NZ621245B2 - Pyrimidine pde10 inhibitors - Google Patents
Pyrimidine pde10 inhibitors Download PDFInfo
- Publication number
- NZ621245B2 NZ621245B2 NZ621245A NZ62124512A NZ621245B2 NZ 621245 B2 NZ621245 B2 NZ 621245B2 NZ 621245 A NZ621245 A NZ 621245A NZ 62124512 A NZ62124512 A NZ 62124512A NZ 621245 B2 NZ621245 B2 NZ 621245B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- methoxy
- cyclopropyl
- pyrimidinamine
- thiadiazolyl
- Prior art date
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title claims description 29
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- -1 (1) pyridyl Chemical group 0.000 claims description 408
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 229
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- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 117
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- 201000010099 disease Diseases 0.000 claims description 58
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- RQSCFNPNNLWQBJ-UHFFFAOYSA-N 2-methyl-1,3,4-thiadiazole Chemical compound CC1=NN=CS1 RQSCFNPNNLWQBJ-UHFFFAOYSA-N 0.000 claims description 30
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- 229950009253 perlapine Drugs 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 150000002990 phenothiazines Chemical class 0.000 description 1
- 201000001552 phobic disease Diseases 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229940096701 plain lipid modifying drugs HMG CoA reductase inhibitors Drugs 0.000 description 1
- 231100000773 point of departure Toxicity 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- GIIPADVFWNGSKY-UHFFFAOYSA-N potassium;ethyl(trifluoro)boranuide Chemical compound [K+].CC[B-](F)(F)F GIIPADVFWNGSKY-UHFFFAOYSA-N 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
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- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
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- FWLKYEAOOIPJRL-UHFFFAOYSA-N prop-1-yn-1-ol Chemical compound CC#CO FWLKYEAOOIPJRL-UHFFFAOYSA-N 0.000 description 1
- DFWRZHZPJJAJMX-UHFFFAOYSA-N propanimidamide;hydrochloride Chemical compound Cl.CCC(N)=N DFWRZHZPJJAJMX-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960001964 quazepam Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000003252 repetitive Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 201000010757 separation anxiety disease Diseases 0.000 description 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 239000000952 serotonin receptor agonist Substances 0.000 description 1
- 229940121356 serotonin receptor antagonists Drugs 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- WZAIVXXKOAWTGQ-UHFFFAOYSA-N spiro[2,3-dihydronaphthalene-4,3'-piperidine]-1,2',6'-trione Chemical compound O=C1NC(=O)CCC11C2=CC=CC=C2C(=O)CC1 WZAIVXXKOAWTGQ-UHFFFAOYSA-N 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
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- 230000035882 stress Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- XPZWKUUKBBWIPK-UHFFFAOYSA-N tert-butyl-[[2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl]methoxy]-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCC1CC1C1=CC=C(CCC2)C2=N1 XPZWKUUKBBWIPK-UHFFFAOYSA-N 0.000 description 1
- VPYJHKWXPHLMSE-UHFFFAOYSA-N tert-butyl-dimethyl-[[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]methoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OCC1CC1B1OC(C)(C)C(C)(C)O1 VPYJHKWXPHLMSE-UHFFFAOYSA-N 0.000 description 1
- DBUXTCMGJCJPJJ-UHFFFAOYSA-N tert-butylazanium;chloride;hydrate Chemical compound O.[Cl-].CC(C)(C)[NH3+] DBUXTCMGJCJPJJ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- ODGCEQLVLXJUCC-UHFFFAOYSA-N tetrafluoroborate Chemical class F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- NZFNXWQNBYZDAQ-UHFFFAOYSA-N thioridazine hydrochloride Chemical compound Cl.C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C NZFNXWQNBYZDAQ-UHFFFAOYSA-N 0.000 description 1
- 150000005075 thioxanthenes Chemical class 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002936 tranquilizing Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 102000003995 transcription factors Human genes 0.000 description 1
- 108090000464 transcription factors Proteins 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YYQKQPYPLADFMK-UHFFFAOYSA-N tributyl(1,3-thiazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CSC=N1 YYQKQPYPLADFMK-UHFFFAOYSA-N 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- 229960001147 triclofos Drugs 0.000 description 1
- BXDAOUXDMHXPDI-UHFFFAOYSA-N trifluoperazine hydrochloride Chemical compound [H+].[H+].[Cl-].[Cl-].C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 BXDAOUXDMHXPDI-UHFFFAOYSA-N 0.000 description 1
- PBDNIOPZROFNME-UHFFFAOYSA-N trimethyl-[2-(5-methylpyridin-2-yl)ethynyl]silane Chemical compound CC1=CC=C(C#C[Si](C)(C)C)N=C1 PBDNIOPZROFNME-UHFFFAOYSA-N 0.000 description 1
- 229950001577 trimetozine Drugs 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 229960004010 zaleplon Drugs 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
Classifications
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Disclosed are pyrimidine compounds of formula (I), wherein the substituents are as defined in the specification. The compounds are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10) including neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction. An example of a compound of formula (I) is: 2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-6-[(2-pyridin-2-ylcyclopropyl)methoxy]pyrimidin-4-amine sorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction. An example of a compound of formula (I) is: 2-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-6-[(2-pyridin-2-ylcyclopropyl)methoxy]pyrimidin-4-amine
Description
MRL-NOP-00136
TITLE OF THE INVENTION
PYRIMIDINE PDE10 INHIBITORS
FIELD OF THE INVENTION
The invention relates generally to compounds which act as inhibitors of the
phosphodiesterase (PDE) 10 enzyme, compositions and therapeutic uses thereof.
BACKGROUND OF THE INVENTION
Schizophrenia is a debilitating disorder affecting the psychic and motor functions
of the brain. It is typically diagnosed in individuals in their early to mid-twenties and symptoms
include hallucinations and delusions or at the other extreme, anhedonia or social withdrawal.
Across the spectrum, the symptoms are indicative of cognitive impairment and functional
disabilities. Notwithstanding improvements in antipsychotic treatments, current therapies,
including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, have been
less than acceptable and result in an extremely high rate of noncompliance or discontinuation of
medication. Dissatisfaction with therapy is attributed to lack of efficacy or intolerable and
unacceptable side affects. The side effects have been associated with significant metabolic,
extrapyramidal, prolactic and cardiac adverse events. See, Lieberman et al., N. Engl. J. Med.
(2005) 353:1209-1223.
While multiple pathways are believed to be involved with the pathogenesis of
schizophrenia leading to psychosis and cognition deficits, much attention has focused on the role
of glutamate/NMDA dysfunction associated with cyclic guanosine monophosphate (cGMP)
levels and the dopaminergic D2 receptor associated with cyclic adenosine monophosphate
(cAMP). These ubiquitous second messengers are responsible for altering the function of many
intracellular proteins. Cyclic AMP is thought to regulate the activity of cAMP-dependent protein
kinase (PKA), which in turns phosphorylates and regulates many types of proteins including ion
channels, enzymes and transcription factors. Similarly, cGMP is also responsible for
downstream regulation of kinases and ion channels.
One pathway for affecting the levels of cyclic nucleotides, such as cAMP and
cGMP, is to alter or regulate the enzymes that degrade these enzymes, known as 3', 5'-cyclic
nucleotide specific phosphodiesterases (PDEs). The PDE superfamily includes twenty one genes
that encode for eleven families of PDEs. These families are further subdivided based on catalytic
domain homology and substrate specificity and include the 1) cAMP specific, PDE4A-D, 7A and
MRL-NOP-00136
7B, and 8A and 8B, 2) cGMP specific, PDE 5A, 6A-C, and 9A, and 3) those that are dual
substrate, PDE 1A-C, 2A, 3A and 3B, 10A, and 11A. The homology between the families,
ranging from 20% to 45% suggests that it may be possible to develop selective inhibitors for each
of these subtypes.
The identification of PDE10 was reported by three groups independently and was
distinguished from other PDEs on the basis of its amino acid sequence, functional properties, and
tissue distribution (Fujishige et al., J. Biol. Chem. (1999) 274:18438-18445; Loughney et al.,
Gene (1999) 234: 109-117; Soderling et al., PNAS, USA (1999) 96: 7071-7076). The PDE10
subtype at present consists of a sole member, PDE10A, having alternative splice variants at both
the N-terminus (three variants) and C-terminus (two variants), but that does not affect the GAF
domain in the N-terminus or the catalytic site in C-terminus. The N-terminus splice variants,
PDE10A1 and PDE10A2, differ in that the A2 variant has a PKA phosphorylation site that upon
activation, i.e. PKA phosphorylation in response to elevated cAMP levels, results in intracellular
changes to the localization of the enzyme. PDE10A is unique relative to other PDE families also
having the conserved GAF domain in that its ligand is cAMP, while for the other GAF-domain
PDEs the ligand is cGMP (Kehler et al., Expert Opin. Ther. Patents (2007) 17(2): 147-158).
PDE10A has limited but high expression in the brain and testes. The high expression in the brain
and, in particular, the neurons of the striatum, unique to PDE10, suggests that inhibitors thereto
may be well suited from treating neurological and psychiatric disorders and conditions.
Inhibition of PDE10 is believed to be useful in the treatment of schizophrenia and
a wide variety of conditions or disorders that would benefit from increasing levels of cAMP
and/or cGMP within neurons, including a variety neurological, psychotic, anxiety and/or
movement disorders. Accordingly, agents that inhibit PDE10 and especially PDE10A would be
desirable as therapeutics for neurological and psychiatric disorders.
SUMMARY OF THE INVENTION
The present invention is directed to pyrimidine compounds which are useful as
therapeutic agents for the treatment of central nervous system disorders associated with
phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds
for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or
Huntington's disease, and those associated with striatal hypofunction or basal ganglia
dysfunction.
MRL-NOP-00136
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of the formula I:
wherein:
A is selected from the group consisting of:
(1) pyridyl,
(2) quinolinyl,
(3) naphthyridinyl,
(4) thiazolyl,
(5) pyridazinyl,
(6) oxazolyl, and
(7) pyrazolyl,
(8) dihydropyrrolopyrazolyl,
(9) dihydrocyclopentapyridinyl,
(10) imidazopyridazinyl, and
(11) pyrazolopyrimidinyl;
B is selected from the group consisting of:
(1) thiazolyl,
(2) pyrazolyl,
(3) thiadiazolyl,
(4) isoxazolyl,
(5) isothiazolyl,
(6) pyridyl, and
(7) pyrimidinyl;
1a 1b 1c
R , R and R are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
MRL-NOP-00136
(4) -(C=O) -O -C alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0,
m n 1-6
a bond is present) and where the alkyl is unsubstituted or substituted with one or more
substituents selected from R ,
(5) -(C=O) -O -C cycloalkyl, where the cycloalkyl is unsubstituted or substituted
m n 3-6
with one or more substituents selected from R ,
(6) -(C=O) -C alkenyl, where the alkenyl is unsubstituted or substituted with one
m 2-4
or more substituents selected from R ,
(7) -(C=O) -C alkynyl, where the alkynyl is unsubstituted or substituted with one
m 2-4
or more substituents selected from R ,
(8) -(C=O) -O -phenyl or -(C=O) -O -naphthyl, where the phenyl or naphthyl is
m n m n
unsubstituted or substituted with one or more substituents selected from R ,
(9) -(C=O) -O -heteroaryl, where the heteraryl is unsubstituted or substituted with
one or more substituents selected from R ,
11
(10) -(C=O) -NR R ,
11
(11) -S(O) -NR R ,
12 12
(12) -S(O) -R , where q is 0, 1 or 2 and where R is selected from the definitions of
11
R and R ,
(13) -CO H,
(14) -CN, and
(15) -NO ;
2a 2b 2c
R , R and R are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) -(C=O) -O -C alkyl, where the alkyl is unsubstituted or substituted with one
m n 1-6
or more substituents selected from R ,
(5) -(C=O) -O -C cycloalkyl, where the cycloalkyl is unsubstituted or substituted
m n 3-6
with one or more substituents selected from R ,
(6) -(C=O) -C alkenyl, where the alkenyl is unsubstituted or substituted with one
m 2-4
or more substituents selected from R ,
(7) -(C=O) -C alkynyl, where the alkynyl is unsubstituted or substituted with one
m 2-4
or more substituents selected from R ,
(8) -(C=O) -O -phenyl or -(C=O) -O -naphthyl, where the phenyl or naphthyl is
m n m n
unsubstituted or substituted with one or more substituents selected from R ,
(9) -(C=O) -O -heterocyclyl, where the heterocyclyl is unsubstituted or substituted
with one or more substituents selected from R ,
MRL-NOP-00136
11
(10) -(C=O) -NR R ,
11
(11) -S(O) -NR R ,
(12) -S(O) -R ,
(13) -CO H,
(14) -CN, and
(15) -NO ;
R is selected from the group consisting of:
(1) CH ,
(2) CF ,
(3) CH F,
(4) CH CH ,
(5) cyclopropyl,
(6) cyano,
(7) hydrogen,
(8) NH ,
(9) C(O)OR ,
(10) -O-C alkyl,
(11) -(CO)NH ,
(12) C alkylOH,
(13) C(O) C alky, and
(14) halogen;
R is selected from the group consisting of:
(1) hydrogen,
(2) halo,
(3) -C alkyl, and
(4) cyano,
R is selected from the group consisting of:
(1) hydrogen, and
(2) C alkyl;
R is selected from the group consisting of:
(1) hydrogen,
(2) C alkyl, and
(3) OC alkyl;
MRL-NOP-00136
11
R and R are independently selected from the group consisting of:
(a) hydrogen,
(b) C alkyl, which is unsubstituted or substituted with R ,
(c) C alkenyl, which is unsubstituted or substituted with R ,
(d) C alkynyl, which is unsubstituted or substituted with R ,
(e) C cycloalkyl which is unsubstituted or substituted with R ,
(f) C alkoxyl, which is unsubstituted or substituted with R ,
(g) phenyl, which is unsubstituted or substituted with R , and
(h) heteroaryl, which is unsubstituted or substituted with R ,
R is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) -(C=O) -O -C alkyl, where the alkyl is unsubstituted or substituted with one
m n 1-6
or more substituents selected from R ,
(4) -O -(C )perfluoroalkyl,
n 1-3
(5) -(C=O) -O -C cycloalkyl, where the cycloalkyl is unsubstituted or substituted
m n 3-6
with one or more substituents selected from R ,
(6) -(C=O) -C alkenyl, where the alkenyl is unsubstituted or substituted with one
m 2-4
or more substituents selected from R ,
(7) -(C=O) -C alkynyl, where the alkynyl is unsubstituted or substituted with one
m 2-4
or more substituents selected from R ,
(8) -(C=O) -O -phenyl or -(C=O) -O -naphthyl, where the phenyl or naphthyl is
m n m n
unsubstituted or substituted with one or more substituents selected from R ,
(9) -(C=O) -O -heteroaryl, where the heteroaryl is unsubstituted or substituted with
one or more substituents selected from R ,
11
(10) -(C=O) -NR R ,
11
(11) -S(O) -NR R ,
(12) -S(O) -R ,
(13) -CO H,
(14) -CN, and
(15) -NO ;
R is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C alkyl,
MRL-NOP-00136
(4) -C cycloalkyl,
(5) -O-C alkyl,
(6) -O(C=O)-C alkyl,
(7) -NH-C alkyl,
(8) phenyl,
(9) heteroaryl,
(10) -CO H, and
(11) -CN;
or a pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ia:
1a 1b 1c 2a 2b 2c 3 4 5
wherein A, B, R , R , R , R , R , R , R , R , and R are defined herein; or a
pharmaceutically acceptable salt thereof.
An embodiment of the present invention includes compounds of the formula Ib:
1a 1b 1c 2a 2b 2c
wherein A, B, R , R , R , R , R , and R are defined herein; or a pharmaceutically
acceptable salt thereof.
An embodiment of the present invention includes compounds wherein A is
selected from the group consisting of:
(1) pyridyl,
(2) quinolinyl,
MRL-NOP-00136
(3) naphthyridinyl,
(4) thiazolyl,
(5) pyridazinyl,
(6) oxazolyl, and
(7) pyrazolyl.
An embodiment of the present invention includes compounds wherein A is
selected from the group consisting of:
(1) pyridyl,
(2) quinolinyl, and
(3) naphthyridinyl.
An embodiment of the present invention includes compounds wherein A is
selected from the group consisting of:
An embodiment of the present invention includes compounds wherein A is
pyridyl. An embodiment of the present invention includes compounds wherein A is quinolinyl.
An embodiment of the present invention includes compounds wherein A is naphthyridinyl.
An embodiment of the present invention includes compounds wherein the
cyclopropyl group which connects the group A to the -CH O- group is substituted in an (S,S)
stereochemical orientation.
An embodiment of the present invention includes compounds of the formula Ic:
N N N
1a 1b 1c 2a 2b 2c
wherein B, R , R , R , R , R , and R are defined herein; or a pharmaceutically
acceptable salt thereof.
MRL-NOP-00136
An embodiment of the present invention includes compounds wherein B is
selected from the group consisting of:
(1) thiazolyl,
(2) pyrazolyl, and
(3) thiadiazolyl.
An embodiment of the present invention includes compounds wherein B is
thiazolyl. An embodiment of the present invention includes compounds wherein B is pyrazolyl.
An embodiment of the present invention includes compounds wherein B is thiadiazolyl.
An embodiment of the present invention includes compounds wherein B is
selected from the group consisting of:
An embodiment of the present invention includes compounds wherein B is
selected from the group consisting of:
An embodiment of the present invention includes compounds wherein B is:
An embodiment of the present invention includes compounds wherein B is:
An embodiment of the present invention includes compounds wherein B is:
MRL-NOP-00136
1a 1b
An embodiment of the present invention includes compounds wherein R , R ,
R are selected from the group consisting of:
(1) C alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(2) -O-C alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
(3) phenyl, which is unsubstituted or substituted with halogen, hydroxyl,
-NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl,
2 1-6 1-6 1-6 1-6 1-6
which is unsubstituted or substituted with fluoro,
(4) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl,
-NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl,
2 1-6 1-6 1-6 1-6 1-6
which is unsubstituted or substituted with fluoro,
(5) -O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl,
-NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl,
2 1-6 1-6 1-6 1-6 1-6
which is unsubstituted or substituted with fluoro, and
(6) -O-heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl,
-NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl,
2 1-6 1-6 1-6 1-6 1-6
which is unsubstituted or substituted with fluoro.
1a 1b
An embodiment of the present invention includes compounds wherein R , R ,
R are selected from the group consisting of:
(1) hydrogen,
(2) chloro,
(3) fluoro,
(4) bromo,
(5) methyl,
(6) methoxy,
(7) (methyl)cyclopropyl-,
(8) cyclopropyl,
(9) (methoxy)phenyl-, and
(10) (methyl)phenyl-.
2a 2b
An embodiment of the present invention includes compounds wherein R , R
and R are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
MRL-NOP-00136
(4) C alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl
or naphthyl,
(5) -O-C alkyl, which is unsubstituted or substituted with halogen, hydroxyl or
phenyl,
(6) heterocyclyl, wherein heterocyclyl is selected from imidazolyl, isothiazolyl,
oxazolyl, morpholinyl, pyrazolyl, pyridyl, tetrazolyl, and thiazolyl, which is unsubstituted or
substituted with halogen, hydroxyl, C alkyl, -O-C alkyl or-NO , and
1-6 1-6 2
(7) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C alkyl,
-O-C alkyl or-NO .
1-6 2
An embodiment of the present invention includes compounds wherein is R is
2a 2b
hydrogen and R and R are independently selected from the group consisting of:
(1) hydrogen,
(2) chloro,
(3) fluoro,
(4) bromo,
(5) methyl,
(6) cyclopropyl;
(7) isopropoxy,
(8) methoxy, and
(9) t-butoxy.
An embodiment of the present invention includes compounds wherein is R is
2a 2b
hydrogen and R and R are independently selected from the group consisting of:
(1) hydrogen,
(2) methyl, and
(3) cyclopropyl.
An embodiment of the present invention includes compounds wherein is R is
2b 2a
hydrogen, R is hydrogen or methyl and R is methyl or cyclopropyl.
An embodiment of the present invention includes compounds wherein R is
selected from the group consisting of CH , CF , and CH F.
3 3 2
An embodiment of the present invention includes compounds wherein R is CH .
An embodiment of the present invention includes compounds wherein R is
selected from the group consisting of hydrogen and fluoro. An embodiment of the present
invention includes compounds wherein R is hydrogen.
An embodiment of the present invention includes compounds wherein R is
selected from the group consisting of hydrogen and methyl. An embodiment of the present
invention includes compounds wherein R is hydrogen.
MRL-NOP-00136
Specific embodiments of the present invention include a compound which is
selected from the group consisting of the subject compounds of the Examples herein and
pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
As appreciated by those of skill in the art, halogen or halo as used herein are
intended to include fluorine, chlorine, bromine and iodine. Similarly, "alkyl", as well as other
groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains which may be
linear or branched or combinations thereof. C , as in C alkyl is defined to identify the group
1-6 1-6
as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such as methyl, ethyl, n-
propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. "Alkylene"
means a straight or branched chain of carbon atoms with a group substituted at both ends, such as
-CH CH - and -CH CH CH -. "Alkenyl" means a carbon chain which contains at least one
2 2 2 2 2
carbon-carbon double bond, and which may be linear or branched or combinations thereof such
that C alkenyl is defined to identify the group as having 2, 3, 4, 5 or 6 carbons which
incorporates at least one double bond, which may be in a E- or a Z- arrangement, including vinyl,
allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methylbutenyl, and
the like. "Alkynyl" means a carbon chain which contains at least one carbon-carbon triple bond,
and which may be linear or branched or combinations thereof, such as ethynyl, propargyl, 3-
methylpentynyl, 2-heptynyl and the like. “Cycloalkyl” means a mono-, bi- or tri-cyclic
structure, optionally combined with linear or branched structures, having the indicated number of
carbon atoms, such as cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl,
2-ethyl bicyclo[4.4.0]decyl, and the like. “Alkoxy” means an alkoxy group of a straight or
branched chain having the indicated number of carbon atoms. C alkoxy, for example, includes
methoxy, ethoxy, propoxy, isopropoxy, and the like. The term "heterocyclyl" as used herein
includes both unsaturated heterocyclic moieties comprising a mono- or bicyclic aromatic rings
with at least one ring containing a heteroatom selected from N, O and S, and each ring containing
or 6 atoms (i.e. "heteroaryl") and saturated heterocyclic moieties comprising mono- or bicyclic
saturated rings with at least one ring containing a heteroatom selected from N, O and S, and each
ring containing 3, 5 or 6 atoms. Examples of "heteroaryl" include benzoimidazolyl,
benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl,
benzothiophenyl, benzoxazepin, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl,
furo(2,3-b)pyridyl, imidazolyl, indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,
isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,
MRL-NOP-00136
oxazolyl, oxazoline, isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,
pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,
tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and
N-oxides thereof. Examples of saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl,
hexahydroazepinyl, piperazinyl, piperidinyl, pyridinonyl, pyrrolidinyl, morpholinyl,
tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof
A group which is designated as being substituted with substituents may be
substituted with multiple numbers of such substituents. A group which is designated as being
independently substituted with substituents may be independently substituted with multiple
numbers of such substituents. The term “substituted” means that one or more hydrogens on the
designated group is(are) replaced with a selection from the indicated group, provided that the
designated group’s normal valency under the existing circumstances is not exceeded, and that the
substitution results in a stable compound. Combinations of substituents and/or variables are
permissible only if such combinations result in stable compounds. A reference to a “stable
compound’ or “stable structure” means that the compound is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and to survive formulation into an
efficacious therapeutic agent.
The compounds of the present invention may contain one or more stereogenic
centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric
mixtures and individual diastereomers. Additional asymmetric centers may be present depending
upon the nature of the various substituents on the molecule. Each such asymmetric center will
independently produce two optical isomers and it is intended that all of the possible optical
isomers and diastereomers in mixtures and as pure or partially purified compounds are included
within the ambit of this invention. Any formulas, structures or names of compounds described in
this specification that do not specify a particular stereochemistry are meant to encompass any and
all existing isomers as described above and mixtures thereof in any proportion. When
stereochemistry is specified, the invention is meant to encompass that particular isomer in pure
form or as part of a mixture with other isomers in any proportion.
The independent syntheses of these diastereomers or their chromatographic
separations may be achieved as known in the art by appropriate modification of the methodology
disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography
of crystalline products or crystalline intermediates which are derivatized, if necessary, with a
reagent containing an asymmetric center of known absolute configuration. If desired, racemic
MRL-NOP-00136
mixtures of the compounds may be separated so that the individual enantiomers are isolated. The
separation can be carried out by methods well known in the art, such as the coupling of a racemic
mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture,
followed by separation of the individual diastereomers by standard methods, such as fractional
crystallization or chromatography. The coupling reaction is often the formation of salts using an
enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the
pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the
compounds can also be separated directly by chromatographic methods utilizing chiral stationary
phases, which methods are well known in the art. Alternatively, any enantiomer of a compound
may be obtained by stereoselective synthesis using optically pure starting materials or reagents of
known configuration by methods well known in the art. The small molecule X-ray crystal
structure of the compound of Example 2-29 indicated that the absolute sterochemical designation
at the 1- and the 2-positions of the cylopropyl ring was (S,S). The absolute stereochemical
designation for all of the other compounds in the Examples was assigned based on this structural
determination of the compound of Example 2-29.
The present invention also includes all pharmaceutically acceptable isotopic
variations of a compound of the Formula I in which one or more atoms is replaced by atoms
having the same atomic number, but an atomic mass or mass number different from the atomic
mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the
compounds of the invention include isotopes of hydrogen such as H and H, carbon such as
11 13 14 13 15 15 17 18
C, C and C, nitrogen such as N and N, oxygen such as O, O and O,
32 35 18 23 125
phosphorus such as P, sulfur such as S, fluorine such as F, iodine such as I and I,
and chlorine such as Cl. Certain isotopically-labelled compounds of Formula I, for example
those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution
3 14
studies. The radioactive isotopes tritium, i.e. H, and carbon-14, i.e. C, are particularly useful
for this purpose in view of their ease of incorporation and ready means of detection. Substitution
with heavier isotopes such as deuterium, i.e. H, may afford certain therapeutic advantages
resulting from greater metabolic stability, for example, increased in vivo half-life or reduced
dosage requirements, and hence may be preferred in some circumstances. Substitution with
11 18 15 13
positron emitting isotopes, such as C, F, O and N, can be useful in Positron Emission
Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labelled
compounds of Formula I can generally be prepared by conventional techniques known to those
MRL-NOP-00136
skilled in the art or by processes analogous to those described in the accompanying Examples
using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously
employed.
It will be understood that, as used herein, references to the compounds of present
invention are meant to also include the pharmaceutically acceptable salts, and also salts that are
not pharmaceutically acceptable when they are used as precursors to the free compounds or in
other synthetic manipulations. The compounds of the present invention may be administered in
the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts”
refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the
compound of the present invention is acidic, its corresponding salt can be conveniently prepared
from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
Salts derived from such inorganic bases include aluminum, ammonium, calcium, cupric, cuprous,
ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like
salts. Particular embodiments include the ammonium, calcium, magnesium, potassium, and
sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also
be in the form of hydrates. 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 -dibenzylethylene-diamine, diethylamine, 2-
diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-
morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, 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. Particular embodiments citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
fumaric, and tartaric acids. It will be understood that, as used herein, references to the
compounds of the present invention are meant to also include the pharmaceutically acceptable
salts.
MRL-NOP-00136
Exemplifying the invention are the specific compounds disclosed in the Examples
and herein. The subject compounds are useful in a method of treating a neurological or
psychiatric disorder associated with PDE10 dysfunction in a patient such as a mammal in need of
such inhibition comprising the administration of an effective amount of the compound. In
addition to primates, especially humans, a variety of other mammals can be treated according to
the method described herein. The subject compounds are useful in a method of inhibiting PDE10
activity in a patient such as a mammal in need of such inhibition comprising the administration
of an effective amount of the compound. The subject compounds are also useful for treating a
neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia
dysfunction in a mammalian patient in need thereof. In addition to primates, especially humans,
a variety of other mammals can be treated according to the method described herein.
The present invention is directed to a compound of the present invention or a
pharmaceutically acceptable salt thereof for use in medicine. The present invention is further
directed to a use of a compound of the present invention or a pharmaceutically acceptable salt
thereof for the manufacture of a medicament for treating a neurological or psychiatric disorder
associated with PDE10 dysfunction in a mammalian patient in need thereof. The present
invention is further directed to a use of a compound of the present invention or a
pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a
neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia
dysfunction in a mammalian patient in need thereof.
“Treating” or “treatment of” a disease state includes: 1) preventing the disease
state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may
be exposed to or predisposed to the disease state, but does not yet experience or display
symptoms of the disease state; 2) inhibiting the disease state, i.e., arresting the development of
the disease state or its clinical symptoms; 3) or relieving the disease state, i.e., causing temporary
or permanent regression of the disease state or its clinical symptoms.
The subject treated in the present methods is generally a mammal, in particular, a
human being, male or female, in whom therapy is desired. The term “therapeutically effective
amount” means the amount of the subject compound that will elicit the biological or medical
response of a tissue, system, animal or human that is being sought by the researcher, veterinarian,
medical doctor or other clinician. It is recognized that one skilled in the art may affect the
neurological and psychiatric disorders by treating a patient presently afflicted with the disorders
or by prophylactically treating a patient afflicted with such disorders with an effective amount of
MRL-NOP-00136
the compound of the present invention. As used herein, the terms “treatment” and “treating”
refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or
stopping of the progression of the neurological and psychiatric disorders described herein, but
does not necessarily indicate a total elimination of all disorder symptoms, as well as the
prophylactic therapy to retard the progression or reduce the risk of the noted conditions,
particularly in a patient who is predisposed to such disease or disorder.
Applicants propose that inhibitors of PDE10 and, in particular inhibitors of
PDE10A, may provide therapeutic benefit to those individuals suffering from psychiatric and
cognitive disorders. The unique and exclusive distribution of PDE10A in the medium spiny
projection neurons of the striatum, which form the principle site for cortical and dopaminergic
input within basal ganglia, suggests that it may be possible and desirable to identify inhibitors of
PDE10 to ameliorate or eliminate unwanted cellular signaling within this site. Without wishing
to be bound by any theory, Applicants believe that inhibition of PDE10A in the striatum may
result in increased cAMP/cGMP signaling and striatal output, which has the potential to restore
behavioral inhibition that is impaired in cognitive disease such as schizophrenia. Regulation and
integration of glutamatergic and dopaminergic inputs may enhance cognitive behavior, while
suppressing or reducing unwanted behavior. Thus, in one embodiment, compounds of the
invention provide a method for treating or ameliorating diseases or conditions in which striatal
hypofunction is a prominent feature or ones in which basal ganglia dysfunction plays a role, such
as, Parkinson’s disease, Huntington’s disease, schizophrenia, obsessive-compulsive disorders,
addiction and psychosis. Other conditions for which the inhibitors described herein may have a
desirable and useful effect include those requiring a reduction in activity and reduced response to
psychomotor stimulants or where it would be desirable to reduce conditional avoidance
responses, which is often predictive of clinical antipsychotic activity.
As used herein, the term “’selective PDE10 inhibitor” refers to an organic
molecule that effectively inhibits an enzyme from the PDE10 family to a greater extent than
enzymes from the PDE 1-9 or PDE11 families. In one embodiment, a selective PDE10 inhibitor
is an organic molecule having a Ki for inhibition of PDE10 that is less than or about one-tenth
that for a substance that is an inhibitor for another PDE enzyme. In other words, the organic
molecule inhibits PDE10 activity to the same degree at a concentration of about one-tenth or less
than the concentration required for any other PDE enzyme. Preferably, a selective PDE10
inhibitor is an organic molecule, having a Ki for inhibition of PDE10 that is less than or about
one-hundredth that for a substance that is an inhibitor for another PDE enzyme. In other words,
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the organic molecule inhibits PDE10 activity to the same degree at a concentration of about one-
hundredth or less than the concentration required for any other PDE enzyme. A “selective
PDE10 inhibitor” can be identified, for example, by comparing the ability of an organic molecule
to inhibit PDE10 activity to its ability to inhibit PDE enzymes from the other PDE families. For
example, an organic molecule may be assayed for its ability to inhibit PDE10 activity, as well as
PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D,
PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, and/or PDE11A.
Phosphodiesterase enzymes including PDE10 have been implicated in a wide
range of biological functions. This has suggested a potential role for these enzymes in a variety
of disease processes in humans or other species. The compounds of the present invention have
utility in treating a variety of neurological and psychiatric disorders.
In a specific embodiment, compounds of the present invention provide a method
for treating schizophrenia or psychosis comprising administering to a patient in need thereof an
effective amount of a compound of the present invention. The Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC)
provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated
schizophrenia and substance-induced psychotic disorders. As used herein, the term
“schizophrenia or psychosis” includes the diagnosis and classification of these mental disorders
as described in DSM-IV-TR and the term is intended to include similar disorders described in
other sources. Disorders and conditions encompassed herein include, but are not limited to,
conditions or diseases such as schizophrenia or psychosis, including schizophrenia (paranoid,
disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder,
schizoaffective disorder, for example of the delusional type or the depressive type, delusional
disorder, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic
disorder due to a general medical condition and substance-induced or drug-induced (for example
psychosis induced by alcohol, amphetamine, cannabis, ***e, hallucinogens, inhalants, opioids,
phencyclidine, ketamine and other dissociative anaesthetics, and other psychostimulants),
psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive
psychosis, schizoaffective psychosis, “schizophrenia-spectrum” disorders such as schizoid or
schizotypal personality disorders, personality disorder of the paranoid type, personality disorder
of the schizoid type, illness associated with psychosis (such as major depression, manic
depressive (bipolar) disorder, Alzheimer’s disease and post-traumatic stress syndrome), including
both the positive and the negative symptoms of schizophrenia and other psychoses.
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In another specific embodiment, the compounds of the present invention provide a
method for treating cognitive disorders comprising administering to a patient in need thereof an
effective amount of a compound of the present invention. The DSM-IV-TR also provides a
diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders
and age-related cognitive decline. As used herein, the term “cognitive disorders” includes the
diagnosis and classification of these disorders as described in DSM-IV-TR and the term is
intended to include similar disorders described in other sources. Disorders and conditions
encompassed herein include, but are not limited to, disorders that comprise as a symptom a
deficiency in attention and/or cognition, such as dementia (associated with Alzheimer’s disease,
ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems
or stroke, alcoholic dementia or other drug-related dementia, AIDS, HIV disease, Parkinson’s
disease, Huntington’s disease, Pick’s disease, Creutzfeldt Jacob disease, perinatal hypoxia, other
general medical conditions or substance abuse), Alzheimer’s disease, multi-infarct dementia,
AIDS-related dementia, and Fronto temperal dementia, delirium, amnestic disorders or age
related cognitive decline.
In another specific embodiment, compounds of the present invention provide a
method for treating anxiety disorders comprising administering to a patient in need thereof an
effective amount of a compound of the present invention. The DSM-IV-TR also provides a
diagnostic tool that includes anxiety disorders as generalized anxiety disorder, obsessive-
compulsive disorder and panic attack. As used herein, the term “anxiety disorders” includes the
diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is
intended to include similar disorders described in other sources. Disorders and conditions
encompassed herein include, but are not limited to, anxiety disorders such as, acute stress
disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack,
panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific
phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.
In another specific embodiment, compounds of the present invention provide a
method for treating substance-related disorders and addictive behaviors comprising administering
to a patient in need thereof an effective amount of a compound of the present invention. The
DSM-IV-TR also provides a diagnostic tool that includes persisting dementia, persisting
amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse, and
tolerance of, dependence on or withdrawal from substances of abuse. As used herein, the term
“substance-related disorders and addictive behaviors” includes the diagnosis and classification of
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these mental disorders as described in DSM-IV-TR and the term is intended to include similar
disorders described in other sources. Disorders and conditions encompassed herein include, but
are not limited to, substance-related disorders and addictive behaviors, such as substance-induced
delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety
disorder, drug addiction, tolerance, and dependence or withdrawal from substances including
alcohol, amphetamines, cannabis, ***e, hallucinogens, inhalants, nicotine, opioids,
phencyclidine, sedatives, hypnotics or anxiolytics.
In another specific embodiment, compounds of the present invention provide a
method for treating obesity or eating disorders associated with excessive food intake, and
complications associated therewith, comprising administering to a patient in need thereof an
effective amount of a compound of the present invention. At present, obesity is included in the
tenth edition of the International Classification of Diseases and Related Health Problems (ICD-
) (1992 World Health Organization) as a general medical condition. The DSM-IV-TR also
provides a diagnostic tool that includes obesity in the presence of psychological factors affecting
medical condition. As used herein, the term “obesity or eating disorders associated with
excessive food intake” includes the diagnosis and classification of these medical conditions and
disorders described in ICD-10 and DSM-IV-TR and the term is intended to include similar
disorders described in other sources. Disorders and conditions encompassed herein include, but
are not limited to, obesity, bulimia nervosa and compulsive eating disorders.
In another specific embodiment, compounds of the present invention provide a
method for treating mood and depressive disorders comprising administering to a patient in need
thereof an effective amount of a compound of the present invention. As used herein, the term
“mood and depressive disorders” includes the diagnosis and classification of these medical
conditions and disorders described in the DSM-IV-TR and the term is intended to include similar
disorders described in other sources. Disorders and conditions encompassed herein include, but
are not limited to, bipolar disorders, mood disorders including depressive disorders, major
depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a
hypomanic mood episode, a depressive episode with atypical features, a depressive episode with
melancholic features, a depressive episode with catatonic features, a mood episode with
postpartum onset, post-stroke depression; major depressive disorder, dysthymic disorder, minor
depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of
schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as
delusional disorder or schizophrenia, a bipolar disorder, for example, bipolar I disorder, bipolar II
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disorder, cyclothymic disorder, depression including unipolar depression, seasonal depression
and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder
(PDD), mood disorders due to a general medical condition, and substance-induced mood
disorders.
In another specific embodiment, compounds of the present invention provide a
method for treating pain comprising administering to a patient in need thereof an effective
amount of a compound of the present invention. Particular pain embodiments are bone and joint
pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular
injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and
neuropathic pain.
In other specific embodiments, compounds of the invention provide methods for
treating other types of cognitive, learning and mental related disorders including, but not limited
to, learning disorders, such as a reading disorder, a mathematics disorder, or a disorder of written
expression, attention-deficit/hyperactivity disorder, age-related cognitive decline, pervasive
developmental disorder including autistic disorder, attention disorders such as attention-deficit
hyperactivity disorder (ADHD) and conduct disorder; an NMDA receptor-related disorder, such
as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury;
a neurodegenerative disorder or condition, such as neurodegeneration associated with cerebral
trauma, stroke, cerebral infarct, epileptic seizure, neurotoxin poisoning, or hypoglycemia-induced
neurodegeneration; multi-system atrophy; movement disorders, such as akinesias and akinetic-
rigid syndromes (including, Parkinson’s disease, drug-induced parkinsonism, post-encephalitic
parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal
degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), medication-
induced parkinsonism (such as, neuroleptic-induced parkinsonism, neuroleptic malignant
syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-
induced tardive dyskinesia and medication-induced postural tremor), Huntington’s disease,
dyskinesia associated with dopamine agonist therapy, Gilles de la Tourette’s syndrome, epilepsy,
muscular spasms and disorders associated with muscular spasticity or weakness including
tremors; dyskinesias, including tremor (such as, rest tremor, postural tremor, intention tremor and
essential tremor), restless leg syndrome, chorea (such as Sydenham’s chorea, Huntington’s
disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced
chorea and hemiballism), myoclonus (including, generalised myoclonus and focal myoclonus),
tics (including, simple tics, complex tics and symptomatic tics), dystonia (including, generalised,
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iodiopathic, drug-induced, symptomatic, paroxymal, and focal (such as blepharospasm,
oromandibular, spasmodic, spasmodic torticollis, axial dystonia, hemiplegic and dystonic
writer’s cramp)); urinary incontinence; neuronal damage (including ocular damage, retinopathy
or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema);
emesis; and sleep disorders, including insomnia and narcolepsy. Of the disorders above, the
treatment of schizophrenia, bipolar disorder, depression, including unipolar depression, seasonal
depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual
dysphoric disorder (PDD), learning disorders, pervasive developmental disorders, including
autistic disorder, attention disorders including Attention-Deficit/Hyperactivity Disorder, autism,
tic disorders including Tourette’s disorder, anxiety disorders including phobia and post traumatic
stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer’s,
Parkinson’s, Huntington’s disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing
impairment and loss are of particular importance.
The activity of the compounds in accordance with the present invention as PDE10
inhibitors may be readily determined without undue experimentation using a fluorescence
polarization (FP) methodology that is well known in the art (Huang, W., et al., J. Biomol Screen,
2002, 7: 215). In particular, the compounds of the following examples had activity in reference
assays by exhibiting the ability to inhibit the hydrolysis of the phosphosphate ester bond of a
cyclic nucleotide. Any compound exhibiting a Ki (inhibitory constant) below 1 μM would be
considered a PDE10 inhibitor as defined herein.
In a typical experiment the PDE10 inhibitory activity of the compounds of the
present invention was determined in accordance with the following experimental method.
PDE10A2 was amplified from human fetal brain cDNA (Clontech, Mountain View, CA) using a
forward primer corresponding to nucleotides 56-77 of human PDE10A2 (Accession No.
AF127480, Genbank Identifier 4894716), containing a Kozak consensus sequence, and a reverse
primer corresponding to nucleotides 2406-2413 of human PDE10A2 (Accession No. AF127480,
Genbank Identifier 4894716). Amplification with Easy-A polymerase (Stratagene, La Jolla, CA)
was 95 ºC for 2 minutes followed by thirty three cycles of 95°C for 40 seconds, 55ºC for 30
seconds, and 72ºC for 2 minutes 48 seconds. Final extension was 72ºC for 7 minutes. The PCR
product was TA cloned into pcDNA3.2-TOPO (Invitrogen, Carlsbad, CA) according to standard
protocol. AD293 cells with 70-80% confluency were transiently transfected with human
PDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to manufacturer specifications
(Invitrogen, Carlsbad, CA). Cells were harvested 48 hours post-transfection and lysed by
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sonication (setting 3, 10 X 5 sec pulses) in a buffer containing 20 mM HEPES, 1 mM EDTA and
protease inhibitor cocktail (Roche). Lysate was collected by centrifugation at 75,000 xg for 20
minutes. Supernatant containing the cytoplasmic fraction was used for evaluation of PDE10A2
activity. The fluorescence polarization assay for cyclic nucleotide phosphodiesterases was
performed using an IMAP FP kit supplied by Molecular Devices, Sunnyvale, CA (product #
R8139). IMAP technology has been applied previously to phosphodiesterase assays (Huang,
W., et al., J. Biomol Screen, 2002, 7: 215). Assays were performed at room temperature in 384-
well microtiter plates with an incubation volume of 20.2 μL. Solutions of test compounds were
prepared in DMSO and serially diluted with DMSO to yield 8 μL of each of 10 solutions
differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition is
determined using a known PDE10 inhibitor, which can be any compound that is present at 5,000
times its Ki value in the assay described as follows, such as papaverine (see Siuciak, et al.
Neuropharmacology (2006) 51:386–396; Becker, et al. Behav Brain Res (2008) 186(2):155-60;
Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785–795), 2-{4-[pyridinyl(2,2,2-
trifluoroethyl)-1H-pyrazolyl]phenoxymethyl}quinoline succinic acid or 2-[4-(1-methyl
pyridinyl-1H-pyrazolyl)-phenoxymethyl]quinoline succinic acid (see Schmidt, et al. J
Pharmacol Exp Ther (2008) 325:681-690; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):
785–795). 0% of inhibition is determined by using DMSO (1% final concentrations).
A Labcyte Echo 555 (Labcyte, Sunnyvale, CA) is used to dispense 200 nL from
each well of the titration plate to the 384 well assay plate. A solution of enzyme (1/1600 dilution
from aliquots; sufficient to produce 20% substrate conversion) and a separate solution of FAM-
labeled cAMP PDE from Molecular Devices (product # R7506), at a final concentration of 50
nM are made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl , 0.05% NaN 0.01%
Tween-20, and 1 mM DTT). The enzyme and the substrate are then added to the assay plates in
two consecutive additions of 10 μL, and then shaken to mix. The reaction is allowed to proceed
at room temperature for 30 minutes. A binding solution is then made from the kit components,
comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the
total binding solution. The enzymatic reaction is stopped by addition of 60 μL of the binding
solution to each well of the assay plates and the plates are sealed and shaken for 10 seconds. The
plate was incubated at room temperature for at least one hour prior to determining the
fluorescence polarization (FP). The parallel and perpendicular fluorescence of each well of the
plate was measured using a Perkin Elmer EnVision™ plate reader (Waltham, MA).
Fluorescence polarization (mP) was calculated from the parallel (S) and
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perpendicular (P) fluorescence of each sample well and the analogous values for the median
control well, containing only substrate (So and Po), using the following equation:
Polarization (mP) = 1000*(S/So-P/Po)/(S/So+P/Po).
Dose-inhibition profiles for each compound were characterized by fitting the mP
data to a four-parameter equation given below. The apparent inhibition constant (K ), the
maximum inhibition at the low plateau relative to “100% Inhibition Control” (Imax; e.g. 1=>
same as this control), the minimum inhibition at the high plateau relative to the “0% Inhibition
Control” (Imin, e.g. 0=> same as the no drug control) and the Hill slope (nH) are determined by a
non-linear least squares fitting of the mP values as a function of dose of the compound using an
in-house software based on the procedures described by Mosser et al., JALA, 2003, 8: 54-63,
using the following equation:
(0%mP−100%mP)(Imax−Imin)
mP = +100%mP+(0%mP−100%mP)(1−Imax)
[Drug]
1+ [ ]
[Substrate]
(10 (1+ )
The median signal of the “0% inhibition controls” (0%mP) and the median signal
of the “100% inhibition controls” (100%mP) are constants determined from the controls located
in columns 1-2 and 23-24 of each assay plate. An apparent (K ) for FAM-labeled cAMP of 150
nM was determined in separate experiments through simultaneous variation of substrate and
selected drug concentrations.
Selectivity for PDE10, as compared to other PDE families, was assessed using the
IMAP technology. Rhesus PDE2A3 and Human PDE10A2 enzyme was prepared from
cytosolic fractions of transiently transfected HEK cells. All other PDE's were GST Tag human
enzyme expressed in insect cells and were obtained from BPS Bioscience (San Diego, CA):
PDE1A (Cat# 60010), PDE3A (Cat# 60030), PDE4A1A (Cat# 60040), PDE5A1 (Cat# 60050),
PDE6C (Cat# 60060), PDE7A (Cat# 60070), PDE8A1 (Cat# 60080), PDE9A2 (Cat# 60090),
PDE11A4 (Cat# 60110).
Assays for PDE 1 through 11 were performed in parallel at room temperature in
384-well microtiter plates with an incubation volume of 20.2 μL. Solutions of test compounds
were prepared in DMSO and serially diluted with DMSO to yield 30 μL of each of ten solutions
differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition was
determined by adding buffer in place of the enzyme and 0% inhibition is determined by using
DMSO (1% final concentrations). A Labcyte POD 810 (Labcyte, Sunnyvale, CA) was used to
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dispense 200 nL from each well of the titration plate to make eleven copies of the assay plate for
each titration, one copy for each PDE enzyme. A solution of each enzyme (dilution from
aliquots, sufficient to produce 20% substrate conversion) and a separate solution of FAM-
labeled cAMP or FAM-labeled cGMP from Molecular Devices ( Sunnyvale, CA, product #
R7506 or cGMP#R7508), at a final concentration of 50 nM were made in the assay buffer (10
mM Tris HCl, pH 7.2, 10 mM MgCl , 0.05% NaN 0.01% Tween-20, and 1 mM DTT). Note
that the substrate for PDE2 is 50 nM FAM cAMP containing 1000 nM of cGMP. The enzyme
and the substrate were then added to the assay plates in two consecutive additions of 10 μL and
then shaken to mix. The reaction was allowed to proceed at room temperature for 60 minutes. A
binding solution was then made from the kit components, comprised of 80% Solution A, 20%
Solution B and binding reagent at a volume of 1/600 the total binding solution. The enzymatic
reaction was stopped by addition of 60 μL of the binding solution to each well of the assay plate.
The plates were sealed and shaken for 10 seconds. The plates were incubated at room
temperature for one hour, then the parallel and perpendicular fluorescence was measured using a
Tecan Genios Pro plate reader (Tecan, Switzerland). The apparent inhibition constants for the
compounds against all 11 PDE's was determined from the parallel and perpendicular fluorescent
readings as described for PDE10 FP assay using the following apparent K values for each
enzyme and substrate combination: PDE1A (FAM cGMP) 70 nM, rhesus PD2A3 (FAM
cAMP) 10,000 nM, PDE3A (FAM cAMP) 50 nM, PDE4A1A (FAM cAMP) 1500 nM, PDE5A1
(FAM cGMP) 400 nM, PDE6C (FAM cGMP) 700 nM, PDE7A (FAM cAMP) 150 nM, PDE8A1
(FAM cAMP) 50 nM, PDE9A2 (FAM cGMP) 60 nM, PDE10A2 (FAM cAMP) 150nM,
PDE11A4 (FAM cAMP) 1000 nM. The intrinsic PDE10 inhibitory activity of a compound
which may be used in accordance with the present invention may be determined by these assays.
All of the final compounds of the following examples had activity in inhibiting the
human PDE10 enzyme in the aforementioned assays, generally with an Ki of less than about 1
µM. In particular, all of the final compounds of the following examples had activity in inhibiting
the human PDE10 enzyme in the aforementioned assays, generally with an Ki of less than about
0.1 µM. Additional data is provided in the following Examples. Such a result is indicative of
the intrinsic activity of the compounds in use as inhibitors of the PDE10 enzyme. In general, one
of ordinary skill in the art would appreciate that a substance is considered to effectively inhibit
PDE10 activity if it has a Ki of less than or about 1 µM, preferably less than or about 0.1 µM.
The present invention also includes compounds within the generic scope of the invention which
possess activity as inhibitors of other phosphodiesterase enzymes. With respect to 2-alkoxy
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pyrimidine compounds, the present compounds exhibit unexpected properties, such as regarding
increased potency, oral bioavailability, metabolic stability, and/or decreased off target activity.
The subject compounds are further useful in a method for the prevention,
treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions
noted herein. The subject compounds are further useful in a method for the prevention,
treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders
and conditions in combination with other agents. The compounds of the present invention may
be used in combination with one or more other drugs in the treatment, prevention, control,
amelioration, or reduction of risk of diseases or conditions for which compounds of the present
invention or the other drugs may have utility, where the combination of the drugs together are
safer or more effective than either drug alone. Such other drug(s) may be administered, by a
route and in an amount commonly used therefor, contemporaneously or sequentially with a
compound of the present invention. When a compound of the present invention is used
contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage
form containing such other drugs and the compound of the present invention may be desirable.
However, the combination therapy may also includes therapies in which the compound of the
present invention and one or more other drugs are administered on different overlapping
schedules. It is also contemplated that when used in combination with one or more other active
ingredients, the compounds of the present invention and the other active ingredients may be used
in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of
the present invention include those that contain one or more other active ingredients, in addition
to a compound of the present invention. The above combinations include combinations of a
compound of the present invention not only with one other active compound, but also with two
or more other active compounds. Likewise, compounds of the present invention may be used in
combination with other drugs that are used in the prevention, treatment, control, amelioration, or
reduction of risk of the diseases or conditions for which compounds of the present invention are
useful. Such other drugs may be administered, by a route and in an amount commonly used
therefor, contemporaneously or sequentially with a compound of the present invention.
Accordingly, the pharmaceutical compositions of the present invention include those that also
contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the present invention to the second active ingredient may be
varied and will depend upon the effective dose of each ingredient. Generally, an effective dose
of each will be used. Thus, for example, when a compound of the present invention is combined
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with another agent, the weight ratio of the compound of the present invention to the other agent
will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200.
Combinations of a compound of the present invention and other active ingredients will generally
also be within the aforementioned range, but in each case, an effective dose of each active
ingredient should be used.
In such combinations the compound of the present invention and other active
agents may be administered separately or in conjunction. In addition, the administration of one
element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
Accordingly, the subject compounds may be used alone or in combination with
other agents which are known to be beneficial in the subject indications or other drugs that affect
receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted
side effects or toxicity of the compounds of the present invention. The subject compound and
the other agent may be co-administered, either in concomitant therapy or in a fixed combination.
In one embodiment, the subject compound may be employed in combination with
anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA
reductase inhibitors, NSAID's including ibuprofen, vitamin E, and anti-amyloid antibodies.
In another embodiment, the subject compound may be employed in combination
with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones,
imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists,
melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as:
adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital,
amoxapine, aripiprazole, atypical antipsychotics, bentazepam, benzoctamine, brotizolam,
bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral
hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate,
chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone,
divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam,
flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam,
glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam,
lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate,
methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,
olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine,
phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam,
quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam,
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thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam,
tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine,
zaleplon, ziprasidone, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the
like, or the subject compound may be administered in conjunction with the use of physical
methods such as with light therapy or electrical stimulation.
In another embodiment, the subject compound may be employed in combination
with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as
carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or
lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as
entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic
agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor
agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and
pramipexole. It will be appreciated that the dopamine agonist may be in the form of a
pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate,
fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and
pramipexol are commonly used in a non-salt form.
In another embodiment, the subject compound may be employed in combination
with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine,
butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable
examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine,
fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include
chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a
butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An
example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and
risperidone. It will be appreciated that the neuroleptic agents when used in combination with
thesubject compound may be in the form of a pharmaceutically acceptable salt, for example,
chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride,
acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine
decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate,
loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine,
haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject
compound may be employed in combination with acetophenazine, alentemol, aripiprazole,
amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine,
MRL-NOP-00136
diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide,
levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine,
pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride,
tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.
In another embodiment, the subject compound may be employed in combination
with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors
(including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake
inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine
oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin
releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin-1 receptor
antagonists, atypical anti-depressants, benzodiazepines, 5-HT agonists or antagonists,
especially 5-HT partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific
agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine,
desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and
sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine;
duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam,
chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and
prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts
thereof.
The compounds of the present invention may be administered by oral, parenteral
(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion,
subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or
topical routes of administration and may be formulated, alone or together, in suitable dosage unit
formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants
and vehicles appropriate for each route of administration. In addition to the treatment of warm-
blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the
compounds of the invention are effective for use in humans. The terms "administration of" and
or "administering a" compound should be understood to mean providing a compound of the
invention or a prodrug of a compound of the invention to the individual in need of treatment.
The term "composition" as used herein is intended to encompass a product
comprising specified ingredients in predetermined amounts or proportions, as well as any product
which results, directly or indirectly, from combination of the specified ingredients in the
specified amounts. Such term in relation to pharmaceutical composition, is intended to
MRL-NOP-00136
encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up
the carrier, as well as any product which results, directly or indirectly, from combination,
complexation or aggregation of any two or more of the ingredients, or from dissociation of one or
more of the ingredients, or from other types of reactions or interactions of one or more of the
ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately
bringing the active ingredient into association with a liquid carrier or a finely divided solid
carrier or both, and then, if necessary, shaping the product into the desired formulation. In the
pharmaceutical composition the active object compound is included in an amount sufficient to
produce the desired effect upon the process or condition of diseases. Accordingly, the
pharmaceutical compositions of the present invention encompass any composition made by
mixing a compound of the present invention and a pharmaceutically acceptable carrier.
Pharmaceutical compositions intended for oral use may be prepared according to
any method known to the art for the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the
manufacture of tablets. The tablets may be uncoated or they may be coated by known techniques
to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained
action over a longer period. Compositions for oral use may also be presented as hard gelatin
capsules wherein the active ingredients are mixed with an inert solid diluent, for example,
calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive
oil. Aqueous suspensions, oily suspensions, dispersible powders or granules, oil-in-water
emulsions, and sterile injectable aqueous or oleagenous suspension may be prepared by standard
methods known in the art. By "pharmaceutically acceptable" it is meant the carrier, diluent or
excipient must be compatible with the other ingredients of the formulation and not deleterious to
the recipient thereof.
The subject compounds are further useful in a method for the prevention,
treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions
noted herein. The dosage of active ingredient in the compositions of this invention may be
varied, however, it is necessary that the amount of the active ingredient be such that a suitable
dosage form is obtained. The active ingredient may be administered to patients (animals and
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human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
The selected dosage depends upon the desired therapeutic effect, on the route of administration,
and on the duration of the treatment. The dose will vary from patient to patient depending upon
the nature and severity of disease, the patient's weight, special diets then being followed by a
patient, concurrent medication, and other factors which those skilled in the art will recognize.
Generally, dosage levels of between 0.001 to 10 mg/kg. of body weight daily are administered to
the patient, e.g., humans and elderly humans. The dosage range will generally be about 0.5 mg to
1.0 g. per patient per day which may be administered in single or multiple doses. In one
embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another
embodiment about 0.5 mg to 200 mg per patient per day; and in yet another embodiment about 5
mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be
provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active
ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical
composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10
mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the
compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the
active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600,
750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of
the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to
4 times per day, such as once or twice per day.
Several methods for preparing the compounds of this invention are illustrated in
the following Schemes and Examples. Starting materials and the requisite intermediates are in
some cases commercially available, or can be prepared according to literature procedures or as
illustrated herein. The compounds of this invention may be prepared by employing reactions as
shown in the following schemes, in addition to other standard manipulations that are known in
the literature or exemplified in the experimental procedures. Substituent numbering as shown in
the schemes does not necessarily correlate to that used in the claims and often, for clarity, a
single substituent is shown attached to the compound where multiple substituents are allowed
under the definitions hereinabove. Reactions used to generate the compounds of this invention
are prepared by employing reactions as shown in the schemes and examples herein, in addition to
other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may
be known in the literature or exemplified in the experimental procedures. Starting materials are
made according to procedures known in the art or as illustrated herein. The following
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abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn:
benzyl; Ac: acetyl; THF: tetrahydrofuran; Boc: tert-butyloxycarbonyl; DIPEA: N,N-
diisopropylethylamine; DPPA: diphenylphosphorylazide; EDC: N-(3-Dimethylaminopropyl)-N’-
ethylcarbodiimide; EtOAc: ethyl acetate; HOBt: hydroxybenzotriazole hydrate; TEA:
triethylamine; DMF: N,N-dimethylformamide; rt: room temperature; HPLC: high performance
liquid chromatography; NMR: nuclear magnetic resonance; TLC: thin-layer chromatography.
In some cases the final product may be further modified, for example, by
manipulation of substituents. These manipulations may include, but are not limited to, reduction,
oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those
skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be
varied to facilitate the reaction or to avoid unwanted reaction products. The following examples
are provided so that the invention might be more fully understood. These examples are
illustrative only and should not be construed as limiting the invention in any way.
REACTION SCHEME A
ethyldiazoacetate
toluene
Acis
Atrans
racemic
racemic
LAH, THF
resolution
trans ethyl 2-(pyridinyl)cyclopropanecarboxylate (Atrans)
A solution of 2-vinylpyridine (2 g, 19.02 mmol) in toluene (40 mL) was treated
with ethyl diazoacetate (1.973 ml, 19.02 mmol) and stirred at reflux overnight. The mixture was
concentrated in vacuo and the residue was purified by gradient elution on silica gel (0 to 50%
EtOAc in hexanes) to elute peak 1 (Atrans) (1.6 g, 44%), then the solvent gradient was
increased to 100% EtOAc to elute peak 2 (Acis). (914 mg, 25%), both as yellow oils.
Enantiomers of Atrans can be resolved by chiral preparative supercritical fluid
chromatography (SFC) (3.0 cm i.d. x 25 cm ChiralTech IC, 7% EtOH/CO , 70 mL/min) and
analyzed by chiral analytical SFC (4.6 mm i.d. x 25 cm ChiralTech IC, 7% EtOH/CO , 2.4
mL/min) ent = 3.6 min, ent = 4.1 min to give the title compound. ¹H NMR δ (500 MHz,
CDCl ): 8.44 (m, 1H), 7.56 (td, J= 7.6, 1.7 Hz, 1H), 7.22 (dd, J= 7.8, 1.0 Hz, 1H), 7.08 (ddd, J=
7.6, 4.9, 1.2 Hz, 1H), 4.17 (q, J= 7.3 Hz, 2H), 2.58 (ddd, J= 10.0, 6.1, 3.9 Hz, 1H), 2.25 (ddd, J=
MRL-NOP-00136
9.5, 5.6, 3.9 Hz, 1H), 1.61, (m, 2H), 1.28 (t, J= 7.1 Hz, 3H). LRMS (ES) calculated M + H for
C11H13NO2S: 192.2; Found: 192.1.
(S,S) trans 2-(pyridinyl)cyclopropyl]methanol (A-4)
A solution of Atrans (751 mg, 3.93 mmol) in THF (20 mL) was cooled to 0 ºC
and treated slowly with lithium aluminum hydride (3.93 mL, 3.93 mmol, 1 M solution in THF).
The solution was warmed to room temperature and stirred for 20 min. The reaction mixture was
then re-cooled to 0 °C and treated sequentially dropwise with 0.15 mL of water, 0.15 ml of 15%
NaOH, and 0.45 mL of water. Sodium sulfate was added to the mixture. After stirring at room
temperature for 10 min, the mixture was filtered through a pad of Celite and the filtrate was
concentrated in vacuo to afford the title compound as a pale yellow oil. The material was
sufficiently pure to use in the subsequent step without further purification. ¹H NMR (500 MHz,
CDCl ): δ 8.41 (d, J = 4.2 Hz, 1H), 7.52 (td, J= 7.6, 1.7 Hz, 1H), 7.10 (d, J= 7.8 Hz, 1H), 7.03
(ddd, J= 7.3, 4.9, 0.7 Hz, 1H), 3.72 (dd, J= 11,2, 6.4 Hz, 1H), 3.57 (dd, J= 11.2, 7.1 Hz, 1H),
2.26 (bs, 1H), 1.98 (m, 1H), 1.74 (m, 1H), 1.25 (m, 1H), 0.96 (m, 1H) ppm; LRMS (ES)
calculated M + H for C H NO: 150.2; Found: 150.1. As an alternate means to resolving
9 11
enantiomers of this building block, the enantiomer A-4 was resolved from its corresponding
enantiomer by chiral preparative SFC (3.0 cm i.d. x 25 cm ChiralPak AD-H, 3:7:90
MeCN/MeOH/CO , 70 mL/min) and analyzed by chiral analytical SFC (4.6 mm i.d. x 25 cm
ChiralPak AD-H, 3:7:90 MeCN/MeOH/CO , 2.4 mL/min) ent = 7.5 min, ent = 8.4 min. Using
2 1 2
this method, the (S,S) enantiomer was determined to be the second eluting peak and was isolated
in 98.7% ee.
REACTION SCHEME B
2-vinylquinoline (B-1)
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A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL,
9.17 mmol) in toluene (30 mL) was treated with Pd(PPh ) (0.706 g, 0.611 mmol) and heated to
reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified
directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title
compound as a colorless oil (941 mg, 99%). LRMS m/z (M+H) 156.1 found, 156.2 required.
ethyl 2-(quinolinyl)cyclopropanecarboxylate (Btrans)
A solution of B-1 (941 mg, 6.06 mmol) in toluene (20 ml) was treated with ethyl
diazoacetate (0.629 mL, 6.06 mmol) and stirred at reflux overnight. The mixture was
concentrated and the residue was purified by gradient elution on silica gel (0 to 30% EtOAc in
hexanes) to elute peak 1 (trans diastereomer). The eluent was then ramped up (50% EtOAc in
hexanes) to elute peak 2 (cis diastereomer). This afforded the title compound as a pale yellow oil
(706 mg, 40%, ca. 70% pure), which could be used in the subsequent step without further
purification. LRMS m/z (M+H) 242.2 found, 242.3 required.
(S,S) 2-(quinolinyl)cyclopropyl]methanol (B-4)
A solution of the Btrans (200 mg, 0.829 mmol) in THF (20 mL) was cooled to
0 ºC and treated slowly with a 1M THF solution of LiAlH (0.829 mL, 0.829 mmol). The
solution was warmed to room temperature and stirred for 20 min. The mixture was re-cooled to
0 °C and treated dropwise with 0.03 mL of water, 0.03 ml of 15% NaOH, and 0.09 mL of water
successively. Sodium sulfate was added to the mixture, and after stirring at room temperature
for 10 min, the mixture was filtered through Celite, eluting exhaustively with CH Cl and
MeOH. The filtrate was concentrated in vacuo, and the resulting residue was purified by gradient
elution on silica gel (0 to 100% EtOAc in hexanes) to afford the title compound as a colorless oil
(130 mg, 79%). ¹H NMR (500 MHz, CDCl ): δ 7.93 (d, J = 3.5 Hz, 1 H), 7.90 (d, J = 3.5 Hz, 1
H), 7.67 (d, J = 8.1 Hz, 1H), 7.59 (td, J = 7.6, 1.4 Hz, 1 H), 7.38 (td, J = 7.6, 1.0 Hz, 1 H), 7.09
(d, J = 8.5 Hz, 1 H), 3.76 (dd, J = 11.4, 6.0 Hz, 1H), 3.56 (dd, J = 11.4, 7.2 Hz, 1H), 2.15 (dt, J =
8.5, 4.4 Hz, 1H), 1.84 (m, 1H), 1.33 (dt, J = 8.6, 4.4 Hz, 1H), 1.01 (ddd, J = 10.4, 5.9, 1.1 Hz,
1H) ppm; LRMS m/z (M+H) 200.1 found, 200.2 required. The enantiomer B-4 was resolved
from its corresponding enantiomer by chiral preparative SFC (3.0 cm i.d. x 25 cm ChiralPak AD-
H, 30% MeOH/CO +0.1% DEA, 70 mL/min) and analyzed by chiral analytical SFC (4.6 mm
i.d. x 25 cm ChiralPak AD-H, 30% MeOH/CO +0.1% DEA, 2.4 mL/min) ent = 2.8 min, ent =
2 1 2
MRL-NOP-00136
3.5 min. Using this method, the (S,S) enantiomer was determined to be the first eluting peak and
was isolated in >99%.
REACTION SCHEME C
N Cl
PdOAc N
S-Phos
K PO
THF/H O
N resolution
LAH, THF N
C-3 racemic
C-2 C-4
ethyl 3-(1,5-naphthyridinyl)propenoate (C-1)
2-chloro-1,5-naphthyridine (101 mg, 0.614 mmol), boronate ester X1 (195 mg,
0.920 mmol), S-Phos (25.2 mg, 0.061 mmol), K PO (391 mg, 1.84 mmol) and PdOAc (6.89
3 4 2
mg, 0.031 mmol) were combined in a 5-mL microwave vial in THF (2.5 mL) and water (500 µl).
The reaction mixture was heated at 100 °C for 15 min. The reaction mixture was diluted with
EtOAc (20 mL), washed with sat. aq. NaHCO (25 mL) and brine (25 mL), dried over MgSO ,
filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on
silica gel (10 to 100% EtOAc in hexanes) to afford the title compound as a pale orange solid (118
mg, 90%). ¹H NMR (500 MHz, DMSO): δ 9.02 (dd, J = 4.1, 1.6 Hz, 1 H), 8.48 (d, J = 8.8 Hz, 1
H), 8.48-8.42 (m, 1 H), 8.25 (d, J = 8.7 Hz, 1 H), 7.84-7.79 (m, 2 H), 7.13 (d, J = 16.0 Hz, 1 H),
4.25 (q, J = 7.1 Hz, 2 H), 1.30 (t, J = 7.1 Hz, 3 H) ppm; LRMS m/z (M+H) 229.2 found, 229.1
required.
ethyl 2-(1,5-naphthyridinyl)cyclopropanecarboxylate (C-2)
To a 5-mL sealed vial was added trimethyl sulfoxonium iodide (170 mg, 0.770
mmol), DMSO (2567 µl), and NaH (26.7 mg, 0.668 mmol). This mixture was stirred for 40 min
at 50 °C. The reaction mixture was then cooled to room temperature and to it was added a
solution of C-1 (110 mg, 0.513 mmol) in DMSO (1.5 mL). The reaction mixture was stirred at
room temperature for 5 min, and then diluted with EtOAc (75 mL) and washed with sat. aq.
NaHCO (4x20 mL). The organics were dried over MgSO , filtered, and concentrated in vacuo.
The resulting residue was purified by gradient elution on silica gel (20 to 100% EtOAc in
hexanes) to afford the title compound (67 mg, 57%). ¹H NMR (500 MHz, CDCl ): δ 8.89 (dd, J
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= 4.2, 1.6 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 8.23 (d, J =8.6 Hz, 1H), 7.60-7.57 (m, 2H), 4.20 (q,
J = 7.1 Hz, 2H), 2.82-2.77 (m, 1H), 2.47-2.42 (m, 1H), 1.79 (ddd, J = 8.6, 6.0, 3.8 Hz, 1H), 1.71
(ddd, J = 8.9, 5.6, 3.8 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H) ppm; LRMS m/z (M+H) 243.3 found,
243.3 required.
(S,S) [2-(1,5-naphthyridinyl)cyclopropyl]methanol (C-4)
The title compound was prepared from C-2 according to the protocol outlined in
Scheme A to afford the title compound as a brown gum. ¹H NMR (500 MHz, CDCl ): δ 8.86
(dd, J = 4.2, 1.6 Hz, 1H), 8.21-8.26 (m, 2H), 7.57 (dd, J = 8.5, 4.2 Hz, 1H), 7.44 (d, J = 8.7 Hz,
1H), 3.77 (dd, J = 11.3, 6.3 Hz, 1H), 3.68 (dd, J = 11.3, 6.9 Hz, 1H), 2.21 (dt, J = 8.6, 4.5 Hz,
1H), 1.99-1.92 (m, 1H), 1.48-1.42 (m, 1H), 1.16-1.10 (m, 1H); LRMS m/z (M+H) 201.3 found,
201.2 required. The enantiomer C-4 was resolved from its corresponding enantiomer by chiral
preparative SFC (3.0 cm i.d. x 25 cm ChiralPak AD-H, 30% MeOH/CO +0.1% DEA, 70
mL/min) and analyzed by chiral analytical SFC (4.6 mm i.d. x 25 cm ChiralPak AD-H, 30%
MeOH/CO +0.1% DEA, 2.4 mL/min) ent = 3.4 min, ent = 4.7 min. Using this method, the
2 1 2
(S,S) enantiomer was determined to be the second eluting peak and was isolated in >99% ee.
REACTION SCHEME D
ethyl 3-(5-methoxypyridinyl)propenoate (D-1)
To a 25-mL microwave vial was added 2-bromomethoxy pyridine (1.88 g, 10
mmol), ethyl acrylate (5.44 ml, 50.0 mmol), Pd(OAc) (0.225 g, 1.000 mmol), K CO (4.15 g,
2 2 3
.0 mmol), and t-butylammonium chloride hydrate (2.96 g, 10.00 mmol). The slurry was heated
in the microwave at 160 °C for 1 h. Upon cooling to room temperature, the mixture was diluted
with EtOAc (100 mL) and washed with sat. aq. NaHCO3 (100 mL). The aqueous layer was
extracted with additional EtOAc (2x 50 mL). The combined organic layers were then washed
with water and brine, dried over Na SO , filtered, and concentrated in vacuo. The resulting
residue was purified by gradient elution on silica gel (0 to 50% EtOAc in hexanes) to afford the
MRL-NOP-00136
title compound (1.5 g, 72%). ¹H NMR (500 MHz, CDCl ): δ 8.35 (d, J = 3.0 Hz, 1H), 7.65 (d, J
= 15.7 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.18 (dd, J = 8.6, 3.0 Hz, 1H), 6.76 (d, J = 15.7 Hz,
1H), 4.26 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm; LRMS m/z (M+H)
208.0 found, 208.2 required.
ethyl 2-(5-methoxypyridinyl)cyclopropanecarboxylate (D-2)
The title compound was prepared from D-1 according to the protocol outlined in
Scheme C to afford D-2 as a light yellow solid. ¹H NMR (500 MHz, CDCl ): δ 8.15 (d, J = 2.9
Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 8.0, 2.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.82 (s,
3H), 2.58-2.52 (m, 1H), 2.18-2.12 (m, 1H), 1.56 (m, 1H), 1.54 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H)
ppm; LRMS m/z (M+H) 222.3 found, 222.3 required.
(S,S) [2-(5-methoxypyridinyl)cyclopropyl]methanol (D-4)
The title compound was prepared from D-2 according to the protocol outlined in
Scheme A to afford D-4 as a light yellow oil. ¹H NMR (500 MHz, CDCl ): δ 8.14 (d, J = 2.9
Hz, 1H), 7.09 (dd, J = 8.6, 2.9 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 3.82 (s, 3H), 3.72-3.66 (m, 1H),
3.61-3.55 (m, 1H), 1.97-1.91 (m, 1H), 1.69-1.62 (m, 1H), 1.20-1.14 (m, 1H), 0.91 (1 H, dt, J =
8.71, 5.06 Hz) ppm; LRMS m/z (M+H) 180.1 found, 180.1 required. The enantiomer D-4 was
resolved from its corresponding enantiomer by chiral preparative SFC (3.0 cm i.d. x 25 cm
ChiralPak AD-H, 6.7/13.3/80 MeCN/MeOH/CO , +0.1% DEA, 70 mL/min) and analyzed by
chiral analytical SFC (4.6 cm i.d. x 25 cm ChiralPak AD-H, 6.7/13.3/80 MeCN/MeOH/CO ,
+0.1% DEA, mL/m) ent = 3.7 min, ent = 4.4 min. Using this method, the (S,S) enantiomer was
determined to be the second eluting peak and was isolated in >99% ee.
REACTION SCHEME E
potassium vinyl
trifluoroborate
ethyldiazoacetate
Pd(dppf) Cl toluene
Cs CO
N Br 2 3 N
dioxane/H O
resolution
LAH, THF
Etrans
2-bromo(fluoromethyl)pyridine (E-1)
MRL-NOP-00136
To a stirred solution of 2-bromomethylpyridine (23.8 g, 138.0 mmol) and
potassium vinyl trifluoroborate (20.39 g, 152.0 mmol) in dioxane (235 mL) under nitrogen was
added Pd(dppf) Cl (11.30 g, 13.8 mmol), cesium carbonate (135.0 g, 415.0 mmol), and water
(41.5 mL). The resulting mixture heated to 100°C for 2 hours. The reaction was partitioned
between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was
concentrated and flash column separation using a 0-30% ethyl acetate/ hexane gradient gave E-1
as a volatile oil, which was carried on directly to next step.
ethyl 2-(5-methylpyridinyl)cyclopropanecarboxylate (Etrans)
To a stirred solution of E-1 (16.44 g, 138.0 mmol) in toluene (300 mL) was added
ethyl diazoacetate (42.9 ml, 414.0 mmol) and the resulting mixture was heated to 100°C for 3
hours. The mixture was allowed to cool and partitioned between ethyl acetate and saturated
sodium bicarbonate solution. The organic phase was concentrated and flash column separation
using a 0-20% ethyl acetate/ hexane gradient gave Etrans as an oil. (11.7 g, 41%). LRMS
(ES) (M+H) : observed = 206.2, calculated = 206.2.
(S,S) 2-(5-methylpyridinyl)cyclopropyl]methanol (E-3)
A solution of Etrans (5.0 g, 24.36 mmol) in THF (80 mL) was cooled to 0 ºC
and treated slowly with lithium aluminum hydride (55.0 mL, 55.0 mmol, 1 M solution in THF).
The solution was stirred for 30 min at 0°C. The reaction mixture was then treated sequentially
dropwise with 2.0 mL of water, 2.0 ml of 15% NaOH, and 6.0 mL of water. Sodium sulfate was
added to the mixture. After stirring at room temperature for 4 hours, the mixture was filtered and
the filtrate was concentrated in vacuo to afford the title compound as a pale yellow oil. (3.4 g,
85.4%). LRMS (ES) (M+H) : observed = 164.2, calculated = 164.2. ¹H NMR (400 MHz,
DMSO-d ): δ 8.21 (m, 1H), 7.41 (m, 1H), 7.12 (m, 1H), 4.57 (m, 1H) 3.44 (m, 1H), 3.33 (m,
1H), 2.21 (s, 3H), 1.88 (m, 1H), 1.44 (m, 1H), 0.98 (m, 1H), 0.81 (m, 1H). The enantiomer E-3
was resolved from its corresponding enantiomer by chiral preparative SFC (3.0 cm i.d. x 25 cm
ChiralPak AS-H, 10% iPrOH/CO +0.1% DEA, 80 mL/min) and analyzed by chiral analytical
SFC (4.6 mm i.d. x 15 cm ChiralPak AS-H, 15% iPrOH/CO +0.1% DEA, 2.4 mL/min) ent = 3.7
min, ent = 4.5 min to give the title compound. Using this method, the (S,S) enantiomer was
determined to be the second eluting peak and was isolated in >99% ee.
MRL-NOP-00136
REACTION SCHEME F
2-bromo(fluoromethyl)pyridine (F-1)
To a stirred solution of (6-bromopyridinyl)methanol (1.00 g, 5.32 mmol) in
dichloromethane (25 mL) at 0°C was added DAST (0.70 mL, 5.32 mmol) and the resulting
solution was stirred at 0°C for one hour. The mixture was washed with a saturated sodium
bicarbonate solution and concentrated. Flash column separation using a 0-10% ethyl acetate/
hexane gradient gave F-1 (0.37 g, 37%). LRMS (ES) (M+H) : observed = 190.0/192.0,
calculated = 190.0/192.0.
-(fluoromethyl)vinylpyridine (F-2)
To a stirred solution of F-1 (1.09 g, 5.74 mmol) and potassium vinyl
trifluoroborate ( 1.54 g, 11.47 mmol) in dioxane (9.75 mL) under nitrogen was added
Pd(dppf) Cl (0.47 g, 0.57 mmol), cesium carbonate (5.61 g, 17.21 mmol), and water (1.72 mL).
The resulting mixture heated to 100°C for 90 minutes. The reaction was partitioned between
ethyl acetate and saturated sodium bicarbonate solution. The organic phase was concentrated and
flash column separation using a 0-15% ethyl acetate/ hexane gradient gave F-2 as an oil (0.53 g,
67%). LRMS (ES) (M+H) : observed = 138.0, calculated = 138.1.
ethyl 2-(5-(fluoromethyl)pyridinyl)cyclopropanecarboxylate (Ftrans)
The title compound was prepared from F-2 according to the protocol outlined in
Scheme A, carried through as the trans racemate without chiral resolution, to afford Ftrans as
a brown oil. LRMS (ES) (M+H) : observed = 224.2, calculated = 224.2.
2-(5-(fluoromethyl)pyridinyl)cyclopropyl)methanol (F-4)
MRL-NOP-00136
The title compound was prepared from Ftrans according to the protocol
outlined in Scheme A to afford F-4 as a yellow oil. LRMS (ES) (M+H) : observed = 182.2,
calculated = 182.2.
REACTION SCHEME G
2-chloro(difluoromethyl)pyridine (G-1)
The title compound was prepared from 2-chloropyridinecarboxaldehyde
according to the protocol outlined in Scheme F to afford G-1. LRMS (ES) (M+H) : observed =
164.1, calculated = 164.5.
-(difluoromethyl)vinylpyridine (G-2)
The title compound was prepared from G-1 according to the protocol outlined in
Scheme F to afford G-2 as an oil. LRMS (ES) (M+H) : observed = 156.1, calculated = 156.1.
ethyl 2-(5-(difluoromethyl)pyridinyl)cyclopropanecarboxylate (Gtrans)
The title compound was prepared from G-2 according to the protocol outlined in
Scheme A, carried through as the trans racemate without chiral resolution, to afford Gtrans as
an oil. LRMS (ES) (M+H) : observed = 242.2, calculated = 242.2.
2-(5-(difluoromethyl)pyridinyl)cyclopropyl)methanol (G-4)
The title compound was prepared from Gtrans according to the protocol
outlined in Scheme A to afford G-4 as a yellow oil. LRMS (ES) (M+H) : observed = 200.2,
calculated = 200.2.
MRL-NOP-00136
REACTION SCHEME H
potassium vinyl
trifluoroborate
ethyldiazoacetate
Pd(dppf) Cl toluene
Cs CO
N Cl 2 3 N
dioxane/H O H-1
LAH, THF
N OH
N O N O
Hcis
Htrans
3-methylvinylpyridazine (H-1)
The title compound was prepared from 3-chloromethylpyridazine according to
the protocol outlined in Scheme F to afford H-1 as an oil. LRMS (ES) (M+H) : observed =
121.1, calculated = 121.1.
ethyl 2-(6-methylpyridazinyl)cyclopropanecarboxylate (Htrans)
The title compound was prepared from H-1 according to the protocol outlined in
Scheme A, carried through as the trans racemate without chiral resolution to afford Htrans as
an oil. LRMS (ES) (M+H) : observed = 207.2, calculated = 207.2.
2-(6-methylpyridazinyl)cyclopropyl)methanol (H-3)
The title compound was prepared from Htrans according to the protocol
outlined in Scheme A to afford H-3 as an oil. LRMS (ES) (M+H) : observed = 165.2, calculated
= 165.2.
REACTION SCHEME I
-bromovinylpyridine (I-1)
The title compound was prepared from 2,5-dibromopyridine according to the
protocol outlined in Scheme F to afford I-1 as an oil. LRMS (ES) (M+H) : observed =
184.0/186.0, calculated = 184.0/186.0.
ethyl 2-(5-bromopyridinyl)cyclopropanecarboxylate (Itrans)
MRL-NOP-00136
The title compound was prepared from I-1 according to the protocol outlined in
Scheme A, carried through as the trans racemate without chiral resolution, to afford Itrans as
an oil. LRMS (ES) (M+H) : observed = 270.1/272.1, calculated = 270.1/272.1.
2-(5-bromopyridinyl)cyclopropyl)methanol (I-3)
The title compound was prepared from Itrans according to the protocol
outlined in Scheme A to afford I-3 as an oil. LRMS (ES) (M+H) : observed = 228.1/230.1,
calculated = 228.1/230.1.
REACTION SCHEME J
ethyl 2-(5-fluoropyridinyl)cyclopropanecarboxylate (Jtrans)
2-bromofluoropyridine was used to prepare J-1 according to the protocol
outlined in Scheme F. J-1 was used directly to prepare the title compound according to the
protocol outlined in Scheme A to afford Jtrans as an oil. LRMS (ES) (M+H) : observed =
210.2, calculated = 210.2.
2-(5-fluoropyridinyl)cyclopropyl)methanol (J-4)
The title compound was prepared from Jtrans according to the protocol
outlined in Scheme A to afford J-4 as an oil. LRMS (ES) (M+H) : observed = 168.0, calculated
= 168.2.
MRL-NOP-00136
REACTION SCHEME K
potassiumvinyl
trifluoroborate
ethyldiazoacetate
Pd(dppf)Cl
toluene
CsCO
N Br 2 3 N
dioxane/HO K-1
LAH,THF
N N N
Ktrans Kcis
-(trifluoromethyl)vinylpyridine (K-1)
The title compound was prepared from 2-bromotrifluoromethylpyridine
according to the protocol outlined in Scheme F to afford K-1 as an oil. LRMS (ES) (M+H) :
observed = 174.0, calculated = 174.1.
ethyl 2-(5-(trifluoromethyl)pyridinyl)cyclopropanecarboxylate (Ktrans)
The title compound was prepared from K-1 according to the protocol outlined in
Scheme A, carried through as the trans racemate without chiral resolution, to afford Ktrans as
an oil. LRMS (ES) (M+H) : observed = 260.1, calculated = 260.2.
2-(5-(trifluoromethyl)pyridinyl)cyclopropyl)methanol (K-3)
The title compound was prepared from Ktrans according to the protocol
outlined in Scheme A to afford K-4 as an oil. LRMS (ES) (M+H) : observed = 218.1, calculated
= 218.2.
REACTION SCHEME L
3-fluoromethylvinylpyridine (L-1)
The title compound was prepared from 2-chlorofluoromethylpyridine
according to the protocol outlined in Scheme F to afford L-2 as an oil. LRMS (ES) (M+H) :
observed = 138.0, calculated = 138.1.
ethyl 2-(3-fluoromethylpyridinyl)cyclopropanecarboxylate (Ltrans)
MRL-NOP-00136
The title compound was prepared from L-1 according to the protocol outlined in
Scheme A, carried through as the trans racemate without chiral resolution, to afford Ltrans as
an oil. LRMS (ES) (M+H) : observed = 224.2, calculated = 224.2.
2-(3-fluoromethylpyridinyl)cyclopropyl)methanol (L-3)
The title compound was prepared from Ltrans according to the protocol
outlined in Scheme A, to afford L-3 as an oil. LRMS (ES) (M+H) : observed = 182.1, calculated
= 182.2.
REACTION SCHEME M
(E)-ethyl 3-(pyrazolo[1,5-a]pyridinyl)acrylate (M-1)
The title compound was prepared from 2-chloropyrazolo[1,5-a]pyridine according
to the protocol outlined in Scheme C to afford M-1 as a solid. LRMS (ES) (M+H) : observed =
203.2, calculated = 203.2.
ethyl 2-(pyrazolo[1,5-a]pyridinyl)cyclopropanecarboxylate (Mtrans)
The title compound was prepared from M-1 according to the protocol outlined in
Scheme C, carried through as the trans racemate without chiral resolution to afford Mtrans as
a solid. LRMS (ES) (M+H) : observed = 217.1, calculated = 217.2.
2-(pyrazolo[1,5-a]pyridinyl)cyclopropyl)methanol (M-3)
The title compound was prepared from Mtrans according to the protocol
outlined in Scheme A, to afford M-3 as an oil. LRMS (ES) (M+H) : observed = 189.2,
calculated = 189.2.
MRL-NOP-00136
REACTION SCHEME N
ethyl 3-(2-methylthiazolyl)acrylate (N-1)
To a stirred solution of sodium hydride (1.04 g, 26.0 mmol) in THF (47.2 mL)
was added triethyl phosphonoacetate (5.19 mL, 26.0 mmol) portionwise at room temperature.
The resulting mixture was stirred for 30 minutes at room temperature. To this mixture was added
a solution of 2-methylthiazolecarbaldehyde (3.0 g, 23.6 mmol) dissolved in THF (30 mL) with
vigorous stirring. The reaction was stirred for 1 hour, partitioned between ethyl acetate and
saturated sodium bicarbonate solution. The organic phase was washed with brine, dried over
sodium sulfate, and concentrated to give the title compound as a yellow oil (4.3 g, 92%). LRMS
(ES) (M+H) : observed = 198.1, calculated = 198.2.
ethyl 2-(2-methylthiazolyl)cyclopropanecarboxylate (Ntrans)
The title compound was prepared from N-1 according to the protocol outlined in
Scheme C to afford Ntrans. LRMS (ES) (M+H) : observed = 212.2, calculated = 212.2.
2-(2-methylthiazolyl)cyclopropyl)methanol (N-4)
The title compound was prepared from Ntrans according to the protocol
outlined in Scheme A to afford N-4 as a solid. LRMS (ES) (M+H) : observed = 170.1,
calculated = 170.2.
MRL-NOP-00136
REACTION SCHEME O
(E)-ethyl 3-(2-methyloxazolyl)acrylate (O-2)
The title compound was prepared from O-1 according to the protocol outlined in
Scheme N, to afford O-2. LRMS (ES) (M+H) : observed = 182.1, calculated = 182.1.
ethyl 2-(2-methyloxazolyl)cyclopropanecarboxylate (Otrans)
The title compound was prepared from O-2 according to the protocol outlined in
Scheme C, carried through as the trans racemate without chiral resolution to afford Otrans as
an oil. LRMS (ES) (M+H) : observed = 196.2, calculated = 196.2.
2-(2-methyloxazolyl)cyclopropyl)methanol (O-4)
The title compound was prepared from Otrans according to the protocol
outlined in Scheme A, to afford O-4 as a solid. LRMS (ES) (M+H) : observed = 154.1,
calculated = 154.1.
REACTION SCHEME P
(E)-ethyl 3-(3-methoxypyridinyl)acrylate (P-2)
MRL-NOP-00136
The title compound was prepared from P-1 according to the protocol outlined in
Scheme N, to afford P-2. LRMS (ES) (M+H) : observed = 208.1, calculated = 208.2.
ethyl 2-(3-methoxypyridinyl)cyclopropanecarboxylate (Ptrans)
The title compound was prepared from P-2 according to the protocol outlined in
Scheme C, carried through as the trans racemate without chiral resolution to afford Ptrans as
an oil. LRMS (ES) (M+H) : observed = 222.2, calculated = 222.2.
2-(3-methoxypyridinyl)cyclopropyl)methanol (P-4)
The title compound was prepared from Ptrans according to the protocol
outlined in Scheme A, to afford P-4 as a solid. LRMS (ES) (M+H) : observed = 180.2,
calculated = 180.2.
REACTION SCHEME Q
ethyl 2-(1-methyl-1H-pyrazolyl)cyclopropanecarboxylate (Q2-trans)
The title compound was prepared from 1-methyl-1H-pyrazolecarbaldehyde
according to the protocol outlined in Scheme N to afford Q-1, which was carried on directly
using the protocol outlined in Scheme C, carried through as the trans racemate without chiral
resolution, to afford Qtrans as an oil. LRMS (ES) (M+H) : observed = 195.3, calculated =
195.2.
2-(1-methyl-1H-pyrazolyl)cyclopropyl)methanol (Q-3)
The title compound was prepared from Qtrans according to the protocol
outlined in Scheme A to afford Q-3 as a solid. LRMS (ES) (M+H) : observed = 153.2,
calculated = 153.2.
MRL-NOP-00136
REACTION SCHEME R
(E)-ethyl 3-(thiazolyl)acrylate (R-1)
The title compound was prepared from thiazolecarbaldehyde according to the
protocol outlined in Scheme N to afford R-2. LRMS (ES) (M+H) : observed = 184.1, calculated
= 184.2.
ethyl 2-(thiazolyl)cyclopropanecarboxylate (Rtrans)
The title compound was prepared from R-1 according to the protocol outlined in
Scheme C, carried through as the trans racemate without chiral resolution, to afford Rtrans.
LRMS (ES) (M+H) : observed = 198.1, calculated = 198.2.
2-(thiazolyl)cyclopropyl)methanol (R-3)
The title compound was prepared from Rtrans according to the protocol
outlined in Scheme A to afford R-3. LRMS (ES) (M+H) : observed = 156.1, calculated = 156.2.
MRL-NOP-00136
REACTION SCHEME S
Cl O
Si Pd(OAc) ,
OH O Si
O Si CH N
S-1 S-2
BIS(CYCLOPENT
ADIENYL)ZIRCON
IUM CHLORIDE
HYDRIDE
O Si
O Si
N Cl
NaIO , NH OAc
4 4 HO
Pd(OAc) , Cs CO ,
2 2 3
Acetone/water
Di(1-adamantyl)-n-
butylphosphine,
toluene/water
O Si
THF, TBAF
tert-butyldimethyl(propynyloxy)silane (S-1)
To a mixture of propynol (168 g, 3 mol), Et N (412 g, 4.08 mol) in CH Cl
3 2 2
(3500 mL) was added a solution of TBSCl (543 g, 3.45 mol) in CH Cl (500 mL) at 0 C. Then
the reaction mixture was warmed up to room temperature and stirred overnight. The mixture was
washed by water (3000 mL), dried over Na SO , and concentrated to give crude product, which
was purified by flash chromatography (petroleum ether) and distillation to give compound S-1 as
a yellow liquid. (110 g, 43%)
(E)-tert-butyldimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)allyloxy)silane (S-2)
The mixture of bis(cyclopentadienyl)zirconium chloride hydride (16.2 g, 0.062
mol), pinacolborane (160.5 g, 1.25 mol) and TEA (8.7 mL, 0.062 mol) in THF (1200 mL) was
heated to 50 °C for 10 min and compound S-1 (106 g, 0.62 mol) was added. Then the mixture
was stirred at 50°C overnight. The reaction mixture was cooled, quenched with water and
concentrated to remove majority of THF. The residue was extracted with ethyl acetate (2000
mL). The organic layer was washed with brine, dried over anhydrous Na SO and concentrated in
vacuum to give the crude product, which was purified by flash chromatography (petroleum ether)
to afford compound S-2 as yellow liquid. (139 g, 74.7 %)
tert-butyldimethyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)cyclopropyl)methoxy)silane
(S-3)
To a mixture of compound S-2 (65 g, 0.218 mol) and Pd(OAc) (5g, 0.0218 mol)
in THF (200 mL) was added a solution of CH N (fresh, 2.18 mol) in ether (1200 mL) at -78 C.
Then the reaction mixture was warmed up to room temperature and stirred overnight. The
MRL-NOP-00136
mixture was filtered and the filtrate was concentrated to give crude product, which was purified
by flash chromatography (petroleum ether) to afford compound S-3 as yellow oil. (27.5 g, 40 %)
2-((tert-butyldimethylsilyloxy)methyl)cyclopropylboronic acid (S-4)
To a mixture of compound S-3 (36 g, 0.115 mol) in acetone (360 mL) and water
(180 mL) was added NaIO (148 g, 0.69 mol) and NaOAc (53.2 g, 0.69 mol) at room
temperature. Then reaction mixture was stirred at 25 °C overnight. The mixture was filtered and
the filtrate was concentrated to remove acetone, extracted with ethyl acetate (600 mL). The
organic layer was washed by water, brine, dried over Na SO , and concentrated to give crude
product, which was purified by chromatography (petroleum ether/ethyl acetate=10:1 to 4:1 and
then MeOH/ CH Cl = 25:1) to give S-4 as yellow liquid.(19.3, 73 %)
2-(2-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (S-
To a stirred solution of S-4 (3.0 g, 13.0 mol) in toluene (50 mL) was added 2-
chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (2.0 g, 13.0 mmol), palladium acetate (0.29 g, 1.30
mmol), di(1-adamantyl)-n-butylphosphine (1.40 g, 3.91 mmol), cesium carbonate (12.74 g, 39.10
mmol) and water (16.6 mL). The resulting mixture was heated to 100°C overnight. The reaction
was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic
phase was concentrated and flash column separation using a 0-10% ethyl acetate/ hexane gradient
gave S-5 as an oil. (3.19 g, 65%)
((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methanol (S-6)
To a stirred solution of S-5 (3.19 g, 10.5 mmol) in THF (40 mL) was added
tetrabutyl ammonium fluoride solution 1M (10.5 mL, 10.5 mmol). The resulting mixture was
stirred 2 hours at room temperature and concentrated. Flash column separation using a 10-100%
ethyl acetate/ hexane gradient gave S-6 as an oil. (1.44 g, 72%)
MRL-NOP-00136
EXAMPLE 1
N N H N triethylamine
dioxane
Cl Cl
A-4,
NaH, THF
O NH
6-chloromethyl-N-((1-methyl-1H-pyrazolyl)methyl)pyrimidinamine (1-1)
To a stirred solution of 4,6-dichloromethylpyrimidine (100 mg, 0.61 mmol) in
dioxane (1 mL) was added triethylamine (0.3 mL, 2.15 mmol) and (1-methyl-1H-pyrazol
yl)methanamine (68 mg, 0.61 mmol). The resulting mixture was microwave irradiated at 150°C
for 30 minutes. The reaction was diluted with ethyl acetate and washed with saturated sodium
bicarbonate solution. The organic phase was concentrated and flash column separation using a
-100% ethyl acetate/ hexane gradient gave 1-1 as a white solid (121mg, 83%). MS (M+H) :
observed = 238.0857, calculated = 238.0854.
2-methyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridinylcyclopropyl)methoxy]
pyrimidinamine (1-2)
To a stirred solution of A-4 (188 mg, 1.26 mmol) in THF (2.5 mL) was added
sodium hydride 60% dispersion (74 mg, 1.85 mmol) and the resulting solution was stirred at
room temperature for 20 minutes. To this was added 1-1 (200 mg, 0.84 mmol) and the resulting
mixture was microwave irradiated at 100°C for 90 minutes. The reaction was concentrated and
purified using reverse phase chromatography (10-30%, 0.1% TFA in H O/acetonitrile) to give 1-
2 as a white solid (231mg, 78%). MS (M+H) : observed = 351.1927, calculated = 351.1928.
MRL-NOP-00136
EXAMPLE 2
4-Chloromethyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)-pyrimidine (2-1)
To a suspension of sodium hydride (103 mg, 2.57 mmol) in THF (6.0 mL) was added (S,S) E-3
(350 mg, 2.14 mmol). The resulting mixture was stirred for 30 min before 4,6-dichloro
methylpyridine (419mg, 2.57 mmol) was added. After heating at 80˚C for 1 hour, the reaction
was diluted with ethyl acetate and washed with water and brine. The organic phase was
concentrated and flash column chromatography using a 0-40% ethyl acetate/ hexane gradient
gave 2-1 as a colorless oil (453 mg, 73%). MS (M+H) : observed = 290.35, calculated = 290.10.
tert-Butyl ((5-methyl-1,3,4-thiadiazolyl)methyl)(2-methyl(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinyl)carbamate (2-2)
A solution of 2-1 (100 mg, 0.35 mmol), tert-butyl ((5-methyl-1,3,4-thiadiazol
yl)methyl)carbamate (119 mg, 0.52 mmol; for preparation, see D. C. Pryde et al. J. Med Chem.
2006, 49, 4409 – 4424), 1 M potassium tert-butoxide (1.03 mL in THF) and 2-di-tert-
butylphosphino-2′,4′,6′-triisopropylbiphenyl (14.6 mg, 0.035mmol) in 2-Methylbutanol (1.7
ml) was purged with N for 5 min. Tris(dibenzylideneacetone)-dipalladium(0) (31.6 mg, 0.035
mmol) was added and the mixture was heated at 60°C for 1 hour. The reaction was cooled to
room temperature and diluted with ethyl acetate and sat. NaHCO . The organic phase was
washed with water, brine and concentrated. The residue was purified by flash column
chromatography using a 20-60% ethyl acetate/ hexane gradient gave 2-2 as a colorless oil (117
mg, 70%). MS (M+H) : observed = 483.10, calculated = 483.21.
MRL-NOP-00136
2-Methyl{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-
thiadiazolyl)methyl]pyrimidinamine (2-3")
To a solution of 2-2 (51.0 mg, 0.11 mmol) in MeOH (0.53 mL) was added K CO (17.5 mg, 0.13
mmol). The resulted suspension was stirred at 70˚C for 2 hour. The mixture was diluted with
EtOAc, and then extracted with 1N HCl. The aqueous layer was basified with 5N NaOH and
extracted with DCM three times. The combined DCM layers were dried over Na SO and
concentrated to give 2-3"as an off white solid (29 mg, 72%). MS (M+H) : observed =
383.1654, calculated = 383.1649. ¹H NMR (400 MHz, DMSO-d ): δ 8.22 (s, 1H), 7.82 (br t, J=
.0 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.17 (d, J= 7.7 Hz, 1H), 5.64 (s, 1H), 4.76 (d, J= 5.0 Hz,
2H), 4.23 (m, 1H), 4.14 (m, 1H), 2.65 (s, 3H), 2.31 (s, 3H), 2.22 (s, 3H), 2.09 (m, 1H), 1.71 (m,
1H), 1.12 (m, 1H), 0.98 (m, 1H)
TABLE 1
The following compounds were prepared in an analogous manner to Examples 1
and 2, using an appropriately substituted 4,6-dichloropyrimidine, amine, and alcohols previously
described in Schemes A through R. Starting materials not previously illustrated were
commercially available, described in the literature, or readily synthesized by one skilled in the art
of organic synthesis without undue experimentation.
Cpd Structure Name HRMS/LRMS
S,S-N-[(2,4-dimethyl-
C20H23N5OS
1,3-thiazolyl)methyl]-
N N N
[M+H]
2-3 2-methyl[(2-pyridin
calc 382.1696
ylcyclopropyl)methoxy]p
obs 382.1700
yrimidinamine
S,S-N -[(1,3-dimethyl-
1H-pyrazolyl)methyl]- C24H26N6O
2-methyl[(2-quinolin- [M+H]
2- calc 415.2241
ylcyclopropyl)methoxy]p obs 415.2242
yrimidinamine
S,S-N -[(1,3-dimethyl-
C23H25N7O
1H-pyrazolyl)methyl]-
[M+H]
2-5 2-methyl{[2-(1,5-
calc 416.2193
naphthyridin
obs 416.2192
yl)cyclopropyl]methoxy}
MRL-NOP-00136
pyrimidinamine
S,S-N -[(1,3-dimethyl-
1H-pyrazolyl)methyl]- C21H26N6O
2-methyl{[2-(5- [M+H]
methylpyridin calc 379.2241
yl)cyclopropyl]methoxy} obs 379.2244
pyrimidinamine
S,S-N -[(1,3-dimethyl-
1H-pyrazolyl)methyl]- C21H26N6O2
6-{[2-(5-methoxypyridin- [M+H]
2-yl)cyclopropyl]- calc 395.2190
methoxy} obs 395.2191
methylpyrimidinamine
S,S-N -[(1,3-dimethyl-
1H-pyrazolyl)methyl]- C20H24N6O
2-methyl[(pyridin- [M+H]
2-ylcyclopropyl)- calc 365.2084
methoxy]pyrimidin obs 365.2092
amine
S,Smethyl-N-[(1-
methyl-1H-pyrazol C23H24N6O
yl)methyl][(2- [M+H]
quinolin calc 401.2084
ylcyclopropyl)methoxy]p obs 401.2066
yrimidinamine
S,Smethyl-N-[(1-
methyl-1H-pyrazol C23H24N6O
yl)methyl][(2- [M+H]
2-10
quinolin calc 401.2084
ylcyclopropyl)methoxy]p obs 401.2088
yrimidinamine
S,Smethyl-N-[(1-
methyl-1H-pyrazol C22H23N7O
yl)methyl]{[2-(1,5- [M+H]
2-11
naphthyridin calc 402.2037
yl)cyclopropyl]methoxy} obs 402.2040
pyrimidinamine
MRL-NOP-00136
S,S{[2-(5-
methoxypyridin
C20H24N6O2
yl)cyclopropyl]methoxy}
[M+H]
2-12 methyl-N-[(1-methyl-
calc 381.2034
1H-pyrazol
obs 381.2039
yl)methyl]pyrimidin
amine
S,Smethyl-N-[(1-
methyl-1H-pyrazol C20H24N6O
yl)methyl]{[(5- [M+H]
2-13
methylpyridin calc 365.2084
yl)cyclopropyl]methoxy} obs 365.2091
pyrimidinamine
6-{[2-(3-methoxypyridin-
C20H24N6O2
yl)cyclopropyl]methoxy}
N N N
[M+H]
2-14 methyl-N-[(1-methyl-
O N calc 381.2034
1H-pyrazol
obs 381.2040
yl)methyl]pyrimidin
amine
S,S{[2-(5-
fluoropyridin
C19H21FN6O
yl)cyclopropyl]methoxy}
[M+H]
2-15 methyl-N-[(1-methyl-
calc 369.1834
1H-pyrazol
obs 369.1830
yl)methyl]pyrimidin
amine
6-({2-[5-
(fluoromethyl)pyridin
C20H23FN6O
yl]cyclopropyl}methoxy)
F N N N
[M+H]
2-16 methyl-N-[(1-methyl-
calc 383.1990
1H-pyrazol
obs 383.1988
yl)methyl]pyrimidin
amine
MRL-NOP-00136
6-({2-[5-
(difluoromethyl)pyridin-
2- C20H22F2N6O
F N N N
yl]cyclopropyl}methoxy) [M+H]
2-17
O N methyl-N-[(1-methyl- calc 401.1896
1H-pyrazol obs 401.1893
yl)methyl]pyrimidin
amine
2-methyl-N-[(1-methyl-
1H-pyrazolyl)methyl]-
C20H21F3N6O
6-({2-[5-
F N N N
[M+H]
2-18 (trifluoromethyl)pyridin-
O N calc 419.1802
obs 419.1805
yl]cyclopropyl}methoxy)
pyrimidinamine
2-methyl-N-[(1-methyl-
C17H20N6OS
1H-pyrazolyl)methyl]-
N N N
[M+H]
2-19 6-{[2-(1,3-thiazol
O N calc 357.1495
yl)cyclopropyl]methoxy}
pyrimidinamine
S,Smethyl-N-[(2-
methyl-1,3-thiazol C23H23N5OS
yl)methyl][(2- [M+H]
2-20
quinolin calc 418.1696
ylcyclopropyl)methoxy]p obs 418.1677
yrimidinamine
S,Smethyl-N-[(2-
methyl-1,3-thiazol C22H22N6OS
yl)methyl]{[2-(1,5- [M+H]
2-21
naphthyridin calc 419.1649
yl)cyclopropyl]methoxy} obs 419.1628
pyrimidinamine
S,Smethyl{[2-(5-
C20H23N5OS
methylpyridin
[M+H]
2-22 yl)cyclopropyl]methoxy}
calc 382.1696
-N-[(2-methyl-1,3-
obs 382.1680
thiazol
MRL-NOP-00136
yl)methyl]pyrimidin
amine
S,S{[2-(5-
methoxypyridin
C20H23N5O2S
yl)cyclopropyl]methoxy}
[M+H]
2-23 methyl-N-[(2-methyl-
calc 398.1645
1,3-thiazol
obs 398.1628
yl)methyl]pyrimidin
amine
S,Smethyl-N-[(2-
methyl-1,3-thiazol C19H21N5OS
yl)methyl][(2-pyridin- [M+H]
2-24
2- calc 368.1540
ylcyclopropyl)methoxy]p obs 368.1526
yrimidinamine
S,Smethyl-N-[(2-
methyl-1,3-thiazol C19H21N5OS
N N N
yl)methyl][(2-pyridin- [M+H]
2-25
2- calc 368.1540
ylcyclopropyl)methoxy]p obs 368.1545
yrimidinamine
S,Smethyl-N-[(5-
methyl-1,3,4-thiadiazol- C22H22N6OS
2-yl)methyl][(2- [M+H]
2-26
quinolin calc 419.1649
ylcyclopropyl)methoxy]p obs 419.1630
yrimidinamine
S,Smethyl-N-[(5-
methyl-1,3,4-thiadiazol- C21H21N7OS
2-yl)methyl]{[2-(1,5- [M+H]
2-27
naphthyridin calc 420.1601
yl)cyclopropyl]methoxy} obs 420.1602
pyrimidinamine
S,S{[2-(5- C19H22N6O2S
methoxypyridin [M+H]
2-28
yl)cyclopropyl]methoxy} calc 399.1598
methyl-N-[(5-methyl- obs 399.1586
MRL-NOP-00136
1,3,4-thiadiazol
yl)methyl]pyrimidin
amine
S,Smethyl-N-[(5-
methyl-1,3,4-thiadiazol- C18H20N6OS
2-yl)methyl][(2- [M+H]
2-29
pyridin calc 369.1492
ylcyclopropyl)methoxy]p obs 369.1493
yrimidinamine
S,S{[2-(5-
fluoropyridin
C18H19FN6OS
yl)cyclopropyl]methoxy}
[M+H]
2-30 methyl-N-[(5-methyl-
calc 387.1398
1,3,4-thiadiazol
obs 387.1393
yl)methyl]pyrimidin
amine
6-({2-[5-
(fluoromethyl)pyridin
C19H21FN6OS
yl]cyclopropyl}methoxy)
F N N N
[M+H]
2-31 methyl-N-[(5-methyl-
calc 401.1554
1,3,4-thiadiazol
obs 401.1553
yl)methyl]pyrimidin
amine
6-({2-[5-
(difluoromethyl)pyridin-
C19H20F2N6O
F N N N
yl]cyclopropyl}methoxy)
2-32 [M+H]
O N methyl-N-[(5-methyl-
calc 419.1460
1,3,4-thiadiazol
obs 419.1455
yl)methyl]pyrimidin
amine
2-methyl{[2-(6-
methylpyridazin C18H21N7OS
yl)cyclopropyl]methoxy} [M+H]
2-33
N O N
-N-[(5-methyl-1,3,4- calc 384.1601
thiadiazol obs 384.1614
yl)methyl]pyrimidin
MRL-NOP-00136
amine
S,Smethyl-N-[(5-
methyl-1,3,4-thiadiazol- C17H20N6OS2
2-yl)methyl]{[2-(2- [M+H]
2-34
methyl-1,3-thiazol calc 389.1213
yl)cyclopropyl]methoxy} obs 389.1213
pyrimidinamine
2-methyl{[2-(2-
methyl-1,3-oxazol
C17H20N6O2S
yl)cyclopropyl]methoxy}
N N N
[M+H]
2-35 -N-[(5-methyl-1,3,4-
O N calc 373.1441
thiadiazol
obs 373.1440
yl)methyl]pyrimidin
amine
2-methyl{[2-(1-
methyl-1H-pyrazol
C17H21N7OS
yl)cyclopropyl]methoxy}
N N N
[M+H]
2-36 -N-[(5-methyl-1,3,4-
calc 372.1601
thiadiazol
obs 372.1592
yl)methyl]pyrimidin
amine
S,S-N -[(5-cyclopropyl-
1,3,4-thiadiazol C20H22N6OS
yl)methyl]methyl [M+H]
N N N
2-37
[(2-pyridin calc 395.1649
ylcyclopropyl)methoxy]p obs 395.1651
yrimidinamine
S,S-N -[(2,4-dimethyl-
C19H21N5OS
1,3-thiazolyl)methyl]-
[M+H]
2-38 6-[(2-pyridin
calc 368.1540
ylcyclopropyl)methoxy]p
obs 368.1545
yrimidinamine
S,S-N -[(5-methyl-1,3,4-
C21H20N6OS
thiadiazolyl)methyl]-
[M+H]
2-39 6-[(2-quinolin
calc 405.1492
ylcyclopropyl)methoxy]p
obs 405.1476
yrimidinamine
MRL-NOP-00136
S,S-N -[(5-methyl-1,3,4-
thiadiazolyl)methyl]- C20H19N7OS
6-{[2-(1,5-naphthyridin- [M+H]
2-40
2-yl)cyclopropyl]- calc 406.1445
methoxy}pyrimidin obs 406.1433
amine
S,S{[2-(5-
methoxypyridin
C18H20N6O2S
yl)cyclopropyl]methoxy}
[M+H]
2-41 -N-[(5-methyl-1,3,4-
calc 385.1441
thiadiazol
obs 385.1423
yl)methyl]pyrimidin
amine
S,S{[2-(5-
methylpyridin
C18H20N6OS
yl)cyclopropyl]methoxy}
[M+H]
2-42 -N-[(5-methyl-1,3,4-
calc 369.1492
thiadiazol
obs 369.1477
yl)methyl]pyrimidin
amine
S,S-N-[(5-methyl-1,3,4-
C17H18N6OS
thiadiazolyl)methyl]-
[M+H]
2-43 6-[(2-pyridin
calc 355.1336
ylcyclopropyl)methoxy]p
obs 355.1324
yrimidinamine
S,S-N[(5-methyl-
1,3,4-thiadiazol C17H19N7OS
yl)methyl][(2-pyridin- [M+H]
2-44
2- calc 370.1445
ylcyclopropyl)methoxy]p obs 370.1455
yrimidine-2,4-diamine
S,S methoxy-N-[(1-
methyl-1H-pyrazol C19H22N6O2
N N N
yl)methyl][(2-pyridin- [M+H]
2-45
2- calc 367.1877
ylcyclopropyl)methoxy]p obs 367.1859
yrimidinamine
MRL-NOP-00136
S,S-2,5-dimethyl-N-[(1-
methyl-1H-pyrazol C20H24N6O
N N N
yl)methyl][(2-pyridin- [M+H]
2-46
O N 2- calc 365.2084
ylcyclopropyl)methoxy]p obs 365.2090
yrimidinamine
S,S-N -[(2,4-dimethyl-
1,3-thiazolyl)methyl]- C21H25N5OS
N N N
2,5-dimethyl[(2- [M+H]
2-47
pyridin calc 396.1853
ylcyclopropyl)methoxy]p obs 396.1858
yrimidinamine
S,S-N {[2-(5-
methoxypyridin C19H19F3N6O
yl)cyclopropyl]methoxy} 2S
2-48 -N-[(5-methyl-1,3,4- [M+H]
thiadiazolyl)methyl]- calc 453.1315
2-(trifluoromethyl)- obs 453.1309
pyrimidinamine
S,S-{[2-(5-
methylpyridin C19H19F3N6O
yl)cyclopropyl]methoxy} S
2-49 -N-[(5-methyl-1,3,4- [M+H]
thiadiazolyl)methyl]- calc 437.1366
2-(trifluoromethyl)- obs 437.1360
pyrimidinamine
S,S-N-[(5-methyl-1,3,4-
C18H17F3N6O
thiadiazolyl)methyl]-
6-[(2-pyridin
2-50 [M+H]
ylcyclopropyl)methoxy]-
calc 423.1209
2-(trifluoromethyl)-
obs 423.1207
pyrimidinamine
S,S-N -[(1-methyl-1H-
C19H19F3N6O
pyrazolyl)methyl]
[M+H]
N N N
2-51 [(2-pyridin
calc 405.1645
ylcyclopropyl)methoxy]-
obs 405.1626
2-(trifluoromethyl)-
MRL-NOP-00136
pyrimidinamine
6-{[(1S,2S)(5,6-
dihydro-4H-pyrrolo[1,2-
b]pyrazol C19H23N7OS
yl)cyclopropyl]methoxy} [M+H]
2-52 O N
H methyl-N-[(5-methyl- calc 398.1758
1,3,4-thiadiazol obs 398.1757
yl)methyl]pyrimidin
amine
S,S{[(1S,2S)(5-
methoxypyridin
C18H21N7O2S
yl)cyclopropyl]methoxy}
[M+H]
2-53 -N[(5-methyl-1,3,4-
calc 400.1550
thiadiazol
obs 400.1546
yl)methyl]pyrimidine-
2,4-diamine
2-methyl-N-[(5-methyl-
1,3,4-thiadiazol
C19H20N8OS
yl)methyl]{[(1S,2S)-
[M+H]
2-54 2-pyrazolo[1,5-
calc 409.1554
a]pyrimidin
obs 409.1545
ylcyclopropyl]methoxy}p
yrimidinamine
2-methyl-N-[(5-methyl-
1,3,4-thiadiazol
C19H20N8OS
N N N
yl)methyl]{[(1S,2S)-
[M+H]
N O N
2-55 2-pyrazolo[1,5-
calc 409.1554
a]pyrimidin
obs 409.1545
ylcyclopropyl]methoxy}p
yrimidinamine
S,S{[(1S,2S)(5-
bromopyridin C18H19BrN6O
yl)cyclopropyl]methoxy} S
2-56 methyl-N-[(5-methyl- [M+H]
1,3,4-thiadiazol calc 447.0597
yl)methyl]pyrimidin obs 447.0593
amine
MRL-NOP-00136
2-methyl{[(1S,2S)
(2-methylimidazo[1,2-
b]pyridazin C20H22N8OS
yl)cyclopropyl]methoxy} [M+H]
2-57 N O N
-N-[(5-methyl-1,3,4- calc 423.1710
thiadiazol obs 423.1717
yl)methyl]pyrimidin
amine
S,Schloromethyl
{[(1S,2S)(5-
C19H21ClN6O
methylpyridin
yl)cyclopropyl]methoxy}
2-58 [M+H]
-N-[(5-methyl-1,3,4-
calc 417.1259
thiadiazol
obs 417.1268
yl)methyl]pyrimidin
amine
EXAMPLE 3
O O NaOEt
HCl POCl
EtOH
HO OH
N N H N triethylamine
dioxane
Cl Cl N
A-4,
NaH, THF
O NH
4,6-dichloroethylpyrimidine 3-2
To a stirred solution of propionimidamide hydrochloride (1.00 g, 9.21 mmol) in
ethanol (35 mL) was added sodium ethoxide solution 21% in ethanol (17.25 mL). The resulting
solution was stirred 20 minutes at room temperature. To this was added dimethyl malonate (0.97
g, 7.37 mmol) and the resulting solution was heated to 80°C for 5 hours.
The solution was allowed to cool and concentrated to dryness. To this solid was added a
minimum amount of water and neutralized to pH of 5 using 6N HCl solution. The solution was
MRL-NOP-00136
allowed to sit overnight during which time white solid 3-1 precipitated out. The solid 3-1 was
dissolved in phosphorus oxychloride (5 mL) and heated to reflux for 90 minutes. The solution
was concentrated, quenched with ice, and partitioned between ethyl acetate and a saturated
sodium bicarbonate solution. The organic phase was concentrated to give 3-2 as an oil (0.60 g,
37%). LRMS (M+H) : observed = 177.1, calculated = 177.0.
6-chloroethyl-N-((1-methyl-1H-pyrazolyl)methyl)pyrimidinamine 3-3
The title compound was prepared from 2-2 according to the protocol outlined in
Example 1, to afford 3-3 as a solid. LRMS (ES) (M+H) : observed = 252.1, calculated = 252.7.
2-ethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridinylcyclopropyl)methoxy]
pyrimidinamine 3-4
The title compound was prepared from 3-3 according to the protocol outlined in
Example 1, to afford 3-4 as a solid. HRMS (ES) (M+H) : observed = 365.2090, calculated =
365.2084.
TABLE 2
The following compounds were prepared in an analogous manner to Example 3,
using an appropriately substituted dimethylmalonate, imidamide, and alcohols previously
described in Schemes A through R. Starting materials not previously illustrated were
commercially available, described in the literature, or readily synthesized by one skilled in the art
of organic synthesis without undue experimentation.
Cpd. Structure Name HRMS/LRMS
S,S-N-[(2,4-dimethyl-
1,3-thiazolyl)methyl]- C20H22FN5OS
N N N
-fluoromethyl[(2- [M+H]
3-5 S
pyridin calc 400.1602
ylcyclopropyl)methoxy] obs 400.1608
pyrimidinamine
S,Sfluoromethyl-
N-[(1-methyl-1H- C19H21FN6O
N N N
pyrazolyl)methyl] [M+H]
[(pyridin calc 369.1834
ylcyclopropyl)methoxy] obs 369.1840
pyrimidinamine
MRL-NOP-00136
S,Sfluoromethyl-
6-{[2-(5-methylpyridin-
C19H21FN6OS
2-yl)cyclopropyl]-
[M+H]
3-7 methoxy}-N-[(5-methyl-
calc 401.1554
1,3,4-thiadiazol
obs 401.1556
yl)methyl]pyrimidin
amine
S,S(fluoromethyl)-N-
[(5-methyl-1,3,4- C18H19FN6OS
thiadiazolyl)methyl]- [M+H]
6-[(2-pyridin calc 387.1398
ylcyclopropyl)methoxy] obs 387.1396
pyrimidinamine
S,S-N -[(2,4-dimethyl-
C21H25N5OS
1,3-thiazolyl)methyl]-
N N N
[M+H]
3-9 2-ethyl[(2-pyridin
calc 396.1853
H ylcyclopropyl)methoxy]
N obs 396.1858
pyrimidinamine
S,Sethyl-N-[(1-
methyl-1H-pyrazol C20H24N6O
N N N yl)methyl][(2- [M+H]
3-10
pyridin calc 365.2084
N ylcyclopropyl)methoxy] obs 365.2090
pyrimidinamine
S,Scyclopropyl-N-
[(2,4-dimethyl-1,3- C22H25N5OS
thiazolyl)methyl] [M+H]
N N N
3-11
[(2-pyridin calc 408.1853
N ylcyclopropyl)methoxy] obs 408.1859
pyrimidinamine
S,Scyclopropyl-N-
[(1-methyl-1H-pyrazol- C21H24N6O
4-yl)methyl][(2- [M+H]
N N N
3-12
pyridin calc 377.2084
ylcyclopropyl)methoxy] obs 377.2089
pyrimidinamine
MRL-NOP-00136
-fluoro{[(1S,2S)
(5-methoxypyridin C18H20FN7O2
yl)cyclopropyl]methoxy S
3-13 }-N[(5-methyl-1,3,4- [M+H]
thiadiazol calc 418.1456
yl)methyl]pyrimidine- obs 418.1447
2,4-diamine
-fluoro-N[(5-
methyl-1,3,4-thiadiazol-
C20H19FN8OS
2-yl)methyl]
[M+H]
3-14 {[(1S,2S)(1,5-
calc 439.1459
naphthyridin
obs 439.1455
yl)cyclopropyl]methoxy
}pyrimidine-2,4-diamine
-fluoro{[(1S,2S)
(5-methylpyridin
C18H20FN7OS
yl)cyclopropyl]methoxy
[M+H]
3-15 }-N[(5-methyl-1,3,4-
calc 402.1507
thiadiazol
obs 402.1494
yl)methyl]pyrimidine-
2,4-diamine
-fluoro-N[(5-
methyl-1,3,4-thiadiazol- C17H18FN7OS
2-yl)methyl] [M+H]
3-16
{[(1S,2S)pyridin calc 388.1350
ylcyclopropyl]methoxy} obs 388.1346
pyrimidine-2,4-diamine
-fluoro-N[(5-
methyl-1,3,4-thiadiazol- C17H18FN7OS
2-yl)methyl] [M+H]
3-17
{[(1S,2S)pyridin calc 388.1350
ylcyclopropyl]methoxy} obs 388.1346
pyrimidine-2,4-diamine
N (2,4- C22H24FN5O3
dimethoxybenzyl) [M+H]
3-18
fluoro{[(1S,2S) calc 426.1936
pyridin obs 426.1919
MRL-NOP-00136
ylcyclopropyl]methoxy}
pyrimidine-2,4-diamine
6-{[(1S,2S)(5-
chloropyridin C17H17ClFN7
yl)cyclopropyl]methoxy OS
3-19 }fluoro-N[(5- [M+H]
methyl-1,3,4-thiadiazol- calc 422.0961
2-yl)methyl]pyrimidine- obs 422.0946
2,4-diamine
-fluoro{[(1S,2S)
(5-fluoropyridin C17H17F2N7O
yl)cyclopropyl]methoxy S
3-20 }-N[(5-methyl-1,3,4- [M+H]
thiadiazol calc 406.1256
yl)methyl]pyrimidine- obs 406.1243
2,4-diamine
-chloro{[(1S,2S)
(5-methylpyridin C18H20ClN7O
yl)cyclopropyl]methoxy S
3-21 }-N-[(5-methyl-1,3,4- [M+H]
thiadiazol calc 418.1211
yl)methyl]pyrimidine- obs 418.1195
2,4-diamine
6-{[(1S,2S)(4,5-
dimethylpyridin
C19H22FN7OS
yl)cyclopropyl]methoxy
[M+H]
3-22 }-N-[(5-methyl-1,3,4-
calc 416.1663
thiadiazol
obs 416.1664
yl)methyl]pyrimidine-
2,4-diamine
6-(((1S,2S)(5,6-
dihydro-4H-pyrrolo[1,2-
C18H21FN8OS
b]pyrazol
[M+H]
3-23 yl)cyclopropyl)methoxy)
calc 417.1616
fluoro-N4-((5-
obs 417.1619
methyl-1,3,4-thiadiazol-
2-yl)methyl)pyrimidine-
MRL-NOP-00136
2,4-diamine
-fluoro-N4-((5-methyl-
1,3,4-thiadiazol C18H20FN7OS
yl)methyl)(((1S,2S)- [M+H]
3-24
2-(6-methylpyridin calc 402.1507
yl)cyclopropyl)methoxy) obs 402.1507
pyrimidine-2,4-diamine
S,S(((1S,2S)(6,7-
dihydro-5H-
cyclopenta[b]pyridin C20H22FN7OS
yl)cyclopropyl)methoxy) [M+H]
3-25
fluoro-N4-((5- calc 428.1663
methyl-1,3,4-thiadiazol- obs 428.1665
2-yl)methyl)pyrimidine-
2,4-diamine
EXAMPLE 3A
AcOH,
N NaOAc,
S triethylamine
dioxane
Cl Cl N
3A-1
A-4,
NaH, THF
O NH
3A-3
3A-2
6-chloro-N-((2,4-dimethylthiazolyl)methyl)methylpyrimidinamine 3A-1
The title compound was prepared from 4,6-dichloromethylpyrimidine and (2,4-
dimethylthiazolyl)methanamine according to the protocol outlined in Example 1, to afford
3A-1 as a solid. LRMS (ES) (M+H) : observed = 269.1, calculated = 269.7.
-bromochloro-N-((2,4-dimethylthiazolyl)methyl)methylpyrimidinamine 3A-2
To a stirred solution of 3-1 (0.25 g, 0.93 mmol) in acetic acid (4 mL) was added
sodium acetate (0.10 g, 1.21 mmol). To this solution was added bromine (0.05 mL, 1.02 mmol)
dissolved in acetic acid (0.5 mL) dropwise. The resulting solution was stirred at room
temperature for 30 minutes and concentrated. The residue was partitioned between ethyl acetate
and a saturated sodium bicarbonate solution. The organic phase was concentrated and triturated
MRL-NOP-00136
in ether to give the title compound as a solid (0.28 g, 85%). LRMS (ES) (M+H) : observed =
347.0/349.0, calculated = 347.6/349.6.
-bromo-N-((2,4-dimethylthiazolyl)methyl)methyl((2-(pyridin
yl)cyclopropyl)methoxy)pyrimidinamine 3A-3
The title compound was prepared from 3A-2 according to the protocol outlined in
Example 1, to afford 3A-3 as a solid. HRMS (ES) (M+H) : observed = 460.0814, calculated =
460.0801.
EXAMPLE 4
N N N N
Zn(CN)
Pd (dba)
O NH O NH
DPPF, DMF
3A-3 4-1
4-((2,4-dimethylthiazolyl)methylamino)methyl((2-(pyridin
yl)cyclopropyl)methoxy)pyrimidinecarbonitrile 4-1
To a stirred solution of 3A-3 (45 mg, 0.01 mmol), and zinc cyanide (6.9 mg, 0.06
mmol) in DMF (1 mL) under nitrogen was added Pd (dba) (4.5 mg, 0.005 mmol) and DPPF (5.4
mg, 0.010 mmol) and the resulting mixture was heated to 120°C for 3 days. The reaction was
allowed to cool and partititioned between ethyl acetate and a saturated sodium bicarbonate
solution. The organic phase was concentrated and purified using reverse phase chromatography
(15-45%, 0.1% TFA in H O/acetonitrile) to give 4-1 as a solid (7.5 mg, 19%). HRMS (ES)
(M+H) : observed =407.1650, calculated = 407.1649.
EXAMPLE 5
MRL-NOP-00136
6-chloroiodomethylpyrimidinol 5-1
To a stirred solution of 6-chloromethylpyrimidinol (1.45 g, 10.0 mmol) in
DMF (19 mL) was added N-iodosuccinimide (6.78 g, 30.1 mmol). The mixture was heated to
80°C for two hours. The reaction was allowed to cool and partitioned between ethyl acetate and a
saturated ammonium chloride solution. The organic phase was concentrated and flash column
separation using a 0-50% ethyl acetate/ hexane gradient followed by trituration in hexane gave 5-
1 as a solid.(1.83 g, 68%). LRMS (ES) (M+H) : observed = 271.0, calculated = 270.5.
4,6-dichloroiodomethylpyrimidine 5-2
To a RBF containing phosphorus oxychloride (10 mL, 107 mmol) was added 5-1
(1.83 g, 6.77 mmol) and the mixture was heated to reflux for 3 hours. The solution was
concentrated, quenched with ice, and partitioned between ethyl acetate and a saturated sodium
bicarbonate solution. The organic phase was concentrated and flash column separation using a 0-
10% ethyl acetate/ hexane gradient gave 5-2 as solid (1.38 g, 71%). LRMS (ES) (M+H) :
observed = 288.9, calculated = 288.9.
4-chloroiodomethyl((2-(pyridinyl)cyclopropyl)methoxy)pyrimidine 5-3
To a stirred solution of A-4 (93 mg, 0.62 mmol) in THF (1.5 mL) was added
sodium hydride 60% dispersion (31 mg, 0.76 mmol) and the resulting solution was stirred at
room temperature for 20 minutes. To this was added 5-2 (200 mg, 0.69 mmol) and the resulting
mixture was heated 60°C for 2 hours. The reaction allowed to cool and partitioned between ethyl
acetate and a saturated sodium bicarbonate solution. The organic phase was concentrated and
flash column separation using a 0-30% ethyl acetate/ hexane gradient gave 5-3 as a solid (208
mg, 75%). HRMS (ES) (M+H) : observed = 401.9843, calculated = 401.9865.
MRL-NOP-00136
-iodomethyl-N-((1-methyl-1H-pyrazolyl)methyl)((2-(pyridin
yl)cyclopropyl)methoxy)pyrimidinamine 5-4
The title compound was prepared from 5-3 according to the protocol outlined in
Example 1, to afford 5-4 as a solid. LRMS (ES) (M+H) : observed = 477.1, calculated = 477.3.
2-methyl((1-methyl-1H-pyrazolyl)methylamino)((2-(pyridin
yl)cyclopropyl)methoxy)pyrimidinecarbonitrile 5-5
The title compound was prepared from 5-4 according to the protocol outlined in
Example 4, to afford 5-5 as a solid. HRMS (ES) (M+H) : observed = 376.1869, calculated =
376.1880.
EXAMPLE 6
6-chloro-N-((1-methyl-1H-pyrazolyl)methyl)(methylthio)pyrimidinamine 6-1
The title compound was prepared from 4,6-dichloro(methylthio)pyrimidine
according to the protocol outlined in Example 1, to afford 6-1 as a solid. LRMS (ES) (M+H) :
observed = 270.1, calculated = 270.7.
6-chloro-N-((1-methyl-1H-pyrazolyl)methyl)(methylsulfonyl)pyrimidinamine 6-2
To a stirred solution of 6-1 (0.25 g, 0.95 mmol) in dichloromethane (4 mL) was
added mCPBA 70% (0.51 g, 2.08 mmol) and the resulting mixture was stirred at room
temperature for 45 minutes. The reaction mixture was washed twice with 1N NaOH solution and
concentrated to give 6-2 as a solid. (0.25 g, 70%) LRMS (ES) (M+H) : observed = 302.1,
calculated = 302.7
4-chloro((1-methyl-1H-pyrazolyl)methylamino)pyrimidinecarbonitrile 6-3
To a stirred solution of 6-2 (0.13 g, 0.41 mmol) in DMSO (1 mL) was added
sodium cyanide (0.02 g, 0.41 mmol) and the reaction was heated to 100°C for 20 minutes.
MRL-NOP-00136
Purification using reverse phase chromatography (20-60%, 0.1% TFA in H O/acetonitrile) gave
6-3 as a solid (0.02 g, 19%). LRMS (ES) (M+H) : observed = 249.1, calculated = 249.6
4-((1-methyl-1H-pyrazolyl)methylamino)((2-(pyridinyl)cyclopropyl)methoxy)-
pyrimidinecarboxamide 6-4
The title compound was prepared from 6-3 according to the protocol
outlined in Example 1, to afford 6-4 as a solid. HRMS (ES) (M+H) : observed = 380.1830,
calculated = 380.1829.
EXAMPLE 7
4-((1-methyl-1H-pyrazolyl)methylamino)((2-(pyridinyl)cyclopropyl)methoxy)-
pyrimidinecarbonitrile 6-5
To a vial containing phosphorus oxychloride (0.8 mL, 8.58 mmol) was added 6-4
(0.03 g, 0.08 mmol). The mixture was heated to 100°C for 90 minutes. The mixture was
concentrated and purified using reverse phase chromatography (10-35%, 0.1% TFA in
H O/acetonitrile) to give 6-5 as a solid. (11 mg, 39%). HRMS (ES) (M+H) : observed =
362.1726, calculated = 362.1724.
MRL-NOP-00136
EXAMPLE 8
6-chloromethyl-N-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidinamine 8-1
The title compound was prepared from 4,6-dichloromethylpyrimidine and (5-
methyl-1,3,4-thiadiazolyl)methanamine according to the protocol outlined in Example 1, to
afford 8-1 as a solid. LRMS (ES) (M+H) : observed = 256.1, calculated = 256.7.
6-((2-(5-bromopyridinyl)cyclopropyl)methoxy)methyl-N-((5-methyl-1,3,4-thiadiazol
yl)methyl)pyrimidinamine 8-2
The title compound was prepared from 8-1 according to the protocol outlined in
Example 1, to afford 8-2 as a solid. LRMS (ES) (M+H) : observed = 447.0/449.0, calculated =
447.3/449.3.
2-methyl-N-((5-methyl-1,3,4-thiadiazolyl)methyl)((2-(5-(thiazolyl)pyridin
yl)cyclopropyl)methoxy)pyrimidinamine 8-3
To a stirred solution of 8-2 (50 mg, 0.11 mol) in toluene (0.8 mL) was added
Pd(PPh ) (25 mg, 0.02 mmol) and 4-(tributylstannyl)thiazole (84 mg, 0.22 mmol) and the
resulting mixture was microwave irradiated to 140°C for 2 hours. The solution was concentrated
and purified using reverse phase chromatography (10-30%, 0.1% TFA in H O/acetonitrile) to
give 8-3 as a solid. (19 mg, 38%). HRMS (ES) (M+H) : observed = 452.1322, calculated =
452.1322.
TABLE 3
The following compounds were prepared in an analogous manner to Example 8,
using the appropriate tin reagent. Starting materials not previously illustrated were commercially
available, described in the literature, or readily synthesized by one skilled in the art of organic
synthesis without undue experimentation.
MRL-NOP-00136
Cpd. Structure Name HRMS/LRMS
6-{[2-(2,3'-bipyridin-
yl)cyclopropyl]metho C23H23N7OS
N N N N
xy}methyl-N-[(5- [M+H]
8-4 S
methyl-1,3,4- calc 446.1758
thiadiazol obs 446.1760
yl)methyl]pyrimidin-
4-amine
2-methyl-N-[(5-
methyl-1,3,4-
thiadiazol
C21H21N7OS2
yl)methyl]({2-[5-
N N N
[M+H]
8-5 (1,3-thiazol
calc 452.1322
yl)pyridin
obs 452.1321
yl]cyclopropyl}meth
oxy)pyrimidin
amine
6-{[2-(3,4'-bipyridin-
yl)cyclopropyl]metho C23H23N7OS
N N N
xy}methyl-N-[(5- [M+H]
8-6 S
methyl-1,3,4- calc 446.1758
thiadiazol obs 446.1762
yl)methyl]pyrimidin-
4-amine
2-methyl-N-[(5-
methyl-1,3,4-
thiadiazol
C21H21N7OS2
yl)methyl]({2-[5-
N N N
[M+H]
8-7 (1,3-thiazol
calc 452.1322
yl)pyridin
obs 452.1328
yl]cyclopropyl}meth
oxy)pyrimidin
amine
MRL-NOP-00136
6-{[2-(3,3'-bipyridin-
yl)cyclopropyl]metho C23H23N7OS
N N N
xy}methyl-N-[(5- [M+H]
methyl-1,3,4- calc 446.1758
thiadiazol obs 446.1761
yl)methyl]pyrimidin-
4-amine
2-methyl-N-[(5-
methyl-1,3,4-
thiadiazol
C22H22N8OS
yl)methyl]{[2-(5-
N N N
[M+H]
8-9 pyridazin
calc 447.1710
ylpyridin
obs 447.1709
yl)cyclopropyl]metho
xy}pyrimidin
amine
EXAMPLE 9
6-((2-(5-ethylpyridinyl)cyclopropyl)methoxy)methyl-N-((5-methyl-1,3,4-thiadiazol
yl)methyl)pyrimidinamine 9-1
To a stirred solution of 8-2 (100 mg, 0.22 mmol) and potassium ethyl
trifluoroborate (60 mg, 0.45 mmol) in dioxane (0.64 mL) under nitrogen was added Pd(dppf) Cl
(18 mg, 0.02 mmol), cesium carbonate (218 mg, 0.67 mmol), and water (0.11 mL). The resulting
mixture heated to 100°C overnight. The reaction was partitioned between ethyl acetate and
saturated sodium bicarbonate solution. The organic phase was concentrated and purified using
reverse phase chromatography (5-28%, 0.1% TFA in H O/acetonitrile) to give 9-1 as an oil
(13mg, 15%). MS (M+H) : observed = 397.1805, calculated = 397.1805.
MRL-NOP-00136
TABLE 4
The following compounds were prepared in an analogous manner to Example 9,
using the appropriate fluoroborate salt. Starting materials not previously illustrated were
commercially available, described in the literature, or readily synthesized by one skilled in the art
of organic synthesis without undue experimentation.
Cpd. Structure Name HRMS/LRMS
6-{[2-(5-
cyclopropylpyridin
C21H24N6OS
yl)cyclopropyl]methoxy
N N N
[M+H]
9-2 }methyl-N-[(5-
calc 409.1805
methyl-1,3,4-thiadiazol-
obs 409.1806
2-yl)methyl]pyrimidin-
4-amine
EXAMPLE 10
6-((2-(5-(1H-pyrazolyl)pyridinyl)cyclopropyl)methoxy)methyl-N-((5-methyl-1,3,4-
thiadiazolyl)methyl)pyrimidinamine 10-1
To a stirred solution of 8-2 (75 mg, 0.17 mmol) in toluene (0.8 mL) under
nitrogen was added pyrazole (23 mg, 0.34 mmol), copper (I) iodide (6.3 mg, 0.03 mmol), 1,2-
trans-N,N'-dimethyldiaminocyclohexane (10 mg, 0.07 mmol), and potassium carbonate (49 mg,
0.35 mmol). The resulting mixture was heated to 120°C overnight. The reaction was
concentrated and purified using reverse phase chromatography (10-30%, 0.1% TFA in
H O/acetonitrile) to give 10-1 as a solid (36mg, 49%). MS (M+H) : observed = 435.1715,
calculated = 435.1710.
MRL-NOP-00136
EXAMPLE 11
6-(2-((2-methyl((5-methyl-1,3,4-thiadiazolyl)methylamino)pyrimidin
yloxy)methyl)cyclopropyl)nicotinonitrile 11-1
The title compound was prepared from 8-2 according to the protocol outlined in
Example 4, to afford 11-1 as a solid. HRMS (ES) (M+H) : observed = 394.1440, calculated =
394.1445.
EXAMPLE 12
4-chloromethyl((2-(pyridinyl)cyclopropyl)methoxy)pyrimidine 12-1
The title compound was prepared from 4,6-dichloromethylpyrimidine
according to the protocol outlined in Example 5, to afford 12-1 as an oil. LRMS (ES) (M+H) :
observed = 276.1, calculated = 276.7.
2-methyl-N-((5-methylisoxazolyl)methyl)((2-(pyridinyl)cyclopropyl)methoxy)-
pyrimidinamine 12-2
To a stirred solution of 12-1 (50 mg, 0.18 mmol) and (5-methylisoxazol
yl)methanamine (22 mg, 0.20 mmol) in toluene (1.0 mL) was added (R)[(S)
(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (22 mg, 0.04 mmol), Pd (dba)
(17 mg, 0.02 mmol), and cesium carbonate (177 mg, 0.54 mmol). The resulting mixture was
microwave irradiated to 140°C for 2 hours. The reaction was partitioned between ethyl acetate
and saturated sodium bicarbonate solution. The organic phase was concentrated and purified
using reverse phase chromatography (10-35%, 0.1% TFA in H O/acetonitrile) to give 12-2 as an
oil (15 mg, 24%). HRMS (ES) (M+H) : observed = 352.1773, calculated = 352.1768.
MRL-NOP-00136
TABLE 5
The following compounds were prepared in an analogous manner to Example 12,
using the appropriate amine. Starting materials not previously illustrated were commercially
available, described in the literature, or readily synthesized by one skilled in the art of organic
synthesis without undue experimentation.
Cpd. Structure Name HRMS/LRMS
N-[(2-fluoromethyl-
C21H22FN5O
pyridinyl)methyl]
N N N F
[M+H]
12-3 methyl[(2-pyridin
O N N
calc 380.1881
ylcyclopropyl)methoxy]pyri
obs 380.1884
midinamine
S,S-N-(isothiazol C18H19N5OS
ylmethyl)methyl[(2- [M+H]
12-4
pyridinylcyclopropyl)- calc 354.1383
methoxy]pyrimidinamine obs 354.1385
2-methyl-N-[(5-
C20H22N6O
methylpyrazinyl)methyl]-
N N N
[M+H]
12-5 6-[(2-pyridin
calc 363.1928
ylcyclopropyl)methoxy]-
obs 363.1931
pyrimidinamine
2-methyl[(2-pyridin C19H20N6O
N N N
ylcyclopropyl)methoxy]-N- [M+H]
12-6
O N N
(pyrimidinylmethyl)- calc 349.1771
pyrimidinamine obs 349.1774
EXAMPLE 13
MRL-NOP-00136
2-methyl((2-(pyridinyl)cyclopropyl)methoxy)-N-(pyridinylmethyl)pyrimidinamine
13-1
To a solution of 12-1 (50 mg, 0.18 mmol) in THF (0.5 mL) was added pyridin
ylmethanamine (0.25 mL, 2.47 mmol) and the resulting mixture was microwave irradiated to
150°C for 1 hour. The reaction mixture was loaded onto silica gel and flash column separated
using a 0-5% methanol/ methylene chloride gradient. The resulting material was then purified
using reverse phase chromatography (5-28%, 0.1% TFA in H O/acetonitrile) to give 13-1 as an
oil. HRMS (ES) (M+H) : observed = 348.1822, calculated = 348.1819.
TABLE 6
The following compounds were prepared in an analogous manner to Example 13,
using the appropriate amine. Starting materials not previously illustrated were commercially
available, described in the literature, or readily synthesized by one skilled in the art of organic
synthesis without undue experimentation.
Cpd. Structure Name HRMS/LRMS
2-methyl[(2-pyridin-
C20H21N5O
2-ylcyclopropyl)-
N N N
[M+H]
13-2 methoxy]-N-(pyridin
O N N
calc 348.1819
ylmethyl)pyrimidin
obs 348.1824
amine
MRL-NOP-00136
EXAMPLE 14
N-(2,4-dimethoxybenzyl)(3-methylpyridinyl)methanamine 14-1
To a stirred solution of 3-methylisonicotinaldehyde (0.30 g, 2.48 mmol) in DCM
(7 mL) was added (2,4-dimethoxyphenyl)methanamine (0.41 g, 2.48 mmol) and acetic acid (0.7
mL). The resulting solution was stirred overnight at room temperature. To this was added sodium
triacetoxyborohydride (1.05 g, 4.95 mmol). The reaction was quenched with a saturated sodium
bicarbonate solution and extracted with DCM. The combined organic phase was concentrated
and flash column separated using a 0-5% methanol/ methylene chloride gradient to give 14-1 as a
solid (0.18 g, 17%). LRMS (ES) (M+H) : observed = 273.2, calculated = 273.3.
6-chloro-N-(2,4-dimethoxybenzyl)methyl-N-((3-methylpyridinyl)methyl)pyrimidin
amine 14-2
The title compound was prepared from 14-1 and 4,6-dichloromethylpyrimidine
according to the protocol outlined in Example 1, to afford 14-2 as a solid. LRMS (ES) (M+H) :
observed = 399.1, calculated = 399.8.
2-methyl-N-((3-methylpyridinyl)methyl)((2-(pyridinyl)cyclopropyl)methoxy)pyrimidin-
4-amine 14-3
To a stirred solution of A-4 (79 mg, 0.53 mmol) in THF (1 mL) was added sodium
hydride 60% dispersion (28 mg, 0.70 mmol) and the resulting solution was stirred at room
temperature for 20 minutes. To this was added 14-2 (140 mg, 0.35 mmol) and the resulting
mixture was microwave irradiated at 100°C for 90 minutes. The reaction was concentrated. The
residue was taken up in trifluoroacetic acid (2 mL) and stirred at room temperature overnight.
MRL-NOP-00136
The reaction was concentrated and partitioned between ethyl acetate and a saturated sodium
bicarbonate solution. The organic phase was concentrated and purified using reverse phase
chromatography (5-28%, 0.1% TFA in H O/acetonitrile) to give 14-3 as a white solid (32mg,
%). HRMS (ES) (M+H) : observed = 362.1985, calculated = 362.1975.
EXAMPLE 15
NaH,MeI
O NH
1-3 15-1
6-(2-((2-methyl((5-methyl-1,3,4-thiadiazolyl)methylamino)pyrimidin
yloxy)methyl)cyclopropyl)pyridine 15-1
To a stirred solution of 1-3 (25 mg, 0.07 mmol) in THF (1 mL) was added sodium
hydride 60% dispersion (3.0 mg, 0.07 mmol) and the resulting solution was stirred at room
temperature for 20 minutes. To this was added methyl iodide (9.3 mg, 0.07 mmol) and the
resulting solution was stirred room temperature overnight. The reaction was concentrated and
purified using reverse phase chromatography (5-60%, 0.1% TFA in H O/acetonitrile) to give 15-
1 as a white solid (13mg, 25%). HRMS (ES) (M+H) : observed = 396.1858, calculated =
396.1853.
EXAMPLE 16
triethylamine
S NIS,
N dioxane N DMF
Cl Cl
16-1
Zn(CN)2 N N
Pd2(dba)3 E-3,
DPPF, DMF NaH, THF O NH
Cl NH
16-2 16-3 16-4
2-amino{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}{[(5-methyl-1,3,4-
thiadiazolyl)methyl]amino}pyrimidinecarbonitrile (16-4)
6-chloro-N((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine (16-1)
MRL-NOP-00136
To a stirred solution of 4,6-dichloroaminopyrimidine (800 mg, 4.88 mmol) in
dioxane (10 mL) was added triethylamine (2.0 mL, 14.64 mmol) and (5-methyl-1,3,4-thiadiazol-
2-yl)methanamine hydrochloride (1050 mg, 6.34 mmol). The resulting mixture was microwave
irradiated at 150°C for 30 minutes. The reaction was diluted with ethyl acetate and washed with
saturated sodium bicarbonate solution. The organic phase was concentrated and flash column
separation using a 10-100% ethyl acetate/ hexane gradient gave 16-1 as a white solid (600mg,
48%). MS (M+H) : observed = 257.7, calculated = 257.1.
6-chloroiodo-N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine (16-2)
To a stirred solution of 16-1 ( 570 mg, 2.22 mmol) in DMF (6 mL) was added N-
iodosuccinimide (1.25 g, 5.55 mmol) and the resulting mixture was heated to 80°C for 15
minutes. The reaction was allowed to cool, poured into a saturated sodium bicarbonate solution
and extracted several times with ethyl acetate. The combined organic layers were washed several
times with a sodium thiosulfate solution, and concentrated. Flash column separation using a 30-
100% ethyl acetate/ hexane gradient gave 16-2 as a solid (639 mg, 75%). MS (M+H) : observed
= 383.1, calculated = 363.6.
2-aminochloro((5-methyl-1,3,4-thiadiazolyl)methylamino)pyrimidinecarbonitrile (16-
To a stirred solution of 16-2 (639 mg, 1.67 mmol), and zinc cyanide (98 mg, 0.84
mmol) in DMF (6 mL) under nitrogen was added Pd (dba) (76 mg, 0.08 mmol) and DPPF (93
mg, 0.17 mmol) and the resulting mixture was heated to 120°C for 90 minutes. The reaction was
allowed to cool and partititioned between ethyl acetate and a saturated sodium bicarbonate
solution. The organic phase was concentrated and flash column separation using a 10-100% ethyl
acetate/ hexane gradient gave 16-3 as a solid (200 mg, 43%). MS (ES) (M+H) : observed =
282.2, calculated = 282.7.
2-amino{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}{[(5-methyl-1,3,4-
thiadiazolyl)methyl]amino}pyrimidinecarbonitrile (16-4)
The title compound was prepared from 16-3 according to the protocol outlined in
Example 1, to afford 16-4 as a solid. HRMS (ES) (M+H) : observed = 409.1553, calculated =
409.1554.
TABLE 7
The following compounds were prepared in an analogous manner to Example 16,
using the appropriate amine. Starting materials not previously illustrated were commercially
MRL-NOP-00136
available, described in the literature, or readily synthesized by one skilled in the art of organic
synthesis without undue experimentation.
MRL-NOP-00136
Cpd. Structure Name HRMS/LRMS
S,Samino
{[(1S,2S)(5-
methylpyridin C19H20N8OS
yl)cyclopropyl]methoxy} [M+H]
16-5
{[(5-methyl-1,3,4- calc 409.1554
thiadiazol obs 409.1553
yl)methyl]amino}pyrimi
dinecarbonitrile
S,Samino
{[(1S,2S)(5-
methoxypyridin C19H20N8O2S
yl)cyclopropyl]methoxy} [M+H]
16-6
{[(5-methyl-1,3,4- calc 425.1503
thiadiazol obs 425.1505
yl)methyl]amino}pyrimi
dinecarbonitrile
EXAMPLE 17
MRL-NOP-00136
N-methoxy-N-methyl((2-methyl(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinylamino)methyl)-1,3,4-thiadiazolecarboxamide (17-
To the solution of N-methoxymethanamine hydrochloride (361 mg, 3.70 mmol) in
dichloromethane (10 mL) was added trimethylaluminum in toluene (1.8 mL, 3.70 mmol)
dropwise at 0 C. The mixture was stirred for 30 min before ethyl 5-((2-methyl(((1S, 2S)
(5-methylpyridinyl) cyclopropyl)methoxy) pyrimidin- 4-ylamino)methyl)-1,3,4-thiadiazole
carboxylate (9) (355 mg, 0.74 mmol) in dichloromethane (10 mL) was added at 0 C. Then it
was stirred for 1 h and quenched with saturated potassium phosphate (2 mL) to pH = 9 – 10. The
resulting mixture was extracted with ethyl acetate (20 mL*3). The combined organic phase was
concentrated and purified by Pre-TLC (PE/EA = 2/1) to yield product as a white solid (355 mg,
100%). H NMR (400 MHz, CDCl ) δ 8.21 (s, 1H), 7.30 (dd, J = 7.9, 1.2 Hz, 1H), 6.99 (d, J =
7.9 Hz, 1H), 6.16 (s, 1H), 5.62 (s, 1H), 4.95 (t, J = 9.3 Hz, 1H), 4.22 (qd, J = 11.1, 7.0 Hz, 2H),
3.79 (s, 3H), 3.37 (s, 1H), 2.41 (s, 3H), 2.24 (d, J = 11.2 Hz, 3H), 2.08 – 1.89 (m, 1H), 1.89 –
1.58 (m, 1H), 1.34 – 1.08 (m, 1H), 1.04 – 0.62 (m, 1H); LRMS (ESI) calculated M + H for
C21H26N7O3S: 456.5; Found: 456.1.
1-(5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin
ylamino)methyl)-1,3,4-thiadiazolyl)ethanone (17-2)
To the solution of N-methoxy-N-methyl((2-methyl(((1S, 2S)
(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidinylamino)methyl)-1,3,4-thiadiazole
carboxamide (17-1) (355 mg,0.78 mmol) in THF (2 mL) was added CH MgBr (1.3 mL, 3.90
mmol) in toluene dropwise at 0 C. The mixture was stirred for 30 min. Then the solution was
adjusted to pH =9-10 with saturated sodium bicarbonate and extracted with ethyl acetate (20
mL*3). The organic layers were combined, dried over anhydrous sodium sulfate and purified by
Prep TLC (PE/EA = 1:1). The product was obtained as a white solid (248 mg, 77%). H NMR
(400 MHz, CDCl ) δ 8.26 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 5.59 (s,
1H), 5.42 (s, 1H), 4.99 (d, J = 6.3 Hz, 2H), 4.28 (m, 2H), 2.79 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H),
2.07 (m, 1H), 1.89 – 1.81 (m, 1H), 1.32 – 1.27 (m, 1H), 1.04 – 1.02 (m, 1H); LRMS (ES)
calculated M + H for C20H23N6O2S: 411.5; Found:411.1.
1-(5-((2-Methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin
ylamino)methyl)-1,3,4-thiadiazolyl)ethanol (17-3/18)
To the solution of 1-(5-((2-methyl(((1S, 2S)(5-methylpyridinyl)
cyclopropyl)methoxy)pyrimidinylamino)methyl)-1,3,4-thiadiazolyl)ethanone (17-2) (366
MRL-NOP-00136
mg, 0.89 mmol) in THF (2 mL) was added LiAlH (51 mg, 1.34 mmol) in small portions at 0 C.
Then it was brought to rt and stirred for 1 h. The mixture was quenched in sequence with 1 mL
of water, 0.5 mL of sodium hydroxyl aqueous (2.0M) and 1 mL of water. Anhydrous sodium
sulfate was added and it was filtered. The filtrate was evaporated under reduced pressure to give
the product as a white solid (180 mg, 49%). Enantiomers can be resolved by chiral preparative
AS-H (4.6 cm i.d. x 25 cm ChiralTech IC, 20% MeOH/CO , 2.4 mL/min) and analyzed by chiral
analytical AS-H (4.6 mm i.d. x 25 cm ChiralTech IC, 20% MeOH/CO , 2.4 mL/min) ent = 3.08
min, ent = 4.05 min.
ent1: H NMR (400 MHz, CDCl ) δ 8.27 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.9 Hz,
1H), 5.58 (s, 1H), 5.50 (s, 1H), 5.27 (d, J = 6.5 Hz, 1H), 4.90 (d, J = 6.2 Hz, 1H), 4.34 - 4.22 (m,
2H), 2.44 (s, 3H), 2.26 (s, 3H), 2.02 (dd, J = 8.7, 4.4 Hz, 1H), 1.85 – 1.82 (m, 1H), 1.66 (d, J =
6.5 Hz, 3H), 1.31 – 1.07 (m, 1H), 1.05 – 1.02 (m, 1H); LRMS (ESI) calculated M + H for
C20H25N6O2S: 413.5; Found: 413.2.
ent2: H NMR (400 MHz, CDCl ) δ 8.26 (s, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 8.0 Hz,
1H), 5.80 (s, 1H), 5.61 (s, 1H), 5.28 (q, J = 6.5 Hz, 1H), 4.90 (d, J = 6.0 Hz, 2H), 4.33 – 4.20 (m,
2H), 2.46 (s, 3H), 2.29 (s, 3H), 2.08 – 2.04 (m, 1H), 1.86 – 1.81 (m, 1H), 1.66 (d, J = 6.5 Hz,
3H), 1.30 – 1.26 (m, 1H), 1.06 – 1.02 (m, 1H); LRMS (ESI) calculated M + H for
C20H25N6O2S: 413.5; Found: 413.2.
-((2-methyl(((1S, 2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin- 4-
ylamino)methyl)-1, 3,4-thiadiazolecarbonitrile (17-10)
To the solution of 5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)
methoxy)pyrimidinylamino)methyl)-1,3,4-thiadiazolecarboxamide (17-11) (116 mg, 0.15
mmol) in THF was added NEt (0.1 mL, 0.7037 mmol) and TFAA (74 mg, 0.35 mmol) at 0 C.
The mixture was brought to rt and stirred for 1 h. Then it was concentrated under reduced
pressure and purified on silica gel (eluent PE/EA/NEt = 10/1/1% - 5/1/1%) to give the product
as a pale red solid (40 mg, 70%). H NMR (400 MHz, CDCl ) δ 8.26 (s, 1H), 7.38 (dd, J = 7.9,
1.7 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.62 (s, 1H), 5.37 (t, J = 5.9 Hz, 1H), 5.05 (d, J = 6.2 Hz,
2H), 4.29 (ddd, J = 27.7, 11.2, 7.0 Hz, 2H), 2.49 (s, 3H), 2.28 (s, 3H), 2.16 – 2.03 (m, 1H), 1.96
– 1.70 (m, 1H), 1.41 – 1.17 (m, 1H), 1.17 – 0.94 (m, 1H); LRMS (ESI) calculated M + H for
C19H20N7OS: 394.4; Found: 394.1.
-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin
ylamino)methyl)-1,3,4-thiadiazolecarboxamide (17-11)
MRL-NOP-00136
The solution of ethyl 5-((2-methyl(((1S, 2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinylamino)methyl)-1,3,4-thiadiazolecarboxylate (9) (80
mg, 0.18 mmol) in THF (2 mL ) and 28% NH H O (2 mL) was stirred for overnight at room
temperature. The solvent was removed under reduced pressure and the residue was purified by
reverse phase column (Waters Sunfire Prep C18 OBD, 5-75% methanol in water with 0.1%
NH H O modifier) to provide product as a white solid (25 mg, 21.4%).. The title product was
obtained as a white solid (60 mg, 80%). H NMR (500 MHz, CDCl ) δ 8.25 (s, 1H), 7.46 (s,
1H), 7.34 (dd, J = 7.9, 1.6 Hz, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 6.16 (s, 1H), 5.60 (s,
1H), 4.97 (d, J = 6.2 Hz, 2H), 4.25 (ddd, J = 36.6, 11.1, 7.0 Hz, 2H), 2.44 (s, 3H), 2.25 (s, 3H),
2.08 – 2.01 (m, 1H), 1.91 – 1.71 (m, 1H), 1.30 – 1.19 (m, 1H), 1.02 (m, 1H); LRMS (ESI)
calculated M + H for C19H22N7O2S: 412.4; Found: 412.1.
Ethyl 2-hydrazinyloxoacetate (9-2)
To a solution of diethyl oxalate (9-1) (6.0 g, 41.04 mmol) in alcohol (30 mL) was added
hydrazine hydrate (2.4 mL, 49.26 mmol) dropwise at -20 C. After the addition was over, the
solution was stirred for 30 min. The solution was filtered and the filtrate was evaporated to give
the product as a white solid (3.0 g, 55%). The compound was used for the next step directly
without further purification. LRMS (ESI) calculated M + H for C4H9N2O3: 133.1; Found:
133.3.
Ethyl 2-(2-(2-(tert-butoxycarbonylamino)acetyl)hydrazinyl)oxoacetate (9-4)
To a solution of ethyl 2-hydrazinyloxoacetate (9-2) (0.516 g, 3.91 mmol) in dichloromethane
(14 mL) was added EEDQ (0.78 g, 3.175 mmol) at room temperature and it was stirred for 15
MRL-NOP-00136
min. Then 2-(tert-butoxycarbonylamino)acetic acid (9-3) (0.55 g, 3.175 mmol) was added. The
mixture was stirred at room temperature for overnight. Solvent was removed under reduced
pressure and the residue was purified by chromatography on silica gel with gradient eluant
(PE/EA = 3/1 to 1/1). The product was obtained as a white solid (0.787 g, 85%). H NMR (400
MHz, CDCl ) δ 9.35 (s, 1H), 8.99 (s, 1H), 5.19 (s, 1H), 4.40 (dd, J = 21.7, 7.2 Hz, 2H), 3.93 (d, J
= 6.1 Hz, 2H), 1.57 – 1.32 (m, 12H); LRMS (ESI) calculated M + Na for C11H19N3NaO6:
312.2; Found: 312.1.
Ethyl 5-((tert-butoxycarbonylamino) methyl)-1, 3, 4-thiadiazolecarboxylate (9-5)
To the solution of ethyl 2-(2-(2-(tert-butoxycarbonylamino)acetyl) hydrazinyl)oxoacetate (9-
4) (228 mg, 0.6913 mmol) in THF (10 mL) was added lawesson’s reagent (354 mg, 0.8669
mmol). The solution was heated to reflux for 3 h. Then solvent was evaporated under reduced
pressure and the residue was purified by chromatography on silica gel with the eluant
(PE/EA/NEt =10/1/1%; 5/1/1%; 2/1/1%). The yellow solid was obtained as the product (520
mg, 69%). H NMR (500 MHz, CDCl ) δ 5.31 (br, 1H), 4.76 (d, J = 6.1 Hz, 2H), 4.51 (d, J = 14,
7.1 Hz, 2H), 1.60 – 1.39 (m, 12H); LRMS (ESI) calculated M + H for C11H18N3O4S: 288.3;
Found: 288.1.
Ethyl 5-((tert-butoxycarbonyl(2-methyl(((1S,2S)(5-methylpyridinyl)cyclo
propyl)methoxy)pyrimidinyl)amino)methyl)-1,3,4-thiadiazolecarboxylate (9-7)
The mixture of ethyl 5-((tert-butoxycarbonylamino) methyl)-1, 3, 4-thiadiazole- 2-carboxylate (9-
5) (1.0 g, 3.48 mmol), 4-chloromethyl(((1S, 2S)(5 -methylpyridin
yl)cyclopropyl)methoxy)pyrimidine (9-6), Pd(OAc) (66 mg, 0.29 mmol), BINAP (199 mg,
0.319 mmol) and Cesium carbonate (1.133 g, 3.48 mmol) in toluene (10 mL) was heated to 85 C
under nitrogen for overnight. The solvent was removed under reduced pressure and the residue
was purified by chromatography with gradient eluant (PE/EA =10/1; 5/1). The product was
obtained as an orange syrup (1.0 g, 63%). H NMR (500 MHz, CDCl ) δ 8.26 (s, 1H), 7.35 (dd, J
= 7.9, 1.8 Hz, 1H), 7.19 (s, 1H), 7.05 (d, J = 7.9 Hz, 1H), 5.59 (s, 2H), 4.50 (q, J = 7.1 Hz, 2H),
4.35 (m, 2H), 2.53 (s, 3H), 2.27 (s, 3H), 2.13 – 2.03 (m, 1H), 1.89 – 1.87 (m, 1H), 1.48 – 1.43
(m, 12H), 1.32 – 1.24 (m, 1H), 1.05 – 1.02 (m, 1H);; LRMS (ESI) calculated M + H for
C26H32N6O5S: 541.6; Found: 541.2.
Methyl 5-((2-methyl(((1S, 2S)(5-methylpyridinyl)cyclopropyl)methoxy)
pyrimidinylamino) methyl)-1, 3, 4-thiadiazolecarboxylate (17-9)
The solution of ethyl 5-((tert-butoxycarbonyl(2-methyl(((1S, 2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinyl)amino)methyl)-1,3,4-thiadiazolecarboxylate (S-7) (70
MRL-NOP-00136
mg, 0.1294 mmol) in TFA (1 mL) was stirred at room temperature for 1 h. The solvent was
removed under reduced pressure and the residue was purified by reverse phase column (Waters
Sunfire Prep C18 OBD, 5-75% methanol in water with 0.1% NH H O modifier) to provide
product as a white solid (25 mg, 21.4%). H NMR (400 MHz, CDCl ) δ 8.26 (s, 1H), 7.35 (dd, J
= 7.9, 1.7 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 5.60 (s, 1H), 5.48 (s, 1H), 5.02 (d, J = 6.3 Hz, 1H),
4.27 (ddd, J = 24.1, 11.1, 7.0 Hz, 2H), 4.03 (s, 3H), 2.48 (d, J = 5.8 Hz, 3H), 2.19 (s, 3H), 1.87 –
1.85 (m, 1H), 1.85 – 1.80 (m, 1H), 1.32 – 1.29 (m, 1H), 1.06 – 1.02 (m, 1H); LRMS (ESI)
calculated M + H for C20H23N6O3S: 427.5; Found: 427.1.
2-(5-((2-Methyl(((1S, 2S)(5-methylpyridinyl)cyclopropyl)methoxy)
pyrimidinylamino) methyl)-1, 3, 4-thiadiazolyl) propanol (17-6)
To the solution of 17-9 (60 mg, 0.1364 mmol) in THF (1 mL) was added CH MgBr (3 M in
ether, 0.24 mL, 0.68 mmol) dropwise at 0 C. The mixture was brought to rt and stirred for 16 h.
Then it was quenched with potassium phosphate aqueous to PH 9-10 and extracted with ethyl
acetate (20 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate and
purified by column chromatography on silica gel (EtOAc/ Hexane=1/3 to 1/2) to give the target
compound (20 mg, 34%). H NMR (500 MHz, CDCl ) δ 8.28 (s, 1H), 7.37 (dd, J = 8.0, 2.0 Hz,
1H), 7.05 (d, J = 7.9 Hz, 1H), 5.63 (s, 1H), 4.91 (d, J = 6.2 Hz, 2H), 4.35 - 4.24 (m, 2H), 3.02 (s,
1H), 2.48 (s, 3H), 2.29 (s, 3H), 2.04 (m, 1H), 1.88 – 1.84 (m, 1H), 1.86 (s, 9H), 1.32 - 1.28 (m,
1H), 1.07 – 1.03 (m, 1H); LRMS (ESI) calculated M + H for C21H27N6O2S: 427.5; Found:
427.1.
MRL-NOP-00136
2-(6-((1S,2S)(Hydroxymethyl)cyclopropyl)pyridinyl)propanol (8-2)
To the solution of 8-1 (267 mg, 1.18 mmol) in THF (10 mL) was added n-BuLi (1.41 mL, 3.53
mmol) at -78 ºC under nitrogen. The mixture was stirred for 1 h before acetone (0.341 mg, 5.88
mmol) was added and it was stirred for 2 h. The mixture was quenched with ammonium
chloride aqueous solution and extracted with EtOAc (20 mL * 4), dried over MgSO , filtered and
concentrated under reduced pressure. The residue was purified by column chromatography on
silica gel (Petroleum ether: ethyl acetate = 3:1-1:1) to give the title product as a yellow oil (135
mg, 55%). LRMS (ES) calculated M + H for C H BrN O: 208.13; Found: 208.2.
6 9 2
2-(6-((1S,2S)((6-chloromethylpyrimidinyloxy)methyl)cyclopropyl)pyridin
yl)propanol (8-3)
A solution of compound 8-2 (135 mg, 0.652 mmol) and 4, 6-dichloromethylpyrimidine (106.3
mg, 0.65 mmol) in THF (3.0 mL) was treated with Cs CO (281 mg, 0.86 mmol) and heated to
reflux for 12 h. The reaction mixture was filtrated and the filtrate was concentrated and purified
directly by gradient elution on silica gel (Petroleum ether: ethyl acetate = 2:1-1:1) to afford the
title compound as a colorless oil (60 mg, 28%). LRMS (ES) calculated M + H for C H ClN O :
17 20 3 2
334.12; Found: 334.1.
tert-Butyl (5-methyl-1,3,4-thiadiazolyl)methylcarbamate (8-4)
A solution of (5-methyl-1, 3, 4-thiadiazolyl)methanamine hydrochloride (500 mg, 3.0 mmol),
di-tert-butyl dicarbonate (794 mg, 3.64 mmol) and triethylamine (460 mg, 4.55 mmol) in CH Cl
(15.0 mL) stirred for overnight at room temperature. The mixture was diluted with EtOAc (50
mL), washed with sat. NaHCO aq (50 mL) and brine (50 mL), dried over MgSO , filtered, and
MRL-NOP-00136
concentrated in vacuo to yield the title product (560 mg, 81%). LRMS (ES) calculated M + H for
C H N O S: 230.09; Found: 230.2.
9 15 3 2
tert-Butyl(((1S,2S)(5-(2-hydroxypropanyl)pyridinyl)cyclopropyl)methoxy)
methylpyrimidinyl((5-methyl-1,3,4-thiadiazolyl)methyl)carbamate (8-5)
The mixture of 8-3 (60 mg, 0.18 mmol), 8-4 (50 mg, 0.22 mmol), Cs CO (88 mg, 0.27 mmol),
Pd(OAc) (8.1 mg, 0.036 mmol), BINAP (25 mg, 0.040 mmol) in toluene (2.0 mL) was heated at
85 °C for overnight. Then the reaction mixture was diluted with EtOAc (20 mL), filtered and
concentrated in vacuo to give crude product (94 mg) which was used for next step without
further purification. LRMS (ES) calculated M + H for C H N O S: 527.24; Found: 527.2.
26 34 6 4
2-(6-((1S,2S)((2-methyl((5-methyl-1,3,4-thiadiazolyl)methylamino)pyrimidin
yloxy)methyl)cyclopropyl)pyridinyl)propanol (17-8)
Crude 8-5 mixture was treated with TFA (2.0 mL) and the mixture was stirred for 1 h at room
temperature. After concentration, the residue was purified with reverse phase column (Waters
Sunfire Prep C18 OBD, 5-75% methanol in water with 0.1% NH H O modifier) to give the title
product (10 mg, 21%). H NMR (400 MHz, CDCl ) δ 8.57 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.2,
2.3 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 5.70 (s, 1H), 4.86 (d, J = 6.2 Hz, 2H), 4.37 (dd, J = 11.2,
6.4 Hz, 1H), 4.24 (dd, J = 11.1, 7.4 Hz, 1H), 2.74 (s, 3H), 2.49 (s, 3H), 2.14 – 2.09 (m, 1H), 1.89
(d, J = 6.5 Hz, 1H), 1.58 (s, 6H), 1.33 (dd, J = 9.0, 4.6 Hz, 1H), 1.10 – 1.03 (m, 1H).LRMS (ES)
calculated M + H for C H N O S: 427.18; Found: 427.2.
21 26 6 2
-Methyl((trimethylsilyl)ethynyl)pyridine (12-1)
The mixture of 2-bromomethylpyridine( 5.0 g, 29.1 mmol) , ethynyltrimethylsilane (3.42 g,
34.88 mmol), Copper iodide(0.61 g, 332 mg) and Pd(PPh ) Cl (0.61 g, 0.871 mmol) was
3 2 2
dissolved in triethylamine (6.4 mL, 261 mmol). The solution was purged with N 3 times. The
MRL-NOP-00136
solution was stirred for overnight under 25 C. The solvent was removed under reduced
pressure. The residue was separated by silca gel chromatography with the eluent of PE/EA =
/1. The product was obtained as a yellow solid (4.15 g, 76%). H NMR (400 MHz, CDCl ) δ
8.41 (s, 1H), 7.46 (dd, J = 7.9, 1.5 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 2.35 (s, 3H), 0.28 (s, 9H);
LRMS (ES) calculated M + H for C11H16NSi: 190.3; Found: 190.2.
2-Ethynylmethylpyridine (12-2)
To the solution of 5-methyl((trimethylsilyl)ethynyl)pyridine (12-1) (4.16 g, 22 mmol) in THF
was added tetra-n-butylammonium fluoride (44 mL, 44 mmol) at rt and the solution was stirred
for 1 h. The solvent was removed under reduced pressure. The residue was purified by silca gel
chromatography with eluent of PE/EA (20/1). The product was obtained as yellow oil (1.78 g,
69%). H NMR (400 MHz, CDCl ) δ 8.42 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.9 Hz,
1H), 3.10 (s, 1H), 2.35 (s, 3H); LRMS (ES) calculated M + H for C8H8N: 118.2; Found: 118.3.
(Z)(2-tert-butoxyvinyl)methylpyridine (12-3)
To the solution of 2-ethynylmethylpyridine (12-2) (1.38 g, 11.8 mmol) in tert-butyl alcohol
(4.734 g, 63.9 mmol) was added potassium tert-butoxide (531 mg, 4.7 mmol) under nitrogen.
The solution was heated to reflux for overnight. The solvent was removed under reduced
pressure. The residue was purified by silca gel chromatography with the gradient eluent (PE /
EA / NEt = 10/1/1%; 5/1/1%). The product (Z)(2-tert-butoxyvinyl)methylpyridine (12-3)
was obtained as yellow oil (1.40 g, 62%) and by product was (E)(2-tert-butoxyvinyl)
methylpyridine (0.3 g, 13%).
(12-3): H NMR (400 MHz, CDCl ) δ 8.31 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 1.5 Hz,
1H), 6.63 (d, J = 7.3 Hz, 1H), 5.53 (d, J = 7.3 Hz, 1H), 2.28 (s, 3H), 1.40 (s, 9H); LRMS (ES)
calculated M + H for C12H18NO: 192.3; Found: 192.3.
(E)(2-tert-butoxyvinyl)methylpyridine: H NMR (400 MHz, CDCl ) δ 8.28 (s, 1H), 7.60
(d, J = 12.0 Hz, 1H), 7.32 (dd, J = 8.0, 1.5 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 12.0
Hz, 1H), 2.27 (s, 3H), 1.39 (s, 9H); LRMS (ES) calculated M + H for C12H18NO: 192.3; Found:
192.3.
Ethyl 2-tert-butoxy(5-methylpyridinyl)cyclopropanecarboxylate (12-4)
The solution of (Z)(2-tert-butoxyvinyl)methylpyridine (12-3) (1.20 g, 6.27 mmol) in
toluene (20 mL) and anhydrous copper sulfate (100 mg, 0.63 mmol) was heated to 75 C. Then
the solution of ethyl diazoacetate (2.17 g, 18.8 mmol) in toluene (10 mL) was added dropwise
over 2 h. It was heated for another 2 h after the addition was completed. The mixture was
restored to room temperature for overnight. The solvent was removed under reduced pressure
MRL-NOP-00136
and the residue was purified by silca gel chromatography with gradient eluent (PE/EA = 40/1;
/1; 10/1). The product was obtained as a yellow oil (500 mg, 34%). LRMS (ES) calculated M
+ H for C16H24NO3: 278.3; Found: 278.2.
(2-tert-butoxy(5-methylpyridinyl)cyclopropyl)methanol (12-5)
The solution of ethyl 2-tert-butoxy(5-methylpyridinyl) cyclopropanecarboxylate (12-4)
(350 mg, 1.26 mmol) in THF (2 mL) was cooled to 0 C. Then lithium aluminium tetrahydride
(72 mg, 1.89 mmol) was added to the solution at 0 C and it was stirred for 30 min before
restored to the room temperature for 1 h. The reaction was quenched in sequence with 0.1 mL
water, 0.05 mL 15% NaOH aqueous, 0.1 mL water. The resulting mixture was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and
purified by Pre-TLC (PE/EA =1/1). The product was obtained as a white solid (200 mg, 68%).
H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.55 (dd, J = 8.2, 1.7 Hz, 1H), 7.11 (d, J = 8.2 Hz,
1H), 3.66 – 3.58 (m, 3H), 2.33 (s, 3H), 2.13 (t, J = 6.6 Hz, 1H), 1.80 (dd, J = 6.4, 3.7 Hz, 1H),
1.06(s, 9H); LRMS (ES) calculated M + H for C14H22NO2: 236.3; Found: 236.2.
4-((2-Tert-butoxy(5-methylpyridinyl)cyclopropyl)methoxy)chloro
methylpyrimidine (12-6)
To a solution of (2-tert-butoxy(5-methylpyridinyl)cyclopropyl)-
methanol (12-5) (130 mg, 0.55 mmol) in THF, sodium hydride (28 mg, 0.69 mmol) was added at
0 C and it was allowed to stir for 30 min whereupon a solution of 4, 6-di-
chloromethylpyrimidine (113 mg, 0.69 mmol) in THF was added. The solution was heated to
reflux overnight. After cooling, it was quenched with water, extracted with EtOAc, dried over
sodium sulfate, concentrated under reduced pressure and purified by Pre-TLC (PE/ EA = 1:1) to
afford the product as a white solid (111 mg, 56%). H NMR (500 MHz, CDCl ) δ 8.35 (s, 1H),
7.41 (d, J = 6.6 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.59 (s, 1H), 4.49 – 4.40 (m, 2H), 3.62 (dd, J =
6.9, 3.6 Hz, 1H), 2.60 (s, 3H), 2.30 (s, 3H), 2.27 (m, 1H), 2.04 (dd, J = 6.7, 3.7 Hz, 1H), 1.08 (s,
9H); LRMS (ES) calculated M + H for C19H25ClN3O2: 362.8; Found: 362.1.
Tert-Butyl 6-((2-tert-butoxy(5-methylpyridinyl)cyclopropyl)methoxy)-2
-methylpyrimidinyl((5-methyl-1,3,4-thiadiazolyl)methyl)carbamate (12-7)
The mixture of 12-6 (160 mg, 0.4421 mmol), tert-butyl (5-methyl-1, 3, 4-thiadiazol
yl)methylcarbamate (122 mg, 0.53 mmol), BINAP (31 mg, 0.049 mmol) and cesium carbonate
(173 mg, 0.53 mmol) in toluene (2 mL) was stirred for 5 min before Pd(OAc) (10 mg, 0.044
mmol) was added. The mixture was degassed with nitrogen for 5 min, then it was heated to 80
C for overnight. The solvent was removed under reduced pressure and the residue was purified
MRL-NOP-00136
by Pre-TLC (PE/EA = 1/1). The product was obtained as a white solid ( 120 mg, 49%). H
NMR (400 MHz, CDCl ) δ 8.34 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 7.03 (d, J = 8.1
Hz, 1H), 5.52 (s, 2H), 4.52 – 4.18 (m, 2H), 3.64 (dd, J = 6.8, 3.6 Hz, 1H), 2.73 (s, 1H), 2.69 (s,
3H), 2.52 (s, 3H), 2.30 (s, 3H), 2.27 (m, 1H), 2.04 (m, 1H), 1.50 (s, 9H), 1.07 (s, 9H); LRMS
(ES) calculated M + H for C28H39N6O4S: 555.7; Found: 555.1.
6-((2-Tert-butoxy(5-methylpyridinyl)cyclopropyl)methoxy)methyl-N-((5-methyl-
1,3,4-thiadiazolyl)methyl)pyrimidinamine (17-12)
The solution of 12-7 (41 mg , 0.074 mmol) in TFA (0.5 mL) was stirred for 1 h at rt. The excess
TFA was removed under reduced pressure. The residue was dissolved in dichloromethane (10
mL) and adjusted to pH = 9-10 with saturated NaHCO aqueous solution. The mixture was
extracted with EtOAc, dried over sodium sulfate, concentrated under reduced pressure and
purified by reverse phase column (Waters Sunfire Prep C18 OBD, 5-95% methanol in water with
0.1% NH H O modifier). The product was obtained as a white solid (22 mg, 65%). H NMR
(500 MHz, CDCl ) δ 8.36 (s, 1H), 7.51 (s, 1H), 7.12 (d, J = 4.8 Hz, 1H), 5.63 (s, 1H), 5.43 (s,
1H), 4.91 (d, J = 6.3 Hz, 2H), 4.36 (d, J = 6.8 Hz, 2H), 3.66 (s, 1H), 2.73 (s, 3H), 2.47 (s, 3H),
2.33 (m, 4H), 2.03 (m, 1H), 1.06 (s, 9H); LRMS (ES) calculated M + H for C23H31N6O2S:
455.6; Found:455.2.
Tert-butyl 2-oxo(2-pivaloylhydrazinyl)ethylcarbamate (15-1)
A mixture of 2-(tert-butoxycarbonylamino)acetic acid (200 mg, 1.14 mmol) and EEDQ (282 mg,
1.26 mmol) in DCM (5 mL) was stirred at room temperature for 15 min, then pivalohydrazide
(145 mg, 1.26 mmol) was added and the mixture was continued stirring overnight. The reaction
mixture was concentrated and purified by reverse phase chromatography to afford the title
compound (100 mg, 32%) as a white solid. H NMR (400 MHz, CDCl ) δ 8.98 (s, 1H), 8.28 (s,
MRL-NOP-00136
1H), 5.24 (s, 1H), 3.92 (d, J = 5.8 Hz, 2H), 1.46 (s, 9H), 1.26 (s, 9H); LRMS (ES) calculated M +
Na for C H N O : 296.2; Found: 296.0.
21 25 5 4
Tert-butyl (5-tert-butyl-1,3,4-thiadiazolyl)methylcarbamate (15-2)
To a solution of 15-1 (100 mg, 0.37 mmol) in THF (10 mL) was added lawesson’s reagent (153
mg, 0.38 mmol) and it was refluxed for 3 h. The reaction mixture was concentrated and purified
by gradient elution on silica gel (0 to 50% EtOAc in petroleum ) to afford the title compound (93
mg, 92%). LRMS (ES) calculated M + H for C H N O S:272.4; Found: 272.2.
12 21 3 2
Tert-butyl(5-tert-butyl-1,3,4-thiadiazolyl)methyl(2-methyl(((1S,2S)(5-
methylpyridinyl)cyclopropyl)methoxy)pyrimidinyl)carbamate (15-4)
-2 (181 mg, 0.67 mmol) and (15-3) (200 mg, 0.69 mmol) was combined in 2-Methylbutanol
(3 ml) and purged with N for 3 min. The solution was then warmed up to 50 °C. After addition
of KO Bu (92 mg, 0.83 mmol), X-Phos (16 mg, 0.03 mmol) and Pd (dba) (31 mg, 0.03 mmol),
the mixture was heated at 60 °C for 60 min. Then it was quenched with sat. NH Cl (2 mL) and
extracted with EtOAc (15 mL x 4). Combined organic phases were washed with water (5 mL)
and brine (5 mL), dried and concentrated. The residue was purified by gradient elution on silica
gel (20% to 30% EtOAc /Petroleum) to afford the title compound (70 mg, 20%). LRMS (ES)
calculated M + H for C H N O S:525.7; Found: 525.0.
27 36 6 3
N-((5-tert-butyl-1,3,4-thiadiazolyl)methyl)methyl(((1R,2R)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinamine (17-15)
-4 (40 mg, 0.06 mmol) was treated with HCl (4 M in 1,4-dioxane) (2 mL) and the mixture was
stirred at room temperature for 6 h. Then it was concentrated, diluted with water (1 mL), and
adjusted to pH 11 with aq NaOH (4 N). The resulting mixture was extracted with DCM (10 mL
x 4) and the organic layer was dried over Na SO concetrated to afford the title compound (30
2 4,
mg, 93%). H NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 8.0
Hz, 1H), 5.60 (s, 1H), 4.16 (dd, J = 10.9, 6.5 Hz, 1H), 4.03 (dd, J = 10.8, 7.5 Hz, 1H), 3.02 (s,
2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.05 – 1.96 (m, 1H), 1.69 (d, J = 6.2 Hz, 1H), 1.34 (s, 9H), 1.15 –
1.04 (m, 1H), 1.04 – 0.91 (m, 1H). LRMS (ES) calculated M + H for C H N OS: 425.6; Found:
22 28 6
425.2.
MRL-NOP-00136
2-chloro-N-((5-methyl-1,3,4-thiadiazolyl)methyl)(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinamine (17-19) and 4-chloro-N-((5-methyl-1,3,4-
thiadiazolyl)methyl)(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinamine (13-5) and 6-chloro-N-((5-methyl-1,3,4-
thiadiazolyl)methyl)(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinamine (13-6)
A 50 mL reaction flask was charged with ((1S,2S)(5-methylpyridinyl)cyclopropyl)methanol
(13-1) (890 mg, 5.5 mmol), NaH (196 mg, 8.2 mmol) and THF (20 mL). The mixture was
stirred at rt for 30 min. Then it was added to the solution of 2,4,6-trichloropyrimidine (1 g, 5.6
mmol) in THF (20 mL) and the mixture was stirred at rt for 16 h. Aqueous sodium bicarbonate
(20 mL) was carefully added and the mixture was extracted with EtOAc (2 x 50 mL). The
combined organics were dried over MgSO , filtered and concentrated to afford the title
compound as a yellow oil, which was one spot on TLC and one peak on LCMS. LRMS (ES)
calculated M + H for C H Cl N O: 310.0; Found: 310.0. This crude 13-2 and 13-3 mixture was
14 14 2 3
used in the subsequent step without further purification.
A 100 mL flask was charged with the above mixture of 13-2 and 13-3 (2.0 g, 6.0 mmol), (5-
methyl-1,3,4-thiadiazolyl)methanamine hydrochloride (990 mg, 6.0mmol), DIPEA (2.4 g,
17.6 mmol) and DMF (30 mL). The reaction mixture was heated to 50 C with stirring for 24 h.
Water (100 mL) was added and the mixture was extracted with EtOAc(2 x 50 mL). The
combined organics were washed with brine (30 mL), dried over Na SO , filtered, and
concentrated in vacuo. The resulting residue was purified by silica gel column chromatogaphy
(Petroleum ether/ EtOAc =1/2) to afford 17-19 (70 mg, 3%): H NMR (400 MHz, DMSO) δ 8.40
(s, 1H), 8.23 (s, 1H), 7.45 (dd, J = 7.9, 1.7 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 5.85 (s, 1H), 4.80
MRL-NOP-00136
(d, J = 3.6 Hz, 2H), 4.24 (dd, J = 11.1, 6.8 Hz, 1H), 4.16 (dd, J = 11.1, 7.6 Hz, 1H), 2.67 (s, 3H),
2.22 (s, 3H), 2.17 – 2.08 (m, 1H), 1.76 – 1.67 (m, 1H), 1.14 (m, J = 8.7, 4.4 Hz, 1H), 1.04 – 0.97
(m, 1H). ppm; LRMS m/z (M+H) 403.0 found, 403.1 required. 13-5 (860 mg, 36%): , H NMR
(400 MHz, DMSO) δ 8.41 (d, J = 30.9 Hz, 1H), 8.22 (s, 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.16 (s,
1H), 6.24 (s, 1H), 4.76 (s, 2H), 4.27 (d, J = 33.3 Hz, 2H), 2.65 (s, 3H), 2.22 (s, 3H), 2.18 – 1.98
(m, 1H), 1.70 (m, 1H), 1.12 (m, 1H), 0.97 (m, 1H). ppm; LRMS m/z (M+H) 403.0 found, 403.1
required. 13-6 (750 mg, 30%): H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.23 (s, 1H), 7.45
(dd, J = 7.9, 1.7 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.28 (s, 1H), 4.86 (d, J = 5.5 Hz, 2H), 4.28
(dd, J = 11.3, 6.7 Hz, 1H), 4.13 (dd, J = 11.3, 7.7 Hz, 1H), 2.66 (s, 3H), 2.22 (s, 3H), 2.09 (m,
1H), 1.72 (m, 1H), 1.12 (m, 1H), 1.03 – 0.94 (m, 1H). LRMS m/z (M+H) 403.0 found, 403.1
required.
2-ethyl-N-((5-methyl-1,3,4-thiadiazolyl)methyl)(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinamine (17-13)
Diethylzinc (0.4 mL, 0.4 mmol)) was added dropwise to a solution of (17-19) (70 mg, 0.17
mmol) and Pd(dppf)Cl (7 mg, 0.009mmol) in dioxane (5 mL). The mixture was stirred at rt for 2
h then at reflux for 16 h under argon. The mixture was poured into sat. NaCl aq. and extracted
with EtOAc (3x20 mL). The combined organic phases were washed with NaCl (sat., aq.; 100
mL), dried over Na SO and concentrated. The residue was purified by Pre-TLC (Petroleum
ether/ EtOAc =1/2) to give the title compound (40 mg, 60%). H NMR (500 MHz, CD3OD) δ
8.06 (s, 1H), 7.37 (dd, J = 8.0, 1.8 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 5.59 (s, 1H), 4.77 (d, J = 6.2
Hz, 2H), 4.18 (dt, J = 10.9, 5.4 Hz, 1H), 4.04 (dd, J = 10.9, 7.4 Hz, 1H), 2.59 (d, J = 7.5 Hz, 3H),
2.52 (q, J = 7.6 Hz, 2H), 2.17 (s, 3H), 2.02 – 1.96 (m, 1H), 1.71 – 1.65 (m, 1H), 1.15 – 1.05 (m,
4H), 1.00 – 0.93 (m, 1H); LRMS m/z (M+H) 397.1 found, 397.1 required.
MRL-NOP-00136
ethyl2-((5-methyl-1,3,4-thiadiazolyl)methylamino)(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinecarboxylate (17-5)
4-chloro-N-((5-methyl-1,3,4-thiadiazolyl)methyl)(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinamine (13-5) (567 mg, 1.4 mmol), Pd(dppf)Cl (57 mg,
0.07 mmol), was suspended in EtOH(60 mL) and Et N(6 mL) in a steal pressure vessel. The
mixture was heated at 120 C under 2.0 MPa pressure of carbon monoxide for 36 h. The mixture
was concentrated and purified by Prep-HPLC to give 5 (250 mg, 41%) and 17-4 (110 mg, 20%).
17-5: H NMR (400 MHz, DMSO) δ 8.22 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.17 (s, 1H), 6.58 (s,
1H), 4.79 (d, J = 6.0 Hz, 2H), 4.41 – 4.17 (m, 4H), 2.64 (s, 4H), 2.22 (s, 3H), 2.12 – 2.01 (m,
1H), 1.73 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.12 (m, 1H), 0.97 (m, 1H). LRMS m/z (M+H) 441.1
found, 441.1 required. 17-4: H NMR (400 MHz, MeOD) δ 8.05 (s, 1H), 7.36 (d, J = 7.1 Hz,
1H), 6.98 (d, J = 8.0 Hz, 1H), 5.88 (s, 1H), 4.87 (s, 3H), 4.28 (m, 2H), 2.58 (s, 3H), 2.17 (s, 3H),
2.05 (m, 2H), 1.67 (m, 1H), 1.11 (m, 1H), 0.98 (m, 1H). LRMS m/z (M+H) 413.1 found, 413.1
required.
2-(2-((5-methyl-1,3,4-thiadiazolyl)methylamino)(((1S,2S)(5-methylpyridin
yl)cyclopropyl)methoxy)pyrimidinyl)propanol (17-14)
A 50 mL reaction flask was charged with ethyl2-((5-methyl-1,3,4-thiadiazolyl)methylamino)-
6-(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidinecarboxylate (17-5) (100
mg, 0.23 mmol) and THF (5 mL) and cooled to 0 C. Then methylmagnesium bromide (0.57
mL, 1.0 M in THF, 0.57 mmol) was added dropwise to the mixture. The mixture was stirred at
room temperature for 2 h. The mixture was filtered, concentrated and purified by Pre-TLC
(Petroleum ether/ EtOAc =0/1) to give 17-14 (30 mg, 30%) and 17-16 (19 mg, 20%). 17-14: H
NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H),
6.40 (s, 1H), 5.00 (s, 2H), 4.46 (dd, J = 11.5, 6.6 Hz, 1H), 4.38 (d, J = 6.8 Hz, 1H), 2.64 (s, 3H),
2.39 (d, J = 8.5 Hz, 3H), 2.35 (dd, J = 8.6, 4.8 Hz, 1H), 1.99 (dd, J = 12.8, 6.6 Hz, 1H), 1.53 –
1.32 (m, 8H); LRMS m/z (M+H) 427.1 found, 427.1 required. 17-16: H NMR (500 MHz,
MeOD) δ 8.07 (s, 1H), 7.39 (dd, J = 8.0, 1.9 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.44 (s, 1H), 4.81
(d, J = 9.4 Hz, 2H), 4.27 (m, 1H), 4.20 (m, 1H), 2.59 (d, J = 4.1 Hz, 3H), 2.41 (s, 3H), 2.18 (s,
3H), 2.02 (m, 1H), 1.68 (m, 1H), 1.13 (m, 1H), 0.96 (m, 1H); LRMS m/z (M+H) 411.2 found,
411.1 required.
MRL-NOP-00136
TABLE 8
The compounds in Table 8 were prepared in accordance with the example 17
below or an analogous manner to the examples of example 17, using the appropriate starting
materials. Starting materials not previously illustrated were commercially available, described in
the literature, or readily synthesized by one skilled in the art of organic synthesis without undue
experimentation.
Cpd. Structure Name LRMS (M+H)
N-methoxy-N-methyl
((2-methyl(((1S,2S)-
2-(5-methylpyridin
yl)cyclopropyl)methoxy)
17-1 456.5
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazole
carboxamide
1-(5-((2-methyl
(((1S,2S)(5-
methylpyridin
yl)cyclopropyl)methoxy) 411.5
17-2
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazolyl)ethanone
1-(5-((2-methyl
(((1S,2S)(5-
methylpyridin
yl)cyclopropyl)methoxy)
17-3 413.5
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazolyl)ethanol
(ent1)
4-((5-methyl-1,3,4-
thiadiazol 413.1 found,
17-4 yl)methylamino) 413.1 required
(((1R,2R)(5-
methylpyridin
MRL-NOP-00136
yl)cyclopropyl)methoxy)
pyrimidinecarboxylic
acid
ethyl 4-((5-methyl-1,3,4-
thiadiazol
yl)methylamino)
(((1R,2R)(5- 441.1 found,
17-5
methylpyridin 441.1 required
yl)cyclopropyl)methoxy)
pyrimidine
carboxylate
2-(5-((2-methyl
(((1S,2S)(5-
methylpyridin
yl)cyclopropyl)methoxy)
17-6 427.5
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazolyl)propan-
2-ol
2-(6-((1S,2S)((2-
methyl((5-methyl-
1,3,4-thiadiazol
yl)methylamino)pyrimid
17-8 427.2
in
yloxy)methyl)cycloprop
yl)pyridinyl)propan-
2-ol
methyl 5-((2-methyl
(((1S,2S)(5-
methylpyridin
yl)cyclopropyl)methoxy)
17-9 427.5
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazole
carboxylate
MRL-NOP-00136
-((2-methyl
(((1S,2S)(5-
methylpyridin
yl)cyclopropyl)methoxy)
17-10 394.4
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazole
carbonitrile
-((2-methyl
(((1S,2S)(5-
methylpyridin
yl)cyclopropyl)methoxy)
17-11 412.4
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazole
carboxamide
6-(((1S,3S)tert-
butoxy(5-
methylpyridin
yl)cyclopropyl)methoxy)
17-12 455.6
methyl-N-((5-methyl-
1,3,4-thiadiazol
yl)methyl)pyrimidin
amine
2-ethyl-N-((5-methyl-
1,3,4-thiadiazol
yl)methyl)(((1S,2S)-
17-13 397.1
2-(5-methylpyridin
yl)cyclopropyl)methoxy)
pyrimidinamine
2-(4-((5-methyl-1,3,4-
thiadiazol
yl)methylamino) 427.1 found,
17-14 (((1R,2R)(5- 427.1 required
methylpyridin
yl)cyclopropyl)methoxy)
pyrimidinyl)propan-
MRL-NOP-00136
2-ol
N-((5-tert-butyl-1,3,4-
thiadiazolyl)methyl)-
2-methyl(((1S,2S)
17-15 425.6
(5-methylpyridin
yl)cyclopropyl)methoxy)
pyrimidinamine
1-(4-((5-methyl-1,3,4-
thiadiazol
yl)methylamino)
411.2 found,
17-16 (((1R,2R)(5-
411.1 required
methylpyridin
yl)cyclopropyl)methoxy)
pyrimidinyl)ethanone
1-(5-((2-methyl
(((1S,2S)(5-
methylpyridin
17-18 yl)cyclopropyl)methoxy) 413.5
pyrimidin
ylamino)methyl)-1,3,4-
thiadiazolyl)ethanol
2-chloro-N-((5-methyl-
1,3,4-thiadiazol
yl)methyl)(((1S,2S)- 403.0 found,
17-19 2-(5-methylpyridin 403.1 required
yl)cyclopropyl)methoxy)
pyrimidinamine
The compounds of the following examples had activity in inhibiting the human
PDE10 enzyme in the aforementioned assays with an Ki of about 0.001 nM to about 100 nM: 1-
2, 2-2, 2-3, 2-3", 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11, 2-12, 2-13, 2-14, 2-15, 2-16, 2-17, 2-18,
2-19, 2-20, 2-21, 2-22, 2-21, 2-24, 2-25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-33, 2-34, 2-
, 2-36, 2-37, 2-38, 2-39, 2-40, 2-41, 2-42, 2-43, 2-44, 2-45, 2-46, 2-47, 2-48, 2-49, 2-50, 2-51,
2-52, 2-53, 2-54, 2-55, 2-56, 2-57, 2-58, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-14,
3-15, 3-16, 3-17, 3-18, 3-19, 3-10, 3-11, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-
MRL-NOP-00136
21, 3-22, 3-23, 3-24, 3-25, 3A-3, 4-1, 5-5, 6-4, 8-5, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-9, 9-1, 9-2, 10-
1, 11-1, 12-2, 12-3, 12-4, 12-5, 12-6, 13-1, 13-2, 14-3, 15-1, 16-4, 16-5, 16-6.
The compounds of the following examples had activity in inhibiting the human
PDE10 enzyme in the aforementioned assays with an Ki of about 0.001 nM to about 10 nM: 1-2,
2-2, 2-3", 2-4, 2-6, 2-7, 2-8, 2-12, 2-14, 2-17, 2-27, 2-38, 2-54, 2-59, 3-8 , 3-11, 3-13, 3-14, 3-
, 3-19, 3-23, 3-25, 4-1, 5-5, 8-8, 9-1, 9-2, 12-2, 13-1, 14-3, 16-4.
The following table shows representative data for the compounds of the Examples
as PDE10 inhibitors as determined by the foregoing assays wherein the PDE10 Ki is a measure
of the ability of the test compound to inhibit the action of the PDE10 enzyme. Representative
compounds of the invention had the Ki values specified in parentheses immediately following the
compound number in the above-described assay.
Compound PDE10A Ki (nM) Compound PDE10A Ki (nM)
1-2 0.03 3-8 1.1
2-3" 0.04 3-11 1.6
2-4 0.6 3-13 0.5
2-14 3.6 3-19 3.6
2-17 3.5 3-25 0.09
2-27 0.02 8-8 1.0
3.8 0.08
2-37 9-2
2-47 41.7 12-2 1.1
0.05 5.3
2-53 14-3
2-58 3.9 16-4 1.6
While the invention has been described and illustrated with reference to certain
particular embodiments thereof, those skilled in the art will appreciate that various adaptations,
changes, modifications, substitutions, deletions, or additions of procedures and protocols may be
made without departing from the spirit and scope of the invention.
MRL-NOP-00136
Claims (29)
1. A compound of the formula I: wherein: A is selected from the group consisting of: (1) pyridyl, (2) quinolinyl, 10 (3) naphthyridinyl, (4) thiazolyl, (5) pyridazinyl, (6) oxazolyl, and (7) pyrazolyl, 15 (8) dihydropyrrolopyrazolyl, (9) dihydrocyclopentapyridinyl, (10) imidazopyridazinyl, and (11) pyrazolopyrimidinyl; 20 B is selected from the group consisting of: (1) thiazolyl, (2) pyrazolyl, (3) thiadiazolyl, (4) isoxazolyl, 25 (5) isothiazolyl, (6) pyridyl, and (7) pyrimidinyl; 1a 1b 1c R , R and R are independently selected from the group consisting of: 30 (1) hydrogen, MRL-NOP-00136 (2) halogen, (3) hydroxyl, (4) -(C=O) -O -C alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, m n 1-6 a bond is present) and where the alkyl is unsubstituted or substituted with one or more 5 substituents selected from R , (5) -(C=O) -O -C cycloalkyl, where the cycloalkyl is unsubstituted or substituted m n 3-6 with one or more substituents selected from R , (6) -(C=O) -C alkenyl, where the alkenyl is unsubstituted or substituted with one m 2-4 or more substituents selected from R , 10 (7) -(C=O) -C alkynyl, where the alkynyl is unsubstituted or substituted with one m 2-4 or more substituents selected from R , (8) -(C=O) -O -phenyl or -(C=O) -O -naphthyl, where the phenyl or naphthyl is m n m n unsubstituted or substituted with one or more substituents selected from R , (9) -(C=O) -O -heteroaryl, where the heteraryl is unsubstituted or substituted with 15 one or more substituents selected from R , 10 11 (10) -(C=O) -NR R , 10 11 (11) -S(O) -NR R , 12 12 (12) -S(O) -R , where q is 0, 1 or 2 and where R is selected from the definitions of 10 11 R and R , 20 (13) -CO H, (14) -CN, and (15) -NO ; 2a 2b 2c R , R and R are independently selected from the group consisting of: 25 (1) hydrogen, (2) halogen, (3) hydroxyl, (4) -(C=O) -O -C alkyl, where the alkyl is unsubstituted or substituted with one m n 1-6 or more substituents selected from R , 30 (5) -(C=O) -O -C cycloalkyl, where the cycloalkyl is unsubstituted or substituted m n 3-6 with one or more substituents selected from R , (6) -(C=O) -C alkenyl, where the alkenyl is unsubstituted or substituted with one m 2-4 or more substituents selected from R , (7) -(C=O) -C alkynyl, where the alkynyl is unsubstituted or substituted with one m 2-4 35 or more substituents selected from R , (8) -(C=O) -O -phenyl or -(C=O) -O -naphthyl, where the phenyl or naphthyl is m n m n unsubstituted or substituted with one or more substituents selected from R , MRL-NOP-00136 (9) -(C=O) -O -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents selected from R , 10 11 (10) -(C=O) -NR R , 10 11 (11) -S(O) -NR R , 5 (12) -S(O) -R , (13) -CO H, (14) -CN, and (15) -NO ; 10 R is selected from the group consisting of: (1) CH , (2) CF , (3) CH F, (4) CH CH , 15 (5) cyclopropyl, (6) cyano, (7) hydrogen, (8) NH , (9) C(O)OR , 20 (10) -O-C alkyl, (11) -(CO)NH , (12) C alkylOH, (13) C(O) C alky, and (14) halogen; R is selected from the group consisting of: (1) hydrogen, (2) halo, 30 (3) -C alkyl, and (4) cyano, R is selected from the group consisting of: (1) hydrogen, and 35 (2) C alkyl; R is selected from the group consisting of: (1) hydrogen, MRL-NOP-00136 (2) C alkyl, and (3) OC alkyl; 10 11 R and R are independently selected from the group consisting of: 5 (a) hydrogen, (b) C alkyl, which is unsubstituted or substituted with R , (c) C alkenyl, which is unsubstituted or substituted with R , (d) C alkynyl, which is unsubstituted or substituted with R , (e) C cycloalkyl which is unsubstituted or substituted with R , 10 (f) C alkoxyl, which is unsubstituted or substituted with R , (g) phenyl, which is unsubstituted or substituted with R , and (h) heteroaryl, which is unsubstituted or substituted with R , R is selected from the group consisting of: (1) halogen, 15 (2) hydroxyl, (3) -(C=O) -O -C alkyl, where the alkyl is unsubstituted or substituted with one m n 1-6 or more substituents selected from R , (4) -O -(C )perfluoroalkyl, n 1-3 (5) -(C=O) -O -C cycloalkyl, where the cycloalkyl is unsubstituted or substituted m n 3-6 20 with one or more substituents selected from R , (6) -(C=O) -C alkenyl, where the alkenyl is unsubstituted or substituted with one m 2-4 or more substituents selected from R , (7) -(C=O) -C alkynyl, where the alkynyl is unsubstituted or substituted with one m 2-4 or more substituents selected from R , 25 (8) -(C=O) -O -phenyl or -(C=O) -O -naphthyl, where the phenyl or naphthyl is m n m n unsubstituted or substituted with one or more substituents selected from R , (9) -(C=O) -O -heteroaryl, where the heteroaryl is unsubstituted or substituted with one or more substituents selected from R , 10 11 (10) -(C=O) -NR R , 10 11 30 (11) -S(O) -NR R , (12) -S(O) -R , (13) -CO H, (14) -CN, and (15) -NO ; R is selected from the group consisting of: (1) hydroxyl, MRL-NOP-00136 (2) halogen, (3) C alkyl, (4) -C cycloalkyl, (5) -O-C alkyl, 5 (6) -O(C=O)-C alkyl, (7) -NH-C alkyl, (8) phenyl, (9) heteroaryl, (10) -CO H, and 10 (11) -CN; or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 of the formula Ia: 15 Ia or a pharmaceutically acceptable salt thereof.
3. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, whereinwherein A is selected from the group consisting of: 20 (1) pyridyl, (2) quinolinyl, and (3) naphthyridinyl.
4. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, 25 wherein B is selected from the group consisting of: (1) thiazolyl, (2) pyrazolyl, and (3) thiadiazolyl. MRL-NOP-00136
5. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of: 5
6. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, 1a 1b 1c wherein R , R , R are selected from the group consisting of: (1) C alkyl, which is unsubstituted or substituted with halogen or hydroxyl, (2) -O-C alkyl, which is unsubstituted or substituted with halogen or hydroxyl, (3) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, 10 -NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl, 2 1-6 1-6 1-6 1-6 1-6 which is unsubstituted or substituted with fluoro, (4) heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, -NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl, 2 1-6 1-6 1-6 1-6 1-6 which is unsubstituted or substituted with fluoro, 15 (5) -O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, -NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl, 2 1-6 1-6 1-6 1-6 1-6 which is unsubstituted or substituted with fluoro, and (6) -O-heteroaryl, which is unsubstituted or substituted with halogen, hydroxyl, -NH , -NH-C alkyl, or -N(C alkyl)(C alkyl), -O-C alkyl or C alkyl, 2 1-6 1-6 1-6 1-6 1-6 20 which is unsubstituted or substituted with fluoro.
7. The compound of Claim 6, or a pharmaceutically acceptable salt thereof, 1a 1b 1c wherein R , R , R are selected from the group consisting of: (1) hydrogen, 25 (2) chloro, (3) fluoro, (4) bromo, (5) methyl, (6) methoxy, 30 (7) (methyl)cyclopropyl-, MRL-NOP-00136 (8) cyclopropyl, (9) (methoxy)phenyl-, and (10) (methyl)phenyl-. 5
8. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, 2a 2b 2c wherein R , R and R are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, 10 (4) C alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl or naphthyl, (5) -O-C alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (6) heterocyclyl, wherein heterocyclyl is selected from imidazolyl, isothiazolyl, 15 oxazolyl, morpholinyl, pyrazolyl, pyridyl, tetrazolyl, and thiazolyl, which is unsubstituted or substituted with halogen, hydroxyl, C alkyl, -O-C alkyl or-NO , and 1-6 1-6 2 (7) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C alkyl, -O-C alkyl or-NO . 1-6 2 20
9. The compound of Claim 8, or a pharmaceutically acceptable salt thereof, 2c 2a 2b wherein R is hydrogen and R and R are independently selected from the group consisting (1) hydrogen, (2) chloro, 25 (3) fluoro, (4) bromo, (5) methyl, (6) cyclopropyl; (7) isopropoxy, 30 (8) methoxy, and (9) t-butoxy.
10. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of CH , CF , and CH F. 3 3 2
11. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen and methyl. MRL-NOP-00136
12. A compound which is selected from the group consisting of: 2-methyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridinylcyclopropyl)methoxy] pyrimidinamine; 5 S,Smethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridinylcyclopropyl)methoxy] pyrimidinamine; 2-methyl{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; 2-methyl{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4- 10 thiadiazolyl)methyl]pyrimidinamine; N-[(2,4-dimethyl-1,3-thiazolyl)methyl]methyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,S-N-[(2,4-dimethyl-1,3-thiazolyl)methyl]methyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 15 N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl[(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; S,S-N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl[(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl{[2-(1,5-naphthyridin 20 yl)cyclopropyl]methoxy}pyrimidinamine; S,S-N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl{[2-(1,5-naphthyridin yl)cyclopropyl]methoxy}pyrimidinamine; N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl{[2-(5-methylpyridin yl)cyclopropyl]methoxy}pyrimidinamine; 25 S,S-N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl{[2-(5-methylpyridin yl)cyclopropyl]methoxy}pyrimidinamine; N-[(1,3-dimethyl-1H-pyrazolyl)methyl]{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}- 2-methylpyrimidinamine; S,S-N-[(1,3-dimethyl-1H-pyrazolyl)methyl]{[2-(5-methoxypyridin 30 yl)cyclopropyl]methoxy}methylpyrimidinamine; N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl[(pyridin ylcyclopropyl)methoxy]pyrimidinamine; MRL-NOP-00136 S,S-N-[(1,3-dimethyl-1H-pyrazolyl)methyl]methyl[(pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,Smethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; 5 2-methyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; S,Smethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; 2-methyl-N-[(1-methyl-1H-pyrazolyl)methyl]{[2-(1,5-naphthyridin 10 yl)cyclopropyl]methoxy}pyrimidinamine; S,Smethyl-N-[(1-methyl-1H-pyrazolyl)methyl]{[2-(1,5-naphthyridin yl)cyclopropyl]methoxy}pyrimidinamine; 6-{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}methyl-N-[(1-methyl-1H-pyrazol yl)methyl]pyrimidinamine; 15 S,S{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}methyl-N-[(1-methyl-1H-pyrazol yl)methyl]pyrimidinamine; S,Smethyl-N-[(1-methyl-1H-pyrazolyl)methyl]{[(5-methylpyridin yl)cyclopropyl]methoxy}pyrimidinamine; 2-methyl-N-[(1-methyl-1H-pyrazolyl)methyl]{[(5-methylpyridin 20 yl)cyclopropyl]methoxy}pyrimidinamine; 6-{[2-(3-methoxypyridinyl)cyclopropyl]methoxy}methyl-N-[(1-methyl-1H-pyrazol yl)methyl]pyrimidinamine; 6-{[2-(5-fluoropyridinyl)cyclopropyl]methoxy}methyl-N-[(1-methyl-1H-pyrazol yl)methyl]pyrimidinamine; 25 S,S{[2-(5-fluoropyridinyl)cyclopropyl]methoxy}methyl-N-[(1-methyl-1H-pyrazol yl)methyl]pyrimidinamine; 6-({2-[5-(fluoromethyl)pyridinyl]cyclopropyl}methoxy)methyl-N-[(1-methyl-1H-pyrazol- 4-yl)methyl]pyrimidinamine; 6-({2-[5-(difluoromethyl)pyridinyl]cyclopropyl}methoxy)methyl-N-[(1-methyl-1H- 30 pyrazolyl)methyl]pyrimidinamine; 2-methyl-N-[(1-methyl-1H-pyrazolyl)methyl]({2-[5-(trifluoromethyl)pyridin yl]cyclopropyl}methoxy)pyrimidinamine; MRL-NOP-00136 2-methyl-N-[(1-methyl-1H-pyrazolyl)methyl]{[2-(1,3-thiazol yl)cyclopropyl]methoxy}pyrimidinamine; 2-methyl-N-[(2-methyl-1,3-thiazolyl)methyl][(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; 5 S,Smethyl-N-[(2-methyl-1,3-thiazolyl)methyl][(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; 2-methyl-N-[(2-methyl-1,3-thiazolyl)methyl]{[2-(1,5-naphthyridin yl)cyclopropyl]methoxy}pyrimidinamine; S,Smethyl-N-[(2-methyl-1,3-thiazolyl)methyl]{[2-(1,5-naphthyridin 10 yl)cyclopropyl]methoxy}pyrimidinamine; 2-methyl{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(2-methyl-1,3-thiazol yl)methyl]pyrimidinamine; S,Smethyl{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(2-methyl-1,3-thiazol yl)methyl]pyrimidinamine; 15 6-{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}methyl-N-[(2-methyl-1,3-thiazol yl)methyl]pyrimidinamine; S,S{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}methyl-N-[(2-methyl-1,3-thiazol yl)methyl]pyrimidinamine; 2-methyl-N-[(2-methyl-1,3-thiazolyl)methyl][(2-pyridin 20 ylcyclopropyl)methoxy]pyrimidinamine; S,Smethyl-N-[(2-methyl-1,3-thiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 2-methyl-N-[(2-methyl-1,3-thiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 25 S,Smethyl-N-[(2-methyl-1,3-thiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; S,Smethyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-quinolin 30 ylcyclopropyl)methoxy]pyrimidinamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-(1,5-naphthyridin yl)cyclopropyl]methoxy}pyrimidinamine; MRL-NOP-00136 S,Smethyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-(1,5-naphthyridin yl)cyclopropyl]methoxy}pyrimidinamine; 6-{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; 5 S,S{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidinamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,Smethyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridin 10 ylcyclopropyl)methoxy]pyrimidinamine; 6-{[2-(5-fluoropyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; S,S{[2-(5-fluoropyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol- 2-yl)methyl]pyrimidinamine; 15 6-({2-[5-(fluoromethyl)pyridinyl]cyclopropyl}methoxy)methyl-N-[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidinamine; 6-({2-[5-(difluoromethyl)pyridinyl]cyclopropyl}methoxy)methyl-N-[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidinamine 2-methyl{[2-(6-methylpyridazinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol 20 yl)methyl]pyrimidinamine; S,Smethyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-(2-methyl-1,3-thiazol yl)cyclopropyl]methoxy}pyrimidinamine; 2-methyl{[2-(2-methyl-1,3-oxazolyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol- 2-yl)methyl]pyrimidinamine; 25 2-methyl{[2-(1-methyl-1H-pyrazolyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol- 2-yl)methyl]pyrimidinamine; N -[(5-cyclopropyl-1,3,4-thiadiazolyl)methyl]methyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,S-N -[(5-cyclopropyl-1,3,4-thiadiazolyl)methyl]methyl[(2-pyridin 30 ylcyclopropyl)methoxy]pyrimidinamine; N -[(2,4-dimethyl-1,3-thiazolyl)methyl][(2-pyridinylcyclopropyl)methoxy]pyrimidin amine; MRL-NOP-00136 S,S-N -[(2,4-dimethyl-1,3-thiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; N -[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-quinolinylcyclopropyl)methoxy]pyrimidin- 4-amine; 5 S,S-N -[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-quinolin ylcyclopropyl)methoxy]pyrimidinamine; N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-(1,5-naphthyridin yl)cyclopropyl]methoxy}pyrimidinamine; S,S-N -[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-(1,5-naphthyridin 10 yl)cyclopropyl]methoxy}pyrimidinamine; 6-{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; S,S{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; 15 6-{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; S,S{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridinylcyclopropyl)methoxy]pyrimidin 20 amine; S,S-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; N[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidine-2,4-diamine; 25 S,S-N[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidine-2,4-diamine; 2-methoxy-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,Smethoxy-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin 30 ylcyclopropyl)methoxy]pyrimidinamine; 2,5-dimethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; MRL-NOP-00136 S,S-2,5-dimethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; N-[(2,4-dimethyl-1,3-thiazolyl)methyl]-2,5-dimethyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 5 S,S-N-[(2,4-dimethyl-1,3-thiazolyl)methyl]-2,5-dimethyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; N{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl](trifluoromethyl)pyrimidinamine; S,S-N{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol 10 yl)methyl](trifluoromethyl)pyrimidinamine; 6-{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]- 2-(trifluoromethyl)pyrimidinamine; S,S{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl](trifluoromethyl)pyrimidinamine; 15 N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridinylcyclopropyl)methoxy] (trifluoromethyl)pyrimidinamine; S,S-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridinylcyclopropyl)methoxy] (trifluoromethyl)pyrimidinamine; N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridinylcyclopropyl)methoxy] 20 (trifluoromethyl)pyrimidinamine; S,S-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridinylcyclopropyl)methoxy] (trifluoromethyl)pyrimidinamine; 6-{[2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl)cyclopropyl]methoxy}methyl-N-[(5- methyl-1,3,4-thiadiazolyl)methyl]pyrimidinamine; 25 6-{[(1S,2S)(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl)cyclopropyl]methoxy}methyl-N- [(5-methyl-1,3,4-thiadiazolyl)methyl]pyrimidinamine; 6-{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidine-2,4-diamine; S,S{[(1S,2S)(5-methoxypyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4- 30 thiadiazolyl)methyl]pyrimidine-2,4-diamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-pyrazolo[1,5-a]pyrimidin ylcyclopropyl]methoxy}pyrimidinamine; MRL-NOP-00136 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[(1S,2S)pyrazolo[1,5-a]pyrimidin ylcyclopropyl]methoxy}pyrimidinamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-pyrazolo[1,5-a]pyrimidin ylcyclopropyl]methoxy}pyrimidinamine; 5 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[(1S,2S)pyrazolo[1,5-a]pyrimidin ylcyclopropyl]methoxy}pyrimidinamine; 6-{[2-(5-bromopyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; S,S{[(1S,2S)(5-bromopyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4- 10 thiadiazolyl)methyl]pyrimidinamine; 2-methyl{[2-(2-methylimidazo[1,2-b]pyridazinyl)cyclopropyl]methoxy}-N-[(5-methyl- 1,3,4-thiadiazolyl)methyl]pyrimidinamine; 2-methyl{[(1S,2S)(2-methylimidazo[1,2-b]pyridazinyl)cyclopropyl]methoxy}-N-[(5- methyl-1,3,4-thiadiazolyl)methyl]pyrimidinamine; 15 5-chloromethyl{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidinamine; S,Schloromethyl{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5- methyl-1,3,4-thiadiazolyl)methyl]pyrimidinamine; 2-ethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridinylcyclopropyl)methoxy] 20 pyrimidinamine; N-[(2,4-dimethyl-1,3-thiazolyl)methyl]fluoromethyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,S-N-[(2,4-dimethyl-1,3-thiazolyl)methyl]fluoromethyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 25 N-[(2,4-dimethyl-1,3-thiazolyl)methyl]fluoromethyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,S-N-[(2,4-dimethyl-1,3-thiazolyl)methyl]fluoromethyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 5-fluoromethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(pyridin 30 ylcyclopropyl)methoxy]pyrimidinamine; S,Sfluoromethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(pyridin ylcyclopropyl)methoxy]pyrimidinamine; MRL-NOP-00136 5-fluoromethyl{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidinamine; S,Sfluoromethyl{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidinamine; 5 2-(fluoromethyl)-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,S(fluoromethyl)-N-[(5-methyl-1,3,4-thiadiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; N -[(2,4-dimethyl-1,3-thiazolyl)methyl]ethyl[(2-pyridin 10 ylcyclopropyl)methoxy]pyrimidinamine; S,S-N -[(2,4-dimethyl-1,3-thiazolyl)methyl]ethyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 2-ethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 15 S,Sethyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 2-cyclopropyl-N-[(2,4-dimethyl-1,3-thiazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,Scyclopropyl-N-[(2,4-dimethyl-1,3-thiazolyl)methyl][(2-pyridin 20 ylcyclopropyl)methoxy]pyrimidinamine; 2-cyclopropyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,Scyclopropyl-N-[(1-methyl-1H-pyrazolyl)methyl][(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; 25 5-fluoro{[2-(5-methoxypyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4-thiadiazol- 2-yl)methyl]pyrimidine-2,4-diamine; 5-fluoro{[(1S,2S)(5-methoxypyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidine-2,4-diamine; 5-fluoro-N[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-(1,5-naphthyridin 30 yl)cyclopropyl]methoxy}pyrimidine-2,4-diamine; 5-fluoro-N[(5-methyl-1,3,4-thiadiazolyl)methyl]{[(1S,2S)(1,5-naphthyridin yl)cyclopropyl]methoxy}pyrimidine-2,4-diamine; MRL-NOP-00136 5-fluoro{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidine-2,4-diamine; 5-fluoro{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidine-2,4-diamine; 5 5-fluoro-N[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-pyridin ylcyclopropyl]methoxy}pyrimidine-2,4-diamine; 5-fluoro-N[(5-methyl-1,3,4-thiadiazolyl)methyl]{[(1S,2S)pyridin ylcyclopropyl]methoxy}pyrimidine-2,4-diamine; 5-fluoro-N[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-pyridin 10 ylcyclopropyl]methoxy}pyrimidine-2,4-diamine; 5-fluoro-N[(5-methyl-1,3,4-thiadiazolyl)methyl]{[(1S,2S)pyridin ylcyclopropyl]methoxy}pyrimidine-2,4-diamine; N (2,4-dimethoxybenzyl)fluoro{[2-pyridinylcyclopropyl]methoxy}pyrimidine-2,4- diamine; 15 N (2,4-dimethoxybenzyl)fluoro{[(1S,2S)pyridin ylcyclopropyl]methoxy}pyrimidine-2,4-diamine; 6-{[2-(5-chloropyridinyl)cyclopropyl]methoxy}fluoro-N[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidine-2,4-diamine; 6-{[(1S,2S)(5-chloropyridinyl)cyclopropyl]methoxy}fluoro-N[(5-methyl-1,3,4- 20 thiadiazolyl)methyl]pyrimidine-2,4-diamine; 5-fluoro{[2-(5-fluoropyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidine-2,4-diamine; 5-fluoro{[(1S,2S)(5-fluoropyridinyl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidine-2,4-diamine; 25 5-chloro{[2-(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidine-2,4-diamine; 5-chloro{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4- thiadiazolyl)methyl]pyrimidine-2,4-diamine; 6-{[2-(4,5-dimethylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol 30 yl)methyl]pyrimidine-2,4-diamine; 6-{[(1S,2S)(4,5-dimethylpyridinyl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidine-2,4-diamine; MRL-NOP-00136 6-((2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 6-(((1S,2S)(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl)cyclopropyl)methoxy)fluoro-N4- ((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 5 5-fluoro-N4-((5-methyl-1,3,4-thiadiazolyl)methyl)((2-(6-methylpyridin yl)cyclopropyl)methoxy)pyrimidine-2,4-diamine; 5-fluoro-N4-((5-methyl-1,3,4-thiadiazolyl)methyl)(((1S,2S)(6-methylpyridin yl)cyclopropyl)methoxy)pyrimidine-2,4-diamine; 6-((2-(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 10 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; S,S(((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro- N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 6-((2-(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 15 S,S(((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro- N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 6-((2-(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; S,S(((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro- 20 N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 6-((2-(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; S,S(((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro- N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 25 6-((2-(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; S,S(((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro- N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 6-((2-(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 30 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; S,S(((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro- N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; MRL-NOP-00136 6-((2-(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro-N4-((5-methyl- 1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; S,S(((1S,2S)(6,7-dihydro-5H-cyclopenta[b]pyridinyl)cyclopropyl)methoxy)fluoro- N4-((5-methyl-1,3,4-thiadiazolyl)methyl)pyrimidine-2,4-diamine; 5 5-bromo-N-((2,4-dimethylthiazolyl)methyl)methyl((2-(pyridin yl)cyclopropyl)methoxy)pyrimidinamine; 4-((2,4-dimethylthiazolyl)methylamino)methyl((2-(pyridin yl)cyclopropyl)methoxy)pyrimidinecarbonitrile; 2-methyl((1-methyl-1H-pyrazolyl)methylamino)((2-(pyridin 10 yl)cyclopropyl)methoxy)pyrimidinecarbonitrile; 4-((1-methyl-1H-pyrazolyl)methylamino)((2-(pyridinyl)cyclopropyl)methoxy)- pyrimidinecarboxamide; 4-((1-methyl-1H-pyrazolyl)methylamino)((2-(pyridinyl)cyclopropyl)methoxy)- pyrimidinecarbonitrile; 15 2-methyl-N-((5-methyl-1,3,4-thiadiazolyl)methyl)((2-(5-(thiazolyl)pyridin yl)cyclopropyl)methoxy)pyrimidinamine; 6-{[2-(2,3'-bipyridin-6'-yl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]({2-[5-(1,3-thiazolyl)pyridin 20 yl]cyclopropyl}methoxy)pyrimidinamine; 6-{[2-(3,4'-bipyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]({2-[5-(1,3-thiazolyl)pyridin yl]cyclopropyl}methoxy)pyrimidinamine; 25 6-{[2-(3,3'-bipyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol yl)methyl]pyrimidinamine; 2-methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]{[2-(5-pyridazinylpyridin yl)cyclopropyl]methoxy}pyrimidinamine; 6-((2-(5-ethylpyridinyl)cyclopropyl)methoxy)methyl-N-((5-methyl-1,3,4-thiadiazol 30 yl)methyl)pyrimidinamine; 6-{[2-(5-cyclopropylpyridinyl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazol- 2-yl)methyl]pyrimidinamine; MRL-NOP-00136 6-((2-(5-(1H-pyrazolyl)pyridinyl)cyclopropyl)methoxy)methyl-N-((5-methyl-1,3,4- thiadiazolyl)methyl)pyrimidinamine; 6-(2-((2-methyl((5-methyl-1,3,4-thiadiazolyl)methylamino)pyrimidin yloxy)methyl)cyclopropyl)nicotinonitrile; 5 2-methyl-N-((5-methylisoxazolyl)methyl)((2-(pyridinyl)cyclopropyl)methoxy)- pyrimidinamine; N-[(2-fluoromethylpyridinyl)methyl]methyl[(2-pyridin ylcyclopropyl)methoxy]pyrimidinamine; S,S-N-(isothiazolylmethyl)methyl[(2-pyridinylcyclopropyl)methoxy]pyrimidin 10 amine; 2-methyl-N-[(5-methylpyrazinyl)methyl][(2-pyridinylcyclopropyl)methoxy]pyrimidin amine; 2-methyl[(2-pyridinylcyclopropyl)methoxy]-N-(pyrimidinylmethyl)pyrimidinamine; 2-methyl((2-(pyridinyl)cyclopropyl)methoxy)-N-(pyridinylmethyl)pyrimidinamine; 15 2-methyl[(2-pyridinylcyclopropyl)methoxy]-N-(pyridinylmethyl)pyrimidinamine; 2-methyl-N-((3-methylpyridinyl)methyl)((2-(pyridinyl)cyclopropyl)methoxy)pyrimidin- 4-amine; 6-(2-((2-methyl((5-methyl-1,3,4-thiadiazolyl)methylamino)pyrimidin yloxy)methyl)cyclopropyl)pyridine; 20 2-amino{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}{[(5-methyl-1,3,4- thiadiazolyl)methyl]amino}pyrimidinecarbonitrile; 2-amino{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}{[(5-methyl-1,3,4- thiadiazolyl)methyl]amino}pyrimidinecarbonitrile; and S,Samino{[(1S,2S)(5-methylpyridinyl)cyclopropyl]methoxy}{[(5-methyl-1,3,4- 25 thiadiazolyl)methyl]amino}pyrimidinecarbonitrile; and 2-amino{[(1S,2S)(5-methoxypyridinyl)cyclopropyl]methoxy}{[(5-methyl-1,3,4- thiadiazolyl)methyl]amino}pyrimidinecarbonitrile; S,Samino{[(1S,2S)(5-methoxypyridinyl)cyclopropyl]methoxy}{[(5-methyl-1,3,4- thiadiazolyl)methyl]amino}pyrimidinecarbonitrile; 30 N-methoxy-N-methyl((2-methyl(((1S,2S)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinylamino)methyl)-1,3,4-thiadiazolecarboxamide; 1-(5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin ylamino)methyl)-1,3,4-thiadiazolyl)ethanone; MRL-NOP-00136 1-(5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin ylamino)methyl)-1,3,4-thiadiazolyl)ethanol; 4-((5-methyl-1,3,4-thiadiazolyl)methylamino)(((1R,2R)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinecarboxylic acid; 5 ethyl 4-((5-methyl-1,3,4-thiadiazolyl)methylamino)(((1R,2R)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinecarboxylate; 2-(5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin ylamino)methyl)-1,3,4-thiadiazolyl)propanol; 2-(6-((1S,2S)((2-methyl((5-methyl-1,3,4-thiadiazolyl)methylamino)pyrimidin 10 yloxy)methyl)cyclopropyl)pyridinyl)propanol; methyl 5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin ylamino)methyl)-1,3,4-thiadiazolecarboxylate; 5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin ylamino)methyl)-1,3,4-thiadiazolecarbonitrile; 15 5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin ylamino)methyl)-1,3,4-thiadiazolecarboxamide; 6-(((1S,3S)tert-butoxy(5-methylpyridinyl)cyclopropyl)methoxy)methyl-N-((5-methyl- 1,3,4-thiadiazolyl)methyl)pyrimidinamine; 2-ethyl-N-((5-methyl-1,3,4-thiadiazolyl)methyl)(((1S,2S)(5-methylpyridin 20 yl)cyclopropyl)methoxy)pyrimidinamine; 2-(4-((5-methyl-1,3,4-thiadiazolyl)methylamino)(((1R,2R)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinyl)propanol; N-((5-tert-butyl-1,3,4-thiadiazolyl)methyl)methyl(((1S,2S)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinamine; 25 1-(4-((5-methyl-1,3,4-thiadiazolyl)methylamino)(((1R,2R)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinyl)ethanone; 2-methyl-N-((5-methyl-1,3,4-thiadiazolyl)methyl)(((1R,2R)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinamine; 1-(5-((2-methyl(((1S,2S)(5-methylpyridinyl)cyclopropyl)methoxy)pyrimidin 30 ylamino)methyl)-1,3,4-thiadiazolyl)ethanol; 2-chloro-N-((5-methyl-1,3,4-thiadiazolyl)methyl)(((1S,2S)(5-methylpyridin yl)cyclopropyl)methoxy)pyrimidinamine; or a pharmaceutically acceptable salt thereof. MRL-NOP-00136
13. A compound of Claim 1 which is 2-methyl-N-[(1-methyl-1H-pyrazol yl)methyl][(2-pyridinylcyclopropyl)methoxy] pyrimidinamine, or a pharmaceutically acceptable salt thereof.
14. A compound of Claim 1 which is 2-Methyl{[(1S,2S)(5-methylpyridin- 2-yl)cyclopropyl]methoxy}-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]pyrimidinamine, or a pharmaceutically acceptable salt thereof. 10
15. A compound of Claim 1 which is S,S-N -[(1,3-dimethyl-1H-pyrazol yl)methyl]methyl[(2-quinolinylcyclopropyl)methoxy]pyrimidinamine, or a pharmaceutically acceptable salt thereof.
16. A compound of Claim 1 which is S,Smethyl-N-[(5-methyl-1,3,4- 15 thiadiazolyl)methyl]{[2-(1,5-naphthyridinyl)cyclopropyl]methoxy}pyrimidinamine, or a pharmaceutically acceptable salt thereof.
17. A compound of Claim 1 which is S,S{[(1S,2S)(5-methoxypyridin yl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4-thiadiazolyl)methyl]pyrimidine-2,4-diamine, 20 or a pharmaceutically acceptable salt thereof.
18. A compound of Claim 1 which is 2-ethyl-N-[(1-methyl-1H-pyrazol yl)methyl][(2-pyridinylcyclopropyl)methoxy] pyrimidinamine or a pharmaceutically acceptable salt thereof.
19. A compound of Claim 1 which is 5-fluoro{[(1S,2S)(5-methoxypyridin- 2-yl)cyclopropyl]methoxy}-N[(5-methyl-1,3,4-thiadiazolyl)methyl]pyrimidine-2,4-diamine or a pharmaceutically acceptable salt thereof. 30
20. A compound of Claim 1 which is 6-{[2-(3,3'-bipyridin yl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]pyrimidin amine or a pharmaceutically acceptable salt thereof.
21. A compound of Claim 1 which is 6-{[2-(5-cyclopropylpyridin 35 yl)cyclopropyl]methoxy}methyl-N-[(5-methyl-1,3,4-thiadiazolyl)methyl]pyrimidin amine or a pharmaceutically acceptable salt thereof. MRL-NOP-00136
22. A compound of Claim 1 which is 2-methyl-N-((5-methylisoxazol yl)methyl)((2-(pyridinyl)cyclopropyl)methoxy)-pyrimidinamine or a pharmaceutically acceptable salt thereof. 5
23. A compound of Claim 1 which is 2-amino{[(1S,2S)(5-methylpyridin yl)cyclopropyl]methoxy}{[(5-methyl-1,3,4-thiadiazolyl)methyl]amino}pyrimidine carbonitrile or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition which comprises a pharmaceutically 10 acceptable carrier and a compound of Claim 1 or a pharmaceutically acceptable salt thereof.
25. A compound of Claim 1 or a pharmaceutically acceptable salt thereof for use in medicine. 15
26. Use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders. 20
27. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neurological or psychiatric disorder associated with PDE10 dysfunction.
28. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, 25 for the manufacture of a medicament for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction.
29. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating schizophrenia.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161527392P | 2011-08-25 | 2011-08-25 | |
US61/527,392 | 2011-08-25 | ||
PCT/US2012/051522 WO2013028590A1 (en) | 2011-08-25 | 2012-08-20 | Pyrimidine pde10 inhibitors |
Publications (2)
Publication Number | Publication Date |
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NZ621245A NZ621245A (en) | 2014-12-24 |
NZ621245B2 true NZ621245B2 (en) | 2015-03-25 |
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