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WO2015172747A1 - Molécules spirocycliques servant d'inhibiteurs de mth1 - Google Patents

Molécules spirocycliques servant d'inhibiteurs de mth1 Download PDF

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WO2015172747A1
WO2015172747A1 PCT/CN2015/079184 CN2015079184W WO2015172747A1 WO 2015172747 A1 WO2015172747 A1 WO 2015172747A1 CN 2015079184 W CN2015079184 W CN 2015079184W WO 2015172747 A1 WO2015172747 A1 WO 2015172747A1
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ring
membered
aryl
unsubstituted
cycloalkyl
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Zhaoyin Wang
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    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates generally to novel chemical compounds and methods. More particularly, the invention provides novel spirocyclic molecules, having MutT Homolog 1 (MTH1) inhibitory activity, and methods of synthesizing and using such compounds. Preferred compounds are MTH1 inhibitors useful for the treatment of abnormal cell growth, such as cancers.
  • MTH1 MutT Homolog 1
  • MTH1 is a protein known to overcome the incorporation of oxidised nucleotides into DNA, which otherwise can result in misparing, mutations and cell death. Inhibitors of MTH1 have been shown to cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. (Gad, H. et al., Nature, 2014, 508, 215–221. Huber, K.V.M., et al., Nature, 2014, 508, 222-240)
  • This invention concerns a new family of novel spirocyclic compounds that are MTH1 inhibitors and their use in treating cancers and other diseases.
  • Ring A may be a 3 to 12 membered carbocyclic ring, or is a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms may be replaced with one or more O, S, -C (O) -, -C (S) -and NR 1 ; and wherein the Ring A may be unsubstituted or substituted by one or more R c ;
  • Ring B may be a 3 to 12 membered carbocyclic ring, or may be a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms may be optionally replaced with one or more O, S, -C (O) -, -C (S) -and NR 1 ; and wherein the Ring B may be unsubstituted or substituted by one or more R c ;
  • R c may be independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) m R 4 , -S (O) 2 NR 4 R 5 , -S (O) 2 OR 4 , -NO 2 , -NR 4 R 5 , - (CR 6 R 7 ) n OR 4 , -CN, -C (O) R 4 , -OC (O) R 4 , -O (CR 6 R 7 ) n R 4 , -NR 4 C (O) R 5 , - (CR 6 R 7 ) n C (O) OR 4 , - (CR 6 R 7 ) n OR 4 , - (CR 6 R 7 ) n OR 4 , - (CR 6 R 7 ) n
  • each hydrogen in R c may be unsubstituted or substituted by R 8 , and wherein R c groups on adjacent atoms are uncombined or combine to form a C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring;
  • R 2 may be selected from
  • the stereocenter has a S-configuration
  • X may be N or CR 12 ;
  • Ar may be C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and Ar may be unsubstituted or substituted by one or more R c groups;
  • R 4 , R 5 , R 6 and R 7 are independently chosen from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring with the proviso that they are not halogen when they are attached to N, O, S or P;
  • R 4 , R 5 , R 6 and R 7 bound to the same nitrogen atom, together with the nitrogen to which they are bound, may combine to form a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring or a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S;
  • R 4 , R 5 , R 6 and R 7 bound to the same carbon atom may combine to form a C 3- 12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring;
  • R 4 , R 5 , R 6 and R 7 may be unsubstituted or substituted by R 8 , or two hydrogen atoms on the same carbon atom in R 4 , R 5 , R 6 and R 7 may be unsubstituted or are an oxo substituent;
  • R 8 may be independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -NH 2 , -CN, -OH, -O-C 1-12 alkyl, -O- (CH 2 ) n C 3-12 cycloalkyl, -O- (CH 2 ) n C 6-12 aryl, -O- (CH 2 ) n (3-12 membered heteroalicyclic ring) or -O- (CH 2 ) n (5-12 membered heteroaryl ring) ; and each hydrogen in R 8 may be unsubstituted or substituted by R 11 ;
  • R 9 may be independently chosen from a C 1-12 alkyl, aryl, heteroaryl which may be unsubstituted or substituted;
  • R 10 may be independently chosen from a C 1-12 alkyl which may be unsubstituted or substituted;
  • R 11 may be independently chosen from halogen, C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -O-C 1-12 alkyl, -O- (CH 2 ) n C 3-12 cycloalkyl, -O- (CH 2 ) n C 6-12 aryl, -O- (CH 2 ) n (3-12 membered heteroalicyclic ring) , -O- (CH 2 ) n (5-12 membered heteroaryl ring) or -CN, and each hydrogen in R 11 may be unsubstituted or substituted by halogen, -OH, -CN, -C 1-12 alkyl which may be unsubstituted, or partially halogenated or fully halogenated, -O-C 1-12 alkyl which may be unsubstituted or partially halogenated or
  • R a may be independently chosen from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3- 12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, - (CR 6 R 7 ) n OR 4 , -CN, -C (O) R 4 , - (CR 6 R 7 ) n C (O) OR 4 , - (CR 6 R 7 ) n NCR 4 R 5 or -C (O) NR 4 R 5 ; and R a or R b are uncombined or, together with the carbon to which they may be attached to, R a and R b may form a 3-12 membered ring or a 3-12 membered ring which contains one or more heteroatom chosen from NR 4 , O, S, Si; or
  • each m may be independently 0, 1 or 2;
  • each n may be independently 0, 1 , 2, 3 or 4;
  • the compounds of Formula I may be selected from:
  • Ring A may be a 3 to 12 membered carbocyclic ring or a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms may be replaced with one or more O, S, -C (O) -, -C (S) -and NR 1 ; and wherein the Ring A may be unsubstituted or substituted by one or more R c ;
  • Ring B may be a 3 to 12 membered carbocyclic ring or a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms may be replaced with one or more O, S, -C (O) -, -C (S) -and NR 1 ; and wherein the Ring B may be unsubstituted or substituted by one or more R c ;
  • X may be N or CR 12 ;
  • Ar may be C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and wherein Ar may be unsubstituted or substituted by one or more R c groups;
  • R c may be independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) m R 4 , -S (O) 2 NR 4 R 5 , -S (O) 2 OR 4 , -NO 2 , -NR 4 R 5 , - (CR 6 R 7 ) n OR 4 , -CN, -C (O) R 4 , -OC (O) R 4 , -O (CR 6 R 7 ) n R 4 , -NR 4 C (O) R 5 , - (CR 6 R 7 ) n C (O) OR 4 , - (CR 6 R 7 ) n OR 4 , - (CR 6 R 7 ) n OR 4 , - (CR 6 R 7 ) n
  • each hydrogen in R c may be unsubstituted or substituted by R 8 , and wherein R c groups on adjacent atoms are uncombined or combine to form a C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring;
  • R 4 , R 5 , R 6 and R 7 may be independently chosen from hydrogen, , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring; or any two of R 4 , R 5 , R 6 and R 7 bound to the same nitrogen atom, together with the nitrogen to which they are bound, may combine to form a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring or a 3 to 12 membered heteroalicyclic ring or a 5-12 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S; or any two of R 4 , R 5 , R 6 and R 7 bound to the same carbon atom combine to form a C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring
  • R 8 may be independently chosen from halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -NH 2 , -CN, -OH, -O-C 1-12 alkyl, -O- (CH 2 ) n C 3-12 cycloalkyl, -O- (CH 2 ) n C 6-12 aryl, -O- (CH 2 ) n (3-12 membered heteroalicyclic ring) or -O- (CH 2 ) n (5-12 membered heteroaryl ring) ; and each hydrogen in R 8 may be unsubstituted or substituted by R 11 ;
  • R 11 may be independently chosen from halogen, C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -O-C 1-12 alkyl, -O- (CH 2 ) n C 3-12 cycloalkyl, -O- (CH 2 ) n C 6-12 aryl, -O- (CH 2 ) n (3-12 membered heteroalicyclic ring) , -O- (CH 2 ) n (5-12 membered heteroaryl ring) or -CN, and each hydrogen in R 11 is unsubstituted or substituted by halogen, -OH, -CN, -C 1-12 alkyl which may be unsubstituted or partially halogenated or fully halogenated, -O-C 1-12 alkyl which may be unsubstituted or partially halogenated or fully
  • R a may be independently chosen from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3- 12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, - (CR 6 R 7 ) n OR 4 , -CN, -C (O) R 4 , - (CR 6 R 7 ) n C (O) OR 4 , - (CR 6 R 7 ) n NCR 4 R 5 or -C (O) NR 4 R 5 ; and R a or R b are uncombined or, together with the carbon to which they may be attached to, R a and R b may form a 3-12 membered ring or a 3-12 membered ring which contains one or more heteroatom chosen from NR 4 , O, S, Si; or
  • each m may be independently 0, 1 or 2;
  • each n may be independently 0, 1 , 2, 3 or 4;
  • the compound may be selected from:
  • X, Ring-A, Ring-B and R 3 may be as defined above.
  • Ar may be C 6-12 aryl, 5-12 membered heteroaryl ring, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and wherein Ar may be unsubstituted or substituted by one or more R c groups;
  • the compound may be selected from:
  • R 3 Ring-A, Ring-B and R c are defined as above; n is 1 to 4.
  • The may be selected from the group consisting of:
  • the compounds of Formula I may be:
  • composition comprising a combination of a compound of any the present invention and an anti-cancer agent selected from a cytotoxic agent, a antimitotic agent, an anti-metabolite, a proteasome inhibitor, a HDAC inhibitor and a kinase inhibitor.
  • an anti-cancer agent selected from a cytotoxic agent, a antimitotic agent, an anti-metabolite, a proteasome inhibitor, a HDAC inhibitor and a kinase inhibitor.
  • the cancer is chosen from cancer of bladder, cancer of brain, cancer of breast, cancer of uterus, chronic lymphoid leukemia, colon cancer, esophagus cancer, liver cancer, lymphoblastic leukemia, follicular lymphomas, melanomas, malignant homeopathies, myelomas, ovarian cancer, non-small-cell lung
  • a method of treating a patient afflicted with cancer by administering to the patient a therapeutically effective amount of a compound of the present invention in combination with radiotherapy.
  • alkyl, " by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C 1 -C 10 means one to ten carbons) .
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) , ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl" .
  • Fluoroalkyl means alkyl as defined above wherein one or more hydrogen atoms have been replaced by fluoro atoms.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a "lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono-or bicyclic saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms.
  • a “fused analog” of cycloalkyl means a monocyclic rings fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
  • Alkoxy means alkoxy groups of a straight or branched having the indicated number of carbon atoms.
  • C 1-6 alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom (s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S- CH 2 -CH 2 -and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) .
  • chain termini e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like.
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C (O) R', -C (O) NR', -NR'R", -OR',
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R”or the like, it will be understood that the terms heteroalkyl and--NR'R"are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R”or the like.
  • Cycloalkoxy means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
  • Fluoroalkoxy means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by fluoro atoms.
  • Aryl means mono-or bicyclic aromatic rings containing only carbon atoms.
  • a “fused analog” of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1, 4-benzodioxanyl, and the like.
  • Heteroaryl means a mono-or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
  • a “fused analog” of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
  • heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2, 3-b) pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • alkyl groups, cycloalkyl, alkynyl, alkenyl, aryl groups and heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents.
  • the said substituents are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from l to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulf
  • Heterocyclyl means mono-or bicyclic saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • a “fused analog” of heterocyclyl means a monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
  • heterocyclyl and fused analogs thereof include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2, 3-dihydrofuro (2, 3-b) pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted- (1H, 3H) -pyrimidine-2, 4-diones (N-substituted uracils) .
  • halo or halogen, "by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl, " are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C 1 -C 4 ) alkyl” is mean to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the "prodrug” ) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • Compounds of Formula I contain one or more asymmetric centers and can thus occur in single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs by, for example, fractional crystallization from a suitable solvent or a method of chromatograph.
  • any stereoisomers of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • One or more than one of the protons in compounds of Formula I can be replaced with deuterium atom (s) , thus providing deuterated analogs that may have improved pharmacological activities.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzyl ethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorb
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an I atomiser using electrohydrodynamics to produce a fine mist) , or nebuliser, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns) .
  • This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules (made, for example, from gelatin or HPMC) , blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from log to 20mg of the compound of the invention per actuation and the actuation volume may vary from 11 to 1001.
  • a typical formulation may comprise a compound of formula 1, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA) .
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 fig to 10 mg of the compound of formula I.
  • the overall daily dose will typically be in the range 1 lag to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical application shall include mouth washes and gargles.
  • Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • the compounds of the present invention are useful for treating diseases associated with abnormal activities MTH1.
  • the present invention also comprises methods of treating diseases in a patient by using methods comprising administering to the patient a therapeutically effective amount of a compound having formula I.
  • the compounds according to the invention will be useful in the treatment of diseases of abnormal cell growth and/or dysregulated apoptosis, such as mesothioloma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, cervical cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal) , chronic lymphocytic leukemia , esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular
  • Still another embodiment comprises methods of treating mesothioloma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, ovarian cancer, cervical cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal) , chronic lymphocytic leukemia , esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular cancer (hepatic and billiary duct) , primary or secondary central nervous system tumor, primary or secondary brain tumor
  • the present invention relates also to pharmaceutical compositions comprising at least one compound of formula I on its own or in combination with one or more pharmaceutically acceptable excipients.
  • compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per-or transcutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragees, sublingual tablets, sachets, packets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
  • the present invention relates also to the combination of a compound of formula I with one or more anticancer agents selected from cytotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors and kinase inhibitors, and to the use of that type of combination in the manufacture of medicaments for use in the treatment of cancer.
  • anticancer agents selected from cytotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors and kinase inhibitors
  • the compounds of the invention may also be used in combination with radiotherapy in the treatment of cancer.
  • Compounds having formula I are also expected to be useful as chemotherapeutic agents in combination with therapeutic agents that include, but are not limited to, indoleamine-2, 3-dioxygenase inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA4 antibodies, angiogenesis inhibitors, antiproliferative agents, other kinase inhibitors, other receptor tyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinase inhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2 inhibitors, EP4 antagonists, non-steroidal anti-inflammatory drugs (NSAIDS) , antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, platinum containing agents, growth factor inhibitors, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, immunologicals, antibodies, hormonal therapies, retinoids/deltoids plant alkaloids
  • Angiogenesis inhibitors include, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TTE2 inhibitors, IGFlR inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors, thrombospondin analogs such as thrombospondin-1 and N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-He-Arg-Pro-NHCH 2 CH 3 or a salt thereof and analogues of N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-PrO-NHCH 2 CH 3 such as N-Ac-GlyVal-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2 CH 3 or a salt thereof.
  • the compounds of the present invention may be prepared according to the following synthetic scheme:
  • the compounds of present invention can also be prepared according to the following scheme:
  • Cross-coupling reaction of 5 with an appropriate boronic acid or boronate 11 which contains a spiro-moeity can yields the desired product 10.
  • a deprotection step maybe used to produce the final product in various salt forms.
  • DBU means l, 8-diazabicyclo [5.4.0] undec-7-ene
  • DIBAL means diisobutylaluminum hydride
  • DIEA means diisopropylethylamine
  • DMAP means N, N-dimethylaminopyridine
  • DME means 1, 2-dimethoxyethane
  • DMF means N, N-dimethylformamide
  • dmpe means l, 2-bis (dimethyl ⁇ hosphino) ethane
  • DMSO means dimethylsulfoxide
  • dppb means l, 4-bis (diphenylphosphino) butane
  • dppe means 1, 2-bis (diphenylphosphino) ethane
  • dppf means 1, 1’ -bis (diphenylphosphino) ferrocene
  • dppm means 1, 1’ -bis (diphenylphosphino) methane
  • DIAD means diisopropylazo
  • a flame dried bottom flask was filled N 2 , DMSO, the product of Step 4 (4.34 g, 7.48 mmol) and bis (pinacolato) diboron (2.28 g, 8.98 mmol) and potassium acetate (2.93 g, 29.9 mmol) was added.
  • the solution was degassed by cacuum and refilled with N 2 .
  • Pd (dppf) Cl2DCM (0.30 g, 0.37 mmol) was added in one portion.
  • the solution was degassed by vacuum and refilled with N 2 again, then stirred at 80°C for 2 h. The mixture was then filtered through a pad of celite, washed with EA.
  • Step 6 (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine
  • Step 8 (S) -5- (1- (7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
  • Acetyl chloride (0.6 mL) was added to 1.5 mL of anhydrous ethanol over 30 min, maintain a temperature between 5 to 25°C. Following complete addition, the solution was warmed to 20 °C. This acidic solution was promptly added to a solution of tert-butyl (S) -2- (4- (6-amino-5- (1-(2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate (0.14 g, 0.24 mmol) in a mixture of ethanol and dichloromethane (1: 1, 2 mL) over 5 min, maintaining a temperature below 20°C.
  • Acetyl chloride (0.6 mL) was added to 1.5 mL of anhydrous ethanol over 30 min, maintain a temperature between 5 to 25°C. Following complete addition, the solution was warmed to 20 °C. This acidic solution was promptly added to a solution of tert-butyl 2- (4-iodo-1H-pyrazol-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate (0.30 g, 0.72 mmol, prepared according to the methods described in WO2013013308A1 ) in a mixture of ethanol and dichloromethane (1: 1, 2 mL) over 5 min, maintaining a temperature below 20°C. The reaction mixture was warmed to 25°C and stirred for 3 hrs. A white solid was precipitated. The mixture was concentrated and slurry in EA then filtered to give white solid (0.26 g, yield: 100%) , which was used for the next step without further purification
  • Step 1 To a flask was added the product of Step 1 (0.184 g, 0.58 mmol) and 7 mL of DMF at RT, followed by Cs 2 CO 3 (0.76 g, 2.32 mmol) .
  • Step 3 5- (1- ( (2r, 4s) -6-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (S) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
  • MTH1 catalytic assay half-maximal inhibitory concentrations are determined by using the following protocol: serial dilutions of compounds are dissolved in assay buffer (100 mM Tris-acetate pH 7.5, 40 mM NaCl and 10 mM Mg (OAc) 2 containing 0.005%Tween-20 and 2 mM dithiothreitol (DTT) . Upon addition of MTH1 recombinant protein (final concentration 2 nM), plates are incubated on a plate shaker for 15 min at room temperature.
  • assay buffer 100 mM Tris-acetate pH 7.5, 40 mM NaCl and 10 mM Mg (OAc) 2 containing 0.005%Tween-20 and 2 mM dithiothreitol (DTT)
  • PPi pyrophosphate
  • IC50values are determined by fitting a dose–response curve to the data points using nonlinear regression analysis using the GraphPad Prism software.
  • the pharmacokinetic properties of the compounds of present invention were evaluated in SD mice.
  • the mice were dosed via p.o. route with suspensions of compounds in 1%aqueous solution of methocel.
  • the dosing volume was 10 mL/kg.
  • Plasma were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6h, 8 h and 24 h, and were analyzed by a method of LC/MS on a API4000QTRAP instrument. The following parameters were determined for Example 1 and Example 2.
  • Example 2 has an expected long MRT (16.7 hr for Example 2 vs 6.7 hr for S-Crizotinib) and t 1/2 (11.2 hr for Example 2 vs 3.3 hr for S-Crizotinib) .
  • Example 2 is predicted to be suitable for once daily dosing in men.

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Abstract

L'invention concerne des composés spirocycliques présentant une activité inhibitrice de MTH1, et des procédés de synthèse et d'utilisation de tels composés. Les composés préférés sont utiles pour le traitement d'une croissance cellulaire anormale telle que les cancers.
PCT/CN2015/079184 2014-05-16 2015-05-18 Molécules spirocycliques servant d'inhibiteurs de mth1 Ceased WO2015172747A1 (fr)

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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10730863B2 (en) 2017-11-01 2020-08-04 Bristol-Myers Squibb Company Bridged bicyclic compounds as farnesoid X receptor modulators
US11078198B2 (en) 2017-11-01 2021-08-03 Bristol-Myers Squibb Company Spirocyclic compounds as farnesoid X receptor modulators
US11254663B2 (en) 2019-02-15 2022-02-22 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US11286252B2 (en) 2017-11-01 2022-03-29 Bristol-Myers Squibb Company Alkene spirocyclic compounds as farnesoid X receptor modulators
US11370785B2 (en) 2017-11-01 2022-06-28 Bristol-Myers Squibb Company Multicyclic compounds as farnesoid X receptor modulators
US12030835B2 (en) 2019-02-15 2024-07-09 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators
US12227496B2 (en) 2019-02-15 2025-02-18 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12319676B2 (en) 2019-02-15 2025-06-03 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators

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WO2006021881A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes aminoheteroaryle a substitution pyrazole servant d'inhibiteurs de proteine kinase
WO2014033136A1 (fr) * 2012-08-27 2014-03-06 Cemm - Research Center For Molecular Medicine Of The Austrian Academy Of Sciences Composés aminohétéroaryles en tant qu'inhibiteurs de mth1
WO2014084778A1 (fr) * 2012-11-27 2014-06-05 Thomas Helledays Stiftelse För Medicinsk Forskning Dérivés de pyrimidine-2,4-diamine utilisables en vue du traitement du cancer

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WO2006021881A2 (fr) * 2004-08-26 2006-03-02 Pfizer Inc. Composes aminoheteroaryle a substitution pyrazole servant d'inhibiteurs de proteine kinase
WO2014033136A1 (fr) * 2012-08-27 2014-03-06 Cemm - Research Center For Molecular Medicine Of The Austrian Academy Of Sciences Composés aminohétéroaryles en tant qu'inhibiteurs de mth1
WO2014084778A1 (fr) * 2012-11-27 2014-06-05 Thomas Helledays Stiftelse För Medicinsk Forskning Dérivés de pyrimidine-2,4-diamine utilisables en vue du traitement du cancer

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US12122833B2 (en) 2016-05-11 2024-10-22 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US11286252B2 (en) 2017-11-01 2022-03-29 Bristol-Myers Squibb Company Alkene spirocyclic compounds as farnesoid X receptor modulators
US11370785B2 (en) 2017-11-01 2022-06-28 Bristol-Myers Squibb Company Multicyclic compounds as farnesoid X receptor modulators
US11078198B2 (en) 2017-11-01 2021-08-03 Bristol-Myers Squibb Company Spirocyclic compounds as farnesoid X receptor modulators
US10730863B2 (en) 2017-11-01 2020-08-04 Bristol-Myers Squibb Company Bridged bicyclic compounds as farnesoid X receptor modulators
US11254663B2 (en) 2019-02-15 2022-02-22 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US11713312B2 (en) 2019-02-15 2023-08-01 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12030835B2 (en) 2019-02-15 2024-07-09 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators
US12227496B2 (en) 2019-02-15 2025-02-18 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12319676B2 (en) 2019-02-15 2025-06-03 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators

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