Pyrazolopyrimidinone derivatives having pde7 inhibitinig action

专利摘要:
The present invention, Formula IA or IB: [Formula IA] [Formula IB] And the formula IA 'or IB': [Formula IA '] Formula IB ' [Wherein each symbol is defined in the specification] A pyrazolopyrimidinone derivative represented by the following is provided as a target compound. Since the compound has a function of selectively inhibiting PDE7, it can increase intracellular cAMP level, and through inhibition of T cell activation, the compound can be used for the prevention and treatment of various allergic diseases and inflammatory and immune diseases. useful.
公开号:KR20040065156A
申请号:KR10-2003-7012495
申请日:2002-12-13
公开日:2004-07-21
发明作者:이노우에히데까즈；무라후지히데노부；하야시야스히로
申请人:다이이찌 산토리 파마 가부시키가이샤；가부시키가이샤 다이이찌 산토리 세이부쓰 이가쿠 겐큐쇼；
IPC主号:

专利说明:

Pyrazolopyrimidinone derivatives having PDE7 inhibitory activity {PYRAZOLOPYRIMIDINONE DERIVATIVES HAVING PDE7 INHIBITINIG ACTION}
[2] Cyclic AMP (cAMP) or cGMP, which is an intracellular secondary messenger, is degraded and inactivated by phosphodiesterase (PDE1-11). Among these phosphodiesterases, PDE7 is characterized by an enzyme that selectively degrades cAMP and similarly is not inhibited by rolipram, a selective inhibitor of PDE4 that degrades cAMP. It is suggested that PDE7 plays an important role in activating T cells (Beavo et al., Science 283 (1999) 848). Activation of T cells can lead to various diseases such as allergic diseases and inflammatory or immune diseases, such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis , Systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, transplant rejection, GVH disease, and pathological conditions of restenosis after angioplasty [J Allergy Clin Immunol 2000 Nov; 106 (5 Suppl): S221-6, Am J Respir Crit Care Med 1996 Feb; 153 (2): 629-32, Am J Respir Crit Care Med 1999 Nov; 160 (5 Pt 2): S33-7 , Clin Exp Allergy 2000 Feb; 30 (2): 242-54, Hosp Med 1998 Jul: 59 (7): 530-3, Int Arch Allergy Immunol 1998 Mar; 115 (3): 179-90, J Immunol 1991 Feb 15; 146 (4): 1169-74, Osteoarthritis Cartilage 1999 Jul; 7 (4): 401-2, Rheum Dis Clin North Am 2001 May; 27 (2): 317-34, J Autoimmun 2001 May; 16 (3 ): 187-92, Curr Rh eumatol Rep 2000 Feb; 2 (1): 24-31, Trends Immunol 2001 Jan; 22 (1): 21-6, Curr Opin Immunol 2000 Aug; 12 (4): 403-8, Diabetes Care 2001 Sep; 24 ( 9): 1661-7, J Neuroimmunol 2000 Nov 1; 111 (1-2): 224-8, Curr Opin Immunol 1997 Dec; 9 (6): 793-9, JAMA 1999 Sep 15; 282 (11): 1076 -82, Semin Cancer Biol 1996 Apr: 7 (2): 57-64, J Interferon Cytokine Res 2001 Apr; 21 (4): 219-21]. Thus, inhibitors of PDE7 are believed to be useful in treating various allergic diseases and inflammatory or immune diseases involving T cells.
[3] Compounds known as selective inhibitors of these enzymes include imidazopyridine derivatives (WO 01/34601), dihydropurine derivatives (WO 00/68203), pyrrole derivatives (WO 01/32618) and benzothiopyranoimidazolone derivatives (DE19950647 ), But their inhibitory action and selectivity against other PDEs is unknown. Compounds for which inhibitory activity has been disclosed include guanine derivatives (Bioorg. Med. Chem. Lett. 11 (2001) 1081, benzothiadiazine and benzothienothiadiazine derivatives (J. Med. Chem. 43 (2000) 683) ( Eur. J. Med. Chem. 36 (2001) 333) However, their inhibitory activity is poor and their selectivity to other PDEs is also low, making the compounds practically ineffective as PDE7 inhibitors.
[4] As a compound having a pyrazolopyrimidinone skeleton, European Patent Application EP 463756, European Patent Application EP 526004, European Patent Application EP 349239, European Patent Application EP 636626, European Patent Application EP 995751 And the compounds described in Japanese Unexamined Patent Publication No. 1996-25384 are known as cGMP specific PDE5 inhibitors, but their PDE7 inhibitory activity is not shown.
[1] The present invention relates to pyrazolopyrimidinone derivatives having a selective PDE7 (type phosphodiesterase) inhibitory activity, salts or solvates thereof, and PDE7 inhibitors containing them as active ingredients. The compounds are effective in the treatment of various fields, including allergic diseases, and inflammatory or immune diseases.
[5] [Initiation of invention]
[6] It is an object of the present invention to provide novel compounds having PDE7 inhibitory activity and PDE7 inhibitors containing these compounds as active ingredients.
[7] The compounds of the present invention are useful for treating various allergic diseases and inflammatory or immune diseases by selectively inhibiting PDE7 to increase intracellular cAMP levels and inhibiting T cell activation. That is, the compound of the present invention is bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis It is useful as a prophylactic or therapeutic agent for diseases such as sepsis, Crohn's disease, transplant rejection, GVH disease, and restenosis after angioplasty.
[8] We (inventors) have conducted in-depth research in an attempt to develop compounds with good PDE7 inhibitory action. As a result, we found that compounds having pyrazolopyrimidinone skeletons represented by the formulas IA, IB, IA 'and IB' shown below have strong PDE7 inhibitory action and excellent PDE7 inhibitory selectivity. The above findings have led us to complete the present invention.
[9] Embodiments for Carrying Out the Invention
[10] According to the present invention, there may be provided a pyrazolopyrimidinone derivative represented by the following formula (IA or IB), or a pharmaceutical composition and a PDE7 inhibitor containing a salt or solvate thereof as an active ingredient:
[11]
[12]
[13] [In the meal,
[14] A represents N or CR ⁴ ,
[15] B represents a hydrogen atom or a halogen atom,
[16] R ¹ represents optionally substituted C _3-7 cycloalkyl or tert-butyl,
[17] R ² represents hydrogen, methyl or ethyl,
[18] R ³ is hydrogen, nitro, cyano or halogen atom, NR ⁵ R ⁶ , C (= X) R ⁷ , SO ₂ NR ⁵ R ⁶ , OR ⁸ , NR ⁸ CONR ⁵ R ⁶ , NR ⁸ SO ₂ R ⁹ , Heteroaryl group, or optionally substituted C _1-3 alkyl,
[19] R ⁴ represents hydrogen or C _1-3 alkoxy substituted with one or more fluorine atoms as needed,
[20] R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, optionally substituted C _1-6 alkyl or optionally substituted acyl or together with the nitrogen atom to which they are attached azetidinyl, pyrrolidinyl, piperidinyl , Morpholino, thiomorpholino, piperazinyl or homopiperazinyl, each of said groups being optionally substituted C _1-4 alkyl, OH, C _1-3 alkoxy, CO ₂ H or NR ⁵ May be substituted with R ⁶ ,
[21] R ⁷ represents optionally substituted C _1-6 alkyl, OH, OR ⁸ or NR ⁵ R ⁶ ,
[22] R ⁸ represents hydrogen or an optionally substituted C _1-6 alkyl group,
[23] R ⁹ represents an optionally substituted C _1-6 alkyl group,
[24] X represents O, S or NH.
[25] The description represented by "C _O-O " here represents the carbon number in the range from O to O. For example, C _1-6 represent carbon number in the range of 1-6.
[26] In the present invention, examples of substituents associated with the expression "optionally substituted" include optionally substituted linear, branched or cyclic alkyl groups such as methyl, ethyl, propyl or cyclohexyl; Hydroxyl group; Cyano group; Alkoxy groups such as methoxy or ethoxy; Optionally substituted amino groups such as amino, methylamino or dimethylamino; Optionally substituted acyl groups such as acetyl or propionyl; Carboxyl groups; Optionally substituted aryl groups such as phenyl or naphthyl; Optionally substituted heteroaryl groups such as pyridinyl, thiazolyl, imidazolyl or pyrazyl; Optionally substituted saturated or unsaturated heterocycloalkyl groups such as piperazinyl or morphonyl; Optionally substituted carbamoyl group; Optionally substituted amido groups; Halogen atoms such as chlorine, fluorine or bromine; Nitro group; Optionally substituted sulfone group; Optionally substituted sulfonylamido groups; Oxo group; Urea; And optionally substituted linear, branched or cyclic alkenyl groups such as ethenyl, propenyl or cyclohexenyl groups.
[27] In the formulas IA and IB of the present invention, optionally substituted C _3-7 cycloalkyl represented as R ¹ includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred examples are C _5-7 cycloalkyl such as cyclopentyl, cyclohexyl and cycloheptyl, particularly preferred examples are cyclohexyl and cycloheptyl.
[28] Examples of R ² are hydrogen, methyl and ethyl, and a particularly preferred example is methyl.
[29] Examples of R ³ are hydrogen, nitro, cyano or halogen atom, NR ⁵ R ⁶ , C (= X) R ⁷ , SO ₂ NR ⁵ R ⁶ , OR ⁸ , NR ⁸ CONR ⁵ R ⁶ , NR ⁸ SO ₂ R ⁹ , heteroaryl group, or optionally substituted C _1-3 alkyl. Particularly preferred examples are cyano, NR ⁵ R ⁶ , C (= X) R ⁷ , SO ₂ NR ⁵ R ⁶ , OR ⁸ , NR ⁸ CONR ⁵ R ⁶ , NR ⁸ SO ₂ R ⁹ , heteroaryl groups and optionally Substituted C _1-3 alkyl. Halogen atoms refer to fluorine, chlorine, bromine or iodine.
[30] Preferred examples of the heteroaryl group as R ³ are 5 to 7 membered monocyclic heteroaryl groups having 2 to 8 carbon atoms and containing 1 to 4 heteroatoms consisting of oxygen atom, nitrogen atom or sulfur atom, and 2 condensed together Polycyclic heteroaryl groups comprising at least two identical or different monocyclic compounds, examples of monocyclic and polycyclic heteroaryl groups include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyridyl, pyrazyl, Indolyl, quinolyl, isoquinolyl and tetrazolyl.
[31] Examples of A include N or CR ⁴ . Preferred examples include CR ⁴ .
[32] Preferred examples of B are hydrogen or halogen atoms. Halogen atoms refer to fluorine, chlorine, bromine or iodine. Particularly preferred examples of B are hydrogen and fluorine.
[33] Preferred examples of R ⁴ are hydrogen and C _1-3 alkoxy, such as methoxy, ethoxy or propyloxy, substituted by one or more fluorine atoms as necessary. Particularly preferred examples are methoxy, ethoxy, fluoromethoxy and difluoromethoxy groups.
[34] Examples of R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, optionally substituted C _1-6 alkyl or optionally substituted acyl, or azetidinyl, pyrrolidinyl, pipepe together with the nitrogen atom to which they are attached A group capable of forming ridinyl, morpholino, thiomorpholino, piperazinyl or homopiperazinyl. The groups may be further optionally substituted with optionally substituted C _1-4 alkyl, OH, C _1-3 alkoxy, CO ₂ H or NR ⁵ R ⁶ . Particularly preferred examples are C _2-4 alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl and homopiperazinyl substituted with a hydroxyl group, an alkoxy group, an optionally substituted amino group. If desired, the groups may be further substituted with optionally substituted methyl, methoxy, OH, CO ₂ H or NR ⁵ R ⁶ .
[35] Examples of R ⁷ are optionally substituted linear or branched C _1-6 alkyl, OH, OR ⁸ or NR ⁵ R ⁶ . R ⁵ and R ⁶ are defined above. Particularly preferred examples are OH and NR ⁵ R ⁶ .
[36] Examples of R ⁸ include hydrogen or an optionally substituted linear or branched C _1-6 alkyl group. Preferably, hydrogen and optionally substituted C _1-3 alkyl are exemplified.
[37] An example of R ⁹ is an optionally substituted C _1-6 alkyl group, preferably an optionally substituted C _1-3 alkyl group. Particularly preferred examples are optionally substituted methyl and optionally substituted ethyl.
[38] Examples of X are O, S and NH. Particularly preferred example is O.
[39] According to the present invention, pyrazolopyrimidinone derivatives represented by the following formulas IA 'or IB', or salts or solvates of said derivatives may be provided:
[40]
[41]
[42] [In the meal,
[43] A 'represents N or CR ^4' ,
[44] B 'represents a hydrogen atom or a halogen atom,
[45] R ^{1 ′} represents optionally substituted C _3-7 cycloalkyl or tert-butyl,
[46] R ^{2 '} represents hydrogen, methyl or ethyl,
[47] R ^{3 '} is NR ^5' R ^{6 '} , C (= O) R ^7' , SO ₂ NR ^{5 '} R ^6' , OR ^{8 '} , NR ^8' CONR ^{5 '} R ^6' , NR ^{8 '} CO ₂ R ^{9 '} , NR ^8' SO ₂ R ^{9 '} , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkenyl or optionally substituted saturated or unsaturated heterocycloalkyl,
[48] R ^{4 ′} represents hydrogen or C _1-3 alkoxy substituted with one or more fluorine atoms as needed,
[49] R ^{5 '} and R ^6' are the same or different and represent a hydrogen atom, optionally substituted C _1-6 alkyl or optionally substituted heterocycloalkyl, or azetidinyl, pyrrolidinyl together with the nitrogen atom to which they are attached; , Piperidinyl, thiomorpholino, piperazinyl or homopiperazinyl, each of said groups being an NR ^{9 '} C (= 0) R ^7' , oxo group or C (= 0) R ^{7 '} Further substituted by
[50] R ^{7 ′} represents hydrogen, optionally substituted C _1-6 alkyl, OH, OR ^{8 ′} or NR ^{5 ′} R ^{6 ′} ,
[51] R ^{8 ′} represents hydrogen, an optionally substituted C _1-6 alkyl group or optionally substituted heterocycloalkyl,
[52] R ^{9 ′} represents an optionally substituted C _1-6 alkyl group.
[53] In the formulas IA 'and IB' of the present invention, optionally substituted C _3-7 cycloalkyl represented as R ^{1 '} include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred examples are C _5-7 cycloalkyl such as cyclopentyl, cyclohexyl and cycloheptyl, particularly preferred examples are cyclohexyl and cycloheptyl.
[54] Examples of R ^{2 '} are hydrogen, methyl and ethyl, and a particularly preferred example is methyl.
[55] Examples of R ^{3 '} are NR ^5' R ^{6 '} , C (= O) R ^7' , SO ₂ NR ^{5 '} R ^6' , OR ^{8 '} , NR ^8' CONR ^{5 '} R ^6' , NR ^{8 '} CO ₂ R ^{9 ′} , NR ^{8 ′} SO ₂ R ^{9 ′} , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkenyl or optionally substituted saturated or unsaturated heterocycloalkyl. Preferred examples are NR ^{5 ′} R ^{6 ′} , SO ₂ NR ^{5 ′} R ^{6 ′} , OR ^{8 ′} , NR ^{8 ′} CONR ^{5 ′} R ^{6 ′} , NR ^{8 ′} SO ₂ R ^{9 ′} , optionally substituted C _1-6 alkyl , Optionally substituted C _1-6 alkenyl and optionally substituted saturated or unsaturated heterocycloalkyl.
[56] Preferred examples of optionally substituted saturated or unsaturated heterocycloalkyl, as R ^{3 ′} , are 4 to 7 membered groups containing 2 to 8 carbon atoms and containing 1 to 4 heteroatoms consisting of oxygen, nitrogen or sulfur atoms. Examples of monocyclic and polycyclic heterocycloalkyl groups, including acyclic saturated or unsaturated heterocycloalkyl groups, and polycyclic saturated or unsaturated heterocycloalkyl groups comprising two or more identical or different monocyclic compounds condensed together include azetidinyl , Pyrrolidinyl, piperidinyl, thiomorpholino, piperazinyl, homopiperazinyl and tetrahydropyridinyl. As A ', N or CR ^4' is mentioned. As a preferable example, CR ^{4 '} can be mentioned.
[57] Preferred examples of B 'are hydrogen or a halogen atom. Halogen atoms refer to fluorine, chlorine, bromine or iodine. Particularly preferred examples of B 'are hydrogen and fluorine.
[58] Preferred examples of R ^{4 '} are hydrogen and C _1-3 alkoxy, such as methoxy, ethoxy or propyloxy, substituted by one or more fluorine atoms as necessary. Particularly preferred examples are methoxy and ethoxy groups.
[59] Preferred examples of R ^{5 '} and R ^6' are the same or different and represent a hydrogen atom, optionally substituted C _1-6 alkyl or optionally substituted heterocycloalkyl, or azetidinyl, together with the nitrogen atom to which they are attached, Groups capable of forming pyrrolidinyl, piperidinyl, thiomorpholino, piperazinyl or homopiperazinyl. The groups may be further substituted with NR ^{9 ′} C (═O) R ^{7 ′} , oxo group or C (═O) R ^{7 ′} . More preferred examples include hydrogen atom, methyl, ethyl or optionally substituted heterocycloalkyl such as piperidinyl or pyrrolidinyl, or together with the nitrogen atom to which they are attached azetidinyl, pyrrolidinyl, piperidinyl, A group forming thiomorpholino, piperazinyl or homopiperazinyl, said groups being further substituted with NR ^{9 '} C (= 0) R ^7' , oxo group or C (= 0) R ^{7 '} .
[60] Examples of R ^{7 '} are hydrogen atoms, optionally substituted linear or branched C _1-6 alkyl, OH, OR ^8' and NR ^{5 '} R ^6' . R ^{5 '} and R ^6' are defined above. Particularly preferred examples are OH and NR ^{5 '} R ^6' .
[61] Examples of R ^{8 ′} include hydrogen, an optionally substituted linear or branched C _1-6 alkyl group, and an optionally substituted heterocycloalkyl. Examples of optionally substituted linear or branched C _1-6 alkyl groups are carboxymethyl groups, cyanomethyl groups and heteroarylmethyl groups. Preferred examples of heterocycloalkyl groups are 4 to 7 membered monocyclic heterocycloalkyl groups having 2 to 8 carbon atoms and containing 1 to 4 heteroatoms consisting of an oxygen atom, a nitrogen atom or a sulfur atom, and two or more identical condensed together Polycyclic saturated or unsaturated heterocycloalkyl groups comprising monocyclic or different monocyclic compounds, examples of monocyclic and polycyclic heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, thiomorpholino, piperazinyl, Homopiperazinyl and tetrahydropyridinyl.
[62] An example of R ^{9 '} is an optionally substituted C _1-6 alkyl group, preferably an optionally substituted C _1-3 alkyl group. Particularly preferred examples are optionally substituted methyl and optionally substituted ethyl.
[63] The compounds of the formulas IA, IB, IA 'and IB' may exist in the form of tautomers and may exist as individual tautomers and as mixtures of individual tautomers.
[64] Also included in the present invention are radiolabeled derivatives of compounds of formulas IA, IB, IA 'and IB'.
[65] The compounds of the present invention also include compounds having from one to a plurality of asymmetric carbon atoms, and there are (R)-and (S) -optical isomers, racemic variants and diastereomers based thereon. In addition, depending on the type of substituent, the compound has a double bond, so geometrical isomers such as (Z) and (E) compounds also exist. The present invention includes the above isomers, either individually or mixed.
[66] Compounds of the present invention include compounds capable of forming salts with acids. Examples of such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, Acid additives using organic acids such as picric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, aspartic acid and glutamic acid.
[67] The compounds of the present invention may also form pharmaceutically acceptable metal salts with metals, in particular alkali metals or alkaline earth metals. Examples of these salts are sodium salts, potassium salts and calcium salts. Compounds of the invention also include solvates and polymorphs with hydrates, ethanol or isopropanol.
[68] Particularly preferred examples of pyrazolopyrimidinone derivatives of the formulas IA, IB, IA 'and IB' according to the invention are as follows: 1-cyclohexyl-3-methyl-5-phenyl-1,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-3-methyl-5- (4-nitrophenyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- (4-aminophenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; N- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) phenyl] acetamide; 1-cyclohexyl-5- (2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-3-methyl-5- (2-pyridinyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-3-methyl-5- [4- (4-methyl-1-piperazinyl) phenyl] -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -On; 1-cyclohexyl-5- (2-methoxy-4-nitrophenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- (4-amino-2-methoxyphenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; N- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxyphenyl Acetamide; 5- (5-amino-2-pyridinyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; N- [6- (1-cyclohexyl-3-methyl-7-oxo-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-pyridinyl] acetamide; 1-cyclohexyl-5- (2-ethoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [4- (4-hydroxy-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-one; 5- (4-bromo-2-methoxyphenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one; 5- (4-chloro-2-pyridinyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- (5-fluoro-2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; Trans-5- (2-methoxyphenyl) -3-methyl-1- (4-methylcyclohexyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one ; Cis-5- (2-methoxyphenyl) -3-methyl-1- (4-methylcyclohexyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one ; Trans-3-methyl-1- (4-methylcyclohexyl) -5- [4- (4-methyl-1-piperazinyl) phenyl] -1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; Cis-3-methyl-1- (4-methylcyclohexyl) -5- [4- (4-methyl-1-piperazinyl) phenyl] -1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; 3-cyclohexyl-1-methyl-6-phenyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- (2-methoxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-1-methyl-6- (2-pyridinyl) -1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 6- (4-bromo-2-methoxyphenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one; 3-cyclohexyl-6- [4- (1,4-dioxa-8-azaspiro [4,5] deca-8-yl) -2-methoxyphenyl] -1-methyl-1,5-di Hydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (4-oxo-1-piperidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one; 3-cyclohexyl-6- [4- (4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (2-methoxyethoxy) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-one; 6- [4- (benzyloxy) -2-methoxyphenyl] -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one ; 3-cyclohexyl-6- (4-hydroxy-2-methoxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [4- (2-hydroxyethoxy) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-one; 3-cyclohexyl-6- {2-methoxy-4-[(3S) -tetrahydro-3-furanyloxy] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; 3-cyclohexyl-6- {2-methoxy-4-[(3R) -tetrahydro-3-furanyloxy] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; Methyl [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenoxy ]acetate; [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenoxy] Acetic acid; 3-cyclohexyl-6- {2-methoxy-4-[(1-methyl-4-piperidinyl) oxy] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; 3-cyclohexyl-6- (2-methoxy-4-nitrophenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 6- (4-amino-2-methoxyphenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl Acetamide; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -2-methoxyacetamide; 3-cyclohexyl-6- [2-methoxy-4- (methylamino) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one ; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzenesulfonyl chloride ; 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (4-morpholinylsulfonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-one; 3-cyclohexyl-6- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; Ethyl 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-meth Oxyphenyl] sulfonyl} -4-piperidinecarboxylate; 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] sulfonyl} -4-piperidinecarboxylic acid; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- [2- (dimethylamino ) Ethyl] -3-methoxybenzenesulfonamide; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy-N- ( 2-methoxyethyl) benzenesulfonamide; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (2-hydroxyethyl ) -3-methoxybenzenesulfonamide; 3-cyclohexyl-6- [2-methoxy-4- (4-morpholinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- 4-on; 3-cyclohexyl-6- [2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- 4-on; 3-cyclohexyl-6- [2-methoxy-4- (4-methoxy-1-piperidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one; 6- (4-bromo-2-methoxyphenyl) -3-cycloheptyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cycloheptyl-6- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzoic acid; 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1-piperazinyl) carbonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (4-morpholinylcarbonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrid Midin-4-one; 3-cyclohexyl-6- {4-[(4-hydroxy-1-piperidinyl) carbonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- {2-methoxy-4-[(4-methoxy-1-piperidinyl) carbonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; {[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzoyl] Amino} acetic acid ethyl ester; {[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzoyl] Amino} acetic acid; 3-cyclohexyl-6- {2-methoxy-4-[(2-methoxyethyl) (methyl) amino] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one; 3-cyclohexyl-6- (5-fluoro-2-methoxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; Ethyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperazinecarboxylate; 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -4-piperazinecarboxylic acid; 3-cycloheptyl-6- [2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- 4-on; Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -2-fluoro -5-methoxyphenyl] -1-piperazinecarboxylate; 3-cyclohexyl-6- [5-fluoro-2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one; 3-cyclohexyl-6- [5-fluoro-2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- (2-methoxy-4- {methyl [2- (methylamino) ethyl] amino} phenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one; 6- (4-bromo-2-ethoxyphenyl) 3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one; Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-ethoxy Phenyl] -4-piperidinyl (methyl) carbamate; 3-cyclohexyl-6- {2-ethoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Phenyl] -4-piperidinyl (methyl) carbamate; 1-cyclohexyl-5- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperidinyl (methyl) carbamate; 3-cycloheptyl-6- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperidinyl (ethyl) carbamate; 3-cyclohexyl-6- {2-methoxy-4- [4- (ethylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Phenyl] -4-piperidinyl (ethyl) carbamate; 1-cyclohexyl-5- {2-methoxy-4- [4- (ethylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 1-cyclohexyl-5- [4- (benzyloxy) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrid Midin-7-one; 1-cyclohexyl-5- (4-hydroxy-2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- (2-methoxy-4- {methyl [2- (methylamino) ethyl] amino} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; 1-cyclohexyl-5- {4-[(3R) -3- (dimethylamino) pyrrolidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one; 1-cyclohexyl-5- {4-[(3S) -3- (dimethylamino) pyrrolidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one; 5- {4-[(2- (benzyloxy) ethyl] (methyl) amino] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one; 1-cyclohexyl-5- {4-[(2-hydroxyethyl) (methyl) amino] -2-methoxyphenyl} -3-methyl-1,6 -Dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- (4- {4-[(benzyloxy) methyl] -1-piperidinyl} -2-methoxyphenyl ) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- {4- [4- ( Hydroxymethyl) -1-piperidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1- Cyclohexyl-5- (2-methoxy-4- {methyl [3- (methylamino) propyl] amino} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -3-methyl-1,6- Dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- {4-[[2- (benzyloxy) ethyl] (ethyl) amino] -2-methoxyphenyl} -1 -Cyclohex -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- {4-[(2-hydroxyethyl) (ethyl ) Amino] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- (4-bromo-2- Ethoxyphenyl-1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-cyclohexyl-6- {2-ethoxy -4-[(2-methoxyethyl) amino] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxyphenyl] -4-pipe Ridinyl (methyl) formamide; N- {1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1 H-pyrazolo [4,3-d] pyrimidine -5-yl) -3-methoxyphenyl] -4-piperidinyl} -N-methylacetamide; benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7- Dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-ethoxyphenyl] -4-piperidinyl (methyl) carbamate; 1-cyclohexyl-5- {2-ethoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 1-cyclohexyl-5- [4- (4-hydroxy-1-methyl-4-piperidinyl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (1-methyl-1,2,3,6-tetrahydro-4-pyridinyl) phenyl] -3-methyl-1,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (1-methyl-4-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one; 1-cyclohexyl-5- [4- (1,4-diazepane-1-yl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one; 5- [4- (4-acetyl-1,4-diazepan-1-yl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [4- (4-ethyl-1,4-diazepan-1-yl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -2-fluoro -5-methoxyphenyl] -4-piperidinyl (methyl) carbamate; 1-cyclohexyl-5- {5-fluoro-2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H- Pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [4- (4-methyl-1,4-diazepan-1-yl) -2-ethoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; 3-cyclohexyl-6- {4-[[2- (dimethylamino) ethyl] (methyl) amino] -2-methoxyphenyl} -1-methyl- 1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [4- (1,4-diazepane-1-yl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 6- [4-bromo-2- (difluoromethoxy) phenyl] -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine-4 -On; 3-cyclohexyl-6- [2- (difluoromethoxy) -4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] Urea; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -N- (methylsulfonyl) methanesulfonamide; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] Methanesulfonamide; 3-cyclohexyl-6- [2-methoxy-4- (2-oxo-1,3-oxazolidin-3-yl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (2-oxo-1-imidazolidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one; Ethyl 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenylcarba Mate; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -N-methylacetamide; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -N-methylmethanesulfonamide; N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -N-morpholinecarboxamide; 3-cyclohexyl-6- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; N '-[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -N- (2-hydroxyethyl) -N-methylurea; 3-cyclohexyl-6- [2-methoxy-4- (3-methyl-2-oxo-1-imidazolidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- {4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; 3-cyclohexyl-6- [4- (1,1-dioxido-2-isothiazolidinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (2-hydroxyethyl ) -3-methoxy] -N-methylbenzenesulfonamide; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- [2- (dimethylamino ) Ethyl] -3-methoxy-N-methylbenzenesulfonamide; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (3-hydroxypropyl ) -3-methoxybenzenesulfonamide; 3-cyclohexyl-6- [4- (1,4-diazepane-1-ylsulfonyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one; 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H -Pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- {4-[(3-hydroxy-1-pyrrolidinyl) sulfonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (4-thiomorpholinylsulfonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrid Midin-4-one; 3-cyclohexyl-6- [4- (1,4-dioxa-8-azaspiro [4. 5] deca-8-ylsulfonyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- {2-methoxy-4-[(4-oxo-1-piperidinyl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one; 3-cyclohexyl-6- (2-methoxy-4-{[4- (methylamino) -1-piperidinyl] sulfonyl} phenyl) -1-methyl-1,5-dihydro-4H-pyra Zolo [3,4-d] pyrimidin-4-one; Benzyl 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-meth Methoxyphenyl] sulfonyl} -3-pyrrolidinylcarbamate; 6- {4-[(3-amino-1-pyrrolidinyl) sulfonyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one; Benzyl 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-meth Oxyphenyl] sulfonyl} -4-piperidinylcarbamate; 6- {4-[(4-amino-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one; 3-cyclohexyl-6- [2-methoxy-4- (4-thiomorpholinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-one; 6- (4-bromophenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-1-methyl-6- [4- (4-methyl-1-piperazinyl) phenyl] -1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine-4 -On; 6- (4-aminophenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) benzenesulfonyl chloride; 3-cyclohexyl-6- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one; 6- {4- [4- (benzylamino) -1-piperidinyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; 6- [4- (4-amino-1-piperidinyl) -2-methoxyphenyl] -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one; 3-cyclohexyl-1-methyl-6- {4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one; Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) phenyl] -4- Piperidinyl (methyl) carbamate; 3-cyclohexyl-1-methyl-6- {4- [4- (methylamino) -1-piperidinyl] phenyl} -1,5-dihydro-4H-pyrazolo [3,4-d] pyrid Midin-4-one; 3-cyclohexyl-6- [4- (1,4-diazepane-1-ylsulfonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-one; 3-cyclohexyl-6- {4-[(1,1-dioxido-4-thiomorpholinyl) sulfonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H -Pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [4- (1,1-dioxido-4-thiomorpholinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 6- (4-bromo-2-methoxyphenyl) -3-cyclohexyl-1-ethyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-1-ethyl-6- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one; Benzyl 1- [4- (3-cyclohexyl-1-ethyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperidinyl (methyl) carbamate; 3-cyclohexyl-1-ethyl-6- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [3,4-d] pyrimidin-5-yl) -3-methoxybenzenesulfonyl chloride ; 1-cyclohexyl-5- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- (2-hydroxyethyl ) -3-methoxybenzenesulfonamide; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N-methyl Benzenesulfonamide; 1-cyclohexyl-5- [4- (1,4-diazepane-1-ylsulfonyl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy-N-methyl Benzenesulfonamide; 6- (4-amino-2-methoxyphenyl) -3-cyclohexyl-1-ethyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 4- (3-cyclohexyl-1-ethyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzenesulfonyl chloride ; 3-cyclohexyl-1-ethyl-6- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one; 3-cyclohexyl-1-ethyl-6- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1,5-dihydro-4H -Pyrazolo [3,4-d] pyrimidin-4-one; 3-cyclohexyl-6- [4- (1,4-diazepane-1-ylsulfonyl] -2-methoxyphenyl] -1-ethyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one; N- (2-aminoethyl) -4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1 H-pyrazolo [4,3 -d] pyrimidin-5-yl) -3-methoxy-N-methylbenzenesulfonamide; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N- [2- (methylamino) ethyl] benzenesulfonamide; 4- (1-cyclohexyl-3-methyl-7-oxo -6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (dimethylamino) ethyl] -3-methoxybenzenesulfonamide; 4- ( 1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N-methyl- [2 -(Methylamino) ethyl] benzenesulfonamide; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidine-5- Yl) -N- (2-hydroxyethyl) -3-methoxy-N-methylbenzenesulfonamide; 1-cyclohexyl-5- {2-methoxy -4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N-methyl -N- [3- (methylamino) propyl] benzenesulfonamide; 1-cyclohexyl-5- (4-{[4- (2-hydroxyethyl) -1-piperazinyl] sulfonyl} -2- Methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- ( 1-piperazinylsulfonyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- {4- [(4-ethyl-1-piperazinyl) sulfonyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- On; N- (1-benzyl-4-piperidinyl) -4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1 H-pyrazolo [4,3-d] Pyrimidin-5-yl) -3-methoxybenzenesulfonamide; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N- ( 4-piperidinyl) benzenesulfonamide; Benzyl 1-{[4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-meth Methoxyphenyl] sulfonyl} -4-piperidinyl (methyl) carbamate; 1-cyclohexyl-5- (2-methoxy-4-{[4- (methylamino) -1-piperidinyl] sulfonyl} phenyl) -3-methyl-1,6-dihydro-7H-pyra Zolo [4,3-d] pyrimidin-7-one; 5- {4-[(1-benzyl-4-piperidinyl) amino] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (4-piperidinylamino) phenyl] -3-methyl-1,6-dihydro-7H- Pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-4- {2-methoxy-4-[(2-methoxyethyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one; Methyl (2E) -3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1 H-pyrazolo [4,3-d] pyrimidin-5-yl)- 3-methoxyphenyl] -2-propenate; (2E) -3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3 -Methoxyphenyl] -2-propenic acid; Methyl 3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Phenyl] propanoate; 3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxyphenyl Propanoic acid; 1-cyclohexyl-5- (4-{[2- (dimethylamino) ethyl] amino} -2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one; 5- {4-[(1-acetyl-4-piperidinyl) amino] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 1-cyclohexyl-5- {2-methoxy-4-[(1-methyl-4-piperidinyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxybenzaldehyde; 1-cyclohexyl-5- {2-methoxy-4-[(4-methyl-1-piperazinyl) methyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (4-morpholinylmethyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine -7-one; 1-cyclohexyl-5- {4-[(4-hydroxy-1-piperidinyl) methyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one; 1-cyclohexyl-5- (2-methoxy-4-{[(2-methoxyethyl) amino] methyl} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; Ethyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Benzyl] -4-piperidinecarboxylate; 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxybenzyl ] -4-piperidinecarboxylic acid; Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Benzyl] -4-piperidinyl (methyl) carbamate; 1-cyclohexyl-5- (2-methoxy-4-{[4- (methylamino) -1-piperidinyl] methyl} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (tetrahydro-2H-pyran-4-ylamino) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; 1-cyclohexyl-5- [4- (1,4-dioxa-8-azaspiro [4. 5] deca-8-yl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (4-oxo-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one; 1-cyclohexyl-5- {4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 5- {4- [4- (benzylamino) -1-piperidinyl] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 5- [4- (4-amino-1-piperidinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one; 1-cyclohexyl-5- [4- (1,4-dioxa-8-azaspiro [4. 5] deca-8-yl) -2-ethoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl- 5- [2-ethoxy-4- (4-oxo-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -On; 1-cyclohexyl-5- {4- [4- (dimethylamine) -1-piperidinyl] -2-ethoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 5- {4- [4- (benzylamino) -1-piperidinyl] -2-ethoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-ethoxy Phenyl] -4-piperidinyl (ethyl) carbamate; 1-cyclohexyl-5- {2-ethoxy-4- [4- (ethylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one; 5- (4-amino-2-ethoxyphenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-ethoxybenzenesulfonyl chloride ; 1-cyclohexyl-4- {2-ethoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- {2-ethoxy-4-[(4-hydroxy-1-piperidinyl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [4-[(4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; (2E) -3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3 -Methoxyphenyl] -2-propenitrile; 5- [4- (4-amino-1-piperidinyl) -2-ethoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one; 1-cyclohexyl-5- [2-ethoxy-4- (4-hydroxy-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one; 1-cyclohexyl-5- [4- (1,4-diazepane-1-yl) -2-ethoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one; 1-cyclohexyl-5- {2-ethoxy-4-[(2-methoxyethyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one; 1-cyclohexyl-5- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one; Benzyl 4- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -2-fluoro -5-methoxyphenyl] -1,4-diazepane-1-carboxylate; 1-cyclohexyl-5- [4- (1,4-diazepane-1-yl) -5-fluoro-2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- {2-methoxy-4- [methyl (1-methyl-piperidinyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; 1-cyclohexyl-5- [2-ethoxy-4- (1-piperazinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-one; 5- [4-((3R) -3-{[tert-butyl (dimethyl) silyl] oxy} pyrrolidinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-di Hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- {4-[(3R) -3-hydroxypyrrolidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one; 5- [4- (1-benzyl-4-hydroxy-4-piperidinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; 5- [4- (1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one; 1-cyclohexyl-5- [2-methoxy-4- (1,2,3,6-tetrahydro-4-pyridinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one monohydrochloride; 1-cyclohexyl-5- {2-methoxy-4- [methyl (tetrahydro-2H-pyran-4-yl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one; And 1-cyclohexyl-5- [4- (ethylamino) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7- On.
[69] The compounds of the formula (IA) according to the invention can be synthesized for example by the method shown below.
[70]
[71] Wherein A, B, R ¹ , R ² and R ³ are as defined above, L is a C _1-3 lower alkyl group, Y represents a hydroxyl group or a halogen atom, preferably a chlorine atom.
[72] To carry out the above process, compound (IX) is obtained from compound (X) according to a known method. Depending on the reaction, an aqueous solution of an inorganic acid such as hydrochloric acid or sulfuric acid, an aromatic hydrocarbon such as benzene or toluene, an organic acid such as acetic acid, an alcohol such as methanol or ethanol, or a mixture of these substances, or in the absence of a solvent, from room temperature to 120 At a temperature below < RTI ID = 0.0 > C, < / RTI > compound (XI) is reacted with compound (X) in an amount of 1 to 2 equivalents, preferably about 1 equivalent, to compound (X). After the reaction is completed, an aqueous solution of an inorganic base such as sodium hydroxide is added, and the mixture is extracted with an organic solvent which is incompatible with water. The whole organics are washed sequentially with water and saturated aqueous sodium chloride solution, and then the solvent is distilled off to give the desired compound (IX). If necessary, the product can be purified, for example by recrystallization. As the compound (X) which is a starting material, a commercially known or known compound can be used. The compound (XI) used in the above reaction may be a commercially known or known compound, but it is possible to use a compound which is easily synthesized by a known method (for example, J. Org. Chem., 1981, 46 , 5414-5415].
[73] From compound (IX), compound (VIII) can be obtained according to a known method. For compound (IX), 1 to 5 equivalents of halogenating reagent, such as phosphorus oxychloride or thionyl chloride, is added to compound (IX) at room temperature to reflux in an aromatic hydrocarbon such as toluene or benzene, or in the absence of a solvent. To work. After completion of the reaction, the solvent can be distilled off to obtain the target compound (VIII).
[74] From the resulting compound (VIII) it is possible to obtain compound (VII) according to known methods without purification. Nitric acid is used in concentrated sulfuric acid or acetic anhydride at -20 ° C to room temperature. After completion of the reaction, the reaction mixture is poured onto ice and the precipitated solid is collected by filtration to obtain the target compound (VII). If necessary, the compound can be purified by recrystallization or the like.
[75] From compound (VII), compound (VI) can be obtained according to a known method. Metal cyanide such as potassium cyanide or sodium cyanide is used in an amount of 1 to 3 equivalents in a polar solvent such as N, N-dimethylformamide at a temperature from room temperature to 120 ° C. After the reaction is completed, water is added and the mixture is extracted with an organic solvent which is immiscible with water. The whole extract is then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (VI). If necessary, the compound may be purified, that is to say by column chromatography.
[76] According to known methods, compound (V) can be obtained from compound (VI). This reaction is a method of synthesizing acid amides by hydrolysis of nitrile groups, and many methods are available for this purpose. For example, in the presence of a base such as sodium hydroxide or potassium carbonate, water, alcohol such as methanol or ethanol, ether such as 1,4-dioxane or tetrahydrofuran, or a mixture of these substances, from 0 ° C. to room temperature In, let hydrogen peroxide act. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (V). If necessary, the compound can be purified, that is, by recrystallization.
[77] According to known methods, compound (III) can be obtained from compound (V). This reaction is a method of converting a nitro group to an amino group by a reduction reaction, and many methods are available for this purpose. For example, in an inorganic acid such as hydrochloric acid, tin dichloride in an amount of 2 to 10 equivalents to compound (V) is allowed to act on compound (V) at 0 ° C. to reflux temperature. After completion of the reaction, the reaction mixture is neutralized with an inorganic base such as sodium hydroxide and filtered through Celite. The filtrate is then extracted with an organic solvent that is immiscible with water. The extracted organic solvent layer is washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (III). If necessary, the compound can be purified, for example, by column chromatography.
[78] According to known methods, compound (II) can be obtained from compound (III). This reaction is a method for synthesizing acid amides from amine compound (III) and carboxylic acid component (IV), and many methods are available for this purpose. For example, when Y is a halogen atom (preferably a chlorine atom), 1 to 5 equivalents to compound (III), preferably using a catalyst, for example 4-dimethylaminopyridine, if necessary 1 to 1.5 equivalents, preferably 1.2 equivalents to compound (III) in the presence of 2.5 equivalents of tertiary amine, for example triethylamine, in an inert solvent such as dichloromethane at 0 ° C. to room temperature Compound (IV) is used in an amount. If Y is a hydroxyl group, 1 to 1.5 equivalents, preferably 1.2 equivalents of condensing agent, for example 1-ethyl, relative to compound (III) using a catalyst, for example 4-dimethylaminopyridine, if necessary 1 to 1.5 equivalents, preferably 1.2 to compound (III) in the presence of -3- (3-dimethylaminopropyl) carbodiimide hydrochloride at 0 ° C. to room temperature in an inert solvent such as dichloromethane The reaction is carried out using compound (IV) in an amount equivalent. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (II). If necessary, the compound can be purified, for example, by column chromatography.
[79] Known cyclization methods in connection with the formation of pyrimidine rings can be used to obtain compound (IA) from compound (II) (see, eg, Bioorg. Med. Chem. Lett., 6, 1996, 1819-1824]. For example, the cyclization can be carried out by reacting the compound (II) in a ethanol-water solvent at room temperature to reflux using a base such as sodium hydroxide or potassium carbonate in the presence of hydrogen peroxide as needed. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (IA). If necessary, the compound can be purified, for example, by column chromatography or recrystallization.
[80] As an alternative method of synthesizing compound (IA), the compound may be synthesized by, for example, the method shown below.
[81]
[82] In the formula, A, B, R ¹ , R ² and R ³ are as defined above, and Y represents a hydroxyl group or a halogen atom, preferably a chlorine atom.
[83] According to known methods, compound (XIII) can be obtained from compound (VI). This reaction is a method of converting a nitro group to an amino group by a reduction reaction, and many methods are available for this purpose. For example, in an inorganic acid such as hydrochloric acid, tin dichloride acts on compound (VI) in an amount of 2 to 10 equivalents to compound (VI) at 0 ° C. to reflux temperature. After completion of the reaction, the reaction mixture is neutralized with an inorganic base such as sodium hydroxide and filtered through celite. The filtrate is then extracted with an organic solvent that is immiscible with water. The extracted organic solvent is washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (XIII). If necessary, the compound can be purified, for example, by column chromatography.
[84] According to known methods, compound (XII) can be obtained from compound (XIII). This reaction is a method for synthesizing acid amides from amine compound (XIII) and carboxylic acid component (IV), and many methods are available for this purpose. For example, when Y is a halogen atom (preferably a chlorine atom), 1 to 5 equivalents to compound (XIII), preferably using a catalyst, for example 4-dimethylaminopyridine, if necessary 1 to 1.5 equivalents, preferably 1.2 equivalents to compound (XIII) in the presence of 2.5 equivalents of tertiary amine, for example triethylamine, in an inert solvent such as dichloromethane at 0 ° C. to room temperature Compound (IV) is used in an amount. Pyridine can be used instead of tertiary amine as solvent. If Y is a hydroxyl group, 1 to 1.5 equivalents, preferably 1.2 equivalents of condensing agent, for example 1-ethyl, relative to compound (XIII), using a catalyst, for example 4-dimethylaminopyridine, if necessary 1 to 1.5 equivalents, preferably 1.2 to compound (XIII) in the presence of -3- (3-dimethylaminopropyl) carbodiimide hydrochloride at 0 ° C to room temperature in an inert solvent such as dichloromethane The reaction is carried out using compound (IV) in an amount equivalent. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (XII). If necessary, the compound can be purified, for example, by column chromatography.
[85] Known cyclization methods in connection with the formation of pyrimidine rings can be used to obtain compound (IA) from compound (XII) (see, eg, J. Med. Chem., 30, 1987, 91- 96]). For example, cyclization may be performed using a base such as sodium hydroxide or potassium carbonate, water, or an alcohol, such as ethanol, an ether, such as 1,4-dioxane, or a solvent of the solvents, in the presence of hydrogen peroxide as needed. In the mixture, it may be carried out by reacting the compound (XII) at room temperature to reflux temperature. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (IA). If necessary, the compound can be purified, for example, by column chromatography or recrystallization.
[86] The reactions described above are all completely generic and reagents and conditions suitable for carrying out the reaction can be established immediately, with reference to standard textbooks and the examples described later. Alternative and modified methods by which all compounds defined with respect to compound (IA) can be made are apparent to those skilled in the art.
[87] Compounds of formula (IB) according to the invention can be synthesized by the methods given below:
[88]
[89] In the formula, A, B, R ¹ , R ² and R ³ are as defined above, and Y represents a hydroxyl group or a halogen atom, preferably a chlorine atom.
[90] In order to carry out this method, it is possible to obtain compound (XIX) from compound (XX) according to known methods (for example, J. Chem. Soc., Perkin Trans. 1, 1996, 1545-1552). ). Halogenated hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene or benzene, ethers such as diethyl ether or tetrahydrofuran, or mixtures of these substances, for example, from 2 to 2.5 equivalents of alkali metal hydrides relative to compound (XX), such as In the presence of sodium hydride or potassium hydride or the same amount of a tertiary amine such as triethylamine, compounds (XXI) are allowed to act in an amount of 1 to 1.5 equivalents to compound (XX) at 0 ° C. to room temperature. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (XIX). If necessary, the product can be purified, for example, by column chromatography.
[91] According to known methods, the compound (XVIII) can be obtained from the resultant compound (XIX) (eg, J. Chem. Soc., Perkin Trans. 1, 1996, 1545-1552). Methylation reagent in an amount of 5 to 10 equivalents relative to compound (XIX) at room temperature to reflux in an aromatic hydrocarbon such as toluene or benzene, ether such as tetrahydrofuran or 1,4-dioxane, or a mixture of the above materials For example, dimethyl sulfuric acid is used. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (XVIII). If necessary, the product can be purified, for example, by column chromatography.
[92] According to known methods, the compound (XVI) can be obtained from the resultant compound (XVIII) (for example, J. Chem. Soc., Perkin Trans. 1, 1996, 1545-1552). Compound (XVII) in an amount of 1 to 1.5 equivalents relative to compound (XVIII) at room temperature to reflux in an alcohol such as ethanol, ether such as tetrahydrofuran or 1,4-dioxane, or a mixture of these materials use. After completion of the reaction, the solvent can be distilled off to obtain the target compound (XVI). If necessary, the product can be purified, for example, by column chromatography.
[93] According to known methods, compound (XV) can be obtained from compound (XVI). This reaction is a method of synthesizing acid amides by hydrolysis of nitrile groups, and many methods are available for this purpose. For example, water, alcohols such as ethanol or methanol, ethers such as diethyl ether, tetrahydrofuran or dioxane, or mixtures of these materials, at room temperature to 100 ° C., allow a catalyst such as sulfuric acid or hydrochloric acid to function. . After completion of the reaction, the reaction mixture is made slightly alkaline and diluted with an organic solvent which is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (XV). If necessary, the compound can be purified, that is, by recrystallization.
[94] According to known methods, compound (XIV) can be obtained from compound (XV). Generally, when Y is a halogen atom (preferably a chlorine atom), 1 to 5 equivalents, preferably about about, to compound (XV), using a catalyst, for example 4-dimethylaminopyridine, if necessary 1-2 equivalents, preferably about 1.4 equivalents, to compound (XV) in the presence of 2.5 equivalents of tertiary amine, for example triethylamine, at 0 ° C. to room temperature in an inert solvent such as dichloromethane. Compound (IV) is used in the amount of. Pyridine can be used instead of tertiary amine as solvent. If Y is a hydroxyl group, 1 to 1.5 equivalents, preferably about 1.2 equivalents of condensing agent, such as 1-, to compound (XV), if necessary, using a catalyst, for example 4-dimethylaminopyridine, as necessary 1 to 1.5 equivalents, preferably, to compound (XV) in the presence of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at 0 ° C. to room temperature in an inert solvent such as dichloromethane The reaction is carried out using compound (IV) in an amount of about 1.2 equivalents. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (XIV).
[95] The resulting compound (XIV) is used without purification and compounds (IB) can be obtained using known cyclization methods in connection with the formation of pyrimidine rings (for example, [J. Med. Chem] 39, 1996, 1635-1644]. Thus, cyclization can be carried out by reacting the compound (XIV) at reflux temperature in an ethanol-water solvent using a base such as sodium hydroxide or potassium carbonate in the presence of hydrogen peroxide, if necessary. After completion of the reaction, the reaction mixture is diluted with an organic solvent that is immiscible with water. The dilutions are then washed sequentially with water and saturated aqueous sodium chloride solution. The solvent can be distilled off to obtain the target compound (IB). If necessary, the compound can be purified, for example, by column chromatography or recrystallization.
[96] The reactions described above are all completely generic and reagents and conditions suitable for carrying out the reaction can be established immediately by reference to standard textbooks and the examples described below. Alternative and modified methods by which all compounds defined with respect to compound (IB) can be made are apparent to those skilled in the art.
[97] The invention will be described in more detail with reference to the following test examples, examples and preparation examples.
[98] The synthesis of the compounds of the present invention and intermediates for use therein will be explained in detail by the examples and preparations described below. The chemical structures and confirmatory data for the compounds of the invention and intermediates thereof provided in the examples and preparations are listed in the tables presented after the examples. In the tables, each compound of Examples and Preparation Examples is described as the corresponding Example Number and Preparation Example Number.
[99] It goes without saying that the scope of the present invention is not limited by these test examples, examples and preparation examples.
[100] [Test Example]
[101] The inhibitory activity against PDE7 (type phosphodiesterase) of the compounds of the present invention prepared in the following Preparation Examples and Examples was confirmed by the following Test Examples.
[102] Test Example 1 Method for Measuring PDE7 Inhibitory Activity
[103] To evaluate the inhibitory ability of PDE7 (type phosphodiesterase) of the compounds of the present invention, Biochemical Pharmacol. 48 (6), 1219-1223 (1994), partially modified, to carry out the following analysis:
[104] 1) PDE7 (type VII phosphodiesterase) active fractions were obtained. That is, human acute lymphoblastic lymphoma T cell strain MOLT-4 (commercially available from ATCC as ATCC No. CRL-1582) was cultured in RPMI1640 medium containing 10% fetal bovine serum to obtain 5 × 10 ⁸ MOLT cells. The cells were recovered by centrifugation and 10 ml of Buffer A (25 mM Tris-HCl, 5 mM 2-mercaptoethanol, 2 mM benzamidine, 2 mM EDTA, 0.1 mM 4- (2-aminoethyl) benzene Sulfonyl hydrochloride, pH 7 = 7.5). The cells were homogenized in a Polytoron homogenizer and centrifuged (4 ° C., 25,000 G, 10 minutes). The supernatant was further ultracentrifuged (4 ° C., 100,000 G, 60 min) and the resulting supernatant was filtered through a 0.2 μm filter to give a soluble fraction.
[105] 2) The resulting soluble fraction was charged to a HiTrapQ column (5 mL × 2) equilibrated with Buffer A. The phosphodiesterase was eluted with 300 ml of Buffer A containing a linear gradient solution of 0-0.8 M sodium chloride to collect 60 5 ml fractions. Each fraction was tested for cAMP metabolic phosphodiesterase activity. In each fraction, it has the activity of cAMP metabolism, whose metabolic activity is 10 μM of Lolliram (selective inhibitor of type IV phosphodiesterase) or 10 μM of milrinone (selection of type III phosphodiesterase) Fractions that were not lost by the inhibitor) were selected. Of these selected fractions, the fractions eluted primarily as activity peaks around 350 mM sodium chloride were combined and used as stocks to test PDE7 inhibitory activity.
[106] 3) Test compound of desired concentration was added to 20 mM Tris-HCl (pH 7.5), 1 mM MgCl ₂ , 100 μM EDTA, 330 μg / ml bovine serum albumin, 4 μg / ml 5′-nucleotidase, 0.1 The reaction mixture was reacted at 25 ° C. for 2 hours in a reaction mixture containing μCi ³ H-cAMP (0.064 μM cAMP), 10 μM rollipram, and the VII phosphodiesterase stock solution. QAE-Sepadex suspended in 10 mM HEPES-Na (pH 7.0) was added to the reaction mixture and the mixture was left for 5 minutes. The supernatant was then recovered and further QAE-Sepadex was added before the mixture was left for 5 minutes. The resulting supernatant was then measured for radioactivity.
[107] 4) IC ₅₀ , the concentration of the test compound that inhibited 50% of the metabolic activity of PDE7, was calculated for each compound.
[108] PDE7 Inhibitory Activity for Each Compound
[109] The following is the example number of the compound having an IC ₅₀ value of 1 μM or less for phosphodiesterase inhibitory activity measured by the above method:
[110]
[111] Of these compounds, compounds having the following Example numbers exhibited IC ₅₀ values of 0.01 μM or less:
[112]
[113] The phosphodiesterase inhibitory activity test confirmed that the pyrazolopyrimidinone derivative of the present invention showed a very satisfactory PDE7 inhibitory effect.
[114] Compounds of the invention are selective inhibitors for PDE7 and have exhibited at least 10-fold selectivity for other phosphodiesterase isoenzymes. From these findings, few side effects from other isoenzymes are expected.
[115] By way of example, the inhibitory activity of PDE4 (type IV phosphodiesterase) of the compounds of the present invention was confirmed by the following test.
[116] Test Example 2 Method for Measuring PDE4 Inhibitory Activity
[117] To evaluate the PDE4 inhibitory ability of the compounds of the invention that inhibit PDE7, Biochemical Pharmacol. 48 (6), 1219-1223 (1994), partially modified, to carry out the following analysis:
[118] 1) PDE4 active fractions were obtained. That is, livers obtained from three Balb / c mice (female, 12 weeks old) (available from CLEA JAPAN) were treated with 30 ml of buffer B (20 mM bis-tris, 5 mM 2-mercaptoethanol, 2 mM). Benzamidine, 2 mM EDTA, 0.1 mM 4- (2-aminoethyl) benzenesulfonyl hydrochloride, 50 mM sodium acetate, pH = 6.5). The liver was homogenized in a Polytoron homogenizer and centrifuged (4 ° C., 25,000 G, 10 minutes). The supernatant was then further ultracentrifuged (4 ° C., 100,000 G, 60 min) and the resulting supernatant was filtered through a 0.2 μm filter to give a soluble fraction.
[119] 2) The resulting soluble fraction was charged to a 1 × 10 cm DEAE Sepharose column equilibrated with Buffer B. Twenty four 5 ml fractions were collected by eluting phosphodiesterase using 120 ml Buffer B containing a linear gradient solution of 0.05-1 M sodium acetate. Each fraction was tested for cAMP metabolic phosphodiesterase activity. Of each fraction, fractions were selected that had the activity of cAMP metabolism and whose metabolic activity was lost by 30 μM of rolliram (selective inhibitor of PDE4). Of these selected fractions, the eluted fractions were mainly combined as activity peaks near 620 mM sodium acetate and used as stocks to test PDE4 inhibitory activity.
[120] 3) Test compound of desired concentration was added to 20 mM Tris-HCl (pH 7.5), 1 mM MgCl ₂ , 100 μM EDTA, 330 μg / ml bovine serum albumin, 4 μg / ml 5′-nucleotidase, 0.1 In the reactant mixture containing μCi ³ H-cAMP (0.064 μM cAMP) and the PDE4 stock solution, each reaction was carried out at 25 ° C. for 2 hours. QAE-Sepadex suspended in 10 mM HEPES-Na (pH 7.0) was added to the reaction mixture and the mixture was left for 5 minutes. The supernatant was then recovered and further QAE-Sepadex was added before the mixture was left for 5 minutes. The resulting supernatant was then measured for radioactivity.
[121] 4) IC ₅₀ , the concentration of the test compound that inhibited 50% of the metabolic activity of PDE4, was calculated for each compound.
[122] The test indicated that the IC ₅₀ values of the compounds of the present invention for PDE4 are at least 10 times weaker than the inhibitory activity of the same compounds for PDE7.
[123] Compounds of the invention selectively inhibit PDE7, increase intracellular cAMP levels, and also inhibit T cell activation. Thus, the compounds are useful for various allergic diseases and inflammatory or immune diseases. That is, they are bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn It is useful as an agent for the prophylaxis or treatment of diseases such as disease, transplant rejection, GVH disease, and restenosis after angioplasty.
[124] In order to use the active ingredient of the present invention as a pharmaceutical composition or a PDE7 inhibitor, it is recommended to prepare a composition containing at least one compound of the present invention and process them according to conventional methods into dosage forms suitable for the mode of administration. For example, for oral administration, dosage forms such as capsules, tablets, granules, fine granules, syrups and dry syrups are exemplified. For parenteral administration, not only injections, but also transnasal preparations such as vaginal suppositories, sprays, and percutaneously absorbable preparations such as ointments, transdermal absorbent tapes are exemplified.
[125] The dosage of a compound of the invention for clinical use depends on the condition of the patient to be administered, the severity of the disease, the age of the patient and the presence of complications. The dosage also depends on the type of formulation. For oral administration, the compound as an active ingredient may be administered in daily dosages of usually 0.1 to 1,000 mg, preferably 0.1 to 500 mg, more preferably 1 to 100 mg for adults. For parenteral administration, the dosage may be 1/10 to 1/2 times the oral dosage. The dosage may be increased or decreased if necessary, depending on the age and symptoms of the patient.
[126] In addition, the compounds of the present invention are expected to have low toxicity and high stability.
[127] EXAMPLES AND PREPARATION EXAMPLES
[128] The synthesis of the compounds of the invention and intermediates for use therein will be explained by the examples and preparations which will be described later. In the following examples and preparations, the chemical structures and confirmatory data of the compounds will be summarized in the tables presented below. In the table, the compounds of Examples and Preparations are listed as Example Numbers and Preparation Numbers.
[129] Preparation Example 1
[130] 2-cyclohexyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one
[131] A mixture of 14.5 ml (0.134 mol) of methyl acetoacetate and 20.2 g (0.134 mol) of cyclohexylhydrazine hydrochloride was stirred at 120 ° C. for 2 hours and then cooled. The reaction mixture was neutralized with 30 mL of 4M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. Hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 19.0 g (79%) of the title compound.
[132] Preparation Example 2
[133] 5-chloro-1-cyclohexyl-3-methyl-4-nitro-1H-pyrazole
[134] To 9.3 g (51.6 mmol) of the compound obtained in Preparation Example 1, 10 mL (107 mmol) of phosphorus oxychloride was added, and the mixture was stirred at 120 ° C for 10 hours. The reaction mixture was then allowed to come to room temperature and the excess phosphorus oxychloride was distilled off under reduced pressure. The residue was dissolved by adding 45 ml of acetic anhydride, and 9 ml of fuming nitric acid was slowly added dropwise to the solution under ice cooling. After stirring the mixture for 2 hours at the same temperature, the reaction mixture was poured onto ice and the solids were collected by filtration. The solid was dissolved in dichloromethane and the solution was washed with aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution. The washed solution was then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane for purification (hexane) to give 6.28 g (50%) of the title compound. The filtrate was also distilled under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 4.21 g (33%) of the title compound.
[135] Preparation Example 3
[136] 1-cyclohexyl-3-methyl-4-nitro-1H-pyrazole-5-carbonitrile
[137] To 10.3 g (42.4 mmol) of 90 mL N, N-dimethylformamide solution obtained in Preparation Example 2, after addition of 4.2 g (84.9 mmol) of sodium cyanide, the mixture was stirred at 80 ° C. for 1.5 hours. did. The reaction mixture was then brought to room temperature, water was added thereto, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed solution was then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 9.18 g (93%) of the title compound.
[138] Preparation Example 4
[139] 4-amino-1-cyclohexyl-3-methyl-1H-pyrazole-5-carbonitrile
[140] To a mixed suspension in 1.0 g (4.27 mmol) of 10 ml methanol and 10 ml concentrated hydrochloric acid obtained in Preparation Example 3, 1.2 g (21.4 mmol) of iron powder was added, and then the mixture was heated under reflux for 2 hours. did. The reaction mixture was then allowed to come to room temperature, neutralized with an aqueous solution of sodium hydrogen carbonate and then filtered through celite. The filtrate was extracted with dichloromethane and the organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7/1) to give 0.75 g (87%) of the title compound.
[141] Preparation Example 5
[142] 1-cyclohexyl-3-methyl-4-nitro-1H-pyrazole-5-carboxamide
[143] To a 25 ml methanol solution of 9.0 g (38.5 mmol) of the compound obtained in Preparation Example 3, 12 ml of 30% aqueous hydrogen peroxide solution and 30 ml of 3M sodium hydroxide aqueous solution were added, and then the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure to obtain 7.8 g (80%) of the title compound.
[144] Preparation Example 6
[145] 4-amino-1-cyclohexyl-3-methyl-1H-pyrazole-5-carboxamide
[146] To a suspension of 7.7 g (30.6 mmol) of 180 mL concentrated hydrochloric acid obtained in Preparation Example 5, 27.6 g (122 mmol) of tin dichloride dihydrate was added and the mixture was stirred at 80 ° C. for 1.5 hours. The reaction mixture was then allowed to come to room temperature, neutralized with aqueous sodium hydroxide solution and then filtered through celite. The filtrate was extracted with dichloromethane and the organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 6.05 g (89%) of the title compound.
[147] Preparation Example 7
[148] N- (5-cyano-1-cyclohexyl-3-methyl-1H-pyrazol-4-yl) benzamide
[149] To a 2 ml pyridine solution of 188 mg (0.92 mmol) of the compound obtained in Preparation Example 4, 0.13 ml (1.11 mmol) of benzoyl chloride was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled under reduced pressure, and the residue was purified by recrystallization (ethanol) to give 141 mg (50%) of the title compound.
[150] Preparation Example 8
[151] N- (5-cyano-1-cyclohexyl-3-methyl-1H-pyrazol-4-yl) -4-nitrobenzamide
[152] The same reaction as in Preparation Example 7 was carried out except that p-nitrobenzoyl chloride was used instead of benzoyl chloride. In this way, 389 mg (55%) of the title compound were obtained.
[153] Preparation Example 9
[154] 1-cyclohexyl-4-[(2-methoxybenzoyl) amino] -3-methyl-1H-pyrazole-5-carboxamide
[155] A solution of 1 mL (13.7 mmol) thionyl chloride of 136 mg (0.89 mmol) of o-anistic acid was heated under reflux for 2 hours. Excess thionyl chloride was then distilled under reduced pressure to give o-anicin acid chloride.
[156] To the acid chloride was added 180 mg (0.81 mmol) of 5 mL anhydrous dichloromethane suspension of compound obtained in Preparation Example 6, and 0.28 mL (2.03 mmol) triethylamine, and the mixture was stirred at room temperature for 30 minutes. did. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 1/2) to give 267 mg (93%) of the title compound.
[157] Preparation Example 10
[158] 1-cyclohexyl-4-[(2-ethoxybenzoyl) amino] -3-methyl-1H-pyrazole-5-carboxamide
[159] The same reaction as in Production Example 9 was carried out except that 2-ethoxybenzoic acid was used instead of o-anidic acid. In this way, 200 mg (99%) of the title compound were obtained.
[160] Preparation Example 11
[161] N- [5- (aminocarbonyl) -1-cyclohexyl-3-methyl-1H-pyrazol-4-yl] -2-pyridinecarboxamide
[162] To 150 mg (0.68 mmol) of a 2 mL anhydrous dichloromethane suspension of the compound obtained in Preparation Example 6, 144 mg (0.81 mmol) of 2-picolinic acid chloride and 0.21 mL (1.49 mmol) of triethylamine were added, The mixture was stirred at rt for 30 min. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified by recrystallization (ethyl acetate) to give 178 mg (80%) of the title compound.
[163] Preparation Example 12
[164] 1-cyclohexyl-3-methyl-4-{[4- (4-methyl-1-piperazinyl) benzoyl] amino} -1H-pyrazole-5-carboxamide
[165] To 3 mg of anhydrous dichloromethane suspension of 150 mg (0.68 mmol) of the compound obtained in Preparation Example 6, 214 mg (0.81 mmol) of 4- (4-methyl-1-piperazinyl) benzoic acid, 143 mg (0.743 mmol) After 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and catalytic amount of 4-dimethylaminopyridine were added, the mixture was stirred at room temperature for 20 hours. Subsequently, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified by recrystallization (ethyl acetate-hexane) to give 119 mg (42%) of the title compound.
[166] Preparation Example 13
[167] 1-cyclohexyl-4-[(2-methoxy-4-nitrobenzoyl) amino] -3-methyl-1H-pyrazole-5-carboxamide
[168] The same reaction as in Production Example 9 was carried out except that 2-methoxy-4-nitrobenzoic acid was used instead of o-anistic acid. In this way, 301 mg (67%) of the title compound were obtained.
[169] Preparation Example 14
[170] N- [5- (aminocarbonyl) -1-cyclohexyl-3-methyl-1H-pyrazol-4-yl] -5-nitro-2-pyridinecarboxamide
[171] To 5 mg anhydrous dichloromethane suspension of 500 mg (2.25 mmol) of the compound obtained in Preparation Example 6, 453 mg (2.70 mmol) of 5-nitro-2-pyridinecarboxylic acid and 518 mg (2.70 mmol) of 1-ethyl After addition of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride, the mixture was stirred at room temperature for 20 hours. The precipitated solid was then collected by filtration, washed with water and then dried to give 588 mg (70%) of the title compound.
[172] Preparation Example 15
[173] N- [5- (aminocarbonyl) -1-cyclohexyl-3-methyl-1H-pyrazol-4-yl] -4-chloro-2-pyridinecarboxamide
[174] In 500 ml (2.25 mmol) of a 3 ml anhydrous dichloromethane suspension of the compound obtained in Preparation Example 6, 426 mg (2.70 mmol) of 4-chloropicolinic acid and 518 mg (2.70 mmol) of 1-ethyl-3- ( 3-dimethylaminopropyl) carbodiimide hydrochloride was added under ice cooling, and then the mixture was stirred at the same temperature for 3 hours. Subsequently, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 741 mg (91%) of the title compound.
[175] Preparation Example 16
[176] 1-cyclohexyl-4-[(5-fluoro-2-methoxybenzoyl) amino] -3-methyl-1H-pyrazole-5-carboxamide
[177] The same reaction as in Production Example 15 was carried out except that 5-fluoro-2-methoxybenzoic acid was used instead of 4-chloropicolinic acid. In this way, 272 mg (81%) of the title compound were obtained.
[178] Preparation Example 17
[179] t-butyl 2- (4-methylcyclohexylidene) hydrazinecarboxylate
[180] 25.5 g (192 mg) of t-butyl carbazate was added to a 230 mL hexane solution of 23.6 mL (192 mmol) of 4-methylcyclohexanone, and then the mixture was heated at reflux for 20 minutes. Subsequently, the reaction mixture was brought to room temperature, and the precipitated solid was collected by filtration to obtain 38.7 g (89%) of the title compound.
[181] Preparation Example 18
[182] 5-methyl-2- (4-methylcyclohexyl) -2,4-dihydro-3H-pyrazol-3-one (cis / trans mixture)
[183] To 35.8 g (158 mmol) of the compound obtained in Production Example 17, 147 mL of borane-tetrahydrofuran complex (1.08 mol / L 158 mmol in tetrahydrofuran) was added, and then the mixture was stirred at room temperature for 15 minutes. . Next, 79 mL of 6M hydrochloric acid was added dropwise, and the mixture was heated at reflux for 20 minutes. The reaction mixture was allowed to come to room temperature and then distilled under reduced pressure. Tetrahydrofuran was then added to the residue and the insolubles were filtered off. The filtrate was distilled under reduced pressure to obtain crude crystals of 1- (4-methylcyclohexyl) hydrazine hydrochloride. These crude crystals were used as such without further purification, and methyl acetoacetate and mixtures thereof were stirred at 120 ° C. for 1 hour. The reaction mixture was then allowed to come to room temperature, neutralized with aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 13.0 mg (42%) of the title compound as a cis-trans mixture (cis / trans = 1/2).
[184] Preparation Example 19
[185] 5-chloro-3-methyl-1- (4-methylcyclohexyl) -4-nitro-1H-pyrazole (cis / trans mixture)
[186] The same reaction procedure as in Preparation Example 2 was carried out except that the compound obtained in Preparation Example 18 was used instead of the compound obtained in Preparation Example 1. In this way, 7.15 g (77%) of the title compound were obtained as a cis-trans mixture (cis / trans = 1/2).
[187] Preparation Example 20
[188] 3-methyl-1- (4-methylcyclohexyl) -4-nitro-1H-pyrazole-5-carbonitrile (cis / trans mixture)
[189] The same reaction procedure as in Preparation Example 3 was carried out except that the compound obtained in Preparation Example 19 was used instead of the compound obtained in Preparation Example 2. In this way, 5.62 g (88%) of the title compound were obtained as a cis-trans mixture (cis / trans = 1/2).
[190] Preparation Example 21
[191] Trans-3-methyl-1- (4-methylcyclohexyl) -4-nitro-1H-pyrazole-5-carboxamide
[192] Preparation Example 22
[193] Cis-3-methyl-1- (4-methylcyclohexyl) -4-nitro-1H-pyrazole-5-carboxamide
[194] The same reaction procedure as in Preparation Example 5 was carried out except that the compound obtained in Preparation Example 20 was used instead of the compound obtained in Preparation Example 3. In this way, 2.03 g (36%) of the compound of Preparation 21 and 1.31 g (23%) of the compound of Preparation 22 were obtained.
[195] Preparation Example 23
[196] Trans-4-amino-3-methyl-1- (4-methylcyclohexyl) -1H-pyrazole-5-carboxamide
[197] The same reaction procedure as in Preparation Example 6 was carried out except that the compound obtained in Preparation Example 21 was used instead of the compound obtained in Preparation Example 5. In this way, 1.41 g (57%) of the title compound were obtained.
[198] Preparation Example 24
[199] Cis-4-amino-3-methyl-1- (4-methylcyclohexyl) -1H-pyrazole-5-carboxamide
[200] The same reaction procedure as in Preparation Example 6 was carried out except that the compound obtained in Preparation Example 22 was used instead of the compound obtained in Preparation Example 5. In this way, 0.78 g (49%) of the title compound were obtained.
[201] Preparation Example 25
[202] Trans-3-methyl-1- (4-methylcyclohexyl) -4-{[4- (4-methyl-1-piperazinyl) benzoyl] amino} -1H-pyrazole-5-carboxamide
[203] The same reaction procedure as in Preparation Example 12 was carried out except that the compound obtained in Preparation Example 23 was used instead of the compound obtained in Preparation Example 6. In this way, 211 mg (57%) of the title compound were obtained.
[204] Preparation Example 26
[205] Cis-3-methyl-1- (4-methylcyclohexyl) -4-{[4- (4-methyl-1-piperazinyl) benzoyl] amino} -1H-pyrazole-5-carboxamide
[206] The same reaction procedure as in Preparation Example 12 was carried out except that the compound obtained in Preparation Example 24 was used instead of the compound obtained in Preparation Example 6. In this way, 196 mg (53%) of the title compound were obtained.
[207] Preparation Example 27
[208] Trans-4-[(2-methoxybenzoyl) amino] -3-methyl-1- (4-methylcyclohexyl) -1H-pyrazole-5-carboxamide
[209] The same reaction procedure as in Preparation Example 9 was carried out except that the compound obtained in Preparation Example 23 was used instead of the compound obtained in Preparation Example 6. In this way, 192 mg (82%) of the title compound were obtained.
[210] Preparation Example 28
[211] Cis-4-[(2-methoxybenzoyl) amino] -3-methyl-1- (4-methylcyclohexyl) -1H-pyrazole-5-carboxamide
[212] The same reaction procedure as in Preparation Example 9 was carried out except that the compound obtained in Preparation Example 24 was used instead of the compound obtained in Preparation Example 6. In this way, 143 mg (61%) of the title compound were obtained.
[213] Preparation Example 29
[214] 2- [cyclohexyl (hydroxy) methylene] malononitrile
[215] To 3.96 g (0.06 mol) of 60 ml tetrahydrofuran solution of malononitrile, 4.8 g (60% in oil, 0.12 mol) of sodium hydride are added in four portions at 0 ° C. and the mixture is added at 30 ° C. at 30 ° C. Stir for minutes. Then cyclohexanecarboxylic acid chloride was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Then 150 mL of 1M hydrochloric acid was slowly added and the mixture was extracted with ethyl acetate. The extract was then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from diisopropyl ether to give 8.16 g (77%) of the title compound.
[216] Preparation Example 30
[217] 2- [cyclohexyl (methoxy) methylene] malononitrile
[218] To a solution of 2.64 g (15 mmol) of the compound obtained in Production Example 29 was added 10 g of sodium bicarbonate at room temperature in a mixture of 24 ml of 1,4-dioxane and 4 ml of water. Dimethyl sulfate was added dropwise over 5 minutes. After the mixture was heated at 85 ° C. for 2.5 hours, the reaction mixture was returned to room temperature. Water was added and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give 2.35 g (82%) of the title compound.
[219] Preparation Example 31-1
[220] 5-amino-3-cyclohexyl-1-methyl-1H-pyrazole-4-carbonitrile
[221] To 20 ml of ethanol solution of 2.3 g (12.1 mmol) of the compound obtained in Production Example 30, 0.643 ml (12.1 mmol) of methylhydrazine was added at room temperature. The mixture was heated at reflux for 5 hours. The reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 50/1) to give 1.48 g (60%) of the title compound.
[222] Preparation Example 31-2
[223] 5-amino-3-cyclohexyl-1-methyl-1H-pyrazole-4-carbonitrile
[224] Under a stream of nitrogen, 20.8 g (about 60% oil suspension, 520 mmol) of sodium hydride were slowly added at 0 ° C. to 17.2 g (260 mmol) of malononitrile 260 mL tetrahydrofuran solution. Subsequently, 35 mL (260 mmol) of cyclohexanecarbonyl chloride was added dropwise at the same temperature. After the dropwise addition, the reaction mixture was allowed to come to room temperature and stirred for 1.5 hours. Then 30 ml (312 mmol) of dimethylsulfuric acid were added to the reaction mixture, and the mixture was heated at reflux for 3 hours. Then 17.4 mL (125 mmol) triethylamine and 13.8 mL (260 mmol) methylhydrazine were added under ice cooling, and the mixture was heated at reflux for 1 hour. The reaction mixture was allowed to come to room temperature and distilled under reduced pressure. Water was then added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 30/1 to 20/1) to give crude crystals. The crude crystals were further purified by recrystallization (hexane-ethyl acetate) to give 20.7 g (39%) of the title compound. The mother liquor was also purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 11.3 g (21%) of the title compound.
[225] Preparation Example 32
[226] 5-amino-3-cyclohexyl-1-methyl-1H-pyrazole-4-carboxamide
[227] To 25.3 g (124 mmol) of the compound obtained in Preparation Example 31, 75 mL of concentrated hydrochloric acid was added under ice cooling. The mixture was stirred at room temperature for 15 minutes and further stirred at 60 ° C. for 1 hour. The reaction mixture was then poured onto ice, neutralized with aqueous sodium hydroxide solution, and then extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure. The residue was purified by recrystallization (ethyl acetate) to give 20.0 g (73%) of the title compound.
[228] Preparation Example 33
[229] Ethyl 4- (4-hydroxy-1-piperidinyl) benzoate
[230] To 20 g N, N-dimethylformamide solution of 1.0 g (5.95 mmol) of ethyl 4-fluorobenzoate, 662 mg (6.54 mmol) of 4-hydroxypiperidine and 1.23 g (8.92 mmol) of potassium carbonate Was added and the mixture was stirred at 120 ° C. for 24 h. The reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. Water was then added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Subsequently, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the precipitated crystals were collected to give 234 mg (16%) of the title compound.
[231] Preparation Example 34
[232] 4- (4-hydroxy-1-piperidinyl) benzoic acid monohydrochloride
[233] To 1 ml 1,4-dioxane solution of 200 mg (0.802 mmol) of the compound obtained in Production Example 33, 2 ml of 6M hydrochloric acid was added, and the mixture was stirred at 90 ° C for 1.5 hours. The reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure to obtain 190 mg (92%) of the title compound.
[234] Preparation 35
[235] Methyl 2-hydroxy-4- (2-methoxyethoxy) benzoate
[236] To a solution of 4.0 g (23.8 mmol) of methyl 2,4-dihydroxybenzoate in 50 ml tetrahydrofuran, 7.49 g (28.5 mmol) triphenylphosphine, 2.25 ml (28.5 mmol) 2-methoxyethanol and 4.5 mL (28.5 mmol) of diethyl azodicarboxylate was added slowly at 0 ° C. The mixture was allowed to come to room temperature and stirred for 1 hour. The reaction mixture was then diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue was added a solution of 100 ml of ethyl acetate / hexanes (= 1/4) and the insoluble solids were filtered off. The mother liquor was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 4.71 g (87%) of the title compound.
[237] Preparation Example 36
[238] Methyl 2-methoxy-4- (2-methoxyethoxy) benzoate
[239] To a solution of 4.51 g (19.9 mmol) of the compound obtained in Preparation 35, 35 ml N, N-dimethylformamide, 2.48 ml (39.9 mmol) of methyl iodide and 877 mg (about 60% oil suspension 21.9 mmol) of sodium hydride Was added slowly at 0 ° C. The mixture was stirred at rt for 2 h. Then 10 ml of methanol was added to the reaction mixture, and the mixture was diluted with ethyl acetate. The dilution was washed with water and saturated aqueous sodium chloride solution. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 2/1) to give 4.53 g (95%) of the title compound.
[240] Preparation Example 37
[241] 2-methoxy-4- (2-methoxyethoxy) benzoic acid
[242] To a 41 mL methanol solution of 4.11 g (17.11 mmol) of the compound obtained in Production Example 36, 20.5 mL (20.5 mmol) of a 1M sodium hydroxide aqueous solution was added at room temperature. The mixture was stirred at room temperature for 2 hours and at 60 ° C. for 2 hours. The reaction mixture was then concentrated and water was added. After washing the aqueous layer with diethyl ether, 21 ml of 2M hydrochloric acid was slowly added to the aqueous layer. The precipitated solid was collected by filtration to obtain 3.42 g (88%) of the title compound.
[243] Preparation Example 38
[244] N-benzoyl-N- (4-cyano-3-cyclohexyl-1-methyl-1H-pyrazol-5-yl) benzamide
[245] To a solution of 400 mg (1.96 mmol) of 10 mL methylene chloride obtained in Preparation Example 31, 409 μl (2.94 mmol) of triethylamine, 250 μl (2.15 mmol) of benzoyl chloride and 5 mg of 4-dimethylaminopyridine Was added at room temperature and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was then diluted with ethyl acetate and washed with water. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 333 mg (41%) of the title compound.
[246] Preparation Example 39
[247] Benzyl 4-methoxy-1-piperidinecarboxylate
[248] In a 20 ml tetrahydrofuran solution of 1.87 g (7.95 mmol) of benzyl 4-hydroxy-1-piperidinecarboxylate, 413 mg (60% in oil, 10.33 mmol) of sodium hydride and 792 μl (12.72 mmol) Methyl iodide was added at 0 ° C and the mixture was stirred at room temperature for 16.5 hours. The reaction mixture was then diluted with ethyl acetate and washed with water. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 2.08 g (94%) of the title compound.
[249] Preparation Example 40
[250] 4-methoxypiperidine p-toluenesulfonate
[251] To 40 g methanol solution of 2.0 g (8.02 mmol) of the compound obtained in Preparation Example 39, 1.556 g (8.18 mmol) of p-toluenesulfonic acid and 400 mg of 5% palladium carbon were added. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The catalyst was then filtered and the solvent was distilled off under reduced pressure to yield 2.36 g (quantitative) of the title compound.
[252] Preparation Example 41
[253] 5-amino-3-cycloheptyl-1-methyl-1H-pyrazole-4-carbonitrile
[254] The same reaction procedure as in Preparation Example 31-2 was performed except that cycloheptancarbonyl chloride was used instead of cyclohexanecarbonyl chloride. In this way, 20.83 g (55%) of the title compound were obtained.
[255] Preparation Example 42
[256] 5-amino-3-cycloheptyl-1-methyl-1H-pyrazole-4-carboxamide
[257] The same reaction procedure as in Preparation Example 32 was carried out except that the compound obtained in Preparation Example 41 was used instead of the compound obtained in Preparation Example 31. In this way, 16.93 g (92%) of the title compound were obtained.
[258] Preparation Example 43
[259] Methyl 4- (4-benzyl-1-piperazinyl) -2,5-difluorobenzoate
[260] To a 25 mL tetrahydrofuran solution of 4.25 g (22.35 mmol) of methyl 2,4,5-trifluorobenzoate, 3.89 mL (22.35 mmol) of N-benzylpiperazine was added under ice cooling. The mixture was stirred at 0 ° C. for 0.5 h and at rt for 2.5 h. The reaction mixture was then diluted with ethyl acetate and the dilutions washed sequentially with water and saturated aqueous sodium chloride solution. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 2.61 g (34%) of the title compound.
[261] Preparation Example 44
[262] Methyl 4- (4-benzyl-1-piperazinyl) -5-fluoro-2-methoxybenzoate
[263] To 2.20 g (7.10 mmol) of a 20 mL tetrahydrofuran solution obtained in Preparation Example 43, 2.06 g (28% in MeOH, 10.65 mmol) of sodium methylate were added under ice cooling. The mixture was stirred at rt for 13.5 h. The reaction mixture was then diluted with ethyl acetate and the dilutions washed sequentially with water and saturated aqueous sodium chloride solution. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1.5 / 1 to 1/1) to give the title compound and methyl 2- (4-benzyl-1-piperazinyl) -5-fluoro-4- 2.06 g (81%) of a 4: 1 mixture of methoxybenzoate were obtained.
[264] Preparation Example 45
[265] Benzyl 4- [2-fluoro-5-methoxy-4- (methoxycarbonyl) phenyl] -1-piperazinecarboxylate
[266] To 1.37 g (3.82 mmol) of a 20 ml 1,2-dichloroethane solution obtained in Preparation 44, 818 µl (5.73 mmol) of benzyloxycarbonyl chloride was added and the mixture was heated at reflux for 2 hours. . 273 μl (1.91 mmol) of benzyloxycarbonyl chloride was then added and the mixture was heated at reflux for 1 hour. In addition, 273 μl (1.91 mmol) of benzyloxycarbonyl chloride were added and the mixture was heated at reflux for 0.5 h. Subsequently, the reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 to 1.5 / 1) to give 1.20 g (78%) of the title compound.
[267] Preparation Example 46
[268] 4- {4-[(benzyloxy) carbonyl] -1-piperazinyl} -5-fluoro-2-methoxybenzoic acid
[269] The same reaction procedure as in Preparation Example 37 was carried out except that the compound obtained in Preparation Example 45 was used instead of the compound obtained in Preparation Example 36. In this way, 1.02 g (99%) of the title compound were obtained.
[270] Preparation 47
[271] tert-butyl 4-[(benzyloxy) methyl] -1-piperidinecarboxylate
[272] To a solution of 2.4 g (11.15 mmol) of tert-butyl 4-hydroxymethyl-1-piperidinecarboxylate in 30 ml N, N-dimethylformamide, 557 mg (60% in oil, 13.9 mmol) of sodium hydride And 1.86 mL (15.6 mmol) of benzyl bromide were added under ice cooling. The mixture was stirred at rt for 23 h. The reaction mixture was then diluted with ethyl acetate and the dilutions washed sequentially with water and saturated aqueous sodium chloride solution. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 3.5 g (quantitative) of the title compound.
[273] Preparation Example 48
[274] 4-[(benzyloxy) methyl] piperidine monohydrochloride
[275] To 3.4 g (11.1 mmol) of the compound obtained in Production Example 47, 11.3 mL of 4N-hydrochloric acid / 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 1.5 hours. Subsequently, ether was added slowly and the precipitated solid was collected by filtration to obtain 1.26 g (84%) of the title compound.
[276] Preparation 49
[277] N- [2- (benzyloxy) ethyl] -N-ethylamine
[278] To 7.0 g (30 mmol) of 2- (benzyloxy) ethyl methanesulfonate, 75 ml methanol solution of 2M ethylamine was added and the mixture was heated at 110 ° C. for 2 hours in a closed tube. The reaction mixture was then returned to room temperature and then diluted with methylene chloride. The dilution was washed with saturated aqueous sodium hydride solution. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 3.85 g (72%) of the title compound.
[279] Preparation 50
[280] 4- [2- (benzyloxy) ethyl] -N-ethylamine hydrochloride
[281] 6.2 mL of 4N-hydrochloric acid / 1,4-dioxane solution was added to 3.72 g (20.75 mmol) of 100 mL ether solution obtained in Preparation Example 49. The precipitated solid was collected by filtration to obtain 4.09 g (91%) of the title compound.
[282] Preparation Example 51
[283] Methyl 4- {4-[[(benzyloxy) carbonyl] (methyl) amino] -1-piperidinyl} -2,5-difluorobenzoate
[284] The same reaction procedure as in Preparation Example 43 was carried out except that benzyl methyl (4-piperidinyl) carbamate hydrochloride was used instead of N-benzylpiperazine. In this way, 2.0 g (68%) of the title compound were obtained.
[285] Preparation Example 52
[286] Methyl 4- {4-[[(benzyloxy) carbonyl] (methyl) amino] -1-piperidinyl} -5-fluoro-2-methoxybenzoate
[287] The same reaction procedure as in Preparation Example 44 was carried out except that the compound obtained in Preparation Example 51 was used instead of the compound obtained in Preparation Example 43. In this way, 0.46 g (24%) of the title compound were obtained.
[288] Preparation Example 53
[289] 4- {4-[[(benzyloxy) carbonyl] (methyl) amino] -1-piperidinyl} -5-fluoro-2-methoxybenzoic acid
[290] The same reaction procedure as in Preparation Example 37 was carried out except that the compound obtained in Preparation Example 52 was used instead of the compound obtained in Preparation Example 36. In this way, 0.41 g (quantitative) of the title compound were obtained.
[291] Preparation Example 54
[292] Methyl 4-bromo-2- (difluoromethoxy) benzoate
[293] To a solution of 5.0 g (21.7 mmol) of methyl 4-bromo-2-hydroxybenzoate in 70 ml dimethylformamide, 3.4 ml (32.6 mmol) of methyl chlorodifluoroacetate and 3.0 g (21.7 mmol) of potassium carbonate Was added. The mixture was stirred at 60 ° C. for 6 hours and at room temperature for 60 hours. Then water was added to the reaction mixture and the mixture was extracted with ether. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give 1.4 g (23%) of the title compound.
[294] Preparation Example 55
[295] 4-Bromo-2- (difluoromethoxy) benzoic acid
[296] To a mixed solution of 1.36 g (4.84 mmol) of the compound obtained in Production Example 54, a 10 ml methanol / 10 ml tetrahydrofuran mixed solution, an aqueous 2 M sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The solvent was then distilled off under reduced pressure and the residue was dissolved by addition of water. To the solution was added 6M aqueous hydrochloric acid solution. The precipitated solid was collected by filtration to obtain 1.17 g (91%) of the title compound.
[297] Preparation Example 56
[298] 5-amino-3-cyclohexyl-1-ethyl-1H-pyrazole-4-carbonitrile
[299] The same reaction procedure as in Preparation Example 31-2 was performed except that ethyl hydrazine was used instead of methyl hydrazine. In this way, 2.0 g (18%) of the title compound were obtained.
[300] Preparation Example 57
[301] 5-amino-3-cyclohexyl-1-ethyl-1H-pyrazole-4-carboxamide
[302] The same reaction procedure as in Preparation Example 32 was carried out except that the compound obtained in Preparation Example 56 was used instead of the compound obtained in Preparation Example 31. In this way, 1.93 g (99%) of the title compound were obtained.
[303] Preparation 58
[304] Methyl 2-fluoro-4- (4-thiomorpholinyl) benzoate
[305] To 30 mL dimethylsulfoxide solution of 3.44 g (20 mmol) of methyl 2,4-difluorobenzoate, 1.9 mL (20 mmol) of thiomorpholine and 2.76 g (20 mmol) of potassium carbonate are added, and The mixture was stirred at 80 ° C. The reaction mixture was then cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed system was dried over anhydrous sodium sulfate and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to afford 2.96 g (58%) of the title compound.
[306] Preparation Example 59
[307] Methyl 2-methoxy-4- (4-thiomorpholinyl) benzoate
[308] To 30 g of tetrahydrofuran solution of 2.5 g (9.8 mmol) of the compound obtained in Production Example 59, 12.3 mL (11.8 mmol) of sodium methoxide (28% methanol solution) was added, and the mixture was stirred at 80 DEG C for 4 hours. Was stirred. The reaction mixture was then distilled under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed system was dried over anhydrous sodium sulfate and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1 to 3/1) to give 2.59 g (99%) of the title compound.
[309] Preparation Example 60
[310] 2-methoxy-4- (4-thiomorpholinyl) benzoic acid
[311] To a 30 ml methanol solution of 2.47 g (9.3 mmol) of the compound obtained in Production Example 59, 15 ml of an aqueous 1 M sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. Further 2 ml of 4M aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 12 hours and at 50 ° C. for 7 hours. The reaction mixture was then cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved by the addition of water and the solution was washed with ether. The aqueous layer was acidified with 1M aqueous hydrochloric acid solution. The precipitated solid was collected by filtration and dried to give 2.2 g (94%) of the title compound.
[312] Preparation Example 61
[313] Benzyl 4- [2,5-difluoro-4- (methoxycarbonyl) phenyl] -1,4-diazepane-1-carboxylate
[314] The same reaction procedure as in Preparation Example 43 was carried out except that benzyl 1-homopiperazinecarboxylate was used instead of N-benzylpiperazine. In this way, 1.31 g (32%) of the title compound were obtained.
[315] Preparation Example 62
[316] Benzyl 4- [2-fluoro-5-methoxy-4- (methoxycarbonyl) phenyl] -1,4-diazepane-1-carboxylate
[317] The same reaction procedure as in Preparation Example 44 was carried out except that the compound obtained in Preparation Example 61 was used instead of the compound obtained in Preparation Example 43. In this way, 0.31 g (27%) of the title compound were obtained.
[318] Preparation Example 63
[319] 4- {4-[(benzyloxy) carbonyl] -1,4-diazepane-1-yl} -5-fluoro-2-methoxybenzoic acid
[320] The same reaction procedure as in Preparation Example 37 was carried out except that the compound obtained in Preparation Example 62 was used instead of the compound obtained in Preparation Example 36. In this way, 0.28 g (97%) of the title compound were obtained.
[321] Example 1
[322] 1-cyclohexyl-3-methyl-5-phenyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[323] To 150 mg (0.49 mmol) of a 4 mL dioxane / 4.6 mL water mixed solution obtained in Preparation Example 7, 0.12 mL of 30% aqueous hydrogen peroxide solution and 30 mg (0.75 mmol) of sodium hydroxide were added, and the mixture was 80 ° C. Stirred for 2 hours. The reaction mixture was then allowed to come to room temperature and the solvent was distilled off under reduced pressure. The residue was then acidified by adding acetic acid. The precipitated solid was collected by filtration to obtain 103 mg (68%) of the title compound.
[324] Example 2
[325] 1-cyclohexyl-3-methyl-5- (4-nitrophenyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[326] The same reaction procedure as in Example 1 was carried out except that the compound obtained in Preparation Example 8 was used instead of the compound obtained in Preparation Example 7. In this way, 273 mg (44%) of the title compound were obtained.
[327] Example 3
[328] 5- (4-aminophenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[329] To a mixed solution of 222 mg (0.63 mmol) of 4 mL methanol and 2 mL N, N-dimethylformamide obtained in Example 2, 25 mg of 10% palladium carbon was added. After substitution by hydrogen, the mixture was stirred for 2 hours. The reaction mixture was then filtered through celite and the filtrate was distilled off under reduced pressure. The residue was dissolved in 6M hydrochloric acid and the solution was washed with ether. The aqueous layer was neutralized with 28% aqueous ammonia and then extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization (ethanol) to give 77 mg (38%) of the title compound.
[330] Example 4
[331] N- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) phenyl] acetamide
[332] To 4 mg pyridine solution of 110 mg (0.34 mmol) of the compound obtained in Example 3, 39 μl (0.41 mmol) of acetic anhydride were added under ice cooling. The mixture was stirred at the same temperature for 30 minutes. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization (ethanol) to give 43.7 mg (35%) of the title compound.
[333] Example 5
[334] 1-cyclohexyl-5- (2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[335] To 100 mg (0.28 mmol) of 2 mL ethanol solution of the compound obtained in Example 9, 1 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at 90 ° C for 10 hours. The reaction mixture was then allowed to come to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 68.5 mg (72%) of the title compound.
[336] Example 6
[337] 1-cyclohexyl-3-methyl-5- (2-pyridinyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[338] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 11 was used instead of the compound obtained in Preparation Example 9. In this way, 77.8 mg (59%) of the title compound were obtained.
[339] Example 7
[340] 1-cyclohexyl-3-methyl-5- [4- (4-methyl-1-piperazinyl) phenyl] -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -On
[341] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 12 was used instead of the compound obtained in Preparation Example 9. In this way, 59 mg (63%) of the title compound were obtained.
[342] Example 8
[343] 1-cyclohexyl-5- (2-methoxy-4-nitrophenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[344] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 13 was used instead of the compound obtained in Preparation Example 9. In this way, 171 mg (45%) of the title compound were obtained.
[345] Example 9
[346] 5- (4-amino-2-methoxyphenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[347] The same reaction procedure as in Example 3 was carried out except that the compound obtained in Example 8 was used instead of the compound obtained in Example 2. In this way, 52 mg (41%) of the title compound were obtained.
[348] Example 10
[349] N- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxyphenyl Acetamide
[350] The same reaction procedure as in Example 4 was carried out except that the compound obtained in Example 9 was used instead of the compound obtained in Example 3. In this way, 61 mg (quantitative) of the title compound were obtained.
[351] Example 11
[352] 5- (5-amino-2-pyridinyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[353] To 500 mg (1.34 mmol) of 6 mL ethanol suspension of the compound obtained in Production Example 14, 3 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at 90 ° C for 4 hours. The reaction mixture was then allowed to come to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to yield 1-cyclohexyl-3-methyl-5- (5-nitro-2-pyridinyl) -1,6-dihydro-7H-pyrazolo [4,3-d] -7 Crude crystals of -one were obtained. The crude crystals were not purified but dissolved in 6 ml methanol and 5 ml N, N-dimethylformamide. Then 10% palladium carbon was added and the mixture was replaced with hydrogen and stirred for 14 hours. The reaction mixture was then filtered through celite and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 50/1) to give 78.8 mg (18%) of the title compound.
[354] Example 12
[355] N- [6- (1-cyclohexyl-3-methyl-7-oxo-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-pyridinyl ] acetamide
[356] The same reaction procedure as in Example 4 was carried out except that the compound obtained in Example 11 was used instead of the compound obtained in Example 3. In this way, 40 mg (74%) of the title compound were obtained.
[357] Example 13
[358] 1-cyclohexyl-5- (2-ethoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[359] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 10 was used instead of the compound obtained in Preparation Example 9. In this way, 145 mg (90%) of the title compound were obtained.
[360] Example 14
[361] 1-cyclohexyl-5- [4- (4-hydroxy-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-on
[362] 150 mg (0.675 mmol) of the compound obtained in Preparation Example 6, 174 mg (0.675 mmol) of the obtained compound in Preparation Example 34 (0.675 mmol), 1-ethyl in 4 ml of anhydrous dichloromethane / 2 ml of N, N-dimethylformamide solution 155 mg (0.810 mmol) of tri-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 68 mg (0.675 mmol) of triethylamine were added. The mixture was stirred at rt for 2 h. The reaction mixture was then diluted with water and then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a carboxamide intermediate.
[363] In addition, the synthesized carboxamide intermediate was dissolved in 4 ml of ethanol, 2 ml of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at 90 ° C for 24 hours. The reaction mixture was then allowed to come to room temperature, diluted with water and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 19 mg (7%) of the title compound.
[364] Example 15
[365] 5- (4-Bromo-2-methoxyphenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[366] The same reaction procedure as in Example 14 was carried out except that 4-bromo-2-methoxybenzoic acid was used instead of the compound obtained in Preparation Example 34. In this way, 545 mg (48%) of the title compound were obtained.
[367] Example 16
[368] 1-cyclohexyl-5- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one
[369] 166 μl (1.50 mmol) of N-methylpiperazine, 72 mg (0.75 mmol) of sodium tert-butoxide, in 209 mg (0.50 mmol) of a 2 mL toluene solution of the compound obtained in Preparation Example 15 under argon stream 166 mg (0.01 mmol) tri-tert-butylphosphine and 1.6 mg (0.008 mmol) palladium (II) acetate were added and the mixture was stirred at 110 ° C. for 2 hours. Further, 166 mg (0.01 mmol) tri-tert-butylphosphine and 1.6 mg (0.008 mmol) palladium (II) acetate were added and the mixture was stirred at 110 ° C. for 8 hours. The reaction mixture was then allowed to come to room temperature, diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to give 82 mg (38%) of the title compound.
[370] Example 17
[371] 5- (4-chloro-2-pyridinyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[372] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 15 was used instead of the compound obtained in Preparation Example 9. In this way, 496 mg (75%) of the title compound were obtained.
[373] Example 18
[374] 1-cyclohexyl-5- (5-fluoro-2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[375] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 16 was used instead of the compound obtained in Preparation Example 9. In this way, 118 mg (63%) of the title compound were obtained.
[376] Example 19
[377] Trans-5- (2-methoxyphenyl) -3-methyl-1- (4-methylcyclohexyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[378] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 27 was used instead of the compound obtained in Preparation Example 9. In this way, 123 mg (86%) of the title compound were obtained.
[379] Example 20
[380] Cis-5- (2-methoxyphenyl) -3-methyl-1- (4-methylcyclohexyl) -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[381] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 28 was used instead of the compound obtained in Preparation Example 9. In this way, 88 mg (84%) of the title compound were obtained.
[382] Example 21
[383] Trans-3-methyl-1- (4-methylcyclohexyl) -5- [4- (4-methyl-1-piperazinyl) phenyl] -1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[384] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 25 was used instead of the compound obtained in Preparation Example 9. In this way, 116 mg (81%) of the title compound were obtained.
[385] Example 22
[386] Cis-3-methyl-1- (4-methylcyclohexyl) -5- [4- (4-methyl-1-piperazinyl) phenyl] -1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[387] The same reaction procedure as in Example 5 was carried out except that the compound obtained in Preparation Example 26 was used instead of the compound obtained in Preparation Example 9. In this way, 132 mg (92%) of the title compound were obtained.
[388] Example 23
[389] 3-cyclohexyl-1-methyl-6-phenyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[390] To 592 mL 1,4-dioxane solution of 292 mg (0.708 mmol) of the compound obtained in Preparation Example 38, 1.9 mL (1.9 mmol) of 1M aqueous sodium hydroxide solution and 0.5 mL of 30% hydrogen peroxide aqueous solution were added, and the mixture was It stirred at 85 degreeC for 3.5 hours. The reaction mixture was then returned to room temperature and diluted with water. Then 1 ml of 2M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 176 mg (81%) of the title compound.
[391] Example 24
[392] 3-cyclohexyl-6- (2-methoxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[393] To 181 mg (1.19 mmol) of o-anicin acid in 3 mL 1,2-dichloroethane suspension, 158 μL (2.16 mmol) of thionyl chloride was added and the mixture was stirred at 85 ° C. for 1.5 h. The solvent was then distilled off under reduced pressure to give acid chloride as a colorless oily substance.
[394] To a 2 ml pyridine solution of the acid chloride synthesized above, a 2 ml pyridine solution of 240 mg (1.08 mmol) of the compound obtained in Preparation Example 32 was added. The mixture was stirred at 60 ° C. for 18 hours and at room temperature for 2 days. The reaction mixture was then concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 30/1) to give 246 mg (64%) of carboxamide intermediate (3-cyclohexyl-5-[(2-methoxybenzoyl) amino] -1-methyl-1H-pyrazole-4-carboxamide) was obtained.
[395] To a 2.2 ml ethanol solution of 130 mg (0.365 mmol) of the synthesized carboxamide intermediate, 1.1 ml (1.1 mmol) of 1 M aqueous sodium hydroxide solution was added, and the mixture was stirred at 90 ° C. for 20 hours. The reaction mixture was then allowed to come to room temperature, diluted with water and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 30/1) to give 91 mg (74%) of the title compound.
[396] Example 25
[397] 3-cyclohexyl-1-methyl-6- (2-pyridinyl) -1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[398] To an 8 ml chloroform solution of 261 mg (1.17 mmol) of the compound obtained in Preparation Example 32, 409 µl (2.94 mmol) of triethylamine, 14 mg (0.117 mmol) of 4-dimethylaminopyridine and 251 mg (1.41 mmol) Picolinic acid chloride was added and the mixture was stirred at 50 ° C. for 20 hours. Water was then added to the reaction mixture and the mixture was extracted with methylene chloride. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to yield 315 mg of a carboxamide intermediate as crude crystals.
[399] To 2 mL ethanol suspension of the synthesized carboxamide intermediate, 2 mL (2.0 mmol) of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at 80 ° C. for 20 hours. The reaction mixture was then allowed to come to room temperature, diluted with water and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 50/1) to give 109 mg of crude crystals. The crude crystals were further recrystallized from chloroform / hexanes to give 72 mg (20%) of the title compound.
[400] Example 26
[401] 6- (4-bromo-2-methoxyphenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[402] To 5 ml 1,2-dichloroethane suspension of 500 mg (2.25 mmol) of 4-bromo-2-methoxybenzoic acid, 328 μl (4.50 mmol) of thionyl chloride are added and the mixture is stirred at 85 ° C. for 1.5 h. Stirred. The solvent was then distilled off under reduced pressure to give acid chloride as a yellow solid.
[403] To a 1 ml pyridine solution of the acid chloride synthesized above, 500 mg (2.25 mmol) of a 4 ml pyridine solution of the compound obtained in Preparation Example 32 was added. The mixture was stirred at room temperature for 1 hour and at 60 ° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. By the above procedure, a carboxamide intermediate (3-cyclohexyl-5-[(4-bromo-2-methoxybenzoyl) amino] -1-methyl-1H-pyrazole-4-carboxamide) is obtained. did.
[404] To 13.5 mL ethanol solution of the synthesized carboxamide intermediate, 6.75 mL (6.75 mmol) of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred while heating under reflux for 12 hours. The reaction mixture was then allowed to come to room temperature and diluted with water. Then, 3.38 mL of 2M hydrochloric acid was added, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 40/1) and further crystallized by adding diisopropyl ether to give 320 mg (34%) of the title compound.
[405] Example 27
[406] 3-cyclohexyl-6- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one
[407] In an argon stream, 207 μl (1.87 mmol) of N-methylpiperazine, 120 mg (1.25 mmol) of sodium tert-butoxide, in 260 mg (0.623 mmol) of 8 mL toluene solution of the compound obtained in Example 26, 12.6 mg (0.062 mmol) tri-tert-butylphosphine and 7.0 mg (0.031 mmol) palladium (II) acetate were added and the mixture was heated at reflux for 5 hours. The reaction mixture was then allowed to come to room temperature, diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to give 230 mg (85%) of the title compound.
[408] Example 28
[409] 3-cyclohexyl-6- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one monomethanesulfonate
[410] To 450 mg (1.03 mmol) of the compound obtained in Example 27, a 3 ml tetrahydrofuran / 4 ml dioxane mixed solution, 68.6 µl (1.05 mmol) of methanesulfonic acid was added, and the precipitated solid was collected by filtration. The solid was purified by recrystallization (ethanol) to give 364 mg (66%) of the title compound.
[411] Example 29
[412] 3-cyclohexyl-6- [4- (1,4-dioxa-8-azaspiro [4,5] deca-8-yl) -2-methoxyphenyl] -1-methyl-1,5-di Hydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[413] The same reaction procedure was followed as in Example 27, except that 1,4-dioxa-8-azaspiro [4,5] decane was used instead of N-methylpiperazine. In this way, 140 mg (81%) of the title compound were obtained.
[414] Example 30
[415] 3-cyclohexyl-6- [2-methoxy-4- (4-oxo-1-piperidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one
[416] To 850 mg (1.77 mmol) of 50 mL acetone / 5 mL water mixed solution obtained in Example 29, 405 mg (2.13 mmol) of p-toluenesulfonic acid monohydrate were added and the mixture was heated at reflux for 5 hours. did. Subsequently, the reaction mixture was returned to room temperature and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 827 mg of the title compound as crude crystals.
[417] Example 31
[418] 3-cyclohexyl-6- [4- (4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one
[419] To 780 mg (1.79 mmol) of the compound obtained in Example 30, a 30 ml ethanol suspension was added 81 mg (2.15 mmol) of sodium borohydride, and the mixture was stirred at room temperature for 1.5 hours. Acetone was then added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with methylene chloride. The organic layer was washed sequentially with water and saturated aqueous sodium chloride solution. The washed layer was then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 40/1) to give 606 mg (77%) of the title compound.
[420] Example 32
[421] 3-cyclohexyl-6- [4- (4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one monomethanesulfonate
[422] 100 mg (0.23 mmol) of the 3 mL ethanol suspension obtained in Example 31 are heated to 50 ° C. to form a solution. To the solution, 15 μM (0.23 mmol) methanesulfonic acid was added and the mixture was heated at reflux for 10 minutes. The reaction mixture was then allowed to come to room temperature and the solvent was distilled off under reduced pressure. Ether was added to the residue and the solids were collected by filtration to give 101 mg (83%) of the title compound.
[423] Example 33
[424] 3-cyclohexyl-6- [4- (4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one monohydrochloride
[425] A 100 mg (0.23 mmol) of 2 mL tetrahydrofuran suspension of compound obtained in Example 31 is heated to 50 ° C. to form a solution. To the solution, 68 μl (0.27 mmol) of 4M dioxane hydrochloride solution was added. The reaction mixture was then allowed to come to room temperature and ether was added. The precipitated solid was collected by filtration to obtain 96 mg (88%) of the title compound.
[426] Example 34
[427] 3-cyclohexyl-6- [2-methoxy-4- (2-methoxyethoxy) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-on
[428] The same reaction procedure as in Example 26 was carried out except that the compound obtained in Preparation Example 37 was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 90 mg (24%) of the title compound were obtained.
[429] Example 35
[430] 6- [4- (benzyloxy) -2-methoxyphenyl] -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[431] The same reaction procedure was followed as in Example 26, except that 4-benzyloxy-2-methoxybenzoic acid was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 1.3 g (87%) of the title compound were obtained.
[432] Example 36
[433] 3-cyclohexyl-6- (4-hydroxy-2-methoxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[434] To 1.16 g (2.61 mmol) of the compound obtained in Example 35, a 50 ml methanol / 50 ml tetrahydrofuran mixed solution, 300 mg of 5% palladium carbon was added. The mixture was stirred for 3 h at room temperature under atmospheric pressure in a hydrogen atmosphere. The catalyst was then filtered off to afford 0.92 g (99%) of the title compound.
[435] Example 37
[436] 3-cyclohexyl-6- [4- (2-hydroxyethoxy) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-on
[437] To 5 mg N, N-dimethylformamide solution of 150 mg (0.423 mmol) of the compound obtained in Example 36, 87.7 mg (0.635 mmol) of potassium carbonate and 33 μl (0.466 mmol) of 2-bromoethanol were added. did. The mixture was stirred at 100 ° C. for 1 hour and at 120 ° C. for 2 hours. Further 16 μl (0.233 mmol) of 2-bromoethanol was added and the mixture was stirred at 120 ° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and further recrystallized (toluene) to give 60 mg (36%) of the title compound.
[438] Example 38
[439] 3-cyclohexyl-6- {2-methoxy-4-[(3S) -tetrahydro-3-furanyloxy] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[440] To a 10 mL tetrahydrofuran suspension of 150 mL (0.423 mmol) of the compound obtained in Example 36, 133 mg (0.508 mmol) triphenylphosphine, 51 μl (0.635 mmol) of (R)-(-)-3 Hydroxytetrahydrofuran and 80 μl (0.508 mmol) of diethyl azodicarboxylate were added slowly at room temperature and the mixture was stirred at room temperature for 1 hour. Further, 44 mg (0.169 mmol) triphenylphosphine, 17 μl (0.212 mmol) of (R)-(-)-3-hydroxytetrahydrofuran and 27 μl (0.169 mmol) of diethyl azodicar Voxylate was added and the mixture was stirred at rt for 1.5 h. The reaction mixture was then diluted with ethyl acetate and the dilutions washed sequentially with water and saturated aqueous sodium chloride solution. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 1/2) to give 124 mg (69%) of the title compound.
[441] Example 39
[442] 3-cyclohexyl-6- {2-methoxy-4-[(3R) -tetrahydro-3-furanyloxy] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[443] The same reaction procedure was followed as in Example 38, except that (S)-(+)-3-hydroxytetrahydrofuran was used instead of (R)-(-)-3-hydroxytetrahydrofuran. . In this way, 77 mg (64%) of the title compound were obtained.
[444] Example 40
[445] Methyl [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenoxy ]acetate
[446] The same reaction procedure was followed as in Example 37, except that methyl bromoacetate was used instead of 2-bromoethanol. In this way, 160 mg (89%) of the title compound were obtained.
[447] Example 41
[448] [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenoxy] Acetic acid
[449] To 127 mg (0.298 mmol) of the compound obtained in Example 40, 372 μl (0.372 mmol) of 1M sodium hydroxide were added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was returned to room temperature and diluted with 5 mL of water. Next, 0.4 ml of 1M hydrochloric acid was slowly added. The precipitated solid was collected by filtration to give 85 mg (69%) of the title compound.
[450] Example 42
[451] 3-cyclohexyl-6- {2-methoxy-4-[(1-methyl-4-piperidinyl) oxy] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one monomaleate
[452] The same reaction procedure was followed as in Example 38, except that 4-hydroxy-1-methylpiperidine was used instead of (R)-(-)-3-hydroxytetrahydrofuran. In this way, 62 mg (44%) of 3-cyclohexyl-6- {2-methoxy-4-[(1-methyl-4-piperidinyl) oxy] phenyl} -1-methyl-1,5 -Dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one was obtained as a free compound. Subsequently, 9.6 mg (0.082 mmol) of maleic acid were added to a 1 mL ethanol suspension of 62 mg (0.137 mmol) of the free compound, and the mixture was heated to reflux. Then, the temperature was gradually lowered to room temperature, and the precipitated solid was collected by filtration. By the above procedure, 32 mg (41%) of the title compound were obtained.
[453] Example 43
[454] 3-cyclohexyl-6- (2-methoxy-4-nitrophenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[455] The same reaction procedure was followed as in Example 26, except that 2-methyl-4-nitrobenzoic acid was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 2.33 g (40%) of the title compound were obtained.
[456] Example 44
[457] 6- (4-amino-2-methoxyphenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[458] The same reaction procedure as in Example 3 was carried out except that the compound obtained in Example 43 was used instead of the compound obtained in Example 2. In this way, 0.97 g (48%) of the title compound were obtained.
[459] Example 45
[460] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl Acetamide
[461] The same reaction procedure as in Example 4 was carried out except that the compound obtained in Example 44 was used instead of the compound obtained in Example 3. In this way, 79 mg (quantitative) of the title compound were obtained.
[462] Example 46
[463] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -2-methoxyacetamide
[464] In Example 12, except that the compound obtained in Example 45 was used instead of the compound obtained in Example 6, and methoxyacetic acid was used instead of 4- (4-methyl-1-piperazinyl) benzoic acid. The same reaction process was carried out. In this way, 82 g (96%) of the title compound were obtained.
[465] Example 47
[466] 3-cyclohexyl-6- [2-methoxy-4- (methylamino) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[467] The same reaction procedure as in Example 26 was carried out except that 4-{[(benzoyloxy) carbonyl] (methyl) amino} -2-methoxybenzoic acid was used instead of 4-bromo-2-methoxybenzoic acid. Performed. In this way, 500 g (36%) of the title compound were obtained.
[468] Example 48
[469] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzenesulfonyl chloride
[470] To 750 mg (2.12 mmol) of 2.5 mL concentrated hydrochloric acid / 8.5 mL acetic acid mixed solution obtained in Example 44, a 220 mg (3.2 mmol) sodium nitrite solution in 1.5 mL of water was added under ice cooling. The mixture was stirred at the same temperature for 30 minutes. To the resulting solution, 87 mg (0.65 mmol) of copper dichloride and 4.5 ml of a 22% acetic acid solution of sulfur dioxide were added, and the mixture was stirred at room temperature for 6 hours. Subsequently, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The collected solid was redissolved in dichloromethane and the solution was washed with water and saturated aqueous sodium chloride solution. The washed solution was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Ether was added to the residue and the cake was collected by filtration to give 673 mg (73%) of the title compound.
[471] Example 49
[472] 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[473] To 87.2 mg (0.2 mmol) of 2 mL anhydrous dichloromethane solution obtained in Example 48, 26.6 μl (0.24 mmol) of N-methylpiperazine and 70 μl (0.5 mmol) of triethylamine are added and the mixture is It was stirred at room temperature for 20 hours. Then water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 50/1 to 30/1) to give 87 mg (87%) of the title compound.
[474] Example 50
[475] 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one monochloride
[476] To 87 mg (0.17 mmol) of 2 mL dioxane solution obtained in Example 49, 0.1 mL (0.4 mmol) of 4M dioxane hydrochloride solution was added. Ether was added to the resulting solution, and the precipitated solid was collected by filtration. The solid was purified by recrystallization (ethanol) to give 52.1 mg (56%) of the title compound.
[477] Example 51
[478] 3-cyclohexyl-6- [2-methoxy-4- (4-morpholinylsulfonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-on
[479] The same reaction procedure was followed as in Example 49, except that morpholine was used instead of N-methylpiperazine. In this way, 66.6 mg (72%) of the title compound were obtained.
[480] Example 52
[481] 3-cyclohexyl-6- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[482] The same reaction procedure was followed as in Example 49, except that 4-hydroxypiperidine was used instead of N-methylpiperazine. In this way, 84 mg (84%) of the title compound were obtained.
[483] Example 53
[484] Ethyl 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-meth Methoxyphenyl] sulfonyl} -4-piperidinecarboxylate
[485] The same reaction procedure was followed as in Example 49, except that isonipecotinic acid ethyl ester was used instead of N-methylpiperazine. In this way, 104 mg (75%) of the title compound were obtained.
[486] Example 54
[487] 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] sulfonyl} -4-piperidinecarboxylic acid
[488] To 82 mg (0.15 mmol) of a compound obtained in Example 53 of 2 mL methanol / 3 mL tetrahydrofuran mixed solution, 1 mL (1 mmol) of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. did. The solvent was then distilled off under reduced pressure and the residue was diluted with water. The aqueous layer was washed with ether, then acidified with 2M aqueous hydrochloric acid solution and extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 77 mg (99%) of the title compound.
[489] Example 55
[490] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- [2- (dimethylamino ) Ethyl] -3-methoxybenzenesulfonamide
[491] The same reaction procedure was followed as in Example 49, except that N, N-dimethylethylenediamine was used instead of N-methylpiperazine. In this way, 85 mg (87%) of the title compound were obtained.
[492] Example 56
[493] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- [2- (dimethylamino ) Ethyl] -3-methoxybenzenesulfonamide monochloride
[494] The same reaction procedure as in Example 50 was carried out except that the compound obtained in Example 55 was used instead of the compound obtained in Example 49. In this way, 57.5 mg (64%) of the title compound were obtained.
[495] Example 57
[496] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3methoxy-N- (2 -Methoxyethyl) benzenesulfonamide
[497] The same reaction procedure was followed as in Example 49, except that methoxyethylamine was used instead of N-methylpiperazine. In this way, 79.8 mg (84%) of the title compound were obtained.
[498] Example 58
[499] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (2-hydroxyethyl ) -3-methoxybenzenesulfonamide
[500] The same reaction procedure was followed as in Example 49, except that ethanolamine was used instead of N-methylpiperazine. In this way, 65.4 mg (71%) of the title compound were obtained.
[501] Example 59
[502] 3-cyclohexyl-6- [2-methoxy-4- (4-morpholinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- 4-on
[503] The same reaction procedure was followed as in Example 27, except that morpholine was used instead of N-methylpiperazine. In this way, 49 mg (32%) of the title compound were obtained.
[504] Example 60
[505] 3-cyclohexyl-6- [2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- 4-on
[506] The same reaction procedure was followed as in Example 27, except that piperazine was used instead of N-methylpiperazine. In this way, 81 mg (53%) of the title compound were obtained.
[507] Example 61
[508] 3-cyclohexyl-6- [2-methoxy-4- (4-methoxy-1-piperidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one
[509] The same reaction procedure as in Example 27 was performed except that the compound obtained in Preparation Example 40 was used instead of N-methylpiperazine. In this way, 145 mg (89%) of the title compound were obtained.
[510] Example 62
[511] 3-cyclohexyl-6- [2-methoxy-4- (4-methoxy-1-piperidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one monomethanesulfonate
[512] 115 mg (0.255 mmol) of the 1.15 mL ethanol suspension obtained in Example 61 was heated to 60 ° C. To this system, 17.4 μl (0.267 mmol) of methanesulfonic acid were added and the temperature of the mixture was slowly lowered to room temperature. The precipitated solid was collected by filtration to obtain 108 mg (77%) of the title compound.
[513] Example 63
[514] 6- (4-bromo-2-methoxyphenyl) -3-cycloheptyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[515] The same reaction procedure as in Example 26 was carried out except that the compound obtained in Preparation Example 42 was used instead of the compound obtained in Preparation Example 32. In this way, 2.28 g (80%) of the title compound were obtained.
[516] Example 64
[517] 3-cycloheptyl-6- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one
[518] The same reaction procedure as in Example 27 was carried out except that the compound obtained in Example 63 was used instead of the compound obtained in Example 26. In this way, 188 mg (90%) of the title compound were obtained.
[519] Example 65
[520] 4- (3-Cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzoic acid
[521] Under a stream of nitrogen, 1.6 ml of n-butyl lithium (2.5 mmol of 1.56M hexane solution) was added dropwise at -78 ° C to a 500 ml (1.20 mmol) solution of 10 ml tetrahydrofuran solution obtained in Example 26. After the mixture was stirred at the same temperature for 30 minutes, carbon dioxide gas was blown into the reaction mixture for 45 minutes. Further, the reaction mixture was stirred at -78 ° C for 2 hours, then allowed to come to room temperature. The reaction mixture was alkalized by addition of 1M aqueous sodium hydroxide solution and washed with dichloromethane. The aqueous layer was acidified with 6M aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration to obtain 200 mg (44%) of the title compound.
[522] Example 66
[523] 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1-piperazinyl) carbonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[524] To 86 mg (0.23 mmol) of a 2 mL dichloromethane suspension of the compound obtained in Example 65, 31 μl (0.28 mmol) of N-methylpiperazine and 53 mg (0.28 mmol) of 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide hydrochloride was added and the mixture was stirred at rt for 18 h. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 to 10/1) to give 80 mg (75%) of the title compound.
[525] Example 67
[526] 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1-piperazinyl) carbonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one monomethanesulfonate
[527] To 45 mg (0.097 mmol) of the compound obtained in Example 66 of 1 ml methanol / 1 ml tetrahydrofuran mixed solution, 6.4 µl (0.098 mmol) of methanesulfonic acid was added, and the mixture was stirred at room temperature for 10 minutes. Ether was added to the resulting solution, and the precipitated solid was collected by filtration to obtain 43.9 mg (81%) of the title compound.
[528] Example 68
[529] 3-cyclohexyl-6- [2-methoxy-4- (4-morpholinylcarbonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrid Midin-4-one
[530] The same reaction procedure was followed as in Example 66, except that morpholine was used instead of N-methylpiperazine. In this way, 84.3 mg (85%) of the title compound were obtained.
[531] Example 69
[532] 3-cyclohexyl-6- {4-[(4-hydroxy-1-piperidinyl) carbonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[533] The same reaction procedure was followed as in Example 66, except that 4-hydroxypiperidine was used instead of N-methylpiperazine. In this way, 57 mg (47%) of the title compound were obtained.
[534] Example 70
[535] 3-cyclohexyl-6- {2-methoxy-4-[(4-methoxy-1-piperidinyl) carbonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[536] The same reaction procedure as in Example 66 was carried out except that the compound obtained in Preparation Example 40 was used instead of N-methylpiperazine. In this way, 68.7 mg (65%) of the title compound were obtained.
[537] Example 71
[538] {[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzoyl] Amino} acetic acid ethyl ester
[539] The same reaction procedure was followed as in Example 66, except that glycine ethyl ester hydrochloride was used instead of N-methylpiperazine. In this way, 75 mg (73%) of the title compound were obtained.
[540] Example 72
[541] {[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzoyl] Amino} acetic acid
[542] To 60 mg (0.13 mmol) of 1 ml methanol / 3 ml 1,4-dioxane mixed solution obtained in Example 71, 1 ml of 1M aqueous sodium hydroxide solution was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Was stirred. The solvent was then distilled off under reduced pressure, and the residue was diluted with water, then the diluent was washed with ether. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution and then extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 53 mg (93%) of the title compound.
[543] Example 73
[544] 3-cyclohexyl-6- {2-methoxy-4-[(2-methoxyethyl) (methyl) amino] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one
[545] The same reaction procedure was followed as in Example 27, except that N- (2-methoxyethyl) methylamine was used instead of N-methylpiperazine. In this way, 182 mg (86%) of the title compound were obtained.
[546] Example 74
[547] 3-cyclohexyl-6- (5-fluoro-2-methoxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[548] The same reaction procedure was followed as in Example 26, except that 5-fluoro-2-methoxybenzoic acid was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 244 mg (76%) of the title compound were obtained.
[549] Example 75
[550] Ethyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperazinecarboxylate
[551] The same reaction procedure was followed as in Example 27, except that ethyl 4-piperidinecarboxylate was used instead of N-methylpiperazine. In this way, 28 mg (14%) of the title compound were obtained.
[552] Example 76
[553] 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -4-piperazinecarboxylic acid
[554] The same reaction procedure as in Example 41 was carried out except that the compound obtained in Example 75 was used instead of the compound obtained in Example 40. In this way, 40 mg (quantitative) of the title compound were obtained.
[555] Example 77
[556] 3-cycloheptyl-6- [2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- 4-on
[557] The same reaction procedure was followed as in Example 27, except that the compound obtained in Example 63 was used instead of the compound obtained in Example 26 and piperazine was used instead of N-methylpiperazine. In this way, 156 mg (77%) of the title compound were obtained.
[558] Example 78
[559] 3-cycloheptyl-6- [2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- 4-one monomethanesulfonate
[560] The same reaction procedure as in Example 62 was carried out, except that the compound obtained in Example 77 was used instead of the compound obtained in Example 61. In this way, 108 mg (72%) of the title compound were obtained.
[561] Example 79
[562] Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -2-fluoro -5-methoxyphenyl] -1-piperazinecarboxylate
[563] The same reaction procedure as in Example 26 was carried out except that the compound obtained in Preparation 46 was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 366 mg (40%) of the title compound were obtained.
[564] Example 80
[565] 3-cycloheptyl-6- [5-fluoro-2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one
[566] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 79 was used instead of the compound obtained in Example 35. In this way, 144 mg (63%) of the title compound were obtained.
[567] Example 81
[568] 3-cycloheptyl-6- [5-fluoro-2-methoxy-4- (1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one monomethanesulfonate
[569] The same reaction procedure as in Example 62 was carried out except that the compound obtained in Example 80 was used instead of the compound obtained in Example 61. In this way, 62 mg (85%) of the title compound were obtained.
[570] Example 82
[571] 3-cyclohexyl-6- [5-fluoro-2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[572] To 65 mg (0.15 mmol) of a compound obtained in Example 80 in a 2 ml ethanol / 1 ml water solution, 500 µl formalin and 1 ml formic acid were added, and the mixture was heated at reflux for 4 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 30/1 to 20/1) to give 37 mg (55%) of the title compound.
[573] Example 83
[574] 3-cyclohexyl-6- (2-methoxy-4- {methyl [2- (methylamino) ethyl] amino} phenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one
[575] The same reaction procedure was followed as in Example 27, except that N, N'-dimethylethylenediamine was used instead of N-methylpiperazine. In this way, 123 mg (71%) of the title compound were obtained.
[576] Example 84
[577] 3-cyclohexyl-6- (2-methoxy-4- {methyl [2- (methylamino) ethyl] amino} phenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one monomethanesulfonate
[578] The same reaction procedure as in Example 62 was carried out, except that the compound obtained in Example 83 was used instead of the compound obtained in Example 61. In this way, 93 mg (71%) of the title compound were obtained.
[579] Example 85
[580] 6- (4-bromo-2-ethoxyphenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[581] The same reaction procedure was followed as in Example 26, except that 4-bromo-2-ethoxybenzoic acid was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 3.79 g (93%) of the title compound were obtained.
[582] Example 86
[583] 3-cyclohexyl-6- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one
[584] The same reaction procedure as in Example 27 was carried out except that the compound obtained in Example 85 was used instead of the compound obtained in Example 26. In this way, 159 mg (76%) of the title compound were obtained.
[585] Example 87
[586] 3-cyclohexyl-6- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one monomethanesulfonate
[587] The same reaction procedure as in Example 62 was carried out except that the compound obtained in Example 86 was used instead of the compound obtained in Example 61. In this way, 83 mg (50%) of the title compound were obtained.
[588] Example 88
[589] Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-ethoxy Phenyl] -4-piperidinyl (methyl) carbamate
[590] Example 27, except for using the compound obtained in Example 85 instead of the compound obtained in Example 26 and using benzyl methyl (4-piperidinyl) carbamate hydrochloride instead of N-methylpiperazin The same reaction process as in In this way, 234 mg (77%) of the title compound were obtained.
[591] Example 89
[592] 3-cyclohexyl-6- {2-ethoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[593] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 88 was used instead of the compound obtained in Example 35. In this way, 46 mg (32%) of the title compound were obtained.
[594] Example 90
[595] 3-cyclohexyl-6- {2-ethoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one monomethanesulfonate
[596] The same reaction procedure as in Example 62 was carried out, except that the compound obtained in Example 89 was used instead of the compound obtained in Example 61. In this way, 18 mg (38%) of the title compound were obtained.
[597] Example 91
[598] Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Phenyl] -4-pyridinyl (methyl) carbamate
[599] The same reaction procedure was followed as in Example 16, except that benzyl methyl (4-piperidinyl) carbamate hydrochloride was used instead of N-methylpiperazine. In this way, 330 mg (94%) of the title compound were obtained.
[600] Example 92
[601] 1-cyclohexyl-5- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[602] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 91 was used instead of the compound obtained in Example 35. In this way, 322 mg (89%) of the title compound were obtained.
[603] Example 93
[604] Benzyl 1- [4- (3-cycloheptyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperidinyl (methyl) carbamate
[605] Example 27 except for using the compound obtained in Example 63 instead of the compound obtained in Example 26 and using benzyl methyl (4-piperidinyl) carbamate hydrochloride instead of N-methylpiperazin The same reaction process as in In this way, 179 mg (52%) of the title compound were obtained.
[606] Example 94
[607] 3-cycloheptyl-6- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[608] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 93 was used instead of the compound obtained in Example 35. In this way, 124 mg (quantitative) of the title compound were obtained.
[609] Example 95
[610] 3-cycloheptyl-6- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one monomethanesulfonate
[611] The same reaction procedure as in Example 62 was carried out except that the compound obtained in Example 94 was used instead of the compound obtained in Example 61. In this way, 112 mg (81%) of the title compound were obtained.
[612] Example 96
[613] Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperidinyl (ethyl) carbamate
[614] The same reaction procedure was followed as in Example 27, except that benzyl ethyl (4-piperidinyl) carbamate hydrochloride was used instead of N-methylpiperazine. In this way, 195 mg (54%) of the title compound were obtained.
[615] Example 97
[616] 3-cyclohexyl-6- {2-methoxy-4- [4- (ethylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[617] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 96 was used instead of the compound obtained in Example 35. In this way, 108 mg (79%) of the title compound were obtained.
[618] Example 98
[619] Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Phenyl] -4-piperidinyl (ethyl) carbamate
[620] The same reaction procedure was followed as in Example 16, except that benzyl ethyl (4-piperidinyl) carbamate hydrochloride was used instead of N-methylpiperazine. In this way, 272 mg (76%) of the title compound were obtained.
[621] Example 99
[622] 1-cyclohexyl-5- {2-methoxy-4- [4- (ethylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[623] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 98 was used instead of the compound obtained in Example 35. In this way, 131 mg (72%) of the title compound were obtained.
[624] Example 100
[625] 1-cyclohexyl-5- [4- (benzyloxy) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrid Midin-7-on
[626] The same reaction procedure as in Example 14 was carried out except that 4- (benzyloxy) -2-methoxybenzoic acid was used instead of the compound obtained in Preparation Example 34. In this way, 1.37 g (77%) of the title compound were obtained.
[627] Example 101
[628] 1-cyclohexyl-5- (4-hydroxy-2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[629] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 100 was used instead of the compound obtained in Example 35. In this way, 1.08 g (99%) of the title compound were obtained.
[630] Example 102
[631] 1-cyclohexyl-5- (2-methoxy-4- {methyl [2- (methylamino) ethyl] amino} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[632] The same reaction procedure was followed as in Example 16, except that N, N'-dimethylethylenediamine was used instead of N-methylpiperazine. In this way, 107 mg (62%) of the title compound were obtained.
[633] Example 103
[634] 1-cyclohexyl-5- (2-methoxy-4- {methyl [2- (methylamino) ethyl] amino} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one monofumarate
[635] The same reaction procedure was followed as in Example 62, except that the compound obtained in Example 102 was used instead of the compound obtained in Example 61 and fumaric acid was used instead of methanesulfonic acid. In this way, 96 mg (75%) of the title compound were obtained.
[636] Example 104
[637] 1-cyclohexyl-5- {4-[(3R) -3- (dimethylamino) pyrrolidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[638] The same reaction procedure was followed as in Example 16, except that (3R)-(dimethylamino) pyrrolidine was used instead of N-methylpiperazine. In this way, 244 mg (75%) of the title compound were obtained.
[639] Example 105
[640] 1-cyclohexyl-5- {4-[(3S) -3- (dimethylamino) pyrrolidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[641] The same reaction procedure was followed as in Example 16, except that (3S)-(dimethylamino) pyrrolidine was used instead of N-methylpiperazine. In this way, 80 mg (49%) of the title compound were obtained.
[642] Example 106
[643] 5- {4-[[2- (benzyloxy) ethyl] (methyl) amino] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[644] The same reaction procedure was followed as in Example 16, except that N- [2- (benzyloxy) ethyl] -N-methylamine was used instead of N-methylpiperazine. In this way, 80 mg (49%) of the title compound were obtained.
[645] Example 107
[646] 1-cyclohexyl-5- {4-[(2-hydroxyethyl) (methyl) amino] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[647] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 106 was used instead of the compound obtained in Example 35. In this way, 82 mg (64%) of the title compound were obtained.
[648] Example 108
[649] 5- (4- {4-[(benzyloxy) methyl] -1-piperidinyl} -2-methoxyphenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[650] The same reaction procedure as in Example 16 was carried out except that the compound obtained in Preparation 48 was used instead of N-methylpiperazine. In this way, 150 mg (66%) of the title compound were obtained.
[651] Example 109
[652] 1-cyclohexyl-5- {4- [4- (hydroxymethyl) -1-piperidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[653] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 108 was used instead of the compound obtained in Example 35. In this way, 75 mg (77%) of the title compound were obtained.
[654] Example 110
[655] 1-cyclohexyl-5- (2-methoxy-4- {methyl [3- (methylamino) propyl] amino} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[656] The same reaction procedure was followed as in Example 16, except that N, N'-dimethyl-1,3-propanediamine was used instead of N-methylpiperazine. In this way, 95 mg (53%) of the title compound were obtained.
[657] Example 111
[658] 1-cyclohexyl-5- (2-methoxy-4- {methyl [3- (methylamino) propyl] amino} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one monofumarate
[659] The same reaction procedure was followed as in Example 62, except that the compound obtained in Example 110 was used instead of the compound obtained in Example 61, and fumaric acid was used instead of methanesulfonic acid. In this way, 92 mg (84%) of the title compound were obtained.
[660] Example 112
[661] 1-cyclohexyl-5- [2-methoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[662] The same reaction procedure was followed as in Example 16, except that N-methyl homopiperazine was used instead of N-methylpiperazine. In this way, 159 mg (98%) of the title compound were obtained.
[663] Example 113
[664] 5- {4-[[2- (benzyloxy) ethyl] (ethyl) amino] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[665] The same reaction procedure as in Example 16 was carried out except that the compound obtained in Preparation Example 50 was used instead of N-methylpiperazine. In this way, 188 mg (87%) of the title compound were obtained.
[666] Example 114
[667] 1-cyclohexyl-5- {4-[(2-hydroxyethyl) (ethyl) amino] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[668] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 113 was used instead of the compound obtained in Example 35. In this way, 120 mg (81%) of the title compound were obtained.
[669] Example 115
[670] 1-cyclohexyl-5- {4-[(2-hydroxyethyl) (ethyl) amino] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one monohydrochloride
[671] The same reaction procedure as in Example 62 was carried out except that the compound obtained in Example 114 was used instead of the compound obtained in Example 61, and a 4N-hydrochloric acid / 1,4-dioxane solution was used instead of methanesulfonic acid. Performed. In this way, 104 mg (87%) of the title compound were obtained.
[672] Example 116
[673] 5- (4-Bromo-2-ethoxyphenyl-1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[674] The same reaction procedure as in Example 14 was carried out except that 4-bromo-2-ethoxybenzoic acid was used instead of the compound obtained in Preparation 34. In this way, 2.16 g (quantitative) of the title compound were obtained.
[675] Example 117
[676] 3-cyclohexyl-6- {2-ethoxy-4-[(2-methoxyethyl) amino] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] Pyrimidin-4-one
[677] The same reaction procedure was followed as in Example 27, except that the compound obtained in Example 85 was used instead of the compound obtained in Example 26, and 2-methoxyethylamine was used instead of N-methylpiperazine. . In this way, 46 mg (31%) of the title compound were obtained.
[678] Example 118
[679] 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxyphenyl ] -4-piperidinyl (methyl) formamide
[680] To 96 mg (0.21 mmol) of a 3 ml methylene chloride solution of the compound obtained in Example 92, 16 µl (0.43 mmol) of formic acid, 119 µl (0.85 mmol) of triethylamine and 100 µl of propanephosphonic anhydride (25 % Ethyl acetate solution) was added and the mixture was stirred at rt for 1 h. Further 16 μl (0.43 mmol) of formic acid, 119 μl (0.85 mmol) of triethylamine and 100 μl of propanephosphonic anhydride (25% ethyl acetate solution) were added three times, and the mixture was then stirred at room temperature for 14.5 hours. Stirred. Then water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 60/1) to give 92 mg (90%) of the title compound.
[681] Example 119
[682] N- {1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3- Methoxyphenyl] -4-piperidinyl} -N-methylacetamide
[683] To 105 mg (0.23 mmol) of a 4 mL methylene chloride solution of the compound obtained in Example 92, 33 μl (0.35 mmol) of acetic anhydride and 33.7 μl (0.47 mmol) of pyridine are added and the mixture is stirred at room temperature for 1 hour. Stirred. Then water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 60/1) to give 92 mg (80%) of the title compound.
[684] Example 120
[685] Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-ethoxy Phenyl] -4-piperidinyl (methyl) carbamate
[686] Example 16 except for using the compound obtained in Example 116 instead of the compound obtained in Example 15 and using benzyl methyl (4-piperidinyl) carbamate hydrochloride instead of N-methylpiperazine. The same reaction process as in In this way, 176 mg (75%) of the title compound were obtained.
[687] Example 121
[688] 1-cyclohexyl-5- {2-ethoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[689] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 120 was used instead of the compound obtained in Example 35. In this way, 97 mg (82%) of the title compound were obtained.
[690] Example 122
[691] 1-cyclohexyl-5- [4- (4-hydroxy-1-methyl-4-piperidinyl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[692] In argon atmosphere, 0.95 ml of n-butyl lithium (1.59 M / hexane solution, 1.51 mmol) was added dropwise at -78 ° C to 300 mg (0.72 mmol) of a 10 ml anhydrous tetrahydrofuran solution of the compound obtained in Example 15. did. The mixture was stirred at −78 ° C. for 30 minutes, and then 133 μl (1.08 mmol) of 1-methyl-4-piperidone were added, then the mixture was slowly heated to 0 ° C. over a course of 1 hour. Then, after adding water to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/1) to give 179 mg (55%) of the title compound.
[693] Example 123
[694] 1-cyclohexyl-5- [2-methoxy-4- (1-methyl-1,2,3,6-tetrahydro-4-pyridinyl) phenyl] -3-methyl-1,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one
[695] To 160 mg (0.35 mmol) of a 10 ml toluene solution obtained in Example 122, 135 mg (0.71 mmol) of p-toluenesulfonic acid monohydrate were added, and the mixture was refluxed using a Dean-Stark dehydrator for 22 hours. Heated. The reaction mixture was returned to room temperature and washed with saturated aqueous sodium hydrogen carbonate solution. After drying the system with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 30/1) to give 78 mg (51%) of the title compound.
[696] Example 124
[697] 1-cyclohexyl-5- [2-methoxy-4- (1-methyl-4-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one
[698] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 123 was used instead of the compound obtained in Example 35. In this way, 32 mg (62%) of the title compound were obtained.
[699] Example 125
[700] 1-cyclohexyl-5- [4- (1,4-diazepane-1-yl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one
[701] The same reaction procedure was followed as in Example 16, except that homopiperazine was used instead of N-methylpiperazine. In this way, 286 mg (91%) of the title compound were obtained.
[702] Example 126
[703] 5- [4- (4-acetyl-1,4-diazepan-1-yl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[704] The same reaction procedure as in Example 119 was carried out except that the compound obtained in Example 125 was used instead of the compound obtained in Example 92. In this way, 286 mg (91%) of the title compound were obtained.
[705] Example 127
[706] 1-cyclohexyl-5- [4- (4-ethyl-1,4-diazepan-1-yl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[707] To 102 mg (0.23 mmol) of 4 mL N, N-dimethylformamide solution obtained in Example 125, 49 μl (0.35 mmol) of triethylamine and 23 μl (0.29 mmol) of ethyl iodide were added at room temperature And the mixture was stirred for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed sequentially with water and saturated aqueous sodium chloride solution. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 20/1 to 10/1) to give 65 mg (60%) of the title compound.
[708] Example 128
[709] Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -2-fluoro -5-methoxyphenyl] -4-piperidinyl (methyl) carbamate
[710] The same reaction procedure as in Example 14 was carried out except that the compound obtained in Preparation Example 53 was used instead of the compound obtained in Preparation Example 34. In this way, 257 mg (48%) of the title compound were obtained.
[711] Example 129
[712] 1-cyclohexyl-5- {5-fluoro-2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H- Pyrazolo [4,3-d] pyrimidin-7-one
[713] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 128 was used instead of the compound obtained in Example 35. In this way, 129 mg (71%) of the title compound were obtained.
[714] Example 130
[715] 1-cyclohexyl-5- [4- (4-methyl-1,4-diazepan-1-yl) -2-ethoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[716] The same reaction procedure was followed as in Example 16, except that the compound obtained in Example 116 was used instead of the compound obtained in Example 15, and methyl homopiperazine was used instead of N-methylpiperazine. In this way, 94 mg (58%) of the title compound were obtained.
[717] Example 131
[718] 3-cyclohexyl-6- {4-[[2- (dimethylamino) ethyl] (methyl) amino] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[719] The same reaction procedure was followed as in Example 27, except that N, N, N'-trimethylethylenediamine was used instead of N-methylpiperazine. In this way, 174 mg (79%) of the title compound were obtained.
[720] Example 132
[721] 3-cyclohexyl-6- {4-[[2- (dimethylamino) ethyl] (methyl) amino] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one monomethanesulfonate
[722] 130 mg (0.30 mmol) of 2 mL methanol suspension of the compound obtained in Example 131 was heated to 50 ° C. To the system, 20 μl (0.30 mmol) of methanesulfonic acid was added and the mixture was slowly lowered to room temperature. The solvent was then distilled off under reduced pressure and the residue was dissolved by addition of ethyl acetate. Ether was added to the resulting solution, and the precipitated solid was collected by filtration to obtain 89 mg (55%) of the title compound.
[723] Example 133
[724] 3-cyclohexyl-6- [4- (1,4-diazepane-1-yl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one
[725] The same reaction procedure was followed as in Example 27, except that homopiperazine was used instead of N-methylpiperazine. In this way, 165 mg (76%) of the title compound were obtained.
[726] Example 134
[727] 3-cyclohexyl-6- [4- (1,4-diazepane-1-yl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one monomethanesulfonate
[728] To 74 mg (0.17 mmol) of a compound obtained in Example 133, 2 mL methanol solution, 11.2 μL (0.17 mmol) of methanesulfonic acid was added, and the mixture was heated at reflux for 10 minutes. The temperature of the reaction mixture was then slowly lowered to room temperature. Ether was added to the resulting solution, and the precipitated solid was collected by filtration to obtain 62 mg (69%) of the title compound.
[729] Example 135
[730] 3-cyclohexyl-6- [2-methoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[731] To 60 mg (0.14 mmol) of 2 mL ethanol / 2 mL water mixture solution obtained in Example 133, 30 mg of paraformaldehyde and 1 mL of formic acid were added, and the mixture was heated at reflux for 24 hours. The reaction mixture was then brought to room temperature, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to give 53 mg (84%) of the title compound.
[732] Example 136
[733] 3-cyclohexyl-6- [2-methoxy-4- (4-methyl-1,4-diazepan-1-yl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one monomethanesulfonate
[734] The same reaction procedure as in Example 134 was carried out except that the compound obtained in Example 135 was used instead of the compound obtained in Example 133. In this way, 31 mg (60%) of the title compound were obtained.
[735] Example 137
[736] 6- [4-bromo-2- (difluoromethoxy) phenyl] -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine-4 -On
[737] The same reaction procedure as in Example 26 was carried out except that the compound obtained in Preparation Example 55 was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 231 mg (16%) of the title compound were obtained.
[738] Example 138
[739] 3-cyclohexyl-6- [2- (difluoromethoxy) -4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[740] The same reaction procedure as in Example 27 was carried out except that the compound obtained in Example 137 was used instead of the compound obtained in Example 26. In this way, 90 mg (58%) of the title compound were obtained.
[741] Example 139
[742] 3-cyclohexyl-6- [2- (difluoromethoxy) -4- (4-methyl-1-piperazinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one monomethanesulfonate
[743] 65 mg (0.138 mmol) of the 2 mL methanol suspension of the compound obtained in Example 138 were heated to 50 ° C. To the system, 9.1 μl (0.14 mmol) of methanesulfonic acid was added and the mixture was heated at reflux for 15 minutes. Subsequently, the reaction mixture was brought to room temperature, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give 16 mg (20%) of the title compound.
[744] Example 140
[745] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl Urea
[746] To 200 mg (0.567 mmol) of 2 mL water / 4 mL acetic acid solution obtained in Example 44, 377 mg (4.65 mmol) potassium cyanide was added, and the mixture was stirred at room temperature for 3 hours. Subsequently, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to give 126 mg (56%) of the title compound.
[747] Example 141
[748] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -N- (methylsulfonyl) methanesulfonamide
[749] To 114 mg (0.323 mmol) of 6 mL tetrahydrofuran solution obtained in Example 44, 49 μl (0.63 mmol) of methanesulfonyl chloride and 90 μl (0.65 mmol) of triethylamine were added and the mixture was Stir at room temperature for 1 hour. Then 23 μl (0.3 mmol) of methanesulfonyl chloride was further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 30/1) to give 123 mg (75%) of the title compound.
[750] Example 142
[751] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] Methanesulfonamide
[752] To 100 mg (0.20 mg) of 2 mL methanol solution of the compound obtained in Example 141, 1 mL of 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with water and the dilution washed with dichloromethane. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution, the precipitated solid was collected by filtration, dried and recrystallized to give 19 mg (22%) of the title compound. Obtained.
[753] Example 143
[754] 3-cyclohexyl-6- [2-methoxy-4- (2-oxo-1,3-oxazolidin-3-yl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[755] To 150 mg (0.425 mmol) of a 6 mL tetrahydrofuran solution obtained in Example 44, 79 μl (0.765 mmol) of 2-chloroethyl chloroformate and triethylamine were added, and the mixture was stirred at room temperature for 20 hours. Was stirred. Further 30 μl (0.29 mmol) of 2-chloroethyl chloroformate were added and the mixture was stirred at room temperature for 4 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To a 2 ml ethanol solution of the residue, 1 ml 1M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then neutralized with 1M aqueous hydrochloric acid solution and extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 116 mg (65%) of the title compound.
[756] Example 144
[757] 3-cyclohexyl-6- [2-methoxy-4- (2-oxo-1-imidazolidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4- d] pyrimidin-4-one
[758] To 150 mg (0.425 mmol) of a 4 mL tetrahydrofuran solution obtained in Example 44 was added 71 μl (0.829 mmol) of 2-chloroethyl isocyanate and the mixture was stirred at room temperature for 20 hours. Subsequently, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue, 4 ml of ethanol and 2 ml of 1M aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was then neutralized with 1M aqueous hydrochloric acid solution and extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 1/1) to give 95 mg (53%) of the title compound.
[759] Example 145
[760] Ethyl [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenylcart Barmate
[761] To 100 mg (0.283 mmol) of 6 mL tetrahydrofuran suspension obtained in Example 44, 48 μl (0.50 mmol) of ethyl chlorocarbonate and 98 μl (0.707 mmol) of triethylamine are added and the mixture is It was stirred at room temperature for 3 hours. Further 48 μl (0.50 mmol) of ethyl chlorocarbonate and 1 mL of pyridine were added and the mixture was stirred at room temperature for 18 hours. Subsequently, 1M aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 to 2/1) to give 68 mg (57%) of the title compound.
[762] Example 146
[763] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -N-methylacetamide
[764] The same reaction procedure as in Example 4 was carried out except that the compound obtained in Example 47 was used instead of the compound obtained in Example 3. In this way, 94 mg (92%) of the title compound were obtained.
[765] Example 147
[766] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -N-methylmethanesulfonamide
[767] To a 3 ml pyridine solution of 91.8 mg (0.25 mmol) of the compound obtained in Example 47, 23.2 µl (0.3 mmol) of methanesulfonyl chloride were added and the mixture was stirred at room temperature for 20 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1 to ethyl acetate only) to give 97.2 mg (87%) of the title compound.
[768] Example 148
[769] N- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxyphenyl ] -4-morpholine carboxamide
[770] To 100 mg (0.283 mmol) of a 3 ml dichloromethane suspension obtained in Example 44, 28 mg (0.0944 mmol) of triphosphene and 79 μl (0.566 mmol) of triethylamine were added and the mixture was allowed to stand at room temperature. Stir for 15 minutes. Then 25 μl (0.283 mmol) of morpholine were added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 15/1) to give 95 mg (72%) of the title compound.
[771] Example 149
[772] 3-cyclohexyl-6- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[773] To 200 mg (0.46 mmol) of a compound obtained in Example 30 in a 4 ml 1,2-dichloroethane solution, 100 µl (0.92 mmol) of methylamine (30% methanol solution), 146 mg (0.69 mmol) of sodium tria Cetoxyborohydride and 26 μl of acetic acid were added and the mixture was stirred at room temperature for 6 hours. Subsequently, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / chloroform / methanol = 10/10/1) to give 176 mg (85%) of the title compound.
[774] Example 150
[775] 3-cyclohexyl-6- {2-methoxy-4- [4- (methylamino) -1-piperidinyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one monomethanesulfonate
[776] The same reaction procedure as in Example 62 was carried out except that the compound obtained in Example 149 was used instead of the compound obtained in Example 61. In this way, 38 mg (55%) of the title compound were obtained.
[777] Example 151
[778] N '-[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -N- (2-hydroxyethyl) -N-methylurea
[779] The same reaction procedure was followed as in Example 148, except that 2- (methylamino) ethanol was used instead of morpholine. In this way, 162 mg (42%) of the title compound were obtained.
[780] Example 152
[781] 3-cyclohexyl-6- [2-methoxy-4- (3-methyl-2-oxo-1-imidazolidinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[782] In a 3 ml tetrahydrofuran suspension of 114 mg (0.25 mmol) of the compound obtained in Example 151, 52 mg (0.30 mmol) of 1,1'-azobis (N, N-dimethylformamide) and 75 μl (0.30) mmol) n-tributylphosphine was added and the mixture was stirred at room temperature for 20 hours. Then water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 71.6 mg (66%) of the title compound.
[783] Example 153
[784] 3-cyclohexyl-6- {4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[785] The same reaction procedure as in Example 135 was carried out except that the compound obtained in Example 149 was used instead of the compound obtained in Example 133. In this way, 68.3 mg (74%) of the title compound were obtained.
[786] Example 154
[787] 3-cyclohexyl-6- {4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one monomethanesulfonate
[788] To 50 mg (0.108 mmol) of 1 mL ethanol solution of the compound obtained in Example 153, 7.1 mL (0.110 mmol) of methanesulfonic acid was added, and the mixture was heated at reflux for 10 minutes. The reaction mixture was then cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization (ethyl acetate-ethanol) to give 28 mg (46%) of the title compound.
[789] Example 155
[790] 3-cyclohexyl-6- [4- (1,1-dioxido-2-isothiazolidinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[791] To 2 mg pyridine solution of 100 mg (0.280 mmol) of the compound obtained in Example 44, 85.2 μl (0.700 mmol) of 3-chloropropanesulfonyl chloride were added, and the mixture was stirred at room temperature for 8 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. 2 mL of ethanol and 1 M aqueous sodium hydroxide solution were added to the residue, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then neutralized with 1M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution. The washed layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 68 mg (53%) of the title compound.
[792] Example 156
[793] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (2-hydroxyethyl ) -3-methoxy-N-methylbenzenesulfonamide
[794] The same reaction procedure was followed as in Example 49, except that 2- (methylamino) ethanol was used instead of N-methylpiperazine. In this way, 54 mg (57%) of title compound were obtained.
[795] Example 157
[796] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (2- (dimethylamino Ethyl) -3-methoxy-N-methylbenzenesulfonamide
[797] The same reaction procedure was followed as in Example 49, except that N, N, N'-trimethylethylenediamine was used instead of N-methylpiperazine. In this way, 56 mg (56%) of the title compound were obtained.
[798] Example 158
[799] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (2- (dimethylamino Ethyl) -3-methoxy-N-methylbenzenesulfonamide monomethanesulfonate
[800] To 44 mg (0.0876 mmol) of 1 mL ethanol solution of the compound obtained in Example 157, 5.8 μL (0.0894 mmol) of methanesulfonic acid was added, and the mixture was heated under reflux for 10 minutes. The reaction mixture was then cooled to room temperature and ether was added to the reaction mixture. The precipitated solid was collected by filtration. The solid was purified by recrystallization (ethyl acetate-ethanol) to give 22 mg (42%) of the title compound.
[801] Example 159
[802] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -N- (3-hydroxypropyl ) -3-methoxybenzenesulfonamide
[803] The same reaction procedure was followed as in Example 49, except that n-propanolamine was used instead of N-methylpiperazine. In this way, 148 mg (54%) of the title compound were obtained.
[804] Example 160
[805] 3-cyclohexyl-6- [4- (1,4-diazepane-1-ylsulfonyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one
[806] The same reaction procedure was followed as in Example 49, except that homopiperazine was used instead of N-methylpiperazine. In this way, 115 mg (50%) of the title compound were obtained.
[807] Example 161
[808] 3-cyclohexyl-6- [4- (1,4-diazepane-1-ylsulfonyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one monomethanesulfonate
[809] The same reaction procedure as in Example 62 was carried out, except that the compound obtained in Example 160 was used instead of the compound obtained in Example 61. In this way, 15 mg (36%) of the title compound were obtained.
[810] Example 162
[811] 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H -Pyrazolo [3,4-d] pyrimidin-4-one
[812] The same reaction procedure was performed as in Example 135, except that the compound obtained in Example 160 was used instead of the compound obtained in Example 133. In this way, 47.6 mg (77%) of the title compound were obtained.
[813] Example 163
[814] 3-cyclohexyl-6- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H -Pyrazolo [3,4-d] pyrimidin-4-one monomethanesulfonate
[815] The same reaction procedure as in Example 154 was performed except that the compound obtained in Example 162 was used instead of the compound obtained in Example 153. In this way, 20 mg (46%) of the title compound were obtained.
[816] Example 164
[817] 3-cyclohexyl-6- {4-[(3-hydroxy-1-pyrrolidinyl) sulfonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[818] The same reaction procedure was followed as in Example 49, except that 3-pyrrolidinol was used instead of N-methylpiperazine. In this way, 85 mg (76%) of the title compound were obtained.
[819] Example 165
[820] 3-cyclohexyl-6- [2-methoxy-4- (4-thiomorpholinylsulfonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrid Midin-4-one
[821] The same reaction procedure was followed as in Example 49, except that thiomorpholine was used instead of N-methylpiperazine. In this way, 86.3 mg (75%) of the title compound were obtained.
[822] Example 166
[823] 3-cyclohexyl-6- [4- (1,4-dioxa-8-azaspiro [4,5] deca-8-ylsulfonyl) -2-methoxyphenyl] -1-methyl-1,5- Dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[824] The same reaction procedure was followed as in Example 49, except that 1,4-dioxa-8-azaspiro [4,5] decane was used instead of N-methylpiperazine. In this way, 254 mg (68%) of the title compound were obtained.
[825] Example 167
[826] 3-cyclohexyl-6- {2-methoxy-4-[(4-oxo-1-piperidinyl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[827] The same reaction procedure as in Example 30 was carried out except that the compound obtained in Example 166 was used instead of the compound obtained in Example 29. In this way, 182 mg (99%) of the title compound were obtained.
[828] Example 168
[829] 3-cyclohexyl-6- (2-methoxy-4-{[4- (methylamino) -1-piperidinyl] sulfonyl} phenyl) -1-methyl-1,5-dihydro-4H-pyra Solo [3,4-d] pyrimidin-4-one
[830] The same reaction procedure as in Example 149 was carried out except that the compound obtained in Example 167 was used instead of the compound obtained in Example 30. In this way, 92 mg (60%) of the title compound were obtained.
[831] Example 169
[832] 3-cyclohexyl-6- (2-methoxy-4-{[4- (methylamino) -1-piperidinyl] sulfonyl} phenyl) -1-methyl-1,5-dihydro-4H-pyra Solo [3,4-d] pyrimidin-4-one monomethanesulfonate
[833] The same reaction procedure as in Example 154 was performed except that the compound obtained in Example 168 was used instead of the compound obtained in Example 153. In this way, 30.5 mg (43%) of the title compound were obtained.
[834] Example 170
[835] Benzyl 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-meth Methoxyphenyl] sulfonyl} -3-pyrrolidinylcarbamate
[836] The same reaction procedure was followed as in Example 49, except that benzyl 3-pyrrolidinylcarbamate monohydrochloride was used instead of N-methylpiperazine. In this way, 108 mg (76%) of the title compound were obtained.
[837] Example 171
[838] 6- {4-[(3-amino-1-pyrrolidinyl) sulfonyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[839] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 170 was used instead of the compound obtained in Example 35. In this way, 48 mg (76%) of the title compound were obtained.
[840] Example 172
[841] 6- {4-[(3-amino-1-pyrrolidinyl) sulfonyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one monomethanesulfonate
[842] The same reaction procedure as in Example 154 was carried out except that the compound obtained in Example 171 was used instead of the compound obtained in Example 153. In this way, 37 mg (90%) of the title compound were obtained.
[843] Example 173
[844] Benzyl 1-{[4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-meth Methoxyphenyl] sulfonyl} -4-piperidinylcarbamate
[845] The same reaction procedure was followed as in Example 49, except that benzyl 3-piperidinylcarbamate monohydrochloride was used instead of N-methylpiperazine. In this way, 202 mg (93%) of the title compound were obtained.
[846] Example 174
[847] 6- {4-[(4-amino-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[848] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 173 was used instead of the compound obtained in Example 35. In this way, 94 mg (78%) of the title compound were obtained.
[849] Example 175
[850] 6- {4-[(4-amino-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one monomethanesulfonate
[851] The same reaction procedure was followed as in Example 62, except that the compound obtained in Example 174 was used instead of the compound obtained in Example 61. In this way, 60 mg (63%) of the title compound were obtained.
[852] Example 176
[853] 3-cyclohexyl-6- [2-methoxy-4- (4-thiomorpholinyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-on
[854] The same reaction procedure as in Example 26 was carried out except that the compound obtained in Preparation Example 60 was used instead of 4-bromo-2-methoxybenzoic acid. In this way, 126 mg (18%) of the title compound were obtained.
[855] Example 177
[856] 6- (4-bromophenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[857] To a 30 ml pyridine solution of 2.2 g (10 mmol) of the compound obtained in Example 32, 2.8 g (13 mmol) of p-bromobenzoyl chloride was added and the mixture was stirred at room temperature for 3 hours. Further 1.0 g (4.5 mmol) of p-bromobenzoyl chloride was added and the mixture was stirred at rt for 4 h. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue, 80 ml of ethanol and 40 ml of 1M aqueous sodium hydroxide solution were added, and the mixture was heated under reflux for 8 hours. The reaction mixture was then cooled to room temperature and acetic acid was added. The precipitated solid was collected by filtration, the obtained solid was dissolved in chloroform, and the solution was washed sequentially with sodium hydrogencarbonate, water, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized (ethanol) to give 590 mg (15%) of the title compound.
[858] Example 178
[859] 3-cyclohexyl-1-methyl-6- [4- (4-methyl-1-piperazinyl) phenyl] -1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine-4 -On
[860] The same reaction procedure as in Example 27 was carried out except that the compound obtained in Example 177 was used instead of the compound obtained in Example 26. In this way, 143 mg (77%) of the title compound were obtained.
[861] Example 179
[862] 3-cyclohexyl-1-methyl-6- [4- (4-methyl-1-piperazinyl) phenyl] -1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine-4 -On monomethanesulfonate
[863] The same reaction procedure as in Example 62 was carried out except that the compound obtained in Example 178 was used instead of the compound obtained in Example 61. In this way, 106 mg (86%) of the title compound were obtained.
[864] Example 180
[865] 6- (4-aminophenyl) -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[866] To a solution of 2.2 g (10 mmol) of pyridine obtained in Example 32, 2.2 g (13 mmol) of p-nitrobenzoyl chloride were added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then distilled under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue was added 30 ml of methanol and 400 mg of 10% palladium carbon. The mixture was stirred at room temperature and atmospheric pressure under hydrogen atmosphere for 8 hours. The catalyst was then filtered off and the filtrate was distilled off under reduced pressure. To the residue was added 80 ml of ethanol and 40 ml of 1M aqueous sodium hydroxide solution, and then the mixture was heated under reflux for 5 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 30/1) to give 960 mg (30%) of the title compound.
[867] Example 181
[868] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) benzenesulfonyl chloride
[869] The same reaction procedure as in Example 48 was carried out except that the compound obtained in Example 180 was used instead of the compound obtained in Example 44. In this way, 743 mg (65%) of the title compound were obtained.
[870] Example 182
[871] 3-cyclohexyl-6- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] phenyl} -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one
[872] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 181 was used instead of the compound obtained in Example 48 and 4-hydroxypiperidine was used instead of N-methylpiperazine. did. In this way, 72 mg (62%) of the title compound were obtained.
[873] Example 183
[874] 6- {4- [4- (benzylamino) -1-piperidinyl] -2-methoxyphenyl} -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
[875] The same reaction procedure was followed as in Example 149, except that benzylamine was used instead of methylamine. In this way, 236 mg (90%) of the title compound were obtained.
[876] Example 184
[877] 6- [4- (4-amino-1-piperidinyl) -2-methoxyphenyl] -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one
[878] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 183 was used instead of the compound obtained in Example 35. In this way, 126 mg (76%) of the title compound were obtained.
[879] Example 185
[880] 6- [4- (4-amino-1-piperidinyl) -2-methoxyphenyl] -3-cyclohexyl-1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one monomethanesulfonate
[881] The same reaction procedure as in Example 154 was carried out except that the compound obtained in Example 184 was used instead of the compound obtained in Example 153. In this way, 53 mg (43%) of the title compound were obtained.
[882] Example 186
[883] 3-cyclohexyl-1-methyl-6- {4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one
[884] In Example 49, except that the compound obtained in Example 181 was used instead of the compound obtained in Example 48 and N-methyl-1,4-diazacycloheptane was used instead of N-methylpiperazine. The same reaction process was carried out. In this way, 110 mg (45%) of the title compound were obtained.
[885] Example 187
[886] 3-cyclohexyl-1-methyl-6- {4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1,5-dihydro-4H-pyrazolo [3 , 4-d] pyrimidin-4-one monomethanesulfonate
[887] The same reaction procedure as in Example 154 was performed except that the compound obtained in Example 186 was used instead of the compound obtained in Example 153. In this way, 75 mg (72%) of the title compound were obtained.
[888] Example 188
[889] Benzyl 1- [4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) phenyl] -4- Piperidinyl (methyl) carbamate
[890] In Example 27, except that the compound obtained in Example 177 was used instead of the compound obtained in Example 26, and benzyl methyl (4-piperidinyl) carbamate was used instead of N-methylpiperazine. The same reaction process was carried out. In this way, 255 mg (71%) of the title compound were obtained.
[891] Example 189
[892] 3-cyclohexyl-1-methyl-6- {4- [4- (methylamino) -1-piperidinyl] phenyl} -1,5-dihydro-4H-pyrazolo [3,4-d] pyrid Midin-4-one monomethanesulfonate
[893] To 5 ml methanol suspension of the compound obtained in Example 188, 10% palladium carbon and 27 μl (0.41 mmol) of methanesulfonic acid were added. The mixture was stirred at room temperature and atmospheric pressure for 72 hours under hydrogen atmosphere. The catalyst was then filtered off to yield 221 mg (quantitative) of the title compound.
[894] Example 190
[895] 3-cyclohexyl-6- [4- (1,4-diazepane-1-ylsulfonyl) phenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidine -4-on
[896] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 181 was used instead of the compound obtained in Example 48 and homopiperazine was used instead of N-methylpiperazine. In this way, 64 mg (37%) of the title compound were obtained.
[897] Example 191
[898] 3-cyclohexyl-6- {4-[(1,1-dioxido-4-thiomorpholinyl) sulfonyl] -2-methoxyphenyl} -1-methyl-1,5-dihydro-4H -Pyrazolo [3,4-d] pyrimidin-4-one
[899] The same reaction procedure was followed as in Example 49, except that 1,1-dioxide monohydrochloride was used instead of N-methylpiperazine. In this way, 124 mg (67%) of the title compound were obtained.
[900] Example 192
[901] 3-cyclohexyl-6- [4- (1,1-dioxido-4-thiomorpholinyl) -2-methoxyphenyl] -1-methyl-1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[902] The same reaction procedure was followed as in Example 27, except that 1,1-dioxide monohydrochloride was used instead of N-methylpiperazine. In this way, 69 mg (41%) of the title compound were obtained.
[903] Example 193
[904] 6- (4-bromo-2-methoxyphenyl) -3-cyclohexyl-1-ethyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[905] The same reaction procedure as in Example 26 was carried out except that the compound obtained in Preparation Example 57 was used instead of the compound obtained in Preparation Example 32. In this way, 523 mg (53%) of the title compound were obtained.
[906] Example 194
[907] 3-cyclohexyl-1-ethyl-6- [2-methoxy-4- (4-methyl-1-piperazinyl) phenyl] -1,5-dihydro-4H-pyrazolo [3,4-d ] Pyrimidin-4-one
[908] The same reaction procedure as in Example 27 was carried out except that the compound obtained in Example 193 was used instead of the compound obtained in Example 26. In this way, 62 mg (41%) of the title compound were obtained.
[909] Example 195
[910] Benzyl 1- [4- (3-cyclohexyl-1-ethyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy Phenyl] -4-piperidinyl (methyl) carbamate
[911] Except for using the compound obtained in Example 193 instead of the compound obtained in Example 26 and using benzyl methyl (4-piperidinyl) carbamate monohydrochloride instead of N-methylpiperazine The same reaction process was performed as in 27. In this way, 215 mg (90%) of the title compound were obtained.
[912] Example 196
[913] 3-cyclohexyl-1-ethyl-6- {2-methoxy-4- (4-methylamino) -1-piperidinyl} phenyl} -1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one
[914] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 195 was used instead of the compound obtained in Example 35. In this way, 130 mg (quantitative) of the title compound were obtained.
[915] Example 197
[916] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxybenzenesulfonyl chloride
[917] The same reaction procedure as in Example 48 was carried out except that the compound obtained in Example 9 was used instead of the compound obtained in Example 44. In this way, 1.01 g (91%) of the title compound were obtained.
[918] Example 198
[919] 1-cyclohexyl-5- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one
[920] In Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48, and N-methyl-1,4-diazacycloheptane was used instead of N-methylpiperazine. The same reaction process was carried out. In this way, 146 mg (83%) of the title compound were obtained.
[921] Example 199
[922] 1-cyclohexyl-5- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[923] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48, and 4-hydroxypiperidine was used instead of N-methylpiperazine. did. In this way, 145 mg (84%) of the title compound were obtained.
[924] Example 200
[925] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- (2-hydroxyethyl ) -3-methoxybenzenesulfonamide
[926] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48, and ethanolamine was used instead of N-methylpiperazine. In this way, 113 mg (71%) of the title compound were obtained.
[927] Example 201
[928] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N-methyl Benzenesulfonamide
[929] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48, and methylamine (30% ethanol solution) was used instead of N-methylpiperazine. Performed. In this way, 88 mg (60%) of the title compound were obtained.
[930] Example 202
[931] 1-cyclohexyl-5- [4- (1,4-diazepane-1-ylsulfonyl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[932] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48 and homopiperazine was used instead of N-methylpiperazine. In this way, 141 mg (82%) of the title compound were obtained.
[933] Example 203
[934] 1-cyclohexyl-5- [4- (1,4-diazepane-1-ylsulfonyl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one monomethanesulfonate
[935] The same reaction procedure as in Example 154 was performed except that the compound obtained in Example 202 was used instead of the compound obtained in Example 153. In this way, 24 mg (40%) of the title compound were obtained.
[936] Example 204
[937] 4- (3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxy-N-methyl Benzenesulfonamide
[938] The same reaction procedure was followed as in Example 49, except that methylamine (30% ethanol solution) was used instead of N-methylpiperazine. In this way, 102 mg (69%) of the title compound were obtained.
[939] Example 205
[940] 6- (4-amino-2-methoxyphenyl) -3-cyclohexyl-1-ethyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one
[941] To a 10 ml 1,2-dichloroethane suspension of 1.2 g (6.06 mmol) of 2-methoxy-4-nitrobenzoic acid, 0.88 ml (12.1 mmol) of thionyl chloride is added and the mixture is heated under reflux for 1.5 hours. did. The reaction mixture was cooled to room temperature and then distilled under reduced pressure to give an acid chloride.
[942] To a 10 ml pyridine solution of the acid chloride synthesized above, 1.1 g (4.66 mmol) of the compound obtained in Preparation Example 57 were added. The mixture was stirred at rt for 5 h. The reaction mixture was then distilled under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. By the above procedure, a carboxamide intermediate was obtained.
[943] To 30 ml methanol / 10 ml N, N-dimethylformamide mixed solution of the carboxamide intermediate, 170 mg of 5% palladium carbon was added and the mixture was stirred at room temperature and atmospheric pressure for 18 hours under hydrogen atmosphere. The catalyst was then filtered off and the filtrate was distilled under reduced pressure to afford an amine intermediate.
[944] To the amine intermediate, 19 ml of ethanol and 38 ml of 1 M aqueous sodium hydroxide solution were added, and the mixture was heated at reflux for 24 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 30/1) to give 996 mg (58%) of the title compound.
[945] Example 206
[946] 4- (3-cyclohexyl-1-ethyl-4-oxo-4,5-dihydro-1H-pyrazolo [3,4-d] pyrimidin-6-yl) -3-methoxybenzenesulfonyl chloride
[947] The same reaction procedure as in Example 48 was carried out except that the compound obtained in Example 205 was used instead of the compound obtained in Example 44. In this way, 940 g (83%) of the title compound were obtained.
[948] Example 207
[949] 3-cyclohexyl-1-ethyl-6- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] -2-methoxyphenyl} -1,5-dihydro-4H-pyrazolo [ 3,4-d] pyrimidin-4-one
[950] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 206 was used instead of the compound obtained in Example 48, and 4-hydroxypiperidine was used instead of N-methylpiperazine. did. In this way, 155 mg (91%) of the title compound were obtained.
[951] Example 208
[952] 3-cyclohexyl-1-ethyl-6- {2-methoxy-4-[(4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -1,5-dihydro-4H -Pyrazolo [3,4-d] pyrimidin-4-one
[953] In Example 49, except that the compound obtained in Example 206 was used instead of the compound obtained in Example 48 and N-methyl-1,4-diazacycloheptane was used instead of N-methylpiperazine. The same reaction process was carried out. In this way, 129 mg (74%) of the title compound were obtained.
[954] Example 209
[955] 3-cyclohexyl-6- [4- (1,4-diazepane-1-ylsulfonyl) -2-methoxyphenyl] -1-ethyl-1,5-dihydro-4H-pyrazolo [3,4 -d] pyrimidin-4-one
[956] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 206 was used instead of the compound obtained in Example 48 and homopiperazine was used instead of N-methylpiperazine. In this way, 100 mg (59%) of the title compound were obtained.
[957] Example 210
[958] N- (2-aminoethyl) -4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) 3-methoxy-N-methylbenzenesulfonamide (210-1)
[959] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N- [ 2- (methylamino) ethyl] benzenesulfonamide (210-2)
[960] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48 and N-methylethylenediamine was used instead of N-methylpiperazine. In this way, 139 mg (59%) of N- (2-aminoethyl) -4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4, 3-d] pyrimidin-5-yl) -3-methoxy-N-methylbenzenesulfonamide and 39 mg (16%) of 4- (1-cyclohexyl-3-methyl-7-oxo-6,7 -Dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N- [2- (methylamino) ethyl] benzenesulfonamide was obtained.
[961] Example 211
[962] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (dimethylamino ) Ethyl] -3-methoxybenzenesulfonamide
[963] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48, and N, N-dimethylethylenediamine was used instead of N-methylpiperazine. did. In this way, 95.4 mg (85%) of the title compound were obtained.
[964] Example 212
[965] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N-methyl -N- [2- (methylamino) ethyl] benzenesulfonamide
[966] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48, and N, N'-dimethylethylenediamine was used instead of N-methylpiperazine. Performed. In this way, 82 mg (73%) of the title compound were obtained.
[967] Example 213
[968] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- (2-hydroxyethyl ) -3-methoxy-N-methylbenzenesulfonamide
[969] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48, and 2- (methylamino) ethanol was used instead of N-methylpiperazine. did. In this way, 70 mg (64%) of the title compound were obtained.
[970] Example 214
[971] 1-cyclohexyl-5- {2-methoxy-4-[(4-methyl-1-piperazinyl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[972] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48. In this way, 69 mg (60%) of the title compound were obtained.
[973] Example 215
[974] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N-methyl -N- [3- (methylamino) propyl] benzenesulfonamide
[975] In Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48 and N, N'-dimethyl-1,3-propanediamine was used instead of N-methylpiperazine. The same reaction process was carried out. In this way, 36 mg (31%) of the title compound were obtained.
[976] Example 216
[977] 1-cyclohexyl-5- (4-{[4- (2-hydroxyethyl) -1-piperazinyl] sulfonyl} -2-methoxyphenyl) -3-methyl-1,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one
[978] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48 and 1-piperazinethanol was used instead of N-methylpiperazine. In this way, 79 mg (65%) of the title compound were obtained.
[979] Example 217
[980] 1-cyclohexyl-5- [2-methoxy-4- (1-piperazinylsulfonyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrid Midin-7-on
[981] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48 and piperazine was used instead of N-methylpiperazine. In this way, 34 mg (30%) of the title compound were obtained.
[982] Example 218
[983] 1-cyclohexyl-5- {4-[(4-ethyl-1-piperazinyl) sulfonyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[984] The same reaction procedure was followed as in Example 49, except that the compound obtained in Example 197 was used instead of the compound obtained in Example 48 and N-ethylpiperazine was used instead of N-methylpiperazine. In this way, 90 mg (76%) of the title compound were obtained.
[985] Example 219
[986] N- (1-benzyl-4-piperidinyl) -4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidine -5-yl) -3-methoxybenzenesulfonamide
[987] Same reaction as in Example 49, except for using the compound obtained in Example 197 instead of the compound obtained in Example 48 and using 4-amino-1-benzylpiperidine instead of N-methylpiperazin Followed the process. In this way, 39 mg (29%) of the title compound were obtained.
[988] Example 220
[989] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy-N- ( 4-piperidinyl) benzenesulfonamide monohydrochloride
[990] To 30 mg (0.05 mmol) of 2 mL dichloromethane solution of the compound obtained in Example 219, 11 μl (0.101 mmol) of 1-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then distilled under reduced pressure, 2 ml of methanol was added to the residue and the mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 12 mg (45%) of the title compound.
[991] Example 221
[992] Benzyl 1-{[4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-meth Methoxyphenyl] sulfonyl} -4-piperidinyl (methyl) carbamate
[993] Except for using the compound obtained in Example 197 instead of the compound obtained in Example 48 and using benzyl methyl (4-piperidinyl) carbamate monohydrochloride instead of N-methylpiperazine The same reaction procedure was followed as in 49. In this way, 125 mg (84%) of the title compound were obtained.
[994] Example 222
[995] 1-cyclohexyl-5- (2-methoxy-4-{[4- (methylamino) -1-piperidinyl] sulfonyl} phenyl) -3-methyl-1,6-dihydro-7H-pyra Solo [4,3-d] pyrimidin-7-one
[996] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 221 was used instead of the compound obtained in Example 35. In this way, 62 mg (86%) of the title compound were obtained.
[997] Example 223
[998] 5- {4-[(1-benzyl-4-piperidinyl) amino] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[999] The same reaction procedure was followed as in Example 16, except that 4-amino-1-benzylpiperidine was used instead of N-methylpiperazin. In this way, 148 mg (78%) of the title compound were obtained.
[1000] Example 224
[1001] 1-cyclohexyl-5- [2-methoxy-4- (4-piperidinylamino) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine -7-on
[1002] To 120 mg (0.228 mmol) of 3 mL dichloromethane solution of the compound obtained in Example 223, 50 μL (0.456 mmol) of 1-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 4 hours. Further 50 μl (0.456 mmol) of 1-chloroethyl chloroformate and 3 mL of 1,2-dichloroethane were added and the mixture was heated at reflux for 5 hours. The reaction mixture was then distilled under reduced pressure, 3 mL of methanol was added to the residue and the mixture was heated at reflux for 1.5 h. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column chromatography (dichloromethane / methanol = 20/1) to give 62 mg (62%) of the title compound.
[1003] Example 225
[1004] 1-cyclohexyl-5- {2-methoxy-4-[(2-methoxyethyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one
[1005] The same reaction procedure was followed as in Example 16, except that methoxyethylamine was used instead of N-methylpiperazine. In this way, 63 mg (43%) of the title compound were obtained.
[1006] Example 226
[1007] Methyl (2E) -3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1 H-pyrazolo [4,3-d] pyrimidin-5-yl)- 3-methoxyphenyl] -2-propenate
[1008] To 150 mg (0.36 mmol) of a compound obtained in Example 15 in a 2 ml N, N-dimethylformamide solution, 8 mg (0.036 mmol) of palladium acetate, 22 mg (0.072 mmol) tri-o-tolylphosphine , 0.15 mL (1.08 mmol) triethylamine and 97 μL (1.08 mmol) methyl acrylate were added and the mixture was heated at 115 ° C. for 15 h in a closed tube. The reaction mixture was then returned to room temperature, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 130 mg (85%) of the title compound.
[1009] Example 227
[1010] (2E) -3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3 -Methoxyphenyl] -2-propenic acid
[1011] To 45 mg (0.107 mmol) of the compound obtained in Example 226, 1 mL of methanol suspension was added 1 mL of 1M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and the aqueous layer washed with ether. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration to obtain 39 mg (89%) of the title compound.
[1012] Example 228
[1013] Methyl 3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Phenyl] propanoate
[1014] To 63 mg (0.15 mmol) of a compound obtained in Example 226, 2 mL tetrahydrofuran solution, 6 mg of platinum oxide was added, and the mixture was stirred at room temperature and atmospheric pressure under hydrogen atmosphere for 3.5 hours. The catalyst was then filtered off and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give 52 mg (82%) of the title compound.
[1015] Example 229
[1016] 3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxyphenyl Propanoic acid
[1017] The same reaction procedure as in Example 227 was carried out except that the compound obtained in Example 228 was used instead of the compound obtained in Example 226. In this way, 32 mg (71%) of the title compound were obtained.
[1018] Example 230
[1019] 1-cyclohexyl-5- (4-{[2- (dimethylamino) ethyl] amino} -2-methoxyphenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one
[1020] The same reaction procedure was followed as in Example 16, except that N, N-dimethylethylenediamine was used instead of N-methylpiperazine. In this way, 91 mg (50%) of the title compound were obtained.
[1021] Example 231
[1022] 5- {4-[(1-acetyl-4-piperidinyl) amino] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1023] The same reaction procedure was followed as in Example 16, except that 1-acetyl-4-piperidinylamine was used instead of N-methylpiperazine. In this way, 69 mg (60%) of the title compound were obtained.
[1024] Example 232
[1025] 1-cyclohexyl-5- {2-methoxy-4-[(1-methyl-4-piperidinyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1026] The same reaction procedure was followed as in Example 16, except that 1-methyl-4-piperidinylamine was used instead of N-methylpiperazine. In this way, 76 mg (70%) of the title compound were obtained.
[1027] Example 233
[1028] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxybenzaldehyde
[1029] To 150 mg (0.36 mmol) of 3 mL tetrahydrofuran solution of the compound obtained in Example 15, 0.45 mL of n-butyl lithium (0.72 mmol of 1.59M hexane solution) was added dropwise at -78 ° C. After the mixture was stirred at the same temperature for 30 minutes, 33.4 μl (0.43 mmol) of N, N-dimethylformamide was added dropwise to the reaction mixture, and then the mixture was stirred at −78 ° C. for 2 hours. Then, an aqueous ammonium chloride solution was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 73 mg (55%) of the title compound.
[1030] Example 234
[1031] 1-cyclohexyl-5- {2-methoxy-4-[(4-methyl-1-piperazinyl) methyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1032] In a 2 ml 1,2-dichloroethane solution of 61 mg (0.166 mmol) of the compound obtained in Example 233, 37 µl (0.332 mmol) of N-methylpiperazine, 10 µl of acetic acid and 53 mg (0.252 mmol) of Sodium triacetoxyborohydride was added and the mixture was stirred at rt for 1 h. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1) to give 57 mg (76%) of the title compound.
[1033] Example 235
[1034] 1-cyclohexyl-5- [2-methoxy-4- (4-morpholinylmethyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine -7-on
[1035] The same reaction procedure was followed as in Example 234 except that morpholine was used instead of N-methylpiperazine. In this way, 72 mg (quantitative) of the title compound were obtained.
[1036] Example 236
[1037] 1-cyclohexyl-5- {4-[(hydroxy-1-piperidinyl) methyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[1038] The same reaction procedure was followed as in Example 234 except that 4-hydroxypiperidine was used instead of N-methylpiperazine. In this way, 65 mg (88%) of the title compound were obtained.
[1039] Example 237
[1040] 1-cyclohexyl-5- (2-methoxy-4-{[(2-methoxyethyl) amino] methyl} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[1041] The same reaction procedure was followed as in Example 234, except that methoxyethylamine was used instead of N-methylpiperazine. In this way, 66 mg (95%) of the title compound were obtained.
[1042] Example 238
[1043] Ethyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Benzyl] -4-piperidinecarboxylate
[1044] The same reaction procedure was followed as in Example 234 except for using ethyl isonipecontate instead of N-methylpiperazine. In this way, 57 mg (69%) of the title compound were obtained.
[1045] Example 239
[1046] 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxybenzyl ] -4-piperidinecarboxylic acid
[1047] To 43 mg (0.0848 mmol) of 1 mL ethanol solution of the compound obtained in Example 238 was added 1 mL of 1M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then distilled under reduced pressure and the residue was dissolved in water. Acetic acid was added and the precipitated solid was collected by filtration to give 21 mg (52%) of the title compound.
[1048] Example 240
[1049] Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-methoxy Benzyl] -4-piperidinyl (methyl) carbamate
[1050] The same reaction procedure was followed as in Example 234, except that benzyl methyl (4-piperidinyl) carbamate monohydrochloride was used instead of N-methylpiperazine. In this way, 92.5 mg (64%) of the title compound were obtained.
[1051] Example 241
[1052] 1-cyclohexyl-5- (2-methoxy-4-{[4- (methylamino) -1-piperidinyl] methyl} phenyl) -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[1053] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 240 was used instead of the compound obtained in Example 35. In this way, 52 mg (quantitative) of the title compound were obtained.
[1054] Example 242
[1055] 1-cyclohexyl-5- [2-methoxy-4- (tetrahydro-2H-pyran-4-ylamino) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[1056] To 250 mg (0.71 mmol) of 5 mL 1,2-dichloroethane solution of the compound obtained in Example 9 was added 25 μl of acetic acid and 66 μl (0.71 mmol) of tetrahydro-4H-pyran-4-one. The mixture was stirred for 30 minutes. 226 mg (1.07 mmol) of sodium triacetoxyborohydride were then added and the mixture was stirred at rt for 20 h. In addition, 32 μl (0.35 mmol) of tetrahydro-4H-pyran-4-one and 100 mg (0.45 mmol) of sodium triacetoxyborohydride were added. The mixture was stirred at 60 ° C. for 6 hours and at room temperature for 20 hours. Subsequently, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2/1) to give 151 mg (49%) of the title compound.
[1057] Example 243
[1058] 1-cyclohexyl-5- [4- (1,4-dioxa-8-azaspiro [4,5] deca-8-yl) -2-methoxyphenyl] -3-methyl-1,6-di Hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[1059] The same reaction procedure was followed as in Example 16, except that 1,4-dioxa-8-azaspiro [4,5] decane was used instead of N-methylpiperazine. In this way, 459 mg (80%) of the title compound were obtained.
[1060] Example 244
[1061] 1-cyclohexyl-5- [2-methoxy-4- (4-oxo-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one
[1062] The same reaction procedure as in Example 30 was carried out except that the compound obtained in Example 243 was used instead of the compound obtained in Example 29. In this way, 399 mg (quantitative) of the title compound were obtained.
[1063] Example 245
[1064] 1-cyclohexyl-5- {4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1065] The same reaction procedure was followed as in Example 234 except for using the compound obtained in Example 244 instead of the compound obtained in Example 233 and using dimethylamine monohydrochloride instead of N-methylpiperazine. In this way, 32.9 mg (42%) of the title compound were obtained.
[1066] Example 246
[1067] 5- {4- [4- (benzylamino) -1-piperidinyl] -2-methoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1068] The same reaction procedure was followed as in Example 234, except that the compound obtained in Example 244 was used instead of the compound obtained in Example 233 and benzylamine was used instead of N-methylpiperazine. In this way, 115 mg (91%) of the title compound were obtained.
[1069] Example 247
[1070] 5- [4- (4-amino-1-piperidinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one
[1071] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 246 was used instead of the compound obtained in Example 35. In this way, 70 mg (84%) of the title compound were obtained.
[1072] Example 248
[1073] 1-cyclohexyl-5- [4- (1,4-dioxa-8-azaspiro [4,5] deca-8-yl) -2-ethoxyphenyl] -3-methyl-1,6-di Hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[1074] Except for using the compound obtained in Example 116 instead of the compound obtained in Example 15 and using 1,4-dioxa-8-azaspiro [4,5] decane instead of N-methylpiperazine, The same reaction procedure as in Example 16 was carried out. In this way, 416 mg (70%) of the title compound were obtained.
[1075] Example 249
[1076] 1-cyclohexyl-5- [2-ethoxy-4- (4-oxo-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one
[1077] The same reaction procedure as in Example 30 was carried out except that the compound obtained in Example 248 was used instead of the compound obtained in Example 29. In this way, 160 mg (40%) of the title compound were obtained.
[1078] Example 250
[1079] 1-cyclohexyl-5- {4- [4- (dimethylamino) -1-piperidinyl] -2-ethoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1080] The same reaction procedure was followed as in Example 234, except that the compound obtained in Example 249 was used instead of the compound obtained in Example 233 and dimethylamine monohydrochloride instead of N-methylpiperazine. In this way, 46 mg (78%) of the title compound were obtained.
[1081] Example 251
[1082] 5- {4- [4- (benzylamino) -1-piperidinyl] -2-ethoxyphenyl} -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1083] The same reaction procedure was followed as in Example 234, except that the compound obtained in Example 249 was used instead of the compound obtained in Example 233 and benzylamine was used instead of N-methylpiperazine. In this way, 86 mg (quantitative) of the title compound were obtained.
[1084] Example 252
[1085] Benzyl 1- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-ethoxy Phenyl] -4-piperidinyl (ethyl) carbamate
[1086] Except for using the compound obtained in Example 116 instead of the compound obtained in Example 15 and using benzyl ethyl (4-piperidinyl) carbamate monohydrochloride instead of N-methylpiperazin The same reaction procedure as in 16 was carried out. In this way, 134 mg (47%) of the title compound were obtained.
[1087] Example 253
[1088] 1-cyclohexyl-5- {2-ethoxy-4- [4- (ethylamino) -1-piperidinyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one
[1089] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 252 was used instead of the compound obtained in Example 35. In this way, 61 mg (69%) of the title compound were obtained.
[1090] Example 254
[1091] 5- (4-amino-2-ethoxyphenyl) -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[1092] In Example 205, except for using 2-ethoxy-4-nitrobenzoic acid instead of 2-methoxy-4-nitrobenzoic acid and using the compound obtained in Preparation 6 instead of the compound obtained in Preparation 57 The same reaction process was carried out. In this way, 1.19 g (65%) of the title compound were obtained.
[1093] Example 255
[1094] 4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3-ethoxybenzenesulfonyl chloride
[1095] The same reaction procedure as in Example 48 was carried out except that the compound obtained in Example 254 was used instead of the compound obtained in Example 44. In this way, 1.05 g (91%) of the title compound were obtained.
[1096] Example 256
[1097] 1-cyclohexyl-5- {2-ethoxy-4- (4-methyl-1,4-diazepan-1-yl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H- Pyrazolo [4,3-d] pyrimidin-7-one
[1098] In Example 49, except that the compound obtained in Example 255 was used instead of the compound obtained in Example 48 and N-methyl-1,4-diazacycloheptane was used instead of N-methylpiperazine. The same reaction process was carried out. In this way, 145 mg (83%) of the title compound were obtained.
[1099] Example 257
[1100] 1-cyclohexyl-5- {2-ethoxy-4-[(4-hydroxy-1-piperidinyl) sulfonyl] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[1101] The same reaction procedure as in Example 49 was carried out except that the compound obtained in Example 255 was used instead of the compound obtained in Example 48 and N-hydroxypiperidine was used instead of N-methylpiperazine. did. In this way, 147 mg (86%) of the title compound were obtained.
[1102] Example 258
[1103] 1-cyclohexyl-5- [4- (4-hydroxy-1-piperidinyl) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one
[1104] The same reaction procedure as in Example 31 was carried out except that the compound obtained in Example 244 was used instead of the compound obtained in Example 30. In this way, 115 mg (quantitative) of the title compound were obtained.
[1105] Example 259
[1106] (2E) -3- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -3 -Methoxyphenyl] -2-propenenitrile
[1107] The same reaction procedure was followed as in Example 266, except that acrylonitrile was used instead of methyl acrylate. In this way, 89 mg (48%) of the title compound were obtained.
[1108] Example 260
[1109] 5- [4- (4-amino-1-piperidinyl) -2-ethoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one
[1110] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 251 was used instead of the compound obtained in Example 35. In this way, 29 mg (50%) of the title compound were obtained.
[1111] Example 261
[1112] 1-cyclohexyl-5- [2-ethoxy-4- (4-hydroxy-1-piperidinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one
[1113] The same reaction procedure as in Example 31 was carried out except that the compound obtained in Example 249 was used instead of the compound obtained in Example 30. In this way, 117 mg (89%) of the title compound were obtained.
[1114] Example 262
[1115] 1-cyclohexyl-5- [4- (1,4-diazepane-1-yl] -2-ethoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one
[1116] The same reaction procedure was followed as in Example 16, except that the compound obtained in Example 116 was used instead of the compound obtained in Example 15 and homopiperazine was used instead of N-methylpiperazine. In this way, 97 mg (62%) of the title compound were obtained.
[1117] Example 263
[1118] 1-cyclohexyl-5- {2-ethoxy-4-[(2-methoxyethyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one
[1119] The same reaction procedure was followed as in Example 16, except that the compound obtained in Example 116 was used instead of the compound obtained in Example 15, and methoxyethylamine was used instead of N-methylpiperazine. In this way, 55 mg (37%) of the title compound were obtained.
[1120] Example 264
[1121] 1-cyclohexyl-5- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one
[1122] The same reaction procedure as in Example 16 was carried out except that the compound obtained in Example 116 was used instead of the compound obtained in Example 15. In this way, 115 mg (73%) of the title compound were obtained.
[1123] Example 265
[1124] Benzyl 4- [4- (1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -2-fluoro -5-methoxyphenyl] -1,4-diazepane-1-carboxylate
[1125] The same reaction procedure as in Example 14 was carried out except that the compound obtained in Preparation Example 63 was used instead of the compound obtained in Preparation Example 34. In this way, 152 mg (38%) of the title compound were obtained.
[1126] Example 266
[1127] 1-cyclohexyl-5- [4- (1,4-diazepane-1-yl) -5-fluoro-2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[1128] The same reaction procedure as in Example 36 was carried out except that the compound obtained in Example 265 was used instead of the compound obtained in Example 35. In this way, 181 mg (76%) of the title compound were obtained.
[1129] Example 267
[1130] 1-cyclohexyl-5- {2-methoxy-4- [methyl (1-methyl-4-piperidinyl) amino] phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one
[1131] The same reaction procedure was followed as in Example 16, except that 1-methyl-4- (methylamino) piperidine was used instead of N-methylpiperazine. In this way, 181 mg (quantitative) of the title compound were obtained.
[1132] Example 268
[1133] 1-cyclohexyl-5- [2-ethoxy-4- (1-piperazinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-on
[1134] The same reaction procedure was followed as in Example 16, except that the compound obtained in Example 116 was used instead of the compound obtained in Example 15 and piperazine was used instead of N-methylpiperazine. In this way, 86 mg (57%) of the title compound were obtained.
[1135] Example 269
[1136] 5- [4-((3R) -3-{[tert-butyl (dimethyl) silyl] oxy} pyrrolidinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-di Hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[1137] The same reaction procedure was followed as in Example 16, except that (3R) -3-{[tert-butyl (dimethyl) silyl] oxy} pyrrolidine was used instead of N-methylpiperazine. In this way, 263 mg (82%) of the title compound were obtained.
[1138] Example 270
[1139] 1-cyclohexyl-5- {4-[(3R) -3-hydroxypyrrolidinyl] -2-methoxyphenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [4,3 -d] pyrimidin-7-one
[1140] To 343 tetrahydrofuran solution of 243 mg (0.452 mmol) of the compound obtained in Example 269, 0.54 mL of tetrabutylammonium fluoride (0.54 mmol of 1.0M tetrahydrofuran solution) was added and the mixture was stirred at room temperature. Stirred for hours. Then water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30/1 to 20/1) to give 191 mg (quantitative) of the title compound.
[1141] Example 271
[1142] 5- [4- (1-benzyl-4-hydroxy-4-piperidinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[1143] The same reaction procedure was followed as in Example 122, except that 1-benzyl-4-piperidone was used instead of 1-methyl-4-piperidone. In this way, 162 mg (43%) of the title compound were obtained.
[1144] Example 272
[1145] 5- [4- (1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl) -2-methoxyphenyl] -1-cyclohexyl-3-methyl-1,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one
[1146] The same reaction procedure as in Example 123 was performed except that the compound obtained in Example 271 was used instead of the compound obtained in Example 122. In this way, 92 mg (68%) of the title compound were obtained.
[1147] Example 273
[1148] 1-cyclohexyl-5- [2-methoxy-4- (1,2,3,6-tetrahydro-4-pyridinyl) phenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one monohydrochloride
[1149] To 80 mg (0.16 mmol) of 10 mL 1,2-dichloroethane solution obtained in Example 272, 25.4 μL (0.24 mmol) of 1-chloroethyl chloroformate are added and the mixture is refluxed for 40 minutes. Heated during. The reaction mixture was then returned to room temperature and concentrated under reduced pressure. Methanol (10 mL) was added to the residue and the mixture was heated at reflux for 20 minutes. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The precipitated solid was washed with methanol / ether = 1/4 to give 43 mg (60%) of the title compound.
[1150] Example 274
[1151] 1-cyclohexyl-5- {2-methoxy-4- (methyl (tetrahydro-2H-pyran-4-yl) amino) phenyl} -3-methyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one
[1152] The same reaction procedure was followed as in Example 16, except that N-methyltetrahydro-2H-pyran-4-amine hydrochloride was used instead of N-methylpiperazine. In this way, 124 mg (76%) of the title compound were obtained.
[1153] Example 275
[1154] 1-cyclohexyl-5- [4- (ethylamino) -2-methoxyphenyl] -3-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one
[1155] In the reaction of Example 242, 58 mg (21%) of the title compound were obtained as by-product.
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[1243] The pyrazolopyrimidinone derivatives of the present invention selectively have a function of inhibiting PDE7, thereby increasing intracellular cAMP levels and inhibiting T cell activation. Thus, the compounds are useful for the prevention and treatment of various allergic diseases and inflammatory or immune diseases. In addition, since they selectively inhibit PDE7, they exert only minimal effect on other PDEs. Thus, when used as a medicament, it is expected to reduce side effects.

权利要求:
Claims (18)
[1" claim-type="Currently amended] A pyrazolopyrimidinone derivative represented by the following formula (IA) or (IB), or a salt or solvate thereof:
[Formula IA]
[Formula IB]
[In the meal,
A represents N or CR ⁴ ,
B represents a hydrogen atom or a halogen atom,
R ¹ represents optionally substituted C _3-7 cycloalkyl or tert-butyl,
R ² represents hydrogen, methyl or ethyl,
R ³ is hydrogen, nitro, cyano or halogen atom, NR ⁵ R ⁶ , C (= X) R ⁷ , SO ₂ NR ⁵ R ⁶ , OR ⁸ , NR ⁸ CONR ⁵ R ⁶ , NR ⁸ SO ₂ R ⁹ , Heteroaryl group, or optionally substituted C _1-3 alkyl,
R ⁴ represents hydrogen or C _1-3 alkoxy substituted with one or more fluorine atoms as needed,
R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, optionally substituted C _1-6 alkyl or optionally substituted acyl or together with the nitrogen atom to which they are attached azetidinyl, pyrrolidinyl, piperidinyl , Morpholino, thiomorpholino, piperazinyl or homopiperazinyl, each of said groups being optionally substituted C _1-4 alkyl, OH, C _1-3 alkoxy, CO ₂ H or NR ⁵ May be substituted with R ⁶ ,
R ⁷ represents optionally substituted C _1-6 alkyl, OH, OR ⁸ or NR ⁵ R ⁶ ,
R ⁸ represents hydrogen or an optionally substituted C _1-6 alkyl group,
R ⁹ represents an optionally substituted C _1-6 alkyl group,
X represents O, S or NH.
[2" claim-type="Currently amended] A compound according to claim 1, represented by formula IA.
[3" claim-type="Currently amended] A compound according to claim 1, represented by formula IB.
[4" claim-type="Currently amended] The compound of any one of claims 1-3, wherein R ¹ is C _5-7 cycloalkyl.
[5" claim-type="Currently amended] The compound of claim 4, wherein C _5-7 cycloalkyl is selected from the group consisting of cyclopentyl, cyclohexyl and cycloheptyl.
[6" claim-type="Currently amended] The compound of any one of claims 1-5, wherein A is CR ⁴ .
[7" claim-type="Currently amended] The compound of claim 6, wherein R ⁴ is methoxy or ethoxy.
[8" claim-type="Currently amended] 8. Compounds according to any of claims 1 to 7, wherein B is hydrogen or fluorine.
[9" claim-type="Currently amended] The compound of any one of claims 1-8, wherein R ² is methyl.
[10" claim-type="Currently amended] 10. A compound according to any one of claims 1 to 9, wherein R ³ is a substituent other than hydrogen.
[11" claim-type="Currently amended] The compound of claim 10, wherein R ³ consists of NR ⁵ R ⁶ , C (═X) R ⁷ , SO ₂ NR ⁵ R ⁶ , OR ⁸ , NR ⁸ CONR ⁵ R ⁶ , NR ⁸ SO ₂ R ^9, and a heteroaryl group. Is a group selected from the military,
R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl or homopiperazinyl, Groups may be further substituted with optionally substituted C _1-4 alkyl, OH, C _1-3 alkoxy, CO ₂ H or NR ⁵ R ⁶ ,
R ⁷ is optionally substituted linear or branched C _1-6 alkyl, OH, OR ⁸ or NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are defined above;
R ⁸ is hydrogen or an optionally substituted linear or branched C _1-6 alkyl group,
R ⁹ is an optionally substituted C _1-3 alkyl group,
X is O or S,
Heteroaryl groups are selected from the group consisting of optionally substituted pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyridyl, pyrazyl, indolyl, quinolyl, isoquinolyl and tetrazolyl.
[12" claim-type="Currently amended] A pyrazolopyrimidinone derivative represented by the following formula (IA 'or IB'), or a salt or solvate thereof:
[Formula IA ']
Formula IB '

[In the meal,
A 'represents N or CR ^4' ,
B 'represents a hydrogen atom or a halogen atom,
R ^{1 ′} represents optionally substituted C _3-7 cycloalkyl or tert-butyl,
R ^{2 '} represents hydrogen, methyl or ethyl,
R ^{3 '} is NR ^5' R ^{6 '} , C (= O) R ^7' , SO ₂ NR ^{5 '} R ^6' , OR ^{8 '} , NR ^8' CONR ^{5 '} R ^6' , NR ^{8 '} CO ₂ R ^{9 '} , NR ^8' SO ₂ R ^{9 '} , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkenyl or optionally substituted saturated or unsaturated heterocycloalkyl,
R ^{4 ′} represents hydrogen or C _1-3 alkoxy substituted with one or more fluorine atoms as needed,
R ^{5 '} and R ^6' are the same or different and represent a hydrogen atom, optionally substituted C _1-6 alkyl or optionally substituted heterocycloalkyl, or azetidinyl, pyrrolidinyl together with the nitrogen atom to which they are attached; , Piperidinyl, thiomorpholino, piperazinyl or homopiperazinyl, each of said groups being an NR ^{9 '} C (= 0) R ^7' , oxo group or C (= 0) R ^{7 '} Further substituted by
R ^{7 ′} represents hydrogen, optionally substituted C _1-6 alkyl, OH, OR ^{8 ′} or NR ^{5 ′} R ^{6 ′} ,
R ^{8 ′} represents hydrogen or an optionally substituted C _1-6 alkyl group or optionally substituted heterocycloalkyl,
R ^{9 ′} represents an optionally substituted C _1-6 alkyl group.
[13" claim-type="Currently amended] 13. A compound according to claim 12, represented by formula IA '.
[14" claim-type="Currently amended] 13. Compounds according to claim 12, represented by formula IB '.
[15" claim-type="Currently amended] 15. The compound of any one of claims 12-14, wherein R ^{1 '} is selected from the group consisting of cyclopentyl, cyclohexyl and cycloheptyl.
[16" claim-type="Currently amended] 17. The compound of any one of claims 12-16, wherein A is CR ^{4 '} and R ^4' is methoxy or ethoxy.
[17" claim-type="Currently amended] 18. The compound of any one of claims 12-17, wherein R ^{2 '} is methyl.
[18" claim-type="Currently amended] A PDE7 inhibitor comprising the compound according to any one of claims 1 to 17 as an active ingredient.

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CA2692859C|2016-05-10|Imidazo-, pyrazolopyrazines and imidazotriazines and their use

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US7468376B2|2008-12-23|Pyrazolopyridine derivates

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US6028074A|2000-02-22|Pyrazolo[3,4-d]pyrimidineone compounds

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ES2268059T3|2007-03-16|It has | pyrimidindionas as inhibitors of the proliferation of cells t.

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EP0656898B1|1997-01-22|Pyridopyrimidinone antianginal agents

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AU2005259894C1|2009-09-17|Pyrrolotriazine kinase inhibitors

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CA2523831C|2008-11-18|5,7-diaminopyrazolo[4,3-d]pyrimidines useful in the treatment of hypertension

同族专利:

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公开号 | 公开日

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HU228316B1|2013-03-28|

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KR100929513B1|2009-12-03|

---

CN1264843C|2006-07-19|

---

EP1454897A4|2005-11-23|

---

AT375347T|2007-10-15|

---

CA2439784C|2010-11-02|

---

JPWO2003053975A1|2005-04-28|

---

CA2439784A1|2003-07-03|

---

US7268128B2|2007-09-11|

---

WO2003053975A1|2003-07-03|

---

HU0402171A2|2005-02-28|

---

EP1454897A1|2004-09-08|

---

US20050148604A1|2005-07-07|

---

EP1454897B1|2007-10-10|

---

ES2294189T3|2008-04-01|

---

CN1533392A|2004-09-29|

---

DE60222931T2|2008-07-10|

---

BR0207215A|2004-02-10|

---

JP4312603B2|2009-08-12|

---

DE60222931D1|2007-11-22|

---

HU0402171A3|2008-08-28|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-12-13|Priority to JPJP-P-2001-00380483

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2001-12-13|Priority to JP2001380483

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2002-12-13|Application filed by 다이이찌 산토리 파마 가부시키가이샤, 가부시키가이샤 다이이찌 산토리 세이부쓰 이가쿠 겐큐쇼

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2002-12-13|Priority to PCT/JP2002/013083

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2004-07-21|Publication of KR20040065156A

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2009-12-03|Application granted

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2009-12-03|Publication of KR100929513B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-2001-00380483|2001-12-13|

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JP2001380483|2001-12-13|

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PCT/JP2002/013083|WO2003053975A1|2001-12-13|2002-12-13|Pyrazolopyrimidinone derivatives having pde7-inhibitory activity|