• Additional cancers that the compounds described herein may be useful in preventing, treating and studying are, for example, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma.
• cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniophary
• the present application provides for the use of one or more compound as described herein, in the manufacture of a medicament for the treatment of cancer, including without limitation the various types of cancer disclosed herein.
• the compounds of this application are useful for treating cancer, such as colorectal, thyroid, breast, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease.
• cancer such as colorectal, thyroid, breast, and lung cancer
• myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hyper
• the compound as described herein is useful for treating hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), chronic- myelogenous leukemia (CML), acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL).
• AML acute-myelogenous leukemia
• CML chronic- myelogenous leukemia
• ALL acute-promyelocytic leukemia
• ALL acute lymphocytic leukemia
• a compound or its corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a host, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality.
• a compound as described herein can be administered to a host suffering from a Hodgkin’s Lymphoma or a Non-Hodgkin’s Lymphoma.
• the host can be suffering from a Non-Hodgkin’s Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK- Cell Lymphoma; Burkitt’s Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); diffuse small-cleaved cell lymphoma (DSCCL); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic
• a compound or its corresponding pharmaceutically acceptable salt, or isotopic derivative, as described herein can be used in an effective amount to treat a patient, for example a human, with a Hodgkin’s lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin’s Lymphoma (CHL); Mixed Cellularity CHL; Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin’s Lymphoma; or Nodular Lymphocyte Predominant HL.
• CHL Nodular Sclerosis Classical Hodgkin’s Lymphoma
• BMS 14240-WO-PCT, Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin’s Lymphoma; or Nodular Lymphocyte Predominant HL.
• This application further embraces the treatment or prevention of cell proliferative disorders such as hyperplasias, dysplasias and pre-cancerous lesions.
• Dysplasia is the earliest form of pre- cancerous lesion recognizable in a biopsy by a pathologist.
• the compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pre-cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue.
• a compound of the present invention is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a mutation, wherein the mutation is at one of the below listed amino acid sites.
• the mutation may, for example, be selected from one of the listed exemplary mutations, or may be a different mutation.
• the RET protein has two mutations selected from the table above. In other embodiments the RET protein has three mutations selected from the table Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, above. In other embodiments the RET protein has four or more mutations, which may optionally be selected from the table above.
• the tumor or cancer has a mutation in a RET protein that is a substantial or partial driver of tumor of cancer cell proliferation.
• the tumor or cancer has a RET altered protein that is not acting significantly as a driver of abnormal cell proliferation but can be used therapeutically to kill the tumor cell using a selected RET degrader as described herein.
• a compound of the present invention is used to treat a tumor or cancer with a RET protein V804L mutation.
• a compound of the present invention is used to treat a tumor or cancer with a RET protein V804M mutation.
• a compound of the present invention is used to treat a tumor or cancer with a RET protein M918T mutation.
• a compound of the present invention is used to treat a tumor or cancer with a RET protein S891 A mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein L790F mutation. In certain embodiments, a compound of the present invention is used treat a tumor or cancer with a RET protein E768D mutation. In certain embodiments, a compound of the present invention is used treat a tumor or cancer with a RET protein C618S mutation. In certain embodiments, a compound of the present invention is used treat a tumor or cancer with a RET protein C618R mutation.
• a compound of the present invention is used to treat a tumor or cancer with a RET protein 634 missense. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C634R mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C634Y mutation. In certain embodiments, a compound of the present invention is used to treat a tumor or cancer with a RET protein C634G mutation. In certain embodiments a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a G810R mutation.
• a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a G810S mutation.
• a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a G810C mutation.
• a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a C634W mutation.
• a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a M918T mutation.
• a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a V804L mutation.
• a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein with a V804M mutation.
• a compound of the present invention is used to treat an abnormal cell proliferation such as a tumor or cancer that has a RET protein fused to another protein, for example a fusion selected from CCDC6-RET, NCOA4-RET, KIF5B-RET, PRKAR1A-RET, TRIM24-RET, TRIM33-RET, GOLGA5-RET, HOOK3-RET, KTN1-RET, ERC1-RET, MBD1-RET, TRIM27-RET, BRC-RET, FGFR10P-RET, PCM1-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, CUX1-RET, KIAA1468-RET, and KIAA1217-RET.
• a fusion selected from CCDC6-RET, NCOA4-RET, KIF5B-RET, PRKAR1A-RET, TRIM24-RET, TRIM33-RET, GOLGA5-RET,
• a compound of the present invention, or a pharmaceutically acceptable salt thereof is used to treat an abnormal cell proliferation such as a tumor or cancer that has a CCDC6-RET fusion. In certain embodiments a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a NCOA4-RET fusion. [0235] In certain embodiments a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat an abnormal cell proliferation such as a tumor or cancer that has a KIF5B-RET fusion.
• the present application further provides a method for preventing or treating any of the diseases or disorders described above in a patient in need of such treatment, which method comprises administering to said patient a therapeutically effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof.
• a therapeutically effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, or solvate thereof for any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
• a compound of Formula I or a pharmaceutically acceptable salt thereof can be used in an effective amount, either alone or in combination, to treat a patient such as a human with a disorder as described herein or a RET mediated disorder.
• the disclosed compounds described herein can be used in an effective amount alone or in combination with another compound of the present invention or another bioactive agent or second therapeutic agent to treat a patient such as a human with a disorder, including but not limited to those described herein.
• bioactive agent is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy.
• the compound of the present invention and the bioactive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or other pharmacokinetic parameter.
• the compound of the present invention and the bioactive agent are administered to a patient in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other.
• the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor.
• a checkpoint inhibitor including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor.
• VISTA V-domain Ig suppressor of T-cell activation
• the immune modulator is an antibody, such as a monoclonal antibody.
• LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics).
• BMS-986016 Bristol-Myers Squibb
• GSK2831781 GaxoSmithKline
• IMP321 Primary BioMed
• LAG525 Novartis
• MGD013 MicroGenics
• An example of a TIM-3 inhibitor is TSR- 022 (Tesaro).
• the checkpoint inhibitor is selected from nivolumab/OPDIVO®; pembrolizumab/KEYTRUDA®; and pidilizumab/CT-011, MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559, a PDL2/lg fusion protein such as AMP 224 or an inhibitor of B7- H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof.
• B7- H3 e.g., MGA271
• B7-H4 BTLA
• HVEM TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7
• one of the active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including, but not limited to, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist.
• Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
• fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen- resistant tumors.
• anti-estrogen compounds are provided in WO 2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO 2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos.9,078,871, 8,853,423, and 8,703, 810, as well as US 2015/0005286, WO 2014/205136, and WO 2014/205138.
• anti-estrogen compounds include: SERMS such as anordrin, ciprofene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate,
• SERMS
• an active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including, but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist.
• an androgen (such as testosterone) inhibitor including, but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist.
• the prostate or testicular cancer is androgen-resistant.
• anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos.8,455,534 and 8,299,112.
• anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
• the bioactive agent is an ALK inhibitor.
• ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP- TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.
• the bioactive agent is an EGFR inhibitor.
• EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273), josartinib (EGF816), PF- 06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD- 019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; P
• the bioactive agent is an HER-2 inhibitor.
• HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.
• the bioactive agent is a CD20 inhibitor.
• CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.
• the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.
• the bioactive agent is a BCL-2 inhibitor.
• BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Chlorophenyl)-4,4-dimethylcyclohex-1-en- 1-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4- [[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5- yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4- [[(2R)-4-(dimethylamino)-1- phenylsulfanylbutan-2-yl] amino]-3- nitrophenyl]
• the bioactive agent is a kinase inhibitor.
• the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
• PI3K phosphoinositide 3-kinase
• BTK Bruton’s tyrosine kinase
• Syk spleen tyrosine kinase
• PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS- 136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-Isopropyl- 5-methyl- 1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2- methylpropanamide), MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)- methylphosphonate; or Methyl(oxo) ⁇ [(2R)-l-phenoxy-2-butanyl]oxy ⁇
• BTK inhibitors examples include ibrutinib (also known as PCI- 32765)(ImbruvicaTM)(1- [(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidin-1-yl]prop-2-en- 1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5- fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)- 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2- methyl
• Syk inhibitors include, but are not limited to, Cerdulatinib (4-(cyclopropylamino)-2-((4- (4-(ethylsulfonyl)piperazin-1- yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H- indazol-6-yl)-N-(4- morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-( ⁇ 5- Fluoro-2-[(3,4,5- trimethoxyphenyl)amino]-4-pyrimidinyl ⁇ amino)-2,2-dimethyl-3-oxo-2,3- dihydro-4H- pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((
• the bioactive agent is a MEK inhibitor.
• MEK inhibitors are well known, and include, for example, trametinib/GSKl120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-l(2H- yl ⁇ phenyl)acetamide), selumetinib (6-(4-bromo-2- chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)- 3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC 1935369
• the bioactive agent is a Raf inhibitor.
• Raf inhibitors include, for example, Vemurafinib (N-[3-[[5- (4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3- yl]carbonyl]-2,4-difluorophenyl]-1- propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4- methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo- 3,4- dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1- methyl-6- (pyridin
• the bioactive agent is an AKT inhibitor, including, but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, a FLT-3 inhibitor, including, but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof.
• the bioactive agent is an mTOR inhibitor.
• mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus.
• MEK inhibitors include but are not limited to tametinib/GSKl120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, yl ⁇ phenyl)acetamide), selumetinob (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2- hydroxyethoxy)- 3-methylbenzimidazole
• the bioactive agent is a RAS inhibitor.
• RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
• the bioactive agent is a HSP inhibitor.
• HSP inhibitors include but are not limited to Geldanamycin or 17-N- Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
• Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN- 101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- 142886), AMN- 107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK- 0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase (mek) inhibitor, a VEGF trap antibody, pemetre
• the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoi
• the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent.
• Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds.
• General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosul
• chemotherapeutic agents include, but are not limited to 1- dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, ca
• the compound of the present invention is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer).
• chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
• 5 -fluorouracil 5-FU
• leucovorin Attorney Docket No: 055920-567001WO
• BMS: 14240-WO-PCT BMS: 14240-WO-PCT
• LV irenotecan
• oxaliplatin oxaliplatin
• capecitabine paclitaxel
• doxetaxel doxetaxel
• Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duo
• dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epi
• Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the compound of the present invention.
• Suitable dosing regimens of combination chemotherapies are known in the ar. For example combination dosing regimes are described in Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a (1999) and Douillard et al., Lancet 355(9209): 1041 -1047 (2000).
• Additional therapeutic agents that can be administered in combination with a Compound disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib
• the additional therapy is a monoclonal antibody (MAb).
• MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may “coat” the cancer cell surface, triggering its destruction by the immune system.
• bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels.
• VEGF vascular endothelial growth factor
• the bioactive agent is an immunosuppressive agent.
• the immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.
• Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus- 9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g.
• a prodrug thereof e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), inflixima
• the bioactive agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment.
• a biologic such as interferon or an interleukin (e.g., IL-2)
• the biologic is an anti-angiogenic agent, such as an anti- Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, VEGF agent, e.g., bevacizumab (AVASTIN®).
• the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer.
• a monoclonal antibody e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof
• agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer.
• Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-l- 131 ); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tocilizumab); VECTIBIX® (pan
• the combination therapy may include a therapeutic agent which is a non-drug treatment.
• the compound could be administered in addition to radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.
• the first and second therapeutic agents are administered simultaneously or sequentially, in either order.
• the first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.
• the second therapeutic agent is administered on a different dosage schedule than the compound of the present invention.
• the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.
• the first therapeutic agent has a treatment holiday.
• the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.
• both the first and second therapeutic have a treatment holiday.
• a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII, or its pharmaceutically acceptable salt thereof, as described herein can be administered as the neat chemical, but is more typically administered as a pharmaceutical composition, that includes an effective amount for a patient, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective amount of compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein.
• the pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent.
• compositions of the disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
• One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.
• the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
• Examples are dosage forms with at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.
• the patient can be treated with low dosage therapy with a compound of the present invention.
• the pharmaceutical composition can be in a dosage form that contains from about 0.1 ⁇ g to about 2000 ⁇ g, from about 10 ⁇ g to about 1000 ⁇ g, from about 100 ⁇ g to about 800 ⁇ g, or from about 200 ⁇ g to about 600 ⁇ g of the active compound.
• dosage forms with at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 ⁇ g of active compound, or its salt.
• the dose ranges from about 0.01-100 mg/kg of patient body weight, for example at least about 0.01 mg/kg, at least about 0.05 mg/kg, at least about 0.1 mg/kg, at least about 0.5 mg/kg, at least about 1 mg/kg, at least about 1.5 mg/kg, at least about 2 mg/kg, at least about 2.5 mg/kg, at least about 3 mg/kg, at least about 3.5 mg/kg, at least about 4 mg/kg, at least about 4.5 mg/kg, at least about 5 mg/kg, at least about 10 mg/kg, at least about 15 mg/kg, at least about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg, at least about 35 mg/kg, at least about 40 mg/kg, at least about 45 mg/kg, at least about 50 mg/kg, at least about 55 mg/kg, at least about 60 mg/kg, at least
• a pharmaceutically or therapeutically effective amount of the composition will be delivered to the patient.
• the precise effective amount will vary from patient to patient, and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration.
• the effective amount for a given situation can be determined by routine experimentation.
• a therapeutic amount may for example be in the range of about 0.01 mg/kg to about 250 mg/kg body weight, more typically about 0.1 mg/kg to about 10 mg/kg, in at least one dose.
• compositions can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
• compounds disclosed herein or used as described are administered once a day (QD), twice a day (BID), or three times a day (TID).
• compounds disclosed herein or used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer.
• the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day. In certain embodiments the compound of the present invention is administered orally once a day. In certain embodiments the compound of the present invention is administered orally twice a day. In certain embodiments the compound of the present invention is administered orally three times a day. In certain embodiments the compound of the present invention is administered orally four times a day. [0248] In certain embodiments the compound of the present invention is administered intravenously once a day. In certain embodiments the compound of the present invention is administered intravenously twice a day.
• the compound of the present invention is administered intravenously three times a day. In certain embodiments the compound of the present invention is administered intravenously four times a day. [0249] In some embodiments the compound of the present invention is administered with a treatment holiday in between treatment cycles. For example, the compound may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. [0250] The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent.
• the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an anti-inflammatory or immunosuppressing agent.
• these compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt. %) of the compound and usually at least about 5 wt. % of the compound. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound.
• the pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. [0253] In certain embodiments the compound is administered as a pharmaceutically acceptable salt.
• Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesul
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
• composition of the disclosure can be administered as a pharmaceutical formulation including one suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers.
• a typical manner of administration is oral, topical or intravenous, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
• the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
• solid, semi-solid or liquid dosage forms such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrup, suspensions, creams, ointments, lotions, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, a transdermal patch, a subcutaneous patch, an inhalation formulation, in a medical device,
• compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
• Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
• the carrier Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, can be inert or it can possess pharmaceutical benefits of its own.
• the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
• Classes of carriers include, but are not limited to adjuvants, binders, buffering agents, coloring agents, diluents, disintegrants, excipients, emulsifiers, flavorants, gels, glidents, lubricants, preservatives, stabilizers, surfactants, solubilizer, tableting agents, wetting agents or solidifying material.
• Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
• Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers and vegetable oils.
• Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
• Some excipients include, but are not limited, to liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.
• the compound can be provided, for example, in the form of a solid, a liquid, spray dried material, a microparticle, nanoparticle, controlled release system, etc., as desired according to the goal of the therapy.
• Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles.
• a biological buffer can be any solution which is pharmacologically acceptable, and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range.
• buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.
• conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
• Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
• an excipient such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
• the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, triethanolamine sodium acetate, triethanolamine oleate, and the like.
• auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, triethanolamine sodium acetate, triethanolamine oleate, and the like.
• wetting or emulsifying agents for example, sodium acetate, sorbitan monolaurate, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, triethanolamine sodium acetate, tri
• permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
• the pharmaceutical compositions/combinations can be formulated for oral administration.
• the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
• the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
• suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
• the active agent can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well.
• suitable inert carrier such as ethanol, glycerol, water, and the like
• flavoring, coloring and/or sweetening agents can be added as well.
• Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
• the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.
• Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
• sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
• the sterile injectable formulation can also be a sterile injectable solution or a suspension in an acceptably nontoxic parenterally acceptable diluent or solvent.
• acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
• sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
• parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
• Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
• Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
• a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
• Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
• non- aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
• Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
• Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, the other ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• sterile powders for the preparation of sterile injectable solutions typical methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
• a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
• the pharmaceutical compositions of the disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
• suppositories for rectal administration.
• suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
• suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
• Such materials include cocoa butter, beeswax and polyethylene glycols.
• the pharmaceutical compositions of the disclosure can also be administered by nasal aerosol or inhalation.
• compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
• Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art.
• the compounds of the disclosure can also be delivered through the skin or muscosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface.
• the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer.
• the laminated device can contain a single reservoir, or it can contain multiple reservoirs.
• the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
• suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
• the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or it can be a liquid or gel reservoir, or can take some other form.
• the backing layer in these laminates which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility.
• compositions of the disclosure can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
• the compound may, for example generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization.
• the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, tri chlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• CFC chlorofluorocarbon
• the aerosol can conveniently also contain a surfactant such as lecithin.
• the dose of drug can be controlled by a metered valve.
• the active ingredients can be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
• the powder carrier will form a gel in the nasal cavity.
• the powder composition can be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder can be administered by means of an inhaler.
• Formulations suitable for rectal administration are typically presented as unit dose suppositories.
• the pharmaceutical composition is suitable for topical application to the skin using a mode of administration and defined above.
• the pharmaceutical composition is suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
• microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin.
• the microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
• Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI).
• DPI dry powder inhalers
• the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
• nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.
• Synthetic Methodology [0271] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
• Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M.
• Method B Column: XBridge C18, 2.1 mm x 50 mm, 1.7 ⁇ m particles; Mobile Phase A: ACN/H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN/H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL/min; Detection: UV (220 nm) and MS (ESI +).
• Method P Mode: Binary gradient, Pump A: LC ⁇ 20ADXR, Pump B: LC ⁇ 20ADXR, Total Flow: 1.5000 mL/min, B Conc.: 30.0 %, Oven Temperature: 40 °C, PDA Model: SPD ⁇ M20A, Lamp: D2, Start Wavelength: 190 nm, End Wavelength: 400 nm, Column Name: XBridge BEH Shield RP18, Length: 30 mm, Internal Diameter: 4.6 mm, Description: 2.5 um particles, Mobile Phase A: Water/5mM NH4HCO3, Mobile Phase B: Acetonitrile; Acquisition Mode: Scan, Polarity: Positive.
• Method Q Mode: Binary gradient, Pump A: LC ⁇ 40D XR, Pump B: LC ⁇ 40D XR; Oven Temperature: 40 oC; PDA Model: SPD ⁇ M20A, Lamp: D2, Start Wavelength: 190 nm, Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, End Wavelength: 400 nm; Column Name: ACE Excel 2C18, Length: 30 mm, Internal Diameter: 3.0 mm, Column Particle Size: 2.0 um, Mobile phase A: Water + 0.05% TFA, Mobile phase B: Acetonitrile + 0.05% TFA, Start Time: 0.00 min, End Time: 3.00 min, Acquisition Mode: Scan, Polarity: Positive; LCMS5: Waters Acquity BEH C182.1 x 50 mm 1.7 ⁇ m particles; Mobile Phase A: 95:5 water: acetonitrile with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile: water with
• reaction mixture was stirred and allowed to slowly warm to room temperature overnight. After 22 hours, the reaction mixture was diluted with EtOAc then transferred to a separatory funnel where it was carefully washed with slow addition of 10% aqueous citric acid solution (ca.10 mL). The organic layer was washed with water then brine before being dried (anhydrous Na2SO4), filtered and concentrated in vacuo to afford a pale-yellow solid (1.15 g, 78%) which was used without further purification.
• Example 3
• Example 8 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-3-methylbutanamide [0319] The title compound was prepared in 18% yield as a white solid according to the preparation of Example 4 using N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)-3-methylbutanamide in STEP C.
• Example 9 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)cyclopropanecarboxamide [0320] The title compound was prepared in 15% yield as a white solid according to the preparation of Example 4 (using N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4- yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)cyclopropane
• Example 10 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide
• the title compound was prepared in 30% overall yield as a white solid according to the preparation of Example 5 using 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine- 2,6-dione in STEP C.
• Example 14 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide
• BMS 14240-WO-PCT, [0325] The title compound was prepared in 12.2% overall yield as a white solid according to the preparation of Example 6 using tert-butyl 4-oxobutanoate in STEP B.
• Prep- HPLC purification condition Column: Phen Axia C185 ⁇ 30x100mm; Flow rate: 40mL/min Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, flow rate; Mobile Phase A: 95%H2O / 5%MeCN with 0.01M NH4OAc. Mobile Phase B: 5%H2O / 95%MeCN with 0.01M NH4OAc; Gradient: 20-80%B (40 min); Elution: 20.8 – 22.8 minutes; Number of runs: 2.
• Prep-HPLC purification condition Column: Phen Axia C185 ⁇ 30x100mm; Flow rate: 40mL/min flow rate; Mobile Phase A: 95%H2O / 5%MeCN with 0.01M NH4OAc. Mobile Phase B: 5%H2O / 95%MeCN with 0.01M NH4OAc; Gradient: 10-100%B (40 min); Elution: 25.5 – 27.1 minutes; Number of runs: 3. Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, Example 17.
• Prep-HPLC purification condition Column: Phen Axia C185 ⁇ 30x100mm; Flow rate: 40mL/min flow rate; Mobile Phase A: 95%H2O / 5%MeCN with 0.01M NH4OAc. Mobile Phase B: 5%H2O / 95%MeCN with 0.01M NH4OAc; Gradient: 10- 100%B (40 min); Elution: 20.1 – 24.5 minutes; Number of runs: 5.
• Prep-HPLC purification condition Column: Phen Axia C185 ⁇ 30x100mm; Flow rate: 40mL/min flow rate; Mobile Phase A: 95%H2O / 5%MeCN with 0.01M NH4OAc. Mobile Phase B: 5%H2O / 95%MeCN with 0.01M NH4OAc; Gradient: 20-100%B (40 min); Elution: 23.7 – 25.5 minutes; Number of runs: 5.
• Example 34 N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]propanoyl]piperazin-1- yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide [0344] The title compound was prepared in 10.81% overall yield as a white solid according to the preparation of Example 32 using 3-(1-oxo-5-piperazin-1-yl-isoindolin-2- yl)piperidine-2,6-dione in STEP A.
• Benzyl 4-[2-(1,3-dioxolan-2-yl)ethyl] piperazine-1-carboxylate To a solution of benzyl piperazine-1-carboxylate (1000 mg, 4.54 mmol) and 2-(2-bromoethyl)-1,3- dioxolane (822 mg, 4.54 mmol) in DMF (20 mL) was added DIEA (1757 mg, 13.62 mmol), the mixture solution was stirred at 50 °C for overnight. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried, concentrated to afford the desired product (1200 mg, 81.2% yield), which was used in the next step without further purification.
• Example 39
• Example 44
• tert-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)acetate To a solution of 1-[1-methyl-6-(4-piperidyl)indazol-3- yl]hexahydropyrimidine-2,4-dione (60 mg, 0.18 mmol), tert-butyl 2-oxoacetate (47.7 mg, 0.37 mmol) in DCM (10 mL) were added DIEA (0.03 mL, 0.37 mmol), and AcOH (0.02 mL, 0.37 mmol).
• Example 48
• Example 50
• N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2- pyridyl]-4-piperidyl]-2-piperazin-1-yl-acetamide Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, The title compound was prepared in 44.7% overall yield as a white solid according to the preparation of N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]- 4-piperidyl]piperidine-4-carboxamide (Example 52.B) using 2-(4-tert- butoxycarbonylpiperazin-1-yl)acetic acid in STEP A.
• Example 54
• Example 55
• Example 56
• Example 59
• Tert-butyl 4-(3-(4-(tert-butoxy)-1-cyano-4-oxobutyl)phenyl)piperazine-1- carboxylate To a 100 mL round bottle flask, tert-butyl 4-(3-bromophenyl)-4-cyano- butanoate (1.24 g, 3.82 mmol), tert-butyl piperazine-1-carboxylate (854.82 mg, 4.59 mmol), Pd2(dba)3 (174.98 mg, 0.19 mmol), Xphos (127.71 mg, 0.27 mmol) and Cs2CO3 (2.49 g, 7.65 mmol) were suspended in 1,4-Dioxane (30 mL).
• Example 62 N-[1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4- ⁇ [4-(1- ⁇ 2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl ⁇ azetidin-3-yl)piperazin- 1-yl]methyl ⁇ piperidin-4-yl]-2,5-difluorobenzamide N-[1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4-[(4- ⁇ 1-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]azetidin-3- yl
• Example 82 (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1- yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide and Example 81 (S)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2- (2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin
• Example 82 Concentration of the appropriate (earlier eluting) fractions afforded Example 82 (16.5 mg) assigned as (R)-N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2- yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1- yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide (Enantiomer 1).
• Example 81 (20.9 mg) assigned as (S)-N-(1-(5-(3-cyano-6- ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)-piperazin-1-yl)methyl)piperidin-4-yl)-2,5- difluorobenzamide (Enantiomer 2).
• Examples 84-99 were prepared using procedures similar to the ones described in the aforementioned examples.
• Example 84 Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, 6-(4- ⁇ [1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4-(2,5- difluorobenzamido)piperidin-4-yl]methyl ⁇ piperazine-1-carbonyl)-N-[3-(2,4-dioxo-1,3- diazinan-1-yl)-1-methyl-1H-indazol-6-yl]spiro[3.3]heptane-2-carboxamide
• Example 85 N-[1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4- ⁇ [4-(6- ⁇ 4-[2-
• Example 100 N-[1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4-( ⁇ 4-[2-(3- ⁇ 4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl ⁇ -3- oxopropoxy)ethyl]piperazin-1-yl ⁇ methyl)piperidin-4-yl]-2,5-difluorobenzamide
• Example 101 N-[1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4-( ⁇ 4-[2-(3- ⁇ 4-[2- (2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-iso
• Example 106 N-[1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4-[(4- ⁇ 2-[2-(2,6- dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl ⁇ piperazin-1- yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide
• Example 107 N-[1-(5- ⁇ 3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl ⁇ pyridin-2-yl)-4- ⁇ [4-(2- ⁇ [2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindo
• Treated cell plates were placed in an incubator at 37 0C and 5% CO2 for 24 hrs.
• cell media was removed by a FELIX automated liquid hander Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, (Analytik Jena) and 25ul of cell lysis buffer (provided in AlphaLisa kit) was added to each well.
• 5ul cell lysate were transferred into a 384-well microplate (Perkin Elmer) before addition of 2.5ul AlphaLISA Acceptor Bead mix.
• the plates were sealed and kept at room temperature for 1hr before addition of donor bead mixture.
• DC 50 (IC50) values for each compound tested are calculated by analyzing plots of % degradation versus compound concentration, and fitting to the standard 4-parameter logistic curve where, % ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ + [ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ] ⁇ ( ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ) ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ +[ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ] ⁇ .
• the half-maximal degradation concentration (DC 50 ) and % degradation response (Ymax) are included in Table 2. All of the compounds in Table 2 were shown to have a DC50 ⁇ 1 ⁇ M and Ymax >60%, with some compounds having a DC50 value D: DC50 ⁇ 2 nM, some a DC50 value C: 2 nM ⁇ DC50 ⁇ 10 nM, and some a DC 50 value B: 10 nM ⁇ DC 50 ⁇ 100 nM and some a DC 50 value A: 100 nM ⁇ DC 50 ⁇ 2000 nM.
• a compound of Formula I or a pharmaceutically acceptable salt, solvate, isomer, enantiomer, or tautomer thereof, wherein R 1 is –OCH 3 , –OCH 2 CH 3 , –OCF 3 , –OCH 2 CH 2 OH, –OCH 2 CH 2 F, halogen, or 1-methyl- pyrazol-4-yl;
• A is independently H, OH, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more R 2 ; wherein R 2 is independently halogen, OH, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
• B is a moiety that is capable of binding
• Embodiment 2 The compound according to Embodiment 1, wherein the compound has Formula I(a): Attorney Docket No: 055920-567001WO , BMS: 14240-WO-PCT, wherein Het A is 4- to 6-membered heterocycloalkyl.
• Embodiment 3 The compound according to any one of the preceding embodiments, wherein the compound has Formula I(b): wherein Het A is 4- to 6-membered heterocycloalkyl.
• Embodiment 4 The compound according to any one of the preceding embodiments, wherein the compound has Formula I(c): wherein Het A is 4- to 6-membered heterocycloalkyl.
• Embodiment 19 A compound of Formula II: and pharmaceutically acceptable salts, solvates, isomers, enantiomers, and tautomers thereof, wherein R 1 is –OCH 2 CH 3 , –OCH 3 , –OCF 3 , –OCH 2 CH 2 OH, –OCH 2 CH 2 F, 1-methylpyrazol-4-yl, or halogen;
• A1 is independently aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 2 ; wherein R 2 is independently halogen, OH, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
• B is a moiety that is capable of binding a E3 ligase;
• L 4 is independently –(CH 2 ) p –(4- to 12-heterocycloalkyl)–Y 1 –C(O)–Y 2 –, –(CH 2 ) p –(4
• Embodiment 20 The compound according to any one of the preceding embodiments, wherein the compound is selected from: 6 ⁇ [1 ⁇ (3 ⁇ 4 ⁇ [2 ⁇ (2,6 ⁇ dioxopiperidin ⁇ 3 ⁇ yl) ⁇ 1 ⁇ oxo ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ isoindol ⁇ 5 ⁇ yl]piperazin ⁇ 1 ⁇ yl ⁇ propanoyl)piperidin ⁇ 4 ⁇ yl]methoxy ⁇ 4 ⁇ 6 ⁇ [(1R,5S) ⁇ 6 ⁇ [(6 ⁇ methoxypyridin ⁇ 3 ⁇ yl)methyl] ⁇ 3,6 ⁇ diazabicyclo[3.1.1]heptan ⁇ 3 ⁇ yl]pyridin ⁇ 3 ⁇ yl ⁇ pyrazolo[1,5 ⁇ a]pyridine ⁇ 3 ⁇ carbonitrile; 6 ⁇ [1 ⁇ (7 ⁇ 4 ⁇ [2 ⁇ (2,6 ⁇ dioxopiperidin ⁇ 3 ⁇ yl) ⁇ 1 ⁇ oxo ⁇ 2,3 ⁇ dihydro ⁇ 1H ⁇ isoindol ⁇
• Embodiment 21 A pharmaceutical composition comprising a compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• Embodiment 22 A method of treating a RET mediated disorder comprising administering an effective amount of a compound of any one of the preceding embodiments or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, to a patient in need thereof.
• Embodiment 23 The method according to any one of the preceding embodiments, wherein the patient is a human.
• Embodiment 24 The method according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer.
• Embodiment 25 The method according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer.
• the cancer is non-small cell lung cancer.
• Embodiment 26 The method according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain.
• Embodiment 27 The method according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET.
• Embodiment 28 The method according to any one of the preceding embodiments, wherein the RET mediated disorder is a relapsed or refractory cancer.
• Embodiment 29 The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a RET mediated disorder.
• Embodiment 30 The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a RET mediated disorder.
• the RET mediated disorder is cancer.
• the compound according to any one of the preceding embodiments, wherein the cancer is non-small cell lung cancer.
• the compound according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain.
• the compound according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET.
• Embodiment 34 The compound according to any one of the preceding embodiments, wherein the RET mediated disorder is a relapsed or refractory cancer.
• Embodiment 35 The use of a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a RET mediated disorder.
• Embodiment 36 The use according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer.
• Embodiment 37 The use according to any one of the preceding embodiments, wherein the cancer is non-small cell lung cancer.
• Embodiment 38 The use according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain.
• Embodiment 39 The use according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET.
• Embodiment 40 The use according to any one of the preceding embodiments, wherein the RET mediated disorder is mediated by a mutant RET.
• the RET mediated disorder is a relapsed or refractory cancer.
• Embodiment 41 The use of a compound according to any one of the preceding embodiments, a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET mediated disorder.
• Embodiment 42 The use according to any one of the preceding embodiments, wherein the RET mediated disorder is cancer.
• Embodiment 43. The use according to any one of the preceding embodiments wherein the cancer is non-small cell lung cancer., Embodiment 44. The use according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain.
• Embodiment 45 The use according to any one of the preceding embodiments, wherein the cancer has metastasized to the brain.

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