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WO2015172747A1 - Spirocyclic molecules as mth1 inhibitors - Google Patents

Spirocyclic molecules as mth1 inhibitors Download PDF

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Publication number
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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Prior art keywords
ring
membered
aryl
unsubstituted
cycloalkyl
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PCT/CN2015/079184
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French (fr)
Inventor
Zhaoyin Wang
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Zhaoyin Wang
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Publication of WO2015172747A1 publication Critical patent/WO2015172747A1/en

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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

Disclosed are spirocyclic compounds having MTH1 inhibitory activity, and methods of synthesizing and using such compounds. Preferred compounds are useful for the treatment of abnormal cell growth, such as cancers.

Description

SPIROCYCLIC MOLECULES AS MTH1 INHIBITORS BACKGROUND
(a) Field
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.
(b) Related Prior Art
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.
DESCRIPTION OF THE INVENTION
According to an embodiment, there is provided a compound of Formula I
Figure PCTCN2015079184-appb-000001
or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
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 NR1； and wherein the Ring A may be unsubstituted or substituted by one or more Rc；
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 NR1； and wherein the Ring B may be unsubstituted or substituted by one or more Rc；
R1 may be independently chosen from hydrogen, C1-12 alkyl, C1-12 alkyl in which one carbon atom may be replaced with Si, O, S atom, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, -C (O) R4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, - (CR6R7) nNCR4 (R5) 2, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, -C (O) - (CR6R7) n-NR4R5, and wherein each hydrogen in R1 may be unsubstituted or substituted by Rc, or one of the hydrogen in R1 may be replaced with -P (O) (OR9) 2, -P (O) (R9) 2；
Rc may be independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -S (O) 2NR4R5, -S (O) 2OR4, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, -  (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, -NH2, SF5, -OH, -O-C1-12alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) or -O- (CH2) n (5-12 membered heteroaryl ring) ；
and wherein each hydrogen in Rc may be unsubstituted or substituted by R8, and wherein Rc groups on adjacent atoms are uncombined or combine to form a C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring；
R2 may be selected from
Figure PCTCN2015079184-appb-000002
wherein:
the stereocenter has a S-configuration；
X may be N or CR12；
Ar may be C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and Ar may be unsubstituted or substituted by one or more Rc groups；
Figure PCTCN2015079184-appb-000003
may be selected from C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, wherein
Figure PCTCN2015079184-appb-000004
may be unsubstituted or substituted by one, two or three Rc groups；
R3 may be chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, SF5, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and each hydrogen in R3 may be unsubstituted or substituted by R8；
R4, R5, R6 and R7 are independently chosen from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 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；
or any two of R4, R5, R6 and R7 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 R4, R5, R6 and R7 bound to the same carbon atom may combine to form a C3- 12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring；
and each hydrogen in R4, R5, R6 and R7 may be unsubstituted or substituted by R8, or two hydrogen atoms on the same carbon atom in R4, R5, R6 and R7 may be unsubstituted or are an oxo substituent；
R8 may be independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -NH2, -CN, -OH, -O-C1-12alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) or -O- (CH2) n (5-12 membered heteroaryl ring) ； and each hydrogen in R8 may be unsubstituted or substituted by R11；
R9 may be independently chosen from a C1-12 alkyl, aryl, heteroaryl which may be unsubstituted or substituted；
R10 may be independently chosen from a C1-12 alkyl which may be unsubstituted or substituted；
R11 may be independently chosen from halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) , -O- (CH2) n (5-12 membered heteroaryl ring) or -CN, and each hydrogen in R11 may be unsubstituted or substituted by halogen, -OH, -CN, -C1-12 alkyl which may be unsubstituted, or partially halogenated or fully halogenated, -O-C1-12 alkyl which may be unsubstituted or partially halogenated or fully halogenated, or substituted with –C (O) -；
R12 may be chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, SF5, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and each hydrogen in R12 may be unsubstituted or substituted by R3；
Ra may be independently chosen from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3- 12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, - (CR6R7) nOR4, -CN, -C (O) R4, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5 or -C (O) NR4R5； and Ra or Rb are uncombined or, together with the carbon to which they may be attached to, Ra and Rb may form a 3-12 membered ring or a 3-12 membered ring which contains one or more heteroatom chosen from NR4, 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
Figure PCTCN2015079184-appb-000005
may be selected from
Figure PCTCN2015079184-appb-000006
or an aryl, bicyclic aryl, bicyclic heteroaryl, unsubstituted or substituted by one, two or three Rc groups as defined above.
The compounds of Formula I may be selected from:
Figure PCTCN2015079184-appb-000007
wherein:
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 NR1； and wherein the Ring A may be unsubstituted or substituted by one or more Rc；
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 NR1； and wherein the Ring B may be unsubstituted or substituted by one or more Rc；
R1 may be independently chosen from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3- 12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, -C (O) R4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and wherein each hydrogen in R1 may be unsubstituted or substituted by Rc；
X may be N or CR12；
Ar may be C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and wherein Ar may be unsubstituted or substituted by one or more Rc groups；
R3 may be chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, SF5, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and wherein each hydrogen in R3 may be unsubstituted or substituted by R8；
Rc may be independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -S (O) 2NR4R5, -S (O) 2OR4, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, -NH2, SF5,  -OH, -O-C1-12alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) or -O- (CH2) n (5-12 membered heteroaryl ring) ；
and wherein each hydrogen in Rc may be unsubstituted or substituted by R8, and wherein Rc groups on adjacent atoms are uncombined or combine to form a C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring；
R4, R5, R6 and R7 may be independently chosen from hydrogen, , C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring； or any two of R4, R5, R6 and R7 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 R4, R5, R6 and R7 bound to the same carbon atom combine to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring or 5-12 membered heteroaryl ring； and each hydrogen in R4, R5, R6 and R7 may be unsubstituted or substituted by R8, or two hydrogen atoms on the same carbon atom in R4, R5, R6 and R7 may be unsubstituted or an oxo substituent；
R8 may be independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -NH2, -CN, -OH, -O-C1-12alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) or -O- (CH2) n (5-12 membered heteroaryl ring) ； and each hydrogen in R8 may be unsubstituted or substituted by R11；
R11 may be independently chosen from halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) , -O- (CH2) n (5-12 membered heteroaryl ring) or -CN, and each hydrogen in R11 is unsubstituted or substituted by halogen, -OH, -CN, -C1-12 alkyl which may be unsubstituted or partially halogenated or fully halogenated, -O-C1-12 alkyl which may be unsubstituted or partially halogenated or fully halogenated, or substituted with -CO；
R12 may be chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and each hydrogen in R12 may be unsubstituted or substituted by R3；
Ra may be independently chosen from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3- 12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, - (CR6R7) nOR4, -CN, -C (O) R4, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5 or -C (O) NR4R5； and Ra or Rb are uncombined or, together with the carbon to which they may be attached to, Ra and Rb may form a 3-12 membered ring or a 3-12 membered ring which contains one or more heteroatom chosen from NR4, O, S, Si； or
each m may be independently 0, 1 or 2；
each n may be independently 0, 1 , 2, 3 or 4；
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
The compound may be selected from:
Figure PCTCN2015079184-appb-000008
wherein X, Ring-A, Ring-B and R3 may be as defined above.
Ar may be C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and wherein Ar may be unsubstituted or substituted by one or more Rc groups；
The compound may be selected from:
Figure PCTCN2015079184-appb-000009
wherein R3, Ring-A, Ring-B and Rc are defined as above； n is 1 to 4.
The
Figure PCTCN2015079184-appb-000010
may be selected from the group consisting of:
Figure PCTCN2015079184-appb-000011
Figure PCTCN2015079184-appb-000012
Figure PCTCN2015079184-appb-000013
The compounds of Formula I may be:
(S) -5- (1- (2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -3- ( (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
(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；
(S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
5- (1- (cis-6-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (S) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
5- (1- ( (trans-6-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (S) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1-phenylethoxy) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-fluorophenyl) ethoxy) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-chlorophenyl) ethoxy) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-chloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (3, 4-difluorophenyl) ethoxy) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-bromophenyl) ethoxy) pyridin-2-amine；
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-(trifluoromethyl) phenyl) ethoxy) pyridin-2-amine；
(S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) pyridin-2-amine.
According to an embodiment, there is provided a 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.
According to an embodiment, there is provided a method treating a cancer in a patient in need thereof by administering to the patient a therapeutically effective amount of a compound of the present invention, or the composition of the present invention, or both, wherein 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 cancer, prostate cancer, small-cell lung cancer, and lymphoid malignancy of B-cell origin.
According to an embodiment, there is provided 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.
Abbreviations used herein have their conventional meaning within the chemical and biological arts.
"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. C1-C10 means one to ten carbons) . Examples of 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. Examples of 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.
"Alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-, -CH2CH＝CHCH2-, -CH2 C≡CCH2-, -CH2CH2CH (CH2CH2CH3) CH2-. Typically, 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. C1-6alkoxy, 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. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH＝CH-O-CH3, -Si (CH3) 3, -CH2-CH＝N-OCH3, -CH＝CH-N (CH3) -CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si (CH3) 3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2 -CH2-S- CH2-CH2-and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C (O) OR'-represents both-C (O) OR'-and -R'OC (O) -. As described above, heteroalkyl groups, as used herein, 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',
-SR', and/or -SO2R'. Where "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. Examples of heteroaryl 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.
The said 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, aminosulfonyl groups, hydroxy groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy  groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from l to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl) amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl) aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono-or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono-or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono-or di alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono-or di-alkylamino groups having from 1 to 6 carbon atoms, mono-or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms；
"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. Examples of "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 (C1-C4) alkyl" is mean to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
A "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.
Optical Isomers -Diastereomers -Geometric Isomers –Tautomers:
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.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
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. Alternatively, 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.
Stable Isotope-Labeled Analogs:
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 AND FORMULATION
The term "pharmaceutically acceptable 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.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such 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.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
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.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 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 sorbitan monooleate. 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.
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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
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. Among the acceptable vehicles and solvents  that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, 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. For intranasal use, 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.
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.
In the case of dry powder inhalers and aerosols, 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. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, 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. For example, 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.
Features and advantages of the subject matter hereof will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be realized, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. Accordingly, the drawings and the description are to be regarded as illustrative in nature and not as restrictive and the full scope of the subject matter is set forth in the claims.
UTILITIES
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.
More especially, 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 cancer (hepatic and billiary duct) , primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination thereof. 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, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination of one or more of the above cancers in a patient, said methods comprising administering thereto a therapeutically effective amount of a compound having Formula I.
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.
Among the pharmaceutical 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.
Moreover, 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.
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, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase inhibitors (HDAC) inhibitors, purine analogs, pyrimidine analogs, MEK inhibitors, cMet inhibitord, CDK inhibitors, ErbB2 receptor inhibitors, mTOR inhibitors, Bcl inhibitors, Mcl inhibitors and combinations thereof as well as other antitumor agents.
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-NHCH2CH3 or a salt thereof and analogues of N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-PrO-NHCH2CH3 such as N-Ac-GlyVal-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3 or a salt thereof.
SYNTHESIS
The compounds of the present invention may be prepared according to the following synthetic scheme:
Figure PCTCN2015079184-appb-000014
Mitsunobu reaction of optically pure alcohol 1 with 2 under standard conditions provides aryl ether 3, which can be reduced to aniline 4. Bromination of 4 with NBS yields bromide 5. The NH2 group in bromide 5 can be protected with BOC group to give compound 6. Reaction of 6 with 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) and a palladium catalyst gives rise to boronate 7. The Boc group in 7 can be cleaved under acidic conditions to give compound 8. Cross-coupling reaction of 8 with an appropriate coupling partner 9 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.
Alternatively, the compounds of present invention can also be prepared according to the following scheme:
Figure PCTCN2015079184-appb-000015
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.
Compounds of the present invention may be made by the above-mentioned synthetic chemical processes, examples of which are shown herein below. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
The following abbreviations have the meanings indicated. 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 (dimethylρhosphino) 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 diisopropylazodicarboxylate； EDCI means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide； HATU means 2- (7-Aza-1H-benzotriazole-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate； HMPA means hexamethylphosphorarnide； IPA means isopropyl alcohol； LDA means lithium diisopropylamide； LHMDS means lithium bis (hexamethyldisilylamide) ； LAH means lithium aluminum hydride； NCS means N-chlorosuccinimide； PyBOP means benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate； TDA-I means tris (2- (2-methoxyethoxy) ethyl) amine； DCM means dichloromethame； TEA means triethylamine； TFA means trifluoroacetic acid； THF means tetrahydrofuran； NCS means N-chlorosuccinimide； NMM means N-methylmorpholine； NMP means N-methylpyrrolidine； PPh3 means triphenylphosphine, RBF means round-bottom flask.
The following preparations and Examples illustrate the invention but do not limit it in any way. The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.
EXAMPLE 1
(S) -5- (1- (7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
Figure PCTCN2015079184-appb-000016
Step 1 (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-nitropyridine
Figure PCTCN2015079184-appb-000017
(R) -1- (2, 6-dichloro-3-fluorophenyl) ethan-1-ol (47.5 g, 227.2 mmol) was charged to a reactor containing a solution of 3-hydroxy-2-nitropyridine (33.4 g, 238.6 mmol) in toluene (350 mL) at 10℃, and a toluene wash was used to rine the containers and charging lines into the reactor. Triphenylphosphine (71.5 g, 272.7 mmol) was added, and stirred for 10 min. A solution of diisopropylazodicarboxylate (56.1 g, 277.2 mmol) in toluene (70 mL) was then added over 1 h, maintaining a temperature between 8℃ and 25℃. Toluene was used as a line wash. The reactor contents were then warmed to 25℃, and the batch was agitated at this temperature for 4 hrs. Water was added, and the batch was stirred for 20 min, then stand for overnight, no precipitate formed. The batch was then cooled to 3℃, stirred for 1 hrs. The slurry was filtered, and the filter cake was washed with toluene. The combined filtrate was distilled under vacuum to a residual volume of 150 ml, ethanol 300 ml was added, and the resulting solution was distilled under vacuum to a residual volume of 150 ml, maintaining an internal temperature blow 60℃. This operation was repeated twice using ethanol, indicating complete removal of toluene. Ethanol (200 ml) was added, slurry at 0℃ for 2 hrs, then stand for 24 hrs at -15℃. filtered and washed with cold ethanol to give the title compound as a yellow solid (63.13g) . The mother liquid was concentrated, dissolved in toluene, filtered through a pad of silica gel, then concentrate, add EtOH and concentrate again. The residue slurry was suspended in EtOH/H2O (70 ml/30 ml) at 15 ℃ for 24 hrs, filtered, washed with EtOH/H2O (35 ml/15 ml) to give additional 5.67g of the title compound.
1HNMR (500 MHz, CDCl3) :
Figure PCTCN2015079184-appb-000018
8.04 (d, 1 H) , 7.37 (dd, 1 H) , 7.30 (dd, 1 H) , 7.21 (d, 1 H) , 7.09 (t, 1 H) , 6.10 (q, 1 H) , 1.85 (d, 3 H) .
Step 2 (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
Figure PCTCN2015079184-appb-000019
(S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-nitropyridine (31.5 g, 0.095 mol) , ethanol (600 mL) and acetic acid (160 mL) were charged under nitrogen to a flask at 10℃. After stirred for 15 min, Fe powder (26.6 g, 0.47 mol) was added, then heated to 80℃ for 3 h. The reaction mixture filtered through a pad of celite, and the filtrate was concentrated. The residue was dissolved in EA (500 mL) and water (300 mL) , then adjusted to pH＝10 with Na2CO3 solution, extract with EA and washed with water. The organic phase was concentrated slurry in hexane (200 mL) to obtain the title compound as a off-white solid (54.8 g, yield 95％) .
1HNMR (500 MHz, CDCl3) :
Figure PCTCN2015079184-appb-000020
7.59 (d, 1 H) , 7.28 (dd, 1 H) , 7.05 (t, 1 H) , 6.70 (d, 1 H) , 6.46 (dd, 1 H) , 6.01 (q, 1 H) , 4.92 (s, br, 2 H) , 1.82 (d, 3 H) .
Step 3 (S) -5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
Figure PCTCN2015079184-appb-000021
A solution of N-bromosuccinimide (31.37 g, 0. 176 mol) in acetonitrile (300 ml) was added to a solution of the product of Step 2 (51.54 g, 0.171 mol) in dichloromethane (300 ml) at -5℃  over 35 min. maintaining a temperature less than 0℃, followed by an acetonitrile line wash. The reaction was agitated for 10 min, then a solution of sodium metabisulfite and potassium hydroxide in water was added over 10 min, at the same time the reaction temperature was adjusted to 0℃. A water line wash was then applied. The reaction mixture was warmed to 20℃ and stirred for 1 h, then the layers was separated. Water was then added, and following agitation, the layers was separated. Concentrated to dryness, added MTBE, concentrated again, added 150 mL of methanol, slurry in for 2 hrs. The slurry was filtered, and the filter cake was washed with cold methanol and dried to give the title compound as an off-yellow solid (53.71 g, yield 82％) .
1HNMR (500 MHz, CDCl3) :
Figure PCTCN2015079184-appb-000022
7.67 (d, 1 H) , 7.31 (dd, 1 H) , 7.08 (t, 1 H) , 6.83 (s, 1 H) , 4.83 (s, br, 2 H) , 1.82 (t, 3 H) .
Step 4 Bis (Boc) protected (S) -5-bromo-3- (1- (2, 6-dichloro-3-fluoropheny) ethoxy) pyridin-2-amine
Figure PCTCN2015079184-appb-000023
To a solution of (S) -5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine (7.00 g, 0.018 mmol) in dry DMF was added Boc2O (12.06 g, 0.055 mmol) and DMAP (0.45 g, 0.037 mmol) . The resulting yellow solution was stirred at room temperature for 8 hrs. A saturated solution of NaHCO3 was added and stirred for 5 h. The aqueous phase was extracted with EtOAc, washed with H2O, NaHCO3 and brine, dried over anhydrous Na2SO4 and then concentrated. The crude product filtered through a pad of silica gel (MTBE) to afford product as foam solid (11 g, yield 102％) .
1HNMR (500 MHz, CDCl3) :
Figure PCTCN2015079184-appb-000024
8.13 (s, 1 H) , 7.79-7.85 (1H, m) , 7.23 (1H, s) , 7.06-7.13 (1H, m), 5.96-6.02 (1H, m) , 1.70 (3H, d) , 1.38 (9H, s) , 1.45 (9H, s) .
Step 5 Bis (Boc) protected (S) -3- (1- (2, 6-dichloro-3-fluoropheny) ethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine
Figure PCTCN2015079184-appb-000025
A flame dried bottom flask was filled N2, 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 N2. Pd (dppf) Cl2DCM (0.30 g, 0.37 mmol) was added in one portion. The solution was degassed by vacuum and refilled with N2 again, then stirred at 80℃ for 2 h. The mixture was then filtered through a pad of celite, washed with EA. The combined organic solution was washed with water brine, dried over Na2SO4 and concentrated by evaporator in vacuo to give the crude residue which was purified by  chromatography eluted with Hexane/EtOAc to afford the title compound as a foam (2.3 g, yield 49％) .
1HNMR (500 MHz, CDCl3) : δ 8.38 (s, 1 H) , 7.53 (s, 1 H) , 7.28 (dd, 1 H) , 7.03 (t, 1 H) , 6.11 (q, 1 H) , 1.79 (d, 3 H) , 1.39 (m, 32 H) .
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
Figure PCTCN2015079184-appb-000026
To a solution of the product of Step 5 (2.3 g, 3.66 mmol) in DCM (15 mL) was added a solution of HCl/EA/EtOH (prepared via addition of 1 mL of AcCl to 3 mL of anhydrous EtOH at 0℃) . The solution was stirred at RT for 2 h and 40℃ for 2 h. The solution was then concentrated and dissolved in EA, then adjusted to pH＝8 with 1N NaOH solution, washed with water and brine. The organic phase was concentrated to afford product as a pale yellow foam solid (1.5 g, yield 95％) .
1HNMR (500 MHz, CDCl3) : δ 8.00 (s, 1 H) , 7.25 (m, 1 H) , 7.15 (s, 1H) , 7.01 (m H) , 6.12 (q, 1 H) , 5.00 (s, br, 2 H) , 1.79 (d, 3 H) , 1.28 (s, 6 H) , 1.26 (s, 6 H) .
Step 7 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
Figure PCTCN2015079184-appb-000027
The product of Step 6 (0.17 g, 0.40 mmol) and tert-butyl 2- (4-iodo-1H-pyrazol-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate (0.14 g, 0.33 mmol, prepared by the method described in WO2013013308A1) were dissolved in 1, 4-dioxane (2 mL) into a flask, then a solution of Na2CO3 (2.0 M, 1.2 mL) were added. The reaction mixture was vacuumed and refilled with N2 for 3 times. Pd (PPh3) 2Cl2 (0.030 g, 0.046 mmol) was added to the mixture, and the mixture was vacuumed and refilled with N2 for 3 times again. The reaction mixture was heated to 80℃ with stirring for 4 h. The mixture was cooled to RT and concentrated to give black residue which was treated with EA and water, extracted with EA (20 mL×3) washed with brine, concentrated to give black residue which was purified by chromatography (EA/PE, then DCM/PE and EA/DCM)  twice to afford the title compound as a pale yellow solid (140 mg, yield: 71％) , which was used for next step without further purification.
1H NMR (CDCl3, 500 MHz) : δ 7.73 (s, 1 H) , 7.58 (s, 1 H) , 7.46 (s, 1 H) , 7.29 (m, 1 H) , 7.02 (t, 1 H) , 6.83 (s, 1 H) , 6.04 (q, 1 H) , 4.76 (s, br, 2 H) , 4.73 (t, 1 H) , 3.40 (t, 2 H) , 3.32 (t, 2 H) , 2.42 (m, 2 H) , 2.32 (m, 2 H) , 1.82 (d, 3 H) , 1.60-1.66 (m, 4 H) , 1.44 (s, 9 H) .
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
Figure PCTCN2015079184-appb-000028
Acetyl chloride (0.6 mL) was added to 1.5 mL of anhydrous ethanol over 30 min, maintain a temperature between 5 to 25℃. Following complete addition, the solution was warmed to 20 ℃.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℃. The reaction warmed to 25℃ and stirred for 16 hrs. The reaction mixture was then concentrated and treated with DCM and 1 M HCl, washed with DCM (5 mL×3) . The aqueous phase was adjusted to pH＝10, extract with DCM (15 mL) , concentrated to give the title compound as an off-yellow solid (70 mg, yield: 60％) .
1H NMR (CDCl3, 500 MHz) : . 7.74 (s, 1 H) , 7.57 (s, 1 H) , 7.47 (s, 1 H) , 7.27 (m, 1 H) , 7.03 (t, 1 H) , 6.84 (s, 1 H) , 6.05 (q, 1 H) , 4.72 (s, 2 H) , 4.72 (m, 1 H) , 2.84 (t, 2 H) , 2.76 (t, 2 H) , 2.42 (m, 2H) , 2.27 (m, 2 H) , 1.82 (d, 3 H) , 1.65 (m, 4 H) .
MS (ES-API, pos) 490.1 (M+1) +.
EXAMPLE 2
(S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) pyridin-2-amine
Figure PCTCN2015079184-appb-000029
Step 1 2- (4-iodo-1H-pyrazol-1-yl) -7-azaspiro [3.5] nonane hydrochloride
Figure PCTCN2015079184-appb-000030
Acetyl chloride (0.6 mL) was added to 1.5 mL of anhydrous ethanol over 30 min, maintain a temperature between 5 to 25℃. Following complete addition, the solution was warmed to 20 ℃.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℃. The reaction mixture was warmed to 25℃ 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 2 2- (4-iodo-1H-pyrazol-1-yl) -7-methyl-7-azaspiro [3.5] nonane
Figure PCTCN2015079184-appb-000031
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 Cs2CO3 (0.76 g, 2.32 mmol) . A solution of MeI in DMF (1 mL, 0.75 mmol, prepared by dissolving 2, 14 g of MeI in 20 mL 0f DMF) was then added drop-wise at 10℃ during over 10 min. The reaction mixture was stirred for 4 hrs at 20℃, then poured into water (20 mL) . The mixture was extracted with MTBE (15 mL) , and the extract was washed with water (10 mL×3) and brine, concentrated to obtain the title compound as a pale yellow solid (0.108 g, yield 56％) , which was used for the next step without further purification.
Step3 (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) pyridin-2-amine
Figure PCTCN2015079184-appb-000032
(S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)pyridin-2-amine (0.17 g, 0.40 mmol) and 2- (4-iodo-1H-pyrazol-1-yl) -7-methyl-7-azaspiro [3.5] nonane (0.14 g, 0.33 mmol) were dissolved in 1, 4-dioxane (2 mL) into a flask, then a solution of Na2CO3 (2.0 M, 1.2 mL) were added. The reaction mixture was vacuumed and refilled with N2 for 3 times. Pd (PPh3) 2Cl2 (0.030 g, 0.046 mmol) was added to the mixture, and the reaction mixture was vacuumed and refilled with N2 for 3 times again. The reaction mixture was heated to 80℃ with stirring for 4 h. The mixture was cooled to RT and the aqueous phase was removed, then concentrated to give black residue which was treated with DCM (10 mL) and 1 M HCl solution (10 mL) , washed with DCM (10 mL×3) . The aqueous layer was adjusted to pH＝10 with 1 N NaOH solution, and extracted with DCM (20 mL) . The DCM extract was concentrated to give yellow residue which was purified by chromatography (NH4OH/MeOH/DCM) to afford the title compound as a pale yellow solid (80 mg, yield: 48％) .
1H NMR (CDCl3, 500 MHz) : d 7.77 (1H, d) , 7.59 (1H, s) , 7.49 (1H, s) , 7.30 (1H, dd) , 7.05 (1H, t) , 6.87 (1H, d) , 6.07 (1H, q) , 4.75 (2H, bs) , 4.72 (1H, m) , 2.37-2.45 (2H, m) , 2.25-2.33 (2H, m) , 2.26 (3H, s) , 1.86 (3H, d) , 1.65-1.77 (4H, m) .
MS (ES-API, m/e, pos) 504.2 (M+1) +.
EXAMPLE 3
(S) -5- (1- (2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine formate
Figure PCTCN2015079184-appb-000033
Starting from (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine and tert-butyl 6- (4-bromo-1H-pyrazol-1-yl) -2-azaspiro [3.3] heptane-2-carboxylate, the title compound was prepared by using the procedures described in Step 7 and Step 8 of Example 1 except formic acid was used for the removal of Boc group.
1HNMR (300 MHz, CD3OD) : δ 8.49 (s, 1 H) , 7.76 (s, 1 H) , 7.65 (s, 1 H) , 7.58 (s, 1 H) , 7.44 (dd, 1 H) , 7.23 (t, 1 H) , 6.92 (s, 1 H) , 6.17 (q, 1 H) , 4.77 (m, 1 H) , 4.20 (s, 2 H) , 4.14 (s, 2 H) , 2.82 (m, 4 H) , 1.87 (d, 3 H) .
EXAMPLE 4
(S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- ( (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
Figure PCTCN2015079184-appb-000034
Starting from (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine and tert-butyl 2- (4-iodo-1H-pyrazol-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate, the title compound was prepared by using the procedures described in Step 7 and Step 8 of Example 1.
1H NMR (CDCl3, 300 MHz) : δ 7.76 (s, 1 H) , 7.59 (s, 1 H) , 7.49 (s, 1 H) , 7.29 (m, 1 H) , 7.05 (t, 1 H) , 6.86 (s, 1 H) , 6.07 (q, 1 H) , 4.76 (s, 2 H) , 4.74 (t, 1 H) , 2.86 (t, 2 H) , 2.79 (t, 2 H) , 2.36 (m, 5 H) , 1.85 (d, 3 H) , 1.68 (m, 4 H) .
EXAMPLE 5
5- (1- (cis-6-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (S) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
Figure PCTCN2015079184-appb-000035
Step 1 tert-butyl cis-2- (4-iodo-1H-pyrazol-1-yl) -6-azaspiro [3.5] nonane-6-carboxylate
Figure PCTCN2015079184-appb-000036
To a solution of cis/trans mixture of tert-butyl 2- ( (methylsulfonyl) oxy) -6-azaspiro [3.5] nonane-6-carboxylate (260 mg, 0.81 mmol , prepared according to the methods described in WO2013013308A1) and 4-iodopyrazole (381 mg, 0.92mmol ) in 2 ml DMF, Cs2CO3 (2 mmol) was added in one portion at r. t. Then leave the mixture heated at 80℃ overnight, cooled to r. t when TLC indicated the disappearance of tert-butyl 2- ( (methylsulfonyl) oxy) -6-azaspiro [3.5] nonane-6-carboxylate. The reaction mixture was concentrated by rotary evaporator, diluted with 5ml H2O, then the residue was extracted with EtOAc (10 mLx3 ) . The combined organic layer was washed with brine, dried over Na2SO4, purified by silica gel chromatography (eluted with EA: PE＝5-20％) , first eluted was the title compound, tert-butyl cis-2- (4-iodo-1H-pyrazol-1-yl) -6-azaspiro [3.5] nonane-6-carboxylate (161mg, 47.6％) as white crystal, 1H NMR (400 MHz, CDCl3)
Figure PCTCN2015079184-appb-000037
7.53 (s, 1H) , 7.44 (s, 1H) , 4.76 (s, 1H) , 3.39 (s, 2H) , 3.34 (s, 2H) , 3.39 (dd, J＝11.5, 9.6Hz, 2H) , 2.19-2.23 (m, 2H) , 1.55-1.68 (m, 3H) , 1.45 (s, 10H) , followed by the isomer tert-butyl trans-2- (4-iodo-1H-pyrazol-1-yl) -6-azaspiro [3.5] nonane-6-carboxylate (137mg, 40.5％) as white crystal which was determined by x-ray crystallography to have the trans-stereochemistry [1H NMR (400 MHz, CDCl3)
Figure PCTCN2015079184-appb-000038
7.55 (s, 1H), 7.51 (s, 1H) , 4.85-4.66 (m, 1H) , 3.39 (s, 2H) , 3.31-3.34 (m, 2H) , 2.31 (d, J＝8.0Hz, 4H) , 1.55-1.68 (m, 4H) , 1.45 (s, 9H) ] .
Step 2 tert-butyl cis-2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) -6-azaspiro [3.5] nonane-6-carboxylate
Figure PCTCN2015079184-appb-000039
Isopropyl-magnesium chloride (2 M in THF, 0.9ml ) was added to a solution of the product of Step 1 (417mg, 1.0mmol ) in THF (1.5mL ) at -10℃ over 10 min, maintaining a temperature below 0℃. The temperature was adjusted to 20℃ and the mixture was stirred for 1 h. The resulting solution was transferred to a solution of 2-methoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (248mg, 1.57mmol) in THF (2.5mL) over 15 min, maintaining a temperature between 20 and 30℃ throughout the addition. The temperature was adjusted to 25℃ and the reaction agitated for 4h, The reaction was quenched by slowly addition of saturated NH4Cl solution under ice-bath, the mixture was extracted with EtOAc (50mLx3) , and the combined  extracts were washed with brine, dried over Na2SO4, purified by silica gel chromatography (eluted with EA: PE＝10-30％) , to provide the title compound (337mg, 0.808mmol) as white crystal, yield 80.8％.
1H NMR (300 MHz, CDCl3) 
Figure PCTCN2015079184-appb-000040
7.80 (s, 1H) , 7.77 (s, 1H) , 4.78 (m, 1H) , 3.38 (s, 2H) , 3.33 (t, J＝7.2 Hz, 2H) , 2.32 (d, J＝11.2 Hz, 4H) , 1.67-1.71 (m, 2H) , 1.55-1.58 (m, 2H) , 1.44 (s, 9H) , 1.31 (s, 12H) .
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
Figure PCTCN2015079184-appb-000041
Starting from the product of Step 2 and (S) -5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine, the title compound is prepared by using the procedures described in WO2013013308.
1H NMR (400 MHz, CDCl3) 
Figure PCTCN2015079184-appb-000042
7.75 (d, J＝2.0 Hz, 1H) , 7.57 (d, J＝0.8 Hz, 1H) , 7.48 (d, J＝0.8 Hz, 1H) , 7.29 (dd, J＝8.8, 4.8 Hz, 1H) , 7.04 (dd, J＝8.8, 8.0 Hz, 1H) , 6.85 (d, J＝1.6 Hz, 1H) , 6.06 (q, J＝6.8 Hz, 4 1H) , 4.82-4.66 (m, 3H) , 2.80 (s, 2H) , 2.75 (t, J＝5.2 Hz, 2H) , 2.39-2.24 (m, 2H) , 2.32-2.23 (m, 2H) , 1.85 (d, J＝6.8 Hz, 3H) , 1.69 (t, J＝6.0 Hz, 2H) , 1.59-1.52 (m, 2H) .
EXAMPLE 6
5- (1- ( (trans-6-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (S) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine
Figure PCTCN2015079184-appb-000043
Starting from tert-butyl (trans-2- (4-iodo-1H-pyrazol-1-yl) -6-azaspiro [3.5] nonane-6-carboxylate and (S) -5-bromo-3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine, the title compound is prepared by the same procedure described in Step 2 of Example 5 and WO2013013308.
1H NMR (400 MHz, CDCl3)
Figure PCTCN2015079184-appb-000044
7.75 (d, J＝1.6 Hz, 1H) , 7.59 (s, 1H) , 7.48 (s, 1H) , 7.29 (dd, J＝8.8, 4.8 Hz, 1H) , 7.05 (t, J＝8.4 Hz, 1H) , 6.86 (d, J＝1.6 Hz, 1H) , 6.07 (q, J＝6.8 Hz, 1H) , 4.76 (s, 2H) , 4.69 (t, J＝8.4 Hz, 1H) , 2.86 (s, 2H) , 2.79 (t, J＝4.4 Hz, 2H) , 2.53-2.43 (m, 2H) , 2.25-2.30 (m, 2H) , 1.85 (d, J＝6.8 Hz, 3H) , 1.72-1.65 (m, 2H) , 1.53-1.54 (m, 2H) .
EXAMPLE 7
(S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) pyridin-2-amine
Figure PCTCN2015079184-appb-000045
Starting from (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine and tert-butyl 7- (4-iodo-1H-pyrazol-1-yl) -2- azaspiro [3.5] nonane-2-carboxylate (prepared according to the methods described in WO2013013308A1) , the title compound was prepared by using the procedures described for Example 2.
MS (ES-API, m/e, pos) 504.2 (M+1) +.
EXAMPLE 8
(S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) pyridin-2-amine
Figure PCTCN2015079184-appb-000046
Starting from (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine and tert-butyl 6- (4-bromo-1H-pyrazol-1-yl) -2- azaspiro [3.3] heptane-2-carboxylate (prepared according to the methods described in WO2013013308A1) , the title compound was prepared by using the procedures described for Example 2.
MS (ES-API, m/e, pos) 476.1 (M+1) +.
BIOCHEMICAL EVALUATION
MTH1 catalytic assay half-maximal inhibitory concentrations (IC50) 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. After addition of the substrate dGTP (Fermentas, final concentration 100mM) , 8-oxo-dGTP (TriLink Biotechnologies, final concentration 13.2mM) , or 2-OH-dATP (Jena Bioscience, final concentration 8.3mM) the generation of pyrophosphate (PPi) as a result of nucleotide triphosphate hydrolysis by MTH1 is monitored over a time course of 15 min using the PPiLight Inorganic Pyrophosphate Assay kit (Lonza Rockland) . IC50values are determined by fitting a dose–response curve to the data points using nonlinear regression analysis using the GraphPad Prism software.
MTH1 inhibitory activity of examples
Compound Example 1 Example 2 Example 6 SCH51344 S-Crizotinib
IC50 (nM) 96 75 42 1020 420
Assays were conducted at Reaction Biology Corp.
PHARMACOKINETIC ANALYSIS
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.
Figure PCTCN2015079184-appb-000047
Example 2 has an expected long MRT (16.7 hr for Example 2 vs 6.7 hr for S-Crizotinib) and t1/2 (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.
While preferred embodiments have been described above and illustrated in the accompanying drawings, it will be evident to those skilled in the art that modifications may be made without departing from this disclosure. Such modifications are considered as possible variants comprised in the scope of the disclosure.

Claims (12)

  1. A compound of Formula I
    Figure PCTCN2015079184-appb-100001
    or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    Ring A is a 3 to 12 membered carbocyclic ring, or is a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms are replaced with one or more O, S, -C (O) -, -C (S) -, -S (O) 2-and NR1； and wherein said Ring A is unsubstituted or substituted by one or more Rc；
    Ring B is a 3 to 12 membered carbocyclic ring, or is a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms are optionally replaced with one or more O, S, -C (O) -, -C (S) -and NR1； and wherein said Ring B is unsubstituted or substituted by one or more Rc；
    R1 is independently chosen from hydrogen, C1-12 alkyl, C1-12 alkyl in which one carbon atom is replaced with Si, O, S atom, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, -C (O) R4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nP (O) (OR) 2 4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, - (CR6R7) nNCR4 (R5) 2, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, -C (O) - (CR6R7) n-NR4R5, and wherein each hydrogen in R1 is unsubstituted or substituted by Rc, or one of the hydrogen in R1 is replaced with -P (O) (OR9) 2, -P (O) (R9) 2；
    Rc is independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -NH2, -CN, SF5, -OH, -O-C1-12alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) or -O- (CH2) n (5-12 membered heteroaryl ring) ；
    R2 is selected from
    Figure PCTCN2015079184-appb-100002
    wherein:
    X is N or CR12；
    Ar is C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and Ar is unsubstituted or substituted by one or more Rc groups；
    Figure PCTCN2015079184-appb-100003
    is selected from C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, wherein
    Figure PCTCN2015079184-appb-100004
    is unsubstituted or substituted by one, two or three Rc groups；
    R3 is chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, SF5, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and each hydrogen in R3 is unsubstituted or substituted by R8；
    Rc is independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -S (O) 2NR4R5, -S (O) 2OR4, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5,
    and wherein each hydrogen in Rc is unsubstituted or substituted by R8, and wherein Rc groups on adjacent atoms are uncombined or combine to form a C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring；
    R4, R5, R6 and R7 are independently chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 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；
    or any two of R4, R5, R6 and R7 bound to the same nitrogen atom, together with the nitrogen to which they are bound, 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 R4, R5, R6 and R7 bound to the same carbon atom combine to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl ring；
    and each hydrogen in R4, R5, R6 and R7 is unsubstituted or substituted by R8, or two hydrogen atoms on the same carbon atom in R4, R5, R6 and R7 is unsubstituted or are an oxo substituent；
    R8 is independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -NH2, -CN, -OH, -O-C1-12alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) or -O- (CH2) n (5-12 membered heteroaryl ring) ； and each hydrogen in R8 is unsubstituted or substituted by R11；
    R9 is independently chosen from a C1-12 alkyl, aryl, heteroaryl which is unsubstituted or substituted；
    R10 is independently chosen from a C1-12 alkyl which is unsubstituted or substituted；
    R11 is independently chosen from halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) , -O- (CH2) n (5-12 membered heteroaryl ring) or -CN, and each hydrogen in R11 is unsubstituted or substituted by halogen, -OH, -CN, -C1-12 alkyl which is unsubstituted, or partially halogenated or fully halogenated, -O-C1-12 alkyl which is unsubstituted or partially halogenated or fully halogenated, or substituted with -CO；
    R12 is chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, - SO2NR4R5, -S (O) 2OR4, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and each hydrogen in R12 is unsubstituted orsubstituted by R3；
    Ra and Rb is independently chosen from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3- 12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, - (CR6R7) nOR4, -CN, -C (O) R4, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5 or -C (O) NR4R5； and Raor Rb are uncombined or together with the carbon to which they are attached to, Ra or Rbcombine to form a 3-12 membered ring or a 3-12 membered ring which contains one or moreheteroatom chosen from NR4, O, S, Si； or
    Ra and Rb combine with a ring atom of Ar or a substituent of Ar to form a C5-12 cycloalkyl, 5-12 membered heteroalicyclic ring fused to Ar； and each hydrogen in Ra and Rb is unsubstitutedor substituted by Rc；
    each m is independently 0, 1 or 2；
    each n is independently 0, 1 , 2, 3 or 4；
    q is 1 , 2, 3 or 4.
  2. A compound according to Claim 1, wherein
    Figure PCTCN2015079184-appb-100005
    is selected from
    Figure PCTCN2015079184-appb-100006
    or an aryl, bicyclic aryl, bicyclic heteroaryl, unsubstituted or substituted by one, two or three Rc groups as defined above.
  3. The compound of claim 1, wherein said compound is selected from:
    Figure PCTCN2015079184-appb-100007
    wherein:
    Ring A is a 3 to 12 membered carbocyclic ring or a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms are replaced with one or more O, S, -C (O) -, -C (S) -and NR1； and wherein said Ring A is unsubstituted or substituted by one or more Rc；
    Ring B is a 3 to 12 membered carbocyclic ring or a 3 to 12 membered carbocyclic ring in which one or more carbon ring atoms are replaced with one or more O, S, -C (O) -, -C (S) -and NR1； and wherein said Ring B is unsubstituted or substituted by one or more Rc；
    R1 is independently chosen from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, -C (O) R4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and wherein each hydrogen in R1 is unsubstituted or substituted by Rc；
    X is N or CR12；
    Ar is C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring, and wherein Ar is unsubstituted or substituted by one or more Rc groups；
    R3 is chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, SF5, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and wherein each hydrogen in R3 is unsubstituted or substituted by R8；
    Rc is independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -S (O) 2NR4R5, -S (O) 2OR4, SF5, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nOR4, - (CR6R7) nC (O) NR4R5, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and wherein each hydrogen in Rc is unsubstituted or substituted by R8, and wherein Rc groups on adjacent atoms are uncombined or combine to form a C6-12 aryl, 5-12 membered heteroaryl ring, C3-12 cycloalkyl or 3-12 membered heteroalicyclic ring；
    R4, R5, R6 and R7 is independently chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 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；or any two of R4, R5, R6 and R7 bound to the same nitrogen atom, together with the nitrogen to which they are bound, 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 R4, R5, R6 and R7 bound to the same carbon atom combine to form a C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring or 5-12 membered heteroaryl ring； and each hydrogen in R4, R5, R6 and R7 is unsubstituted or substituted by R8, or two hydrogen atoms on the same carbon atom in R4, R5, R6 and R7 is unsubstituted or an oxo substituent；
    R8 is independently chosen from halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -NH2, -CN, -OH, -O-C1-12alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) or -O- (CH2) n (5-12 membered heteroaryl ring) ； and each hydrogen in R8 is unsubstituted or substituted by R11；
    R11 is independently chosen from halogen, C1-12 alkyl, C1-12 alkoxy, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -O-C1-12 alkyl, -O- (CH2) nC3-12 cycloalkyl, -O- (CH2) nC6-12 aryl, -O- (CH2) n (3-12 membered heteroalicyclic ring) , -O- (CH2) n (5-12 membered heteroaryl ring) or -CN, and each hydrogen in R11 is unsubstituted or substituted by halogen, -OH, -CN, -C1-12 alkyl which is unsubstituted or partially halogenated or fully halogenated, -O-C1-12 alkyl which is unsubstituted or partially halogenated or fully halogenated, or substituted with -CO；
    R12 is chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -O (CR6R7) nR4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -C (＝NR6) NR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5, and each hydrogen in R12 is unsubstituted or substituted by R3；
    Ra and Rb is independently chosen from hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, 3-12 membered heteroalicyclic ring, 5-12 membered heteroaryl ring, -S (O) mR4, -SO2NR4R5, -S (O) 2OR4, -NO2, -NR4R5, - (CR6R7) nOR4, -CN, -C (O) R4, -OC (O) R4, -NR4C (O) R5, - (CR6R7) nC (O) OR4, - (CR6R7) nNCR4R5, -NR4C (O) NR5R6, -NR4S (O) 2R5 or -C (O) NR4R5； or together with the carbon to which they are attached to, Ra or Rb combine to form a 3-12 membered ring which may contains one or more heteroatom chosen from NR4, O, S, Si, or Ra and Rb combine with a ring atom of A or a substituent of A to form a C3-12 cycloalkyl, a 3-12 membered heteroalicyclic ring, C6-12 aryl or a 5-12 membered heteroaryl ring fused to A； and each hydrogen in Ra and Rb is unsubstituted or substituted by Rc；
    each m is independently 0, 1 or 2；
    each n is independently 0, 1 , 2, 3 or 4；
    q is 1 , 2, 3 or 4；
    or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  4. The compound of claim 4, wherein said compound is selected from:
    Figure PCTCN2015079184-appb-100008
    wherein R3, Ring-Aand Ring-B are defined as in Claim 3. Ar is phenyl which is unsubstituted or substituted by one or more Rc groups； Rc is defined as in Claim 3.
  5. The compound according to Claim 1, wherein
    Figure PCTCN2015079184-appb-100009
    is selected from the group consisting of:
    Figure PCTCN2015079184-appb-100010
    Figure PCTCN2015079184-appb-100011
    Figure PCTCN2015079184-appb-100012
  6. The compounds of claim 5, wherein said compound is selected from the following group:
    (S) -5- (1- (2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -3- ( (R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
    (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；
    (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) pyridin-2-amine；
    (S) -3- (1- (3, 4-difluorophenyl) ethoxy) -5- (1- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) pyridin-2-amine；
    (S) -3- (1- (4-fluorophenyl) ethoxy) -5- (1- (7-methyl-7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) pyridin-2-amine；
    (S) -5- (1- (7-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- (1- (4-fluorophenyl) ethoxy) pyridin-2-amine
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
    5- (1- (cis-6-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (S) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
    5- (1- ( (trans-6-azaspiro [3.5] nonan-2-yl) -1H-pyrazol-4-yl) -3- ( (S) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1-phenylethoxy) pyridin-2-amine；
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-fluorophenyl) ethoxy) pyridin-2-amine；
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-chlorophenyl) ethoxy) pyridin-2-amine；
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-chloro-3-fluorophenyl) ethoxy) pyridin-2-amine；
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (3, 4-difluorophenyl) ethoxy) pyridin-2-amine；
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4-bromophenyl) ethoxy) pyridin-2-amine；
    (S) -5- (1- (2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) -3- (1- (4- (trifluoromethyl) phenyl) ethoxy) pyridin-2-amine；
    (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) pyridin-2-amine.
    (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) pyridin-2-amine；
    (S) -3- (1- (3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) pyridin-2-amine
    (S) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) pyridin-2-amine
    (S) -3- (1- (3-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) pyridin-2-amine.
    (S) -3- (1- (4-fluorophenyl) ethoxy) -5- (1- (2-methyl-2-azaspiro [3.5] nonan-7-yl) -1H-pyrazol-4-yl) pyridin-2-amine.
  7. Use of a compound of any one of claims 1-6 for preparing pharmaceutical compositions for the treatment or prevention of cancers.
  8. The use of claim 7, wherein the cancer is chosen from the following group: 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 cancer, prostate cancer, small-cell lung cancer, and lymphoid malignancy of B-cell origin.
  9. A pharmaceutical composition, wherein comprises the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, hydrate or solvate thereof, and pharmaceutically acceptable carriers.
  10. A composition comprising a combination of a compound of any one of claims 1-6, and an anti-cancer agent selected from a cytotoxic agent, an antimitotic agent, an anti-metabolite, a proteasome inhibitor, a HDAC inhibitor, an antibody targeting specific receptors on tumor cell surface, an antibody targeting check-point proteins, an IDO inhibitor and another kinase inhibitor.
  11. A method treating a cancer in a patient in need thereof by administering to said patient a therapeutically effective amount of a compound of any one of claims 1-6, or the composition of claim 9, or 10, wherein said 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 cancer, prostate cancer, small-cell lung cancer, and lymphoid malignancy of B-cell origin.
  12. A method of treating a patient afflicted with cancer by administering to the patient a therapeutically effective amount of a compound of any one of claims 1-6, or a composition of claim 9 or 10 in combination with radiotherapy.
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Cited By (10)

* 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
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

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076412A2 (en) * 2003-02-26 2004-09-10 Sugen, Inc. Aminoheteroaryl compounds as protein kinase inhibitors
WO2006021881A2 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
WO2014033136A1 (en) * 2012-08-27 2014-03-06 Cemm - Research Center For Molecular Medicine Of The Austrian Academy Of Sciences Aminoheteroaryl compounds as mth1 inhibitors
WO2014084778A1 (en) * 2012-11-27 2014-06-05 Thomas Helledays Stiftelse För Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076412A2 (en) * 2003-02-26 2004-09-10 Sugen, Inc. Aminoheteroaryl compounds as protein kinase inhibitors
WO2006021881A2 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
WO2014033136A1 (en) * 2012-08-27 2014-03-06 Cemm - Research Center For Molecular Medicine Of The Austrian Academy Of Sciences Aminoheteroaryl compounds as mth1 inhibitors
WO2014084778A1 (en) * 2012-11-27 2014-06-05 Thomas Helledays Stiftelse För Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of 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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