USOO8329,691 B2

(12) United States Patent (10) Patent No.: US 8,329,691 B2 Imaeda et al. (45) Date of Patent: Dec. 11, 2012

(54) AMIDE COMPOUNDS AND USE OF THE 2008. O146619 A1 6/2008 Lu et al. SAME 2009 OO12126 A1 1/2009 Lu et al. 2009, O156612 A1 6/2009 Kuroita et al. 2009/0227560 A1 9, 2009 Kuroita et al. (75) Inventors: Yasuhiro Imaeda, Ann Arbor, MI (US); Takanobu Kuroita, Osaka (JP); FOREIGN PATENT DOCUMENTS Yoshiyuki Fukase, Osaka (JP); EP O 188094 T 1986 EP 0 711 757 5, 1996 Shinkichi Suzuki, Osaka (JP); Michiko EP 1277 741 1, 2003 Tawada, Osaka (JP) EP 2 119 702 11, 2009 JP 61-140568 6, 1986 (73) Assignee: Takeda Pharmaceutical Company JP 3-173870 7, 1991 JP 2002-12587 1, 2002 Limited, Osaka (JP) WO 01.83460 11, 2001 WO 02/20489 3, 2002 (*) Notice: Subject to any disclaimer, the term of this WO 2004/054974 T 2004 patent is extended or adjusted under 35 WO 2004/080463 9, 2004 U.S.C. 154(b) by 30 days. WO 2005/023260 3, 2005 WO 2006/018284 2, 2006 WO 2007 OO6534 1, 2007 (21) Appl. No.: 12/734,150 WO 2007/047447 4/2007 WO 2007 O77OO5 7/2007 (22) PCT Filed: Oct. 14, 2008 WO 2007/094513 8, 2007 WO 2007.118854 10/2007 (86). PCT No.: PCT/UP2008/068595 WO 2008/O16643 2, 2008 WO 2008/053194 5, 2008 S371 (c)(1), WO 2008/093.737 8, 2008 (2), (4) Date: Apr. 14, 2010 WO 2008/123469 10, 2008 WO 2008, 139941 11, 2008 (87) PCT Pub. No.: WO2009/051112 (Continued) PCT Pub. Date: Apr. 23, 2009 OTHER PUBLICATIONS (65) Prior Publication Data CAplus Registry Data, RN 1005754-45-9, STN accessed Feb. 3, 2012.* US 2010/0324O1 O A1 Dec. 23, 2010 (Continued) (30) Foreign Application Priority Data Primary Examiner — Joseph K. McKane Oct. 15, 2007 (JP) ...... 2007-268100 Assistant Examiner — Samantha Shterengarts (74) Attorney, Agent, or Firm — Wenderoth, Lind & Ponack, (51) Int. Cl. LLP. A 6LX3/5377 (2006.01) A6 IK3I/506 (2006.01) (57) ABSTRACT CO7D 413/4 (2006.01) A renin inhibitor comprising a compound represented by the C07D 239/20 (2006.01) formula: (52) U.S. Cl...... 514/235.8: 514/256; 54.4/122; 544/242 (58) Field of Classification Search ...... 544/122, 544/242: 514/235.8, 256 See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 4,734.418 A * 3/1988 Yokoyama et al...... 514,252.16 5,225,402 A 7/1993 Ogawa et al. 5,250,548 A 10, 1993 Winn et al. 5,436,254 A 7/1995 Ogawa et al. 5,652.247 A 7/1997 Ogawa et al. 7.919,511 B2 4/2011 Lu et al. 7,932,270 B2 4/2011 Lu et al. 7,939,534 B2 5, 2011 Lu et al. 7,939,548 B2* 5/2011 Lu et al...... 514,334 wherein each symbol is as defined in the description, or a salt 2003, OO32647 A1 2/2003 Yamada et al. thereof or a prodrug thereof. The compound of the present 2003,0229089 A1 12/2003 Yamada et al. invention has a Superior renin inhibitory activity, and thus is 2003/0229.095 A1 12/2003 Yamada et al. 2004/O142930 A1 7/2004 Yamada et al. useful as an agent for the prophylaxis or treatment of hyper 2006.0089350 A1 4/2006 Hochman et al. tension, various organ damages attributable to hypertension 2008.OO27037 A1 1/2008 Yamada et al. and the like. 2008. O132545 A1 6, 2008 Lu et al. 2008/O139575 A1 6, 2008 Lu et al. 12 Claims, No Drawings US 8,329,691 B2 Page 2

FOREIGN PATENT DOCUMENTS International Search Report issued Dec. 16, 2008 in International WO 2009 OO1915 12/2008 (PCT) Application No. PCT/JP2008/068595. WO 2009,1543OO 12/2009 J. R. Proudfoot et al., “Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 3. Dipyrido2,3-b:2',3'-ediazepinones', OTHER PUBLICATIONS Journal of Medicinal Chemistry, vol. 38, No. 8, pp. 1406-1410, 1995. Supplementary European Search Report issued May 27, 2011 in European Application No. 08839108.1. * cited by examiner US 8,329,691 B2 1. 2 AMIDE COMPOUNDS AND USE OF THE Renin is an enzyme occupying a position at the uppermost SAME stream of the RA System, and converts angiotensinogen to angiotensin I. A renin inhibitory drug inhibits the RA System This application is a U.S. national stage of International by inhibiting the biosynthesis of AII in the same manner as the Application No. PCT/JP2008/068595 filed Oct. 14, 2008. ACE inhibitory drugs do, and thus can be expected to have a blood pressure lowering action or an effect of protecting TECHNICAL FIELD various organs. Since the renin inhibitory drug does not have influence on the metabolism of bradykinin, it is believed to The present invention relates to an amide compound and have no risk of side effects such as dry cough and the like, that the like, which has a superior renin inhibitory activity and is 10 are observed with the ACE inhibitory drugs. Furthermore, useful as an agent for the prophylaxis or treatment of hyper while the ACE inhibitory drugs or ARB increase the PRA tension, Various organ damages attributable to hypertension, level, the renin inhibitory drugs are the only drugs that can and the like. reduce PRA. As renin inhibitors, orally Administrable Aliskiren has BACKGROUND OF THE INVENTION 15 been reported (Chem. Biol., 2000, Vol. 7, pages 493-504; Hypertension, 2003, Vol. 42, pages 1137-1143; J. Hypertens. Hypertension is one of representative lifestyle-related dis 2005, Vol. 23, pages 417-426 etc.). eases. Hypertension which is left untreated for longtime lays Besides the above, the following compounds have been a heavy burden on the cardiovascular system and results in arteriosclerosis to progress, thus causing various disorders in reported as renin inhibitors. important organs, such as cerebral hemorrhage, cerebral inf (1) A compound represented by the formula arction, cardiac failure, angina pectoris, myocardial infarc tion, renal failure and the like. Accordingly, the purpose of H treating hypertension lies not only in lowering the blood N R1 R3 pressure, but also in improving and/or preventing disorders in 25 R7 R8 / important organs including brain, heart and kidney, by con N N trolling the blood pressure. As a method of treating hyperten R21 NT YR4 Sion, there are available fundamental treatments based on improvement in the lifestyle. Such as dietetic therapy, exercise R6 O therapy and the like, as well as an attempt to control the blood 30 pressure by positive pharmaceutical intervention. wherein R1 is hydrogen, unsubstituted or substituted alkyl, The renin-angiotensin (RA) system is a system of biosyn unsubstituted or substituted alkenyl, unsubstituted or sub thesis of angiotensin II (AII), which is a major vasopressor stituted alkynyl, unsubstituted or substituted aryl, unsub factor, and takes an important role in the control of the blood stituted or substituted heterocyclyl, or unsubstituted or pressure and the amount of body fluid. AII exhibits a strong 35 substituted cycloalkyl: vasoconstrictive effect brought by the intervention of AII R2 is unsubstituted or substituted alkyl, unsubstituted or sub receptors on the cellular membrane, thus raising the blood stituted alkenyl, unsubstituted or substituted alkynyl, pressure, and also promotes cellular propagation or produc unsubstituted or substituted aryl, unsubstituted or substi tion of extracellular matrix by directly acting on the AII tuted heterocyclyl, unsubstituted or substituted cycloalkyl, receptors in the cardiac cells or renal cells. Therefore, drugs 40 or acyl: inhibiting increase in the activity of the RA system can be R3 is hydrogen, unsubstituted or substituted aryl, or unsub expected to have a blood pressure lowering action as well as stituted or substituted alkyl: a powerful organ protecting action, and thus active researches R4 is unsubstituted or substituted alkyl, unsubstituted or sub on Such drugs have been conducted so far. stituted alkenyl, unsubstituted or substituted alkynyl, The method of inhibiting the AII action is broadly classi 45 unsubstituted or substituted aryl, unsubstituted or substi fied into methods of inhibiting the biosynthesis of AII and tuted heterocyclyl, unsubstituted or substituted cycloalkyl, methods of inhibiting the binding of AII to AII receptors. For or acyl; or the drugs inhibiting the biosynthesis of AII, angiotensin con R3 and R4 may form together a 3- to 7-membered nitrogen verting enzyme (ACE) inhibitory drugs have been already put containing Saturated hydrocarbon ring which can be to practical use and are being confirmed to have a blood 50 unsubstituted or substituted; pressure lowering action as well as an effect for protecting R6 is hydrogen, halo, unsubstituted alkyl or unsubstituted various organs. However, since ACE is an enzyme identical to alkoxy; kininase II, which is a bradykinin degrading enzyme, ACE R7 and R8 are independently of each other hydrogen or halo: inhibitory drug inhibits the biosynthesis of AII as well as the and degradation of bradykinin. As a result, ACE inhibitory drugs 55 T is methylene or carbonyl, or a salt thereof (see WO2007/ are believed to induce side effects such as dry cough, 077005). angioedema and the like, which are considered to be caused (2) A compound represented by the formula by accumulation of bradykinin. As the drugs inhibiting the binding of AII to AII receptors, H AII type 1 receptor blockers (ARB) have been developed. 60 N ARB has a merit in that it can inhibit, at the receptor level, the R1 R3 action of AII that is biosynthesized by not only ACE but also an enzyme other than ACE. Such as chymase and the like. It is N \ known that administration of ACE inhibitors and ARB R21 NT YR4 increases the plasma renin activity (PRA) as a compensatory 65 feedback effect, since these drugs act on a more peripheral wherein R1 is hydrogen, unsubstituted or substituted alkyl, region of the RA System. unsubstituted or substituted alkenyl, unsubstituted or sub US 8,329,691 B2 3 4 stituted alkynyl, unsubstituted or substituted aryl, unsub On the other hand, as an amide compound, the following stituted or substituted heterocyclyl, or unsubstituted or compounds have been reported. substituted cycloalkyl; (4) In EP71 1757, for example, a compound having the fol R2 is unsubstituted or substituted alkyl, unsubstituted or sub lowing formula has been reported as an O. 1-adrenergic stituted alkenyl, unsubstituted or substituted alkynyl, receptor antagonist: unsubstituted or substituted aryl, unsubstituted or substi tuted heterocyclyl, unsubstituted or substituted cycloalkyl, or acyl: R3 is hydrogen, unsubstituted or substituted aryl, or unsub 10 stituted or substituted alkyl; Y R4 is unsubstituted or substituted alkyl, unsubstituted or sub stituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substi tuted heterocyclyl, unsubstituted or substituted cycloalkyl, 15 OMe \ / or acyl; or R and R may form together a 3- to 7-membered nitrogen containing Saturated hydrocarbon ring which can be (SC)\ / / unsubstituted or substituted; and T is methylene or carbonyl, or a salt thereof (see WO2007/ 006534). (3) A compound represented by the formula (5) In U.S. Pat. No. 5.250,548, for example, a compound 25 having the following formula has been reported as an AII receptor antagonist:

R3d O X )n 30 NR2sR26 R R" 1. u R3a O X^1-1A-X. e N 35 N-Q f H N N \ NS NH 40 N wherein R" is a hydrogen atom, an optionally substituted NR25R26:1-morpholino (Ex. 24) C-calkyl group or the like; R' is a substituted C-calkoxy 4-methoxymethoxy-1-piperidinyl (Ex. 25) group or the like: R' is a hydrogen atom, an optionally - N(CH3)2 (Ex. 26) Substituted Coalkoxy group or the like; R is a hydrogen atom, an optionally Substituted C. alkyl group or the like; 45 R. R. R. and Rare the same or different and each independently is a group:-A-B (wherein A is a single bond, —(CH2).O. , -(CH2)N(R)CO etc., B is a hydrogen (6) In Journal of Medicinal Chemistry, 1995, Vol. 38, pages atom, an optionally substituted Calkyl group etc.) or the 1406-1410, a compound having the following formula has like; R is a hydrogen atom, an optionally substituted C 50 been reported as an intermediate for an HIV-1 reverse alkyl group or the like: s is 0 or the like; n is 1 or the like, or transcriptase inhibitor: a pharmacologically acceptable salt, for example, a com pound of the following formula (see WO2008/093737). HC O 55 V N

2 S. N C I N CH3 60 Et

(7) In WO01/83460, for example, compounds having the 65 following formulas have been reported as compounds hav ing a coMP-specific phosphodiesterase (PDE) inhibitory action (PDE V inhibitory action): US 8,329,691 B2 5 6

Ex. 461 CN

N O) N1 N N- 2N NOH 21 N C H Et O HN YCH, 10 NN O OMe

N C 15 E/ CN OMe

N1 N

2 N C H Me Ex. 474 NN O OMe N O) 25

N r2N NOH 30 Me O HN YCH, However, these reports do not describe a renin inhibitory activity. 35 Other than the above, amide compounds having particular structures are disclosed as a cathepsin Sinhibitor in WO2006/ C 018284, as a kinase inhibitor in WO2004/080463, as a CNS OMe disorder regulator in WO2007/047447, as a Na" K-2Cl cotransporter antagonist in US2006/0089350, as a CCR5 40 antagonist in WO2004/054974, and as a glycine uptake inhibitor in WO2005/023260. patent document 1: WO2007/077005 patent document 2: WO2007/006534 patent document 3: WO2008/093737 Ex. 475 45 patent document 4: EP711757 patent document 5: U.S. Pat. No. 5.250,548 patent document 6: WO01/83460 patent document 7: WO02/20489 patent document 8: WO2006/018284 50 patent document 9: WO2004/080463 patent document 10: WO2007/047447 patent document 11: US2006/0089350 patent document 12: WO2004/054974 patent document 13: WO2005/023260 55 non-patent document 1: Journal of Medicinal Chemistry, 1995, vol. 38, pages 1406-1410 DISCLOSURE OF THE INVENTION

OMe 60 There is a demand on the development of a compound having a Superior renin inhibitory activity, which is useful as a medicament (e.g., an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hyper tension and the like, and the like), and a novel renin inhibitor. (8) In WO02/20489, for example, compounds having the 65 The present inventors have conducted various studies and following formulas have been reported as compounds hav found that a compound represented by the following formula ing a PDE V inhibitory action: (I) and a salt thereof have a superior renin inhibitory activity US 8,329,691 B2 7 8 and are useful as renin inhibitors, which resulted in the I6 the compound of the aforementioned 2, wherein ring B completion of the present invention. Of the compounds rep is a ring represented by the formula resented by the following formula (I) and salts thereof, com pounds represented by the following formulas (A) and (B) and salts thereofare novel compounds. The present invention relates to 1 a renin inhibitor comprising a compound represented by the formula

10 (I)

wherein R'' and R'' are each a hydrogen atom or a substitu 15 ent, or R'' and R' optionally form, together with the carbon atoms bonded thereto, a 5- to 7-membered ring optionally having Substituent(s): 7 the compound of the aforementioned (2), wherein R' is Calkyl, wherein R' and Rare each a hydrocarbon group optionally R" is a 5-membered aromatic group optionally having sub having Substituent(s) or a heterocyclic group optionally stituent(s), having Substituent(s), or ring Aa is a 5- or 6-membered aromatic heterocycle option R" and R optionally form, together with the nitrogen atom ally having Substituent(s), and bonded thereto, a nitrogen-containing heterocycle option ring B is a ring represented by the formula ally having Substituent(s), 25 R is a substituent, and ring A is a homocycle or heterocycle optionally having Sub stituent(s), or a salt thereof hereinafter sometimes to be abbreviated as compound (1) or a prodrug thereof; 2 a compound represented by the formula 30

(A) HN rRb1 -CH2 35 wherein R'' and R'' are each a hydrogen atom or a substitu ent, or R'' and R' optionally form, together with the carbon atoms bonded thereto, a 5- to 7-membered ring optionally having Substituent(s): 40 8 a compound represented by the formula

(B) R4 wherein R' is alkyl optionally having substituent(s), 45 R" is a 5- or 6-membered aromatic group optionally having Substituent(s), ring Aa is a homocycle or heterocycle optionally having Sub stituent(s), ring B is a nitrogen-containing 5- to 7-membered ring option 50 ally having Substituent(s), and in and mare each an integer of 0 to 2, and the total of n and m is 1 to 3, or a salt thereof, excluding 4-(3-chloro-4-meth oxybenzyl)amino-6-cyano-N-ethyl-N-(1-ethylpyrroli din-3-yl)guinoline-3-carboxamide and 4-(3-chloro-4- 55 wherein R'' and Rare each a hydrocarbon group optionally methoxybenzyl)amino-6-cyano-N-methyl-N-(1- having Substituent(s) or a heterocyclic group optionally methylpiperidin-4-yl)cquinoline-3-carboxamide having Substituent(s), or hereinafter sometimes to be abbreviated as compound R'' and Roptionally form, together with the nitrogen atom (A): bonded thereto, a nitrogen-containing heterocycle option (3) the compound of the aforementioned (2), wherein R" is 60 ally having Substituent(s), C. alkyl, R is a substituent, excluding 2-(4-phenylpiperazin-1-yl) 4) the compound of the aforementioned (2), wherein R is a ethyl optionally having Substituent(s) and biphenyl-4-yl 5-membered aromatic group optionally having Substi having Substituent(s), tuent(s): R" is a hydrocarbon group optionally having substituent(s), a 5the compound of the aforementioned 2, whereinring Aa 65 heterocyclic group optionally having Substituent(s), is a 5- or 6-membered aromatic heterocycle optionally excluding a cyclic amino optionally having Substituent(s), having Substituent(s): mercapto optionally having a Substituent or acyl, US 8,329,691 B2 9 10 X and Y are each C or N, and ring Ab is a nitrogen-containing 6-membered ring optionally R4 R4 having substituent(s) in addition to R', or a salt thereof, excluding N-(2-chloro-3-pyridinyl)-2-(ethylamino)-N,6- 21 dimethyl-3-pyridinecarboxamide hereinafter sometimes to be abbreviated as compound (B): S1 N1 O S1N1 9 the compound of the aforementioned 8), wherein R'' and H H R’ are each a hydrocarbon group optionally having Sub stituent(s) or pyrrolidinyl, imidazolidinyl, pyrazolidinyl, O O piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl 10 optionally having Substituent(s): 16 2-tert-butyl-N-(3S.5R)-5-carbamoylpiperidin-3-yl)-4- 10 the compound of the aforementioned 8), wherein R' (furan-2-ylmethyl)amino-N-(2-methylpropyl)pyrimi and R' form, together with the nitrogen atom bonded dine-5-carboxamide or a salt thereof; thereto, piperidine optionally having Substituent(s) or pip 15 17 2-tert-butyl-4-(3-methoxypropyl)amino-N-(2-methyl erazine optionally having Substituent(s): propyl)-N-(3S.5R)-5-(morpholin-4-ylcarbonyl)piperi 11 the compound of the aforementioned 8), wherein R is din-3-ylpyrimidine-5-carboxamide or a salt thereof; (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic 18 2-tert-butyl-N-(2-methylpropyl)-N-(3S.5R)-5-(mor group containing, as a ring-constituting atom besides car pholin-4-ylcarbonyl)piperidin-3-yl)-4-(1,3-oxazol-2-yl bon atom, 1 to 4 heteroatoms selected from an oxygen methyl)aminolpyrimidine-5-carboxamide or a salt atom, a Sulfur atom and a nitrogen atom, and optionally thereof having 1 to 3 C alkyl, 19 a prodrug of the compound of the aforementioned 2 or (2) Co.14 aryl, 8: (3) Co cycloalkyl, 20 a medicament comprising the compound of the afore 25 mentioned 2 or 8 or a prodrug thereof; (4) Ce alkyl optionally having 1 to 3 C alkoxy, or 21 the medicament of the aforementioned 20, which is a (5) Calkoxy-carbonyl: renin inhibitor; 12 the compound of the aforementioned 8), wherein R is a 22 the medicament of the aforementioned 20, which is an hydrocarbon group optionally having Substituent(s) or a agent for the prophylaxis or treatment of hypertension; and heterocyclic group optionally having Substituent(s), 30 23 the medicament of the aforementioned 20, which is an excluding a cyclic amino optionally having Substituent(s): agent for the prophylaxis or treatment of various organ 13 the compound of the aforementioned 8), wherein Risa damages attributable to hypertension. hydrocarbon group optionally having Substituent(s): Furthermore, the present invention also relates to a com 14 the compound of the aforementioned 8), wherein ring pound represented by the formula Ab is a ring represented by the formula 35 (C) R4 R4 21 40 N N1 H H 45 O O wherein R is as defined in the aforementioned 8): 15 the compound of the aforementioned 8), wherein R' wherein R' is alkyl optionally having substituent(s), and R are each a hydrocarbon group optionally having 50 R is a substituent, Substituent(s) or pyrrolidinyl, imidazolidinyl, pyrazolidi Z is C2-alkylene optionally having Substituent(s), C2-alk nyl, piperidinyl, piperazinyl, morpholinyl orthiomorpholi enylene optionally having Substituent(s) or C-alkynylene nyl optionally having Substituent(s), optionally having Substituent(s), R3 is ring Ac is a homocycle or heterocycle optionally having Sub 55 stituent(s), (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic ring Bc is a nitrogen-containing 5- to 7-membered ring group containing, as a ring-constituting atom besides car optionally having Substituent(s), and bon atom, 1 to 4 heteroatoms selected from an oxygen in and m are each an integer of 0 to 2, and the total of n and atom, a Sulfur atom and a nitrogen atom, and optionally m is 1 to 3, or a salt thereof, excluding 4-(1R)-1-cyclohexy having 1 to 3 C alkyl, 60 lethylamino-1-ethyl-N-methyl-N-(1-methylpiperidin (2) C-14 aryl, 4-yl)-1H-pyrazolo 3,4-bipyridine-5-carboxamide, 4 (3) Co cycloalkyl, {(1R)-1-cyclohexylethylamino-N, 1-diethyl-N-(1-eth ylpyrrolidin-3-yl)-1H-pyrazolo 3,4-bipyridine-5-car (4) C alkyl optionally having 1 to 3 C alkoxy, or boxamide and N-(1-benzylpyrrolidin-3-yl)-4-(1R)-1- (5) Calkoxy-carbonyl, 65 cyclohexylethylamino-1-ethyl-N-methyl-1H-pyrazolo R" is a hydrocarbon group optionally having substituent(s), 3,4-bipyridine-5-carboxamide hereinafter sometimes to and ring Ab is a ring represented by the formula be abbreviated as compound (C) and the like. US 8,329,691 B2 11 12 Compound (I), compound (A), compound (B) and com ally condensed with a benzene ring. Examples of the con pound (C) have a Superior renin inhibitory activity, and thus densed group include indanyl, tetrahydronaphthyl, fluorenyl they are useful as agents for the prophylaxis or treatment of and the like. hypertension, various organ damages attributable to hyper Examples of the “Clio cycloalkenyl in the present speci tension, and the like. fication include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, Examples of the "halogen atom' in the present specifica 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. The tion include fluorine, chlorine, bromine and iodine. above-mentioned Co cycloalkenyl is optionally condensed Examples of the “C. alkylenedioxy” in the present speci with a benzene ring. Examples of the condensed group fication include methylenedioxy, ethylenedioxy, trimethyl include indenyl and the like. enedioxy and the like. 10 Examples of the “C. alkyl in the present specification Examples of the “Clio cycloalkadienyl' in the present include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec specification include 2.4-cyclopentadien-1-yl, 2.4-cyclo butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl. hexadien-1-yl, 2.5-cyclohexadien-1-yl and the like. The hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3.3- above-mentioned Cao cycloalkadienyl is optionally con dimethylbutyl, 2-ethylbutyl and the like. 15 densed with a benzene ring. Examples of the “C. alkoxy” in the present specification Examples of the "Caryl” in the present specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, include phenyl, 1-naphthyl 2-naphthyl, biphenylyl, 2-anthryl isobutoxy, sec-butoxy, tert-butoxy and the like. and the like. Among these, Caryl is preferable, and phenyl Examples of the “C. alkoxy-carbonyl' in the present is more preferable. The above-mentioned Caryl is option specification include methoxycarbonyl, ethoxycarbonyl, pro ally condensed with Co cycloalkane (examples of the Co poxycarbonyl, tert-butoxycarbonyl and the like. cycloalkane include rings corresponding to the above-men Examples of the “Calkyl-carbonyl in the present speci tioned Co cycloalkyl). Examples of the condensed group fication include acetyl, propanoyl, butanoyl, isobutanoyl, include tetrahydronaphthyl and the like. pentanoyl, isopentanoyl, hexanoyl and the like. Examples of the “Cz-aralkyl in the present specification The “optionally halogenated in the present specification 25 include benzyl, phenethyl, naphthylmethyl, biphenylylm means being optionally substituted by 1 to 5, preferably 1 to ethyl and the like. 3, halogen atoms. Examples of the "Cs arylalkenyl' in the present specifi Examples of the “hydrocarbon group' of the “hydrocarbon cation include styryl and the like. group optionally having Substituent(s) in the present speci Examples of the "Co cycloalkyl-C alkyl in the fication include alkyl, alkenyl, alkynyl, alkylidene, 30 present specification include cyclopropylmethyl, cyclohexy cycloalkyl, cycloalkenyl, cycloalkadienyl, aryl, aralkyl, ary lmethyl and the like. lalkenyl, cycloalkylalkyl and the like. Preferred are Co The “hydrocarbon group” of the “hydrocarbon group alkyl, Co alkenyl, Co alkynyl, C- alkylidene, Co optionally having Substituent(s) optionally have Substi cycloalkyl, Cao cycloalkenyl, Cao cycloalkadienyl, C-14 tuent(s) (e.g., 1 to 5, preferably 1 to 3, substituents) at substi aryl, C7 aralkyl, Cs, arylalkenyl, Co cycloalkyl-C 35 tutable position(s). When the number of the substituents is alkyl and the like. The above-mentioned Co cycloalkyl, two or more, respective Substituents may be the same or Cocycloalkenyland Cao cycloalkadienyl are each option different. ally condensed with a benzene ring. Examples of the “substituent of the “hydrocarbon group Examples of the “Clio alkyl in the present specification optionally having substituent(s) include the following sub include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec 40 stituents. butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl. (1) halogen atom; hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3.3- (2) nitro: dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and (3) cyano; the like. Among these, Ce alkyl is preferable. (4) hydroxy: Examples of the “Coalkenyl in the present specifica 45 (5) Calkoxy optionally having 1 to 3 halogen atoms; tion include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1- (6) amino; propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-bute (7) mono- or di-C alkylamino; nyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, (8) C. aralkylamino; 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, (9) C- alkoxy-carbonylamino: 1-heptenyl, 1-octenyl and the like. Among these, Calkenyl 50 (10) C. aralkyloxy-carbonylamino; is preferable. (11) Ce alkyl-carbonylamino; Examples of the "Co alkynyl in the present specifica (12) Co cycloalkyl-carbonylamino; tion include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, (13)C alkylsulfonylamino; 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, (14) Carylsulfonylamino; 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 55 (15) C. alkylaminocarbonylamino; 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Among these, (16) Carylaminocarbonylamino; C. alkynyl is preferable. (17) C. alkyl-carbonyl: Examples of the “C. alkylidene' in the present specifica (18) Co cycloalkyl-carbonyl: tion include methylene, ethylidene, propylidene, isopropy (19) carboxy: lidene and the like. 60 (20) Calkoxy-carbonyl: Examples of the “Clio cycloalkyl in the present specifi (21) carbamoyl; cation include cyclopropyl, cyclobutyl, cyclopentyl, cyclo (22) mono- or di-C alkylcarbamoyl; hexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo (23) Cz aralkylcarbamoyl; 2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, (24) mercapto: bicyclo[3.3.1nonyl, bicyclo[4.2.1nonyl, bicyclo4.3.1 de 65 (25) Calkylthio; cyl, adamanty1 and the like. Among these, C. cycloalkyl is (26) C. alkylsulfinyl, preferable. The above-mentioned Co cycloalkyl is option (27) C. alkylsulfonyl: US 8,329,691 B2 13 14 (28) C alkylenedioxy; 2,3-bipyrazin-2-yl, 1H-pyrrolo2,3-bipyrazin-6-yl), imi (29) C- alkyl optionally having 1 to 3 substituents selected dazopyridinyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, from 1H-imidazo[4,5-cpyridin-2-yl, 2H-imidazo 1,2-alpyri (a) a halogen atom, din-3-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b (b) hydroxy, pyrazin-2-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo 4.3-c. (c) Coalkoxy, pyridin-3-yl), pyrazolothienyl (e.g., 2H-pyrazolo 3,4-b (d) C-14 aryl, thiophen-2-yl), pyrazolotriazinyl (e.g., pyrazolo.5.1-c1. (e)amino, 2.4 triazin-3-yl) and the like; and the like. (f) mono- or di-C alkylamino, Examples of the “nonaromatic heterocyclic group' include (g) C7-16 aralkylamino, 10 a 4- to 7-membered (preferably 5- or 6-membered) monocy (h) Calkoxy-carbonylamino, clic nonaromatic heterocyclic group containing, as a ring (i) C. alkyl-carbonyloxy, constituting atom besides carbon atoms, 1 to 4 heteroatoms (i) C. alkylthio, and selected from an oxygen atom, a Sulfur atom and a nitrogen (k) Calkylsulfonyl: atom, and a fused nonaromatic heterocyclic group. Examples (30) Caryl optionally having 1 to 3 halogen atoms; 15 of the fused nonaromatic heterocyclic group include a group (31) Cz aralkyl: derived from a fused ring wherein a ring corresponding to (32) Co cycloalkyl and the like. Such 4- to 7-membered monocyclic nonaromatic heterocyclic Examples of the "heterocyclic group' of the "heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered group optionally having Substituent(s) in the present speci heterocycle containing 1 or 2 nitrogen atoms, a 5-membered fication include an aromatic heterocyclic group and a nonaro heterocycle containing one Sulfur atomanda benzene ring are matic heterocyclic group. condensed, and the like. Examples of the “aromatic heterocyclic group' include a Examples of the “nonaromatic heterocyclic group' include 4- to 7-membered (preferably 5- or 6-membered) monocyclic 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring-constitut nonaromatic heterocyclic groups such as pyrrolidinyl (e.g., ing atom besides carbon atoms, 1 to 4 heteroatoms selected 25 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (e.g., piperidino, from an oxygenatom, a Sulfur atom and a nitrogenatom, and 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl a fused aromatic heterocyclic group. Examples of the fused (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), aromatic heterocyclic group include a group derived from a piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazi fused ring wherein a ring corresponding to such 4- to 7-mem nyl), hexamethyleniminyl (e.g., hexamethylenimin-1-yl), bered monocyclic aromatic heterocyclic group, and 1 or 2 30 oxazolidinyl (e.g., oxazolidin-2-yl), thiazolidinyl (e.g., thia rings selected from a 5- or 6-membered aromatic heterocycle Zolidin-2-yl), imidazolidinyl (e.g., imidazolidin-2-yl, imida containing 1 or 2 nitrogen atoms, a 5-membered aromatic Zolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl), thiazolinyl heterocycle containing one Sulfur atom and a benzene ring are (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl, condensed, and the like. imidazolin-3-yl), dioxolyl (e.g., 1,3-dioxol-4-yl), dioxolanyl Examples of the “aromatic heterocyclic group' include 4 35 (e.g., 1,3-dioxolan-4-yl), dihydrooxadiazolyl (e.g., 4.5-dihy to 7-membered (preferably 5- or 6-membered) monocyclic dro-1,2,4-oxadiazol-3-yl), 2-thioxo-1,3-oxazolidin-5-yl, aromatic heterocyclic groups such as furyl (e.g., 2-furyl, 3-fu pyranyl (e.g., 4-pyranyl), tetrahydropyranyl (e.g., 2-tetrahy ryl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-py dropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thi ridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, opyranyl (e.g., 4-S thiopyranyl), tetrahydrothiopyranyl (e.g., 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazi 40 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahy nyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl drothiopyranyl), 1-oxidotetrahydrothiopyranyl (e.g., 1-oxi (e.g., 1-pyrrolyl 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., dotetrahydrothiopyran-4-yl), 1,1-dioxidotetrahydrothiopyra 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), nyl (e.g., 1,1-dioxidotetrahydrothiopyran-4-yl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiaz tetrahydrofuryl tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), olyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl 45 pyrazolidinyl (e.g., pyrazolidin-1-yl, pyrazolidin-3-yl), pyra (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl Zolinyl (e.g., pyrazolin-1-yl), tetrahydropyrimidinyl (e.g., tet (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., rahydropyrimidin-1-yl), dihydrotriazolyl (e.g., 2,3-dihydro 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (e.g., 2,3,4,5- 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl tetrahydro-1H-1,2,3-triazol-1-yl) and the like; fused (e.g., 1,2,4-thiadiazol-5-yl, 1.3,4-thiadiazol-2-yl), triazolyl 50 nonaromatic heterocyclic groups such as dihydroindolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, (e.g., 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (e.g., 1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5- 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g., yl), triazinyl (e.g., 1,3,5-triazin-2-yl, 1.3.5-triazin-4-yl, 1.2, 2,3-dihydrobenzofuran-5-yl), dihydrobenzodioxinyl (e.g., 3-triazin-4-yl, 1,2,4-triazin-3-yl) and the like: 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl fused aromatic heterocyclic groups such as quinolyl (e.g., 55 (e.g., 3,4-dihydro-2H-1,5-benzodioxepinyl), tetrahydroben 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), iso Zofuranyl (e.g., 4,5,6,7-tetrahydrobenzofuran-3-yl), chrome quinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g., nyl (e.g., 4H-chromen-2-yl, 2H-chromen-3-yl), dihydro 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2-quinox quinolinyl (e.g., 1.2-dihydroquinolin-4-yl), alyl, 6-quinoxalyl), benzofuranyl (e.g., 2-benzofuranyl, tetrahydroquinolinyl (e.g., 1.2.3,4-tetrahydroquinolin-4-yl), 3-benzofuranyl), benzothienyl (e.g., 2-benzothienyl, 60 dihydroisoquinolinyl (e.g., 1,2-dihydroisoquinolin-4-yl), tet 3-benzothienyl), benzoxazolyl (e.g., 2-benzoxazolyl), rahydroisoquinolinyl (e.g., 1.2.3,4-tetrahydroisoquinolin-4- benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl yl), dihydrophthalazinyl (e.g., 1,4-dihydrophthalazin-4-yl) (e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimida and the like; and the like. Zol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzot The "heterocyclic group' optionally has substituent(s) riazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., 65 (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl position(s). When the number of the substituents is two or (e.g., 1H-indazol-3-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo more, respective substituents may be the same or different. US 8,329,691 B2 15 16 Examples of the “substituent of the "heterocyclic group hydro-1H-isoindole, 2,3-dihydro-1H-indole, decahydro optionally having substituent(s) include the following sub quinoline, 4,5,6,7-tetrahydro1.3oxazolo.5,4-bipyridine stituents. and the like. Examples of the Spiro ring include 1,4-dioxa-8- (1) a halogen atom; aZaspiro4.5 decane and the like. (2) nitro: The "nitrogen-containing heterocycle', a fused ring (3) cyano; thereof and a spiro ring thereof optionally have preferably 1 to (4) hydroxy: 3, more preferably 1 or 2 substituents at substitutable posi (5) Calkoxy optionally having 1 to 3 halogen atoms; tion(s). When the number of substituents is two or more, the (6) amino; respective substituents may be the same or different. (7) mono- or di-C alkylamino; 10 (8) C. aralkylamino; Examples of the substituent include the aforementioned (9) C- alkoxy-carbonylamino; groups exemplified as the substituents that the “hydrocarbon (10) C. aralkyloxy-carbonylamino; group' optionally has and the like. Preferable examples of the (11) C. alkyl-carbonylamino; Substituent include a halogen atom; hydroxy, Ce alkoxy (12) Co cycloalkyl-carbonylamino; 15 optionally having 1 to 3 halogen atoms; C alkyl-carbonyl: (13)C alkylsulfonylamino: C. alkoxy-carbonyl: C. alkyl optionally having 1 to 3 (14) Carylsulfonylamino; Substituents selected from halogen atom, hydroxy and C. (15) C. alkylaminocarbonylamino; alkoxy; oxo; Caryl (e.g., phenyl) optionally having 1 to 3 (16) Carylaminocarbonylamino; C- alkoxy, C7-6 aralkyl (e.g., benzyl); C-14 aryloxy (e.g., (17) C. alkyl-carbonyl: phenoxy); C7-6 aralkyloxy (e.g., benzyloxy); Caryl-car (18) Co cycloalkyl-carbonyl: bonyl (e.g., benzoyl); mono- or di-C alkylsulfamoyl: C (19) carboxy: alkylsulfonyl; a 5- or 6-membered heterocyclic group con (20) Calkoxy-carbonyl: taining, as a ring-constituting atom besides carbon atom, 1 to (21) a group represented by the formula: CO N(R)(R) 4 heteroatoms selected from an oxygen atom, a Sulfur atom wherein RandR are each a hydrogenatom or C, alkyl, 25 and a nitrogen atom (e.g., pyridyl, thiazolyl) and the like. or R and R optionally form, together with the nitrogen In the present specification, examples of the "homocycle or atom bonded thereto, a nitrogen-containing heterocycle heterocycle' of the “homocycle or heterocycle optionally optionally having Substituent(s): having Substituent(s) include (i) an aromatic heterocycle or (22) C. aralkylcarbamoyl; a nonaromatic heterocycle containing, as a ring-constituting (23) mercapto: 30 atom besides carbon atom, 1 to 3 heteroatoms selected from (24) Ce alkylthio; an oxygenatom, a Sulfur atom and a nitrogenatom, (ii) cyclic (25) Calkylsulfinyl: hydrocarbon (homocycle) and the like. (26) C. alkylsulfonyl: Examples of the “aromatic heterocycle' include a 5- or (27) C. alkylenedioxy; 6-membered aromatic heterocycle containing, as a ring-con (28) C. alkyl optionally having 1 to 3 substituents selected 35 stituting atom besides carbon atom, 1 to 3 heteroatoms from selected from an oxygen atom, a Sulfur atom and a nitrogen (a) a halogen atom, atom (e.g., pyrazole, pyridine, pyrimidine etc.) and the like. (b) hydroxy, Preferable examples thereof include a 6-membered aromatic (c) Coalkoxy, heterocycle containing, as a ring-constituting atom besides (d) C-14 aryl, 40 carbonatom, 1 or 2 nitrogenatoms (e.g., pyridine, pyrimidine (e)amino, etc.) and the like. (f) mono- or di-C alkylamino, Examples of the “nonaromatic heterocycle' include a 5- to (g) C7-16 aralkylamino, 9-membered (preferably 5- or 6-membered) nonaromatic het (h) Calkoxy-carbonylamino, erocycle containing, as a ring-constituting atom besides car (i) C. alkyl-carbonyloxy, 45 bon atom, 1 to 3 heteroatoms selected from an oxygen atom, (i) C. alkylthio, and a Sulfur atom and a nitrogen atom and the like. (k) Calkylsulfonyl: Examples of the “cyclic hydrocarbon include 3- to (29) C-aryl optionally having 1 to 3 halogen atoms; 10-membered (preferably 5- to 9-membered, more preferably (30) Cz aralkyl: 5- or 6-membered) cyclic hydrocarbon and the like, with (31) Co cycloalkyl and the like. 50 preference given to benzene, Cao cycloalkene, Cao Examples of the “nitrogen-containing heterocycle' of the cycloalkane and the like. "nitrogen-containing heterocycle optionally having Substitu The above-mentioned “homocycle or heterocycle' option ent(s)” formed by RandR together with the nitrogenatom ally has substituent(s) (e.g., 1 to 5, preferably 1 to 3, substitu bonded thereto include a 4- to 7-membered (preferably 5- to ents) at substitutable position(s). Examples of the substi 7-membered) nonaromatic nitrogen-containing heterocycle 55 tuent(s) include groups exemplified as the Substituents that containing, as a ring-constituting atom besides carbon atom, the “hydrocarbon group' optionally has and the like. When one nitrogen atom, and optionally further containing 1 or 2 the number of substituents is two or more, the respective heteroatoms selected from an oxygenatom, a Sulfur atom and substituents may be the same or different. a nitrogenatom. Examples of the nitrogen-containing hetero Examples of the "Ce alkylene' in the present specifica cycle include azetidine, pyrrolidine, imidazolidine, pyrazoli 60 tion include ethylene, trimethylene, tetramethylene, pentam dine, piperidine, piperazine, morpholine, thiomorpholine and ethylene, hexamethylene. —CH(CH)— —C(CH) , the like. —CH(CHCH)— —C(CH2CH) , —CH(CH)— The "nitrogen-containing heterocycle' optionally forms a CH , —CH2—CH(CH)— —C(CH) CH . fused ring with a benzene ring, a cyclohexane ring or an —CH2—C(CH) , —CH(CH)—(CH) , —CH2—CH oxazole ring, or optionally forms a spiro ring with a 1.3- 65 (CH)—CH2—, —(CH2) -CH(CH)— —C(CH)— dioxolane ring. Examples of the fused ring include 1.2.3,4- (CH) , —CH2—C(CH)—CH2—(CH), C(CH) tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-di and the like. US 8,329,691 B2 17 18 Examples of the “Calkenylene' in the present specifi Cs arylalkenyl optionally having Substituent(s), a hetero cation include —CH=CH , —CH=CH-CH , cyclic group optionally having Substituent(s), acyl and the —CH2—CH=CH , —CH=CH-(CH) , —CH2— like. CH=CH-CH -, -(CH) CH=CH-, -CH=CH The aforementioned Co alkyl, Co alkenyl, Cao (CH) , —CH2—CH=CH-(CH) , —(CH)— 5 cycloalkyl, Cao cycloalkenyl, C-14 aryl, C7-6 aralkyl and CH=CH-CH -, -(CH) CH=CH-, -CH=CH Cs arylalkenyl each optionally have substituent(s) (prefer (CH2) , —CH2—CH=CH-(CH2) , —(CH2)— ably 1 to 3 substituents) at substitutable position(s). Examples CH=CH-(CH) , (CH), CH=CH-CH of the substituent include groups similar to the substituents (CH) CH=CH-, - C(CH)—CH-, -CH=C that the aforementioned “hydrocarbon group' optionally has. 10 When the number of substituents is two or more, the respec (CH)— —CH(CH)—CH=CH-CH , —CH2— tive substituents may be the same or different. CH=CH-CH(CH) , -CH=CH-CH=CH- and the Examples of the “mercapto optionally having a Substitu like. ent in the present specification include (1) mercapto or (2) Examples of the “C. alkynylene' in the present specifi mercapto having, instead of the hydrogen atom of mercapto, cation include —C=C , —C=C CH , —CH 15 one group selected from, for example, the aforementioned "hydrocarbon group optionally having Substituent(s), the aforementioned "heterocyclic group optionally having Sub stituent(s), the groups exemplified as the Substituents that the aforementioned "hydrocarbon group optionally having substituent(s) may have and the like. Examples of the “mercapto optionally having a Substitu —CH2—C=C CH(CH)—and the like. ent include mercapto optionally having a Substituent The “C. alkylene”, “C. alkenylene' and “C. alky selected from Co alkyl optionally having substituent(s). nylene' of the "Ce alkylene optionally having Substituent(s) Co alkenyl optionally having Substituent(s), Co ”, “C. alkenylene optionally having Substituent(s) and 25 cycloalkyl optionally having Substituent(s), Co cycloalk “C- alkynylene optionally having Substituent(s) in the enyl optionally having Substituent(s), C aryl optionally present specification optionally have Substituent(s) (e.g., 1 to having Substituent(s), C. aralkyl optionally having Sub 3, preferably 1 or 2 substituents) at substitutable position(s). stituent(s), Csarylalkenyl optionally having substituent(s). When the number of substituents is two or more, respective a heterocyclic group optionally having Substituent(s), acyl substituents may be the same or different. Examples thereof 30 and the like. include the following substituents. The aforementioned Co alkyl, Co alkenyl, Cao (1) oxo; cycloalkyl, Co cycloalkenyl, C-aryl, C7 aralkyl and (2) halogen atom; Cs arylalkenyl each optionally have substituent(s) (prefer (3) nitro: ably 1 to 3 substituents) at substitutable position(s). Examples (4) cyano; 35 of the substituent include groups similar to the substituents (5) hydroxy: that the aforementioned “hydrocarbon group' optionally has. (6) Calkoxy optionally having 1 to 3 halogen atoms; When the number of substituents is two or more, the respec (7) amino; tive substituents may be the same or different. (8) mono- or di-C alkylamino; Examples of the “acyl in the present specification include (9) Czaralkylamino; 40 a group represented by the formula: = COR', —CO OR', (10) Calkoxy-carbonylamino; SOR', SOR", CO NR'R' or CS NR'R'' (11) C. alkyl-carbonylamino; wherein R is a hydrogenatom, a hydrocarbon group option (12) Ce alkyl-carbonyl: ally having Substituent(s) or a heterocyclic group optionally (13) carboxy: having substituent(s), and R" and Rare each a hydrogen (14) Ce alkoxy-carbonyl: 45 atom, a hydrocarbon group optionally having Substituent(s) (15) carbamoyl; or a heterocyclic group optionally having Substituent(s), or (16) mono- or di-C alkylcarbamoyl: R" and R” optionally form, together with the nitrogen atom (17) mercapto: bonded thereto, a nitrogen-containing heterocycle optionally (18) Calkylthio; having Substituent(s) and the like. (19) C- alkylsulfinyl: 50 Examples of the “nitrogen-containing heterocycle' of the (20) Calkylsulfonyl and the like. "nitrogen-containing heterocycle optionally having Substitu Examples of the “hydroxy optionally having a substituent” ent(s)” formed by R." and R” together with the nitrogenatom in the present specification include (1) hydroxy, or (2) bonded thereto include a 5- to 7-membered nonaromatic hydroxy having, instead of the hydrogen atom of hydroxy, nitrogen-containing heterocycle containing, as a ring-consti one group selected from, for example, the aforementioned 55 tuting atom besides carbon atom, one nitrogen atom, and "hydrocarbon group optionally having Substituent(s), the optionally further containing 1 or 2 heteroatoms selected aforementioned "heterocyclic group optionally having Sub from an oxygen atom, a Sulfur atom and a nitrogen atom. stituent(s), the groups exemplified as the Substituents that Examples of the nitrogen-containing heterocycle include pyr the aforementioned "hydrocarbon group optionally having rolidine, imidazolidine, pyrazolidine, piperidine, piperazine, substituent(s) may have and the like. 60 morpholine, thiomorpholine and the like. Examples of the “hydroxy optionally having a substituent” The "nitrogen-containing heterocycle' optionally has Sub include hydroxy optionally having a Substituent selected stituent(s) (preferably 1 to 3, more preferably 1 or 2 substitu from Co alkyl optionally having substituent(s), Coalk ents) at substitutable position(s). Examples of the substituent enyl optionally having Substituent(s), Co cycloalkyl include groups exemplified as the Substituents that the afore optionally having Substituent(s), Co cycloalkenyl option 65 mentioned “hydrocarbon group' optionally has and the like. ally having Substituent(s), Caryl optionally having Sub When the number of substituents is two or more, the respec stituent(s), C. aralkyl optionally having Substituent(s), tive substituents may be the same or different. US 8,329,691 B2 19 20 Preferable examples of the “acyl include further containing 1 or 2 heteroatoms selected from an (1) formyl; oxygen atom, a Sulfur atom and a nitrogen atom, for (2) carboxy; example, pyrrolidine, imidazolidine, pyrazolidine, piperi (3)C alkyl-carbonyl: dine, piperazine, morpholine, thiomorpholine) optionally (4) Calkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycar- 5 having Substituent(s) (e.g., 1 to 3 Substituents selected from bonyl, propoxycarbonyl, tert-butoxycarbonyl); hydroxy and C alkyl) and the like. (5) a group represented by the formula: CO NR'R'' Examples of the “nitrogen-containing heterocycle' of the wherein R" and R” are each a hydrogen atom, a hydro "nitrogen-containing heterocycle optionally having Substitu carbon group optionally having Substituent(s) or a hetero cyclic group optionally having substituent(s), or R" and 10 ent(s)” formed by R' and R together with the nitrogenatom R” optionally form, together with the nitrogen atom bonded thereto include a 5- to 9-membered (preferably 5- to bonded thereto, a nitrogen-containing heterocycle option 7-membered, more preferably 5- or 6-membered) nonaro ally having Substituent(s) and the like. matic nitrogen-containing heterocycle containing, as a ring The definition of each symbol in the formulas (I), (A), (B) constituting atom besides carbon atom, one nitrogen atom, and (C) is explained in detail in the following. 15 and optionally further containing 1 or 2 heteroatoms selected RandR from an oxygen atom, a Sulfur atom and a nitrogen atom. In the formula (I), R' and Rare each a hydrocarbon group Examples of the "nitrogen-containing heterocycle' optionally having Substituent(s) or a heterocyclic group include pyrrolidine, imidazolidine, pyrazolidine, piperidine, optionally having substituent(s), or R' and R optionally piperazine, morpholine, thiomorpholine, azepane, azocane, form, together with the nitrogenatom bonded thereto, a nitro- 20 aZonane, 1,4-diazepane and the like. gen-containing heterocycle optionally having Substituent(s). The "nitrogen-containing heterocycle' optionally has Sub Examples of the “hydrocarbon group' of the “hydrocarbon stituent(s) (e.g., 1 to 5, preferably 1 to 3, substituents) at group optionally having substituent(s)” for R' or Rinclude substitutable position(s). When the number of substituents is alkyl, cycloalkyl, aralkyl, cycloalkylalkyl and the like. Pref two or more, the respective Substituents may be the same or erable examples thereof include C. alkyl, Co cycloalkyl, 25 different. Examples of the substituent include groups exem C. aralkyl, Co cycloalkyl-C alkyl and the like. plified as the substituents that the aforementioned “hydrocar Examples of the “substituent of the “hydrocarbon group bon group' optionally has and the like. Preferable examples optionally having substituent(s)” for R' or R include 1 to 3 of the substituent include 1 to 3 substituents selected from Substituents selected from a halogen atom, cyano, hydroxy: (1) C. alkyl optionally having 1 to 3 substituents selected amino: Calkoxy-carbonyl; carbamoyl: C. alkylcarbam- 30 from oyl optionally having 1 to 3 substituents selected from hydroxy and a heterocyclic group (preferably, 5- or 6-mem (a) hydroxy, bered heterocyclic group containing, as a ring-constituting (b) Calkoxy, atom besides carbon atom, 1 to 4 heteroatoms selected from (c) C-14 aryl (e.g., phenyl), an oxygen atom, a Sulfur atom and a nitrogen atom, e.g., 35 (d) amino, pyridyl, morpholinyl); C7-caralkylcarbamoyl (e.g., benzyl (e) mono- or di-C alkylamino, carbamoyl) and the like. (f) C. aralkylamino (e.g., benzylamino), and Examples of the "heterocyclic group' of the "heterocyclic (g) C. alkoxy-carbonylamino (e.g., tert-butoxycarbony group optionally having substituent(s)” for R' or Rinclude a lamino), 4- to 7-membered nonaromatic heterocyclic group contain- 40 (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen ing, as a ring-constituting atom besides carbon atom, 1 to 4 atoms, heteroatoms selected from an oxygenatom, a Sulfur atom and (3) Czaralkyl (e.g., benzyl, phenethyl), a nitrogen atom, and the like. Preferable examples thereof (4) Cao cycloalkyl (e.g., cyclohexyl), include a 5- to 7-membered nonaromatic heterocyclic group (5) amino, containing, as a ring-constituting atom besides carbon atom, 45 (6) hydroxy, 1 or 2 heteroatoms selected from an oxygen atom, a Sulfur (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), atom and a nitrogen atom (e.g., pyrrolidinyl, imidazolidinyl, (8) carbamoyl pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thio and the like. morpholinyl) and the like. More preferably is piperidinyl. R" and Rare preferably each The "heterocyclic group' optionally has substituent(s) 50 (1) Ce alkyl optionally having 1 to 3 Substituents selected (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable from position(s). When the number of substituents is two or more, the respective substituents may be the same or different. (a) a halogen atom, Examples of the Substituent include groups exemplified as the (b) cyano, substituents of the aforementioned "heterocyclic group 55 (c) hydroxy, optionally having substituent(s) and the like. (d) amino, Preferable examples of the “substituent of the "heterocy (e) Calkoxy-carbonyl, clic group optionally having substituent(s)” for R' or R (f) carbamoyl, include (g) C. alkylcarbamoyl optionally having 1 to 3 Substitu (1) Ce alkyl optionally having 1 to 3 hydroxy: 60 ents selected from hydroxy and a heterocyclic group (prefer (2) a group represented by the formula: —CO N(R)(R) ably, a 5- or 6-membered heterocyclic group containing, as a wherein RandR are each a hydrogenatom or C, alkyl, ring-constituting atom besides carbon atom, 1 to 4 heteroat or R and R optionally form, together with the nitrogen oms selected from an oxygen atom, a Sulfur atom and a atom bonded thereto, a nitrogen-containing heterocycle nitrogen atom, e.g., pyridyl, morpholinyl), and (preferably, 5- to 7-membered nonaromatic nitrogen-con- 65 (h) C. aralkylcarbamoyl (e.g., benzylcarbamoyl), taining heterocycle containing, as a ring-constituting atom (2) Co cycloalkyl (e.g., cyclopropyl, cyclohexyl). besides carbon atom, one nitrogen atom, and optionally (3) Cz-e aralkyl (e.g., benzyl). US 8,329,691 B2 21 22 (4) Co cycloalkyl-C alkyl (e.g., cyclopropylmethyl), (a) OXo, (5) a group represented by the formula (b) C alkyl optionally having 1 to 3 hydroxy, (c) C-14 aryl. (d) carbamoyl, and (e) Calkoxy-carbonyl, (18') Calkoxy-carbonyl, or (19') a group represented by the formula: —CO N(R)(R) wherein RandR are each a hydrogenatom, C-alkyl or Calkoxy, or 10 Rand Roptionally form, together with the nitrogen atom N . H bonded thereto, a 4- to 7-membered (preferably 5- to 7-membered) nonaromatic nitrogen-containing hetero cycle containing, as a ring-constituting atom besides car O bon atom, one nitrogen atom, and optionally further con (6) a group represented by the formula 15 taining 1 or 2 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogen atom, said nonaromatic nitro gen-containing heterocycle optionally forms a fused ring with a benzene ring, a cyclohexane ring oran oxazole ring, -- or optionally forms a spiro ring with a 1,3-dioxolane ring (e.g., aZetidine, pyrrolidine, imidazolidine, pyrazolidine, Rb2 piperidine, piperazine, morpholine, thiomorpholine, 1,4- oxazepane, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahy HN droisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro Rb1 1H-indole, decahydroquinoline, 4,5,6,7-tetrahydro 1.3 25 oxazolo.5,4-bipyridine, 1,4-dioxa-8-azaspiro4.5 decane, 1.2.3,6-tetrahydropyridine), the 4- to 7-membered nonaro wherein R'' and Rare each matic nitrogen-containing heterocycle, a fused ring thereof (1) a hydrogen atom, and a spiro ring thereof optionally have 1 to 3 substituents (2) cyano, selected from (3') C alkyl optionally having 1 to 3 substituents selected 30 (a) OXo, from (b) a halogen atom, (a) hydroxy, (c) Calkyl optionally having 1 to 3 substituents selected (b) C. alkyl-carbonyloxy, from hydroxy and Calkoxy, (c) C. alkylthio, and (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, (d) Calkylsulfonyl, 35 alkoxy, (4) Co cycloalkyl (e.g., cyclohexyl) optionally having 1 to (e) C7-16 aralkyl (e.g., benzyl). 3 hydroxy, (f) hydroxy, (5') C. aralkylamino (e.g., phenethylamino) optionally (g) Coalkoxy, having 1 to 3 hydroxy, (h) C-14 aryloxy (e.g., phenoxy), (6') Calkoxy-carbonylamino, 40 (i) C7 aralkyloxy (e.g., benzyloxy), (7) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo (i) C. alkyl-carbonyl, nylamino), (k) Caryl-carbonyl (e.g., benzoyl). (8) Calkyl-carbonylamino, (1) mono- or di-C alkylsulfamoyl, (9) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo (m) Co. alkylsulfonyl, and nylamino) optionally having 1 to 3 Substituents selected 45 (n) a 5- or 6-membered heterocyclic group containing, as a from hydroxy and Calkoxy, ring-constituting atom besides carbon atom, 1 to 4 heteroat oms selected from an oxygen atom, a Sulfur atom and a (10') Calkylsulfonylamino, nitrogenatom (e.g., pyridyl, thiazolyl), or R'' and R' option (11') Carylsulfonylamino (e.g., phenylsulfonylamino), ally form, together with the carbon atoms bonded thereto, a (12") Calkylaminocarbonylamino, 50 benzene ring or a cyclohexane ring, or R' and R optionally (13') Carylaminocarbonylamino (e.g., phenylaminocar form, together with the nitrogen atom bonded thereto, a 5- to bonylamino), 9-membered (preferably 5- to 7-membered, more preferably (14) C. alkyl-carbonyl, 5- or 6-membered) nonaromatic nitrogen-containing hetero (15') Co cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl), cycle containing, as a ring-constituting atom besides carbon (16’) carboxy, 55 atom, one nitrogen atom, and optionally further containing 1 (17) a group represented by the formula: W R7 or 2 heteroatoms selected from an oxygenatom, a Sulfur atom wherein W' is a bond, —CH2—, —CHO , NHCO O and a nitrogen atom (e.g., pyrrolidine, imidazolidine, pyra —NHSO , and Zolidine, piperidine, piperazine, thiomorpholine, azepane, R’ is a 5- or 6-membered heterocyclic group containing, as a aZocane, azonane, 1,4-diazepane), and optionally having 1 to ring-constituting atom besides carbonatom, 1 to 4 heteroa 60 3 substituents selected from toms selected from an oxygen atom, a Sulfur atom and a (1) C. alkyl optionally having 1 to 3 substituents selected nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet from rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- (a) hydroxy, oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1,2,4-oxa (b) Coalkoxy, diazolyl, imidazolidinyl, hexahydropyrimidinyl, 65 (c) C-14 aryl (e.g., phenyl), pyrazolyl), the 5- or 6-membered heterocyclic group (d) amino, optionally has 1 to 3 substituents selected from (e) mono- or di-C alkylamino, US 8,329,691 B2 23 24 (f) C. aralkylamino (e.g., benzylamino), and carbon atoms bonded thereto, a 5- to 7-membered ring (g) Calkoxy-carbonylamino (e.g., tert-butoxycarbony optionally having Substituent(s) is preferable. lamino), Examples of the “substituent” for R' or R' include a (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen halogenatom, cyano, a hydrocarbon group optionally having atOmS, 5 Substituent(s), a heterocyclic group optionally having Sub (3) Cz-e aralkyl (e.g., benzyl, phenethyl), stituent(s), acyl, amino optionally having Substituent(s) and (4) Cso cycloalkyl (e.g., cyclohexyl). the like. (5) amino, Examples of the “hydrocarbon group' of the “hydrocarbon (6) hydroxy, group optionally having substituent(s)” for R' or R' include 10 C- alkyl. (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and The “hydrocarbon group' optionally has substituent(s) (8) carbamoyl. (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable R'' and Ring B position(s). When the number of substituents is two or more, In the formula (A), R" is alkyl optionally having substitu the respective substituents may be the same or different. ent(s). 15 Examples of the Substituent include groups exemplified as the Examples of the “alkyl of the “alkyl optionally having substituents that the aforementioned “hydrocarbon group' substituent(s)” for R' include C, alkyl. optionally has and the like. Examples of the “substituent of the “alkyl optionally hav Examples of the “substituent of the “hydrocarbon group ing substituent(s)” for R' include 1 to 3 substituents selected optionally having substituent(s)” for R' or R' include 1 to 3 from a halogen atom, cyano, hydroxy, Co cycloalkyl and Substituents selected from (1) a halogen atom; (2) nitro; (3) the like. cyano; (4) hydroxy; (5) Calkoxy optionally having 1 to 3 AS R", preferred is C. alkyl optionally having Co halogen atoms; (6) amino; (7) mono- or di-C alkylamino; cycloalkyl, more preferably, Ce alkyl. (8) Czaralkylamino; (9) C- alkoxy-carbonylamino; (10) In the formula (A), ring B is a nitrogen-containing Satu Calkyl-carbonylamino; (11)C alkyl-carbonyl: (12) car rated or unsaturated 5- to 7-membered ring optionally having 25 boxy; (13)C alkoxy-carbonyl: (14) carbamoyl: (15) mono Substituent(s). Preferred is a nitrogen-containing Saturated 5 ordi-C alkylcarbamoyl: (16) mercapto: (17) C. alkylthio; to 7-membered ring optionally having Substituent(s). nand m (18) Calkylsulfinyl: (19) C- alkylsulfonyl and the like. are each an integer of 0 to 2, and the total of n and m is 1 to 3. Preferable examples of the “hydrocarbon group optionally Examples of the combination of n and m include (nm) of having substituent(s)” for R' or R' include C, alkyl 30 optionally having 1 to 3 substituents selected from (a) (0,1), (0,2), (1,0), (1,1), (1.2), (2,0) and (2.1). Among these, hydroxy, (b) Coalkyl-carbonyloxy, (c) Calkylthio and (d) both n and m are preferably 1. C. alkylsulfonyl. The "nitrogen-containing 5- to 7-membered ring for ring Examples of the "heterocyclic group' of the "heterocyclic B optionally has substituent(s) (preferably 1 to 3, more pref group optionally having substituent(s)” for R' or R' include erably 1 or 2 substituents) at substitutable position(s). When 35 a 5- to 7-membered aromatic heterocyclic group or nonaro the number of substituents is two or more, the respective matic heterocyclic group containing, as a ring-constituting substituents may be the same or different. Examples of the atom besides carbon atom, 1 to 4 heteroatoms selected from Substituent include groups exemplified as the Substituents of an oxygen atom, a Sulfur atom and a nitrogen atom and the the aforementioned "heterocyclic group optionally having like. substituent(s)' and the like. 40 Examples of the “aromatic heterocyclic group” include a As ring B. 5- or 6-membered aromatic heterocyclic group containing, as (1) a ring represented by the formula a ring-constituting atom besides carbon atom, 1 to 4 heteroa toms selected from an oxygen atom, a Sulfur atom and a nitrogen atom (e.g., furyl, thienyl, pyridyl, pyrimidinyl, 45 pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl pyrazolyl, thia Zolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl) and the like. Examples of the “nonaromatic heterocyclic group' include a 5- to 7-membered nonaromatic heterocyclic group contain N . 50 ing, as a ring-constituting atom besides carbon atom, 1 to 3 H heteroatoms selected from an oxygenatom, a Sulfur atom and a nitrogen atom (e.g., pyrrolidinyl, piperidinyl, morpholinyl, O thiomorpholinyl, piperazinyl, tetrahydrofuryl, 4.5-dihydro-1, (2) a ring represented by the formula 2,4-oxadiazolyl) and the like. 55 The "heterocyclic group' optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable position(s). When the number of substituents is two or more, -- the respective substituents may be the same or different. Examples of the Substituent include the groups exemplified as Rb2 60 the substituents of the aforementioned "heterocyclic group optionally having substituent(s)' and the like. For example, 1 to 3 Substituents selected from (a) oxo, (b) C. alkyl option ally having 1 to 3 hydroxy, (c) Caryl and (d) carbamoyl can be mentioned. 65 Examples of the “acyl” for R' or R' include wherein R'' and R'' are each a hydrogenatom or a substitu (1) formyl; ent, or R'' and R' optionally form, together with the (2) carboxy; US 8,329,691 B2 25 26 (3)C alkyl-carbonyl: Examples of the “5- to 7-membered cyclic hydrocarbon (4) Calkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycar include benzene, Cs, cycloalkene (e.g., cyclopentene, cyclo bonyl, propoxycarbonyl, tert-butoxycarbonyl); hexene, cycloheptene). CS-7 cycloalkane (e.g., cyclopentane, (5) a group represented by the formula: CO N(R)(R) cyclohexane, cycloheptane) and the like. wherein Rand Rare each a hydrogenatom or Calkyl, or The above-mentioned “5- to 7-membered ring optionally Rand Roptionally form, together with the nitrogen atom has substituent(s) (e.g., 1 to 5, preferably 1 to 3, substituents) bonded thereto, a 4- to 7-membered nonaromatic nitrogen at substitutable position(s). When the number of substituents containing heterocycle containing, as a ring-constituting is two or more, the respective Substituents may be the same or atom besides carbon atom, one nitrogen atom, and option different. Examples of the substituent include groups exem ally further containing 1 or 2 heteroatoms selected from an 10 plified as the substituents that the aforementioned “hydrocar Oxygen atom, a Sulfur atom and a nitrogen atom (e.g., bon group' optionally has and the like. aZetidine, pyrrolidine, piperidine, piperazine, morpholine, R'' and Rare each preferably a hydrogenatom, a hydro thiomorpholine), and optionally having 1 to 3 Substituents carbon group optionally having Substituent(s) or acyl. selected from hydroxy and C alkyl and the like. R'' and R'' are each more preferably a hydrogen atom, Examples of the “amino optionally having substituent(s) 15 C. alkyl optionally having Substituent(s) or acyl. for R' or R' include R'' and Rare each still more preferably (1) Calkoxy-carbonylamino, (1) a hydrogen atom, (2) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo (2) Ce alkyl optionally having 1 to 3 hydroxy, nylamino), (3)C alkoxy-carbonyl, or (3)C alkyl-carbonylamino, (4) a group represented by the formula: —CO N(R)(R) (4) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo wherein Rand Rare each a hydrogenatom or C. alkyl, or nylamino) optionally having 1 to 3 Substituents selected Rand Roptionally form, together with the nitrogen atom from hydroxy and C alkoxy and the like. bonded thereto, a 5- to 7-membered nonaromatic nitrogen Examples of the “substituent” for R' or Ralso include a containing heterocycle containing, as a ring-constituting group represented by the formula: W R 25 atom besides carbonatom, one nitrogen atom, and option wherein W is a bond, —CH2—, —CHO or NHCO , ally further containing 1 or 2 heteroatoms selected from an and oxygen atom, a Sulfur atom and a nitrogen atom (e.g., R is a 5- or 6-membered heterocyclic group containing, as a pyrrolidine, piperidine, piperazine, morpholine, thiomor ring-constituting atom besides carbonatom, 1 to 4 heteroa pholine), and optionally having 1 to 3 Substituents selected toms selected from an oxygen atom, a Sulfur atom and a 30 from hydroxy and C alkyl. nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet Particularly preferably, R is a hydrogen atom, and R'' is rahydropyranyl, piperidinyl, tetrazolyl. 4,5-dihydro-1,2,4- (1) a hydrogen atom, oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1,2,4-oxa (2) cyano, diazolyl), the 5- or 6-membered heterocyclic group (3)C alkyl optionally having 1 to 3 Substituents selected optionally has 1 to 3 substituents selected from 35 from (a) OXo, (a) hydroxy, (b) C. alkyl optionally having 1 to 3 hydroxy, (b) C. alkyl-carbonyloxy, (c) C-14 aryl, and (c) alkylthio, and (d) carbamoyl. (d) Ce alkylsulfonyl, Examples of the “5- to 7-membered ring of the “5- to 40 (4) Calkoxy-carbonylamino, 7-membered ring optionally having substituent(s)” formed (5) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo by RandR together with the carbonatoms bonded thereto nylamino), include (i) a 5- to 7-membered aromatic heterocycle or non (6) C. alkyl-carbonylamino, aromatic heterocycle containing, as a ring-constituting atom (7) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo besides carbon atom, 1 to 3 heteroatoms selected from an 45 nylamino) optionally having 1 to 3 Substituents selected oxygen atom, a Sulfur atom and a nitrogen atom, (ii) 5- to from hydroxy and C alkoxy, 7-membered cyclic hydrocarbon and the like. (8) a group represented by the formula: W’ R Examples of the 'aromatic heterocycle' include a 5- or wherein W is a bond, —CH2—, —CHO or NHCO , 6-membered aromatic heterocycle containing, as a ring-con and stituting atom besides carbon atom, 1 to 3 heteroatoms 50 R is a 5- or 6-membered heterocyclic group containing, as a selected from an oxygen atom, a Sulfur atom and a nitrogen ring-constituting atom besides carbonatom, 1 to 4 heteroa atom (e.g., pyridine, pyrazine, pyrimidine, pyridazine, pyr toms selected from an oxygen atom, a Sulfur atom and a role, imidazole, pyrazole, triazole, thiophene, furan, thiazole, nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet isothiazole, oxazole, isoxazole) and the like. rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- Examples of the “nonaromatic heterocycle include a 5- to 55 oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1.2.4-Oxa 7-membered (preferably 5- or 6-membered) nonaromatic het diazolyl), the 5- or 6-membered heterocyclic group erocycle containing, as a ring-constituting atom besides car optionally has 1 to 3 substituents selected from bonatom, 1 to 3 (preferably 1 or 2) heteroatoms selected from (a) OXo, an oxygen atom, a Sulfur atom and a nitrogen atom (e.g., (b) C. alkyl optionally having 1 to 3 hydroxy, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tet 60 (c) C-14 aryl, and rahydropyrimidine, tetrahydropyridazine, dihydropyran, (d) carbamoyl, dihydropyrrole, dihydrothiophene, dihydrofuran, piperidine, (9) C- alkoxy-carbonyl, or piperazine, hexahydropyrimidine, hexahydropyridazine, tet (10) a group represented by the formula: —CO N(R)(R) rahydropyran, morpholine, pyrrolidine, pyrazoline, imidazo wherein RandR are each a hydrogenatom or Calkyl, or lidine, thiazoline, isothiazoline, oxazoline, isoxazoline, pyra 65 Rand Roptionally form, together with the nitrogen atom Zolidine, tetrahydrothiophene, tetrahydrofuran, thiazolidine, bonded thereto, a 4- to 7-membered nonaromatic nitrogen oxazolidine) and the like. containing heterocycle containing, as a ring-constituting US 8,329,691 B2 27 28 atom besides carbon atom, one nitrogen atom, and option Examples of the "heterocyclic group optionally having ally further containing 1 or 2 heteroatoms selected from an substituent(s)” for R' or Rinclude Oxygen atom, a Sulfur atom and a nitrogen atom (e.g., (1) a group represented by the formula aZetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine), and optionally having 1 to 3 Substituents Selected from hydroxy and C alkyl, or R'' and R' optionally form, together with the carbon atoms bonded thereto, a benzene ring or a cyclohexane ring. Of these, further more preferably, R is 10 , and (1) C alkyl optionally having 1 to 3 hydroxy, N (2) Calkoxy-carbonyl, or H (3) a group represented by the formula: CO N(R)(R) wherein Rand Rare each a hydrogenatom or C alkyl, or and Rand Roptionally form, together with the nitrogen atom 15 (2) a group represented by the formula bonded thereto, a 5- to 7-membered nonaromatic nitrogen containing heterocycle containing, as a ring-constituting atom besides carbon atom, one nitrogen atom, and option ally further containing 1 or 2 heteroatoms selected from an -- Oxygen atom, a Sulfur atom and a nitrogen atom (e.g., pyrrolidine, piperidine, piperazine, morpholine, thiomor pholine), and optionally having 1 to 3 Substituents selected from hydroxy and C alkyl, and R’ is a hydrogen atom. 25 Rand R2 In the formula (B), R'' and R'' are each a hydrocarbon group optionally having Substituent(s) or a heterocyclic wherein R’ is a hydrogen atom, and group optionally having Substituent(s), or R is RandR optionally form, together with the nitrogenatom 30 (1) a hydrogen atom, bonded thereto, a nitrogen-containing heterocycle option (2) cyano, ally having substituent(s). (3') Calkyl optionally having 1 to 3 substituents selected Examples of the “hydrocarbon group' of the “hydrocarbon from group optionally having substituent(s)” for R' or Rinclude (a) hydroxy, alkyl, cycloalkyl, aralkyl, cycloalkyl and the like. Preferable 35 (b) C alkyl-carbonyloxy, examples thereof include C. alkyl, Co cycloalkyl, C (c) C. alkylthio, and aralkyl, Co cycloalkyl-C alkyl and the like. (d) Ce alkylsulfonyl, Examples of the “substituent of the “hydrocarbon group (4) Co cycloalkyl (e.g., cyclohexyl) optionally having 1 to optionally having substituent(s)” for R' or R’ include 1 to 3 3 hydroxy, Substituents selected from (a) a halogen atom, (b) cyano, (c) 40 (5') C. aralkylamino (e.g., phenethylamino) optionally hydroxy, (d) amino, (e) Calkoxy-carbonyl, (f) carbamoyl, having 1 to 3 hydroxy, (g) C. alkylcarbamoyl optionally having 1 to 3 substituents (6') Calkoxy-carbonylamino, selected from hydroxy and a heterocyclic group (preferably, a (7) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo 5- or 6-membered heterocyclic group containing, as a ring nylamino), constituting atom besides carbon atom, 1 to 4 heteroatoms 45 (8) Calkyl-carbonylamino, selected from an oxygen atom, a Sulfur atom and a nitrogen atom, e.g., pyridyl, morpholinyl) and (h) C. aralkylcar (9) Clo cycloalkyl-carbonylamino (e.g., cyclohexylcarbo bamoyl (e.g., benzylcarbamoyl). nylamino) optionally having 1 to 3 Substituents selected from hydroxy and C alkoxy, Examples of the "heterocyclic group' of the "heterocyclic (10') Calkylsulfonylamino, group optionally having substituent(s)” for R' or Rinclude 50 a 4- to 7-membered nonaromatic heterocyclic group contain (11') Carylsulfonylamino (e.g., phenylsulfonylamino), ing, as a ring-constituting atom besides carbon atom, 1 to 4 (12") C. alkylaminocarbonylamino, heteroatoms selected from an oxygenatom, a Sulfur atom and (13') Carylaminocarbonylamino (e.g., phenylaminocar a nitrogen atom, and the like. Preferable examples thereof bonylamino), include a 5- to 7-membered nonaromatic heterocyclic group 55 (14) Ce alkyl-carbonyl, containing, as a ring-constituting atom besides carbon atom, (15') Co cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl). 1 or 2 heteroatoms selected from an oxygen atom, a Sulfur (16’) carboxy, atom and a nitrogen atom (e.g., pyrrolidinyl, imidazolidinyl, (17) a group represented by the formula: W. R. pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thio wherein W' is a bond, —CH2—, —CHO , NHCO O morpholinyl) and the like. 60 —NHSO , and The "heterocyclic group' optionally has substituent(s) R’ is a 5- or 6-membered heterocyclic group containing, as a (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable ring-constituting atom besides carbonatom, 1 to 4 heteroa position(s). Examples of the Substituent include groups toms selected from an oxygen atom, a Sulfur atom and a exemplified as the substituents of the aforementioned “het nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet erocyclic group optionally having Substituent(s) and the 65 rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- like. When the number of substituents is two or more, the oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1.2.4-Oxa respective substituents may be the same or different. diazolyl, imidazolidinyl, hexahydropyrimidinyl, US 8,329,691 B2 29 30 pyrazolyl), the 5- or 6-membered heterocyclic group substitutable position(s). When the number of substituents is optionally has 1 to 3 substituents selected from two or more, the respective Substituents may be the same or (a) oXo, different. Examples of the substituent include groups similar (b) C. alkyl optionally having 1 to 3 hydroxy, to the substituents that the aforementioned “hydrocarbon (c) C-14 aryl. group' optionally has. Examples of the substituent include 1 (d) carbamoyl, and to 3 substituents selected from (e) Calkoxy-carbonyl, (1) Ce alkyl optionally having 1 to 3 Substituents selected (18') Calkoxy-carbonyl, or from (19') a group represented by the formula: —CO N(R)(R) (a) hydroxy, wherein RandR are each a hydrogenatom, C-alkyl or 10 Coalkoxy, or (b) Coalkoxy, R and R optionally form, together with the nitrogen atom (c) C-14 aryl (e.g., phenyl), bonded thereto, a 4- to 7-membered nonaromatic nitrogen (d) amino, containing heterocycle containing, as a ring-constituting (e) mono- or di-C alkylamino, atom besides carbon atom, one nitrogen atom, and option 15 (f) C. aralkylamino (e.g., benzylamino), and ally further containing 1 or 2 heteroatoms selected from an (g) C. alkoxy-carbonylamino (e.g., tert-butoxycarbony oxygen atom, a Sulfur atom and a nitrogen atom, said 4- to lamino), 7-membered nonaromatic nitrogen-containing heterocycle (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen optionally forms a fused ring with a benzene ring, a cyclo atoms, hexane ring or an oxazole ring, or optionally forms a spiro (3) Cz-e aralkyl (e.g., benzyl, phenethyl), ring with a 1,3-dioxolane ring (e.g., aZetidine, pyrrolidine, (4) Co cycloalkyl (e.g., cyclohexyl), piperidine, piperazine, morpholine, thiomorpholine, 1,4- (5) amino, oxazepane, 1.2.3,4-tetrahydroquinoline, 1,2,3,4-tetrahy (6) hydroxy, droisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and 1H-indole, decahydroquinoline, 4,5,6,7-tetrahydro1.3 25 (8) carbamoyl. Oxazolo.5,4-bipyridine, 1,4-dioxa-8-azaspiro4.5 decane, Preferably, R'' and R' form, together with the nitrogen 1,2,3,6-tetrahydropyridine), the 4- to 7-membered nonaro atom bonded thereto, piperidine optionally having Substitu matic nitrogen-containing heterocycle, a fused ring thereof ent(s) or piperazine optionally having Substituent(s). and a spiro ring thereof optionally have 1 to 3 Substituents Examples of the Substituents that piperidine or piperazine selected from 30 optionally has include 1 to 3 substituents selected from (a) oXo, (b) a halogen atom, (1) C alkyl selected from optionally having 1 to 3 substitu (c) C alkyl optionally having 1 to 3 substituents selected ents from hydroxy and C alkoxy, (a) hydroxy, (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, 35 (b) Coalkoxy, alkoxy, (c) C-14 aryl (e.g., phenyl), (e) C7-6 aralkyl (e.g., benzyl). (d) amino, (f) hydroxy, (e) mono- or di-C alkylamino, (g) Coalkoxy, (f) C. aralkylamino (e.g., benzylamino), and (h) Caryloxy (e.g., phenoxy), 40 (g) C. alkoxy-carbonylamino (e.g., tert-butoxycarbony (i) C7-16 aralkyloxy (e.g., benzyloxy), lamino), (j) C alkyl-carbonyl, (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen (k) Caryl-carbonyl (e.g., benzoyl), atoms, (1) mono- or di-C alkylsulfamoyl, (3) Cz-e aralkyl (e.g., benzyl, phenethyl), (m) Co. alkylsulfonyl, and 45 (4) Cao cycloalkyl (e.g., cyclohexyl), (n) a 5- or 6-membered heterocyclic group containing, as a (5) amino, ring-constituting atom besides carbon atom, 1 to 4 heteroat (6) hydroxy, oms selected from an oxygen atom, a Sulfur atom and a (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and nitrogen atom (e.g., pyridyl, thiazolyl), or (8) carbamoyl. R'' and R' optionally form, together with the carbon atoms 50 Preferably, R'' and Rare each bonded thereto, a benzene ring or a cyclohexane ring. (1) Ce alkyl optionally having 1 to 3 Substituents selected Examples of the “nitrogen-containing heterocycle' of the from "nitrogen-containing heterocycle optionally having Substitu (a) a halogen atom, ent(s)” formed by RandR together with the nitrogenatom (b) cyano, bonded thereto include a 5- to 9-membered (preferably 5- to 55 (c) hydroxy, 7-membered, more preferably 5- or 6-membered) nonaro (d) amino, matic nitrogen-containing heterocycle containing, as a ring (e) Calkoxy-carbonyl, constituting atom besides carbon atom, one nitrogen atom, (f) carbamoyl, and optionally further containing 1 or 2 heteroatoms selected (g) C. alkylcarbamoyl optionally having 1 to 3 Substitu from an oxygen atom, a Sulfur atom and a nitrogen atom. 60 ents selected from hydroxy and a heterocyclic group (prefer Examples of the "nitrogen-containing heterocycle' ably, 5- or 6-membered heterocyclic group containing, as a include pyrrolidine, imidazolidine, pyrazolidine, piperidine, ring-constituting atom besides carbon atom, 1 to 4 heteroat piperazine, morpholine, thiomorpholine, azepane, azocane, oms selected from an oxygen atom, a Sulfur atom and a aZonane, 1,4-diazepane and the like. Preferred are piperidine nitrogen atom, e.g., pyridyl, morpholinyl), and and piperazine. 65 (h) C. aralkylcarbamoyl (e.g., benzylcarbamoyl), The "nitrogen-containing heterocycle' optionally has Sub (2) Co cycloalkyl (e.g., cyclopropyl, cyclohexyl). stituent(s) (e.g., 1 to 3, preferably 1 to 3 substituents) at (3) Cz-e aralkyl (e.g., benzyl). US 8,329,691 B2 31 32 (4) Co cycloalkyl-C alkyl (e.g., cyclopropylmethyl), (a) OXo, (5) a group represented by the formula (b) C alkyl optionally having 1 to 3 hydroxy, (c) C-14 aryl. (d) carbamoyl, and (e) Calkoxy-carbonyl, (18') Calkoxy-carbonyl, or (19') a group represented by the formula: —CO N(R)(R) wherein R and Rare each a hydrogen atom, C, alkyl or Calkoxy, or 10 Rand Roptionally form, together with the nitrogen atom N . H bonded thereto, a 4- to 7-membered nonaromatic nitrogen containing heterocycle containing, as a ring-constituting atom besides carbonatom, one nitrogen atom, and option O ally further containing 1 or 2 heteroatoms selected from an (6) a group represented by the formula 15 oxygenatom, a Sulfur atom and a nitrogenatom, said 4- to 7-membered nonaromatic nitrogen-containing heterocycle optionally forms a fused ring with a benzene ring, a cyclo hexane ring oran oxazole ring, or optionally forms a spiro -- ring with a 1,3-dioxolane ring (e.g., aZetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,4- Rb2 oxazepane, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahy droisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro HN 1H-indole, decahydroquinoline, 4,5,6,7-tetrahydro 1.3 Rb1 oxazolo.5,4-bipyridine, 1,4-dioxa-8-azaspiro4.5 decane, 25 1.2.3,6-tetrahydropyridine), said 4- to 7-membered non aromatic nitrogen-containing heterocycle, a fused ring wherein R’ is a hydrogen atom, and thereof and a spiro ring thereof optionally have 1 to 3 R is substituents selected from (1) a hydrogen atom, (a) OXo, (2) cyano, 30 (b) a halogen atom, (3') C alkyl optionally having 1 to 3 substituents selected (c) C. alkyl optionally having 1 to 3 Substituents selected from from hydroxy and Calkoxy, (a) hydroxy, (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, (b) C. alkyl-carbonyloxy, alkoxy, (c) C. alkylthio, and 35 (e) C7 aralkyl (e.g., benzyl). (d) Calkylsulfonyl, (f) hydroxy, (4) Co cycloalkyl (e.g., cyclohexyl) optionally having 1 to (g) Coalkoxy, 3 hydroxy, (h) C-14 aryloxy (e.g., phenoxy), (5') C. aralkylamino (e.g., phenethylamino) optionally (i) C7-6 aralkyloxy (e.g., benzyloxy), having 1 to 3 hydroxy, 40 (j) C alkyl-carbonyl, (6') Calkoxy-carbonylamino, (k) Caryl-carbonyl (e.g., benzoyl), (7) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo (l) mono- or di-C alkylsulfamoyl, nylamino), (m) Co. alkylsulfonyl, and (8) Calkyl-carbonylamino, (n) a 5- or 6-membered heterocyclic group containing, as a (9) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo 45 ring-constituting atom besides carbon atom, 1 to 4 heteroat nylamino) optionally having 1 to 3 Substituents selected oms selected from an oxygen atom, a Sulfur atom and a from hydroxy and Calkoxy, nitrogen atom (e.g., pyridyl, thiazolyl), or (10') Calkylsulfonylamino, R'' and R' optionally form, together with the carbon atoms (11') Carylsulfonylamino (e.g., phenylsulfonylamino), bonded thereto, a benzene ring or a cyclohexane ring, or (12") C. alkylaminocarbonylamino, 50 R'' and Roptionally form, together with the nitrogen atom (13') Carylaminocarbonylamino (e.g., phenylaminocar bonded thereto, a 5- to 9-membered (preferably 5- to bonylamino), 7-membered, more preferably 5- or 6-membered) nonaro (14) Ce alkyl-carbonyl, matic nitrogen-containing heterocycle containing, as a (15') Co cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl). ring-constituting atom besides carbon atom, one nitrogen (16’) carboxy, 55 atom, and optionally further containing 1 or 2 heteroatoms (17) a group represented by the formula: W R7 selected from an oxygenatom, a Sulfur atom and a nitrogen wherein W' is a bond, —CH2—, —CHO , NHCO O atom (e.g., pyrrolidine, piperidine, piperazine, morpho —NHSO , and line, thiomorpholine, azepane, azocane, azonane, 1,4-di R’ is a 5- or 6-membered heterocyclic group containing, as a aZepane), and optionally having 1 to 3 Substituents selected ring-constituting atom besides carbonatom, 1 to 4 heteroa 60 from toms selected from an oxygen atom, a Sulfur atom and a (1) C. alkyl optionally having 1 to 3 substituents selected nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet from rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- (a) hydroxy, oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1,2,4-oxa (b) Coalkoxy, diazolyl, imidazolidinyl, hexahydropyrimidinyl, 65 (c) C-14 aryl (e.g., phenyl), pyrazolyl), the 5- or 6-membered heterocyclic group (d) amino, optionally has 1 to 3 substituents selected from (e) mono- or di-C alkylamino, US 8,329,691 B2 33 34 (f) C. aralkylamino (e.g., benzylamino), and the Substituent include groups exemplified as the Substituents (g) Calkoxy-carbonylamino (e.g., tert-butoxycarbony of the aforementioned "heterocyclic group optionally having lamino), substituent(s)' and the like. (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen As ring Bc, a ring represented by the formula atOmS, 5 (3) Cz-e aralkyl (e.g., benzyl, phenethyl), (4) Co cycloalkyl (e.g., cyclohexyl). (5) amino, -- (6) hydroxy, (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and 10 Rb2 (8) carbamoyl. More preferably, Rand Rare each (1) Ce alkyl optionally having 1 to 3 Substituents selected from cyano and hydroxy, (2) Cao cycloalkyl, or 15 (3) Czaralkyl, or wherein R'' and R'' are each a hydrogen atom or a substitu R'' and Roptionally form, together with the nitrogen atom ent, or R'' and R' optionally form, together with the carbon bonded thereto, a 5- to 9-membered (preferably 5- to atoms bonded thereto, a 5- to 7-membered ring optionally 7-membered, more preferably 5- or 6-membered) nonaro having Substituent(s) is preferable. matic nitrogen-containing heterocycle containing, as a Preferable examples of R'' and R' in ring Bc include ring-constituting atom besides carbon atom, one nitrogen those similar to the preferable examples of R'' and R' in the atom, and optionally further containing 1 or 2 heteroatoms aforementioned ring B. Selected from an oxygenatom, a Sulfur atom and a nitrogen In ring Bc, R'' and R'' are each preferably a hydrogen atom (e.g., pyrrolidine, imidazolidine, pyrazolidine, pip atom, a hydrocarbon group optionally having Substituent(s) eridine, piperazine, morpholine, thiomorpholine, azepane, 25 aZocane, azonane, 1,4-diazepane), and optionally having 1 or acyl. to 3 substituents selected from R'' and R are each more preferably a hydrogen atom, (1) C. alkyl optionally having 1 to 3 substituents selected C. alkyl optionally having Substituent(s) or acyl. from R'' and Rare each further preferably (a) hydroxy, 30 (1) a hydrogen atom, (b) Coalkoxy, (2) Ce alkyl optionally having 1 to 3 hydroxy, (c) C-14 aryl (e.g., phenyl), (3)C alkoxy-carbonyl, or (d) amino, (4) a group represented by the formula: —CO N(R)(R) (e) mono- or di-C alkylamino, wherein RandR are each a hydrogenatom or Calkyl, or (f) Cz aralkylamino (e.g., benzylamino), and 35 R and R optionally form, together with the nitrogen atom (g) Coalkoxy-carbonylamino (e.g., tert-butoxycarbony bonded thereto, a 5- to 7-membered nonaromatic nitrogen lamino), containing heterocycle containing, as a ring-constituting (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen atom besides carbonatom, one nitrogen atom, and option atOmS, ally further containing 1 or 2 heteroatoms selected from an (3) Cz aralkyl (e.g., benzyl, phenethyl), 40 oxygen atom, a Sulfur atom and a nitrogen atom (e.g., (4) Cso cycloalkyl (e.g., cyclohexyl). pyrrolidine, piperidine, piperazine, morpholine, thiomor (5) amino, pholine), and optionally having 1 to 3 Substituents selected (6) hydroxy, from hydroxy and C alkyl. (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and Particularly preferably, (8) carbamoyl. 45 R is R" and Ring Bc (1) Ce alkyl optionally having 1 to 3 hydroxy, In the formula (C), R is alkyl optionally having substitu (2) Calkoxy-carbonyl, or ent(s). (3) a group represented by the formula: —CO N(R)(R) Examples of the “alkyl of the “alkyl optionally having wherein Rand Rare each a hydrogenatom or C. alkyl, or substituent(s)” for R' include C, alkyl. 50 Rand Roptionally form, together with the nitrogen atom Examples of the “substituent of the “alkyl optionally hav bonded thereto, a 5- to 7-membered nonaromatic nitrogen ing substituent(s)” for R' include 1 to 3 substituents selected containing heterocycle containing, as a ring-constituting from a halogen atom, cyano, hydroxy and the like. atom besides carbonatom, one nitrogen atom, and option As R', preferred is C alkyl. ally further containing 1 or 2 heteroatoms selected from an In the formula (C), ring Bc is a nitrogen-containing Satu 55 oxygen atom, a Sulfur atom and a nitrogen atom (e.g., rated or unsaturated 5- to 7-membered ring optionally having pyrrolidine, piperidine, piperazine, morpholine, thiomor Substituent(s). Preferred is a nitrogen-containing Saturated 5 pholine), and optionally having 1 to 3 Substituents selected to 7-membered ring optionally having Substituent(s). nand m from hydroxy and C1-alkyl, and R is a hydrogen atom. are each an integer of 0 to 2, and the total of n and m is 1 to 3. R, R, R, Z and R Examples of the combination of n and m include (nm) of 60 In the formula (I), R is a substituent. (0,1), (0,2), (1,0), (1,1), (1.2), (2,0) and (2.1). Among these, Examples of the “substituent” for R include a hydrocar both n and m are preferably 1. bon group optionally having Substituent(s), a heterocyclic The "nitrogen-containing 5- to 7-membered ring for ring group optionally having Substituent(s), acyl and the like. Bc optionally has substituent(s) (preferably 1 to 3, more Examples of the “hydrocarbon group' of the “hydrocarbon preferably 1 or 2 substituents) at substitutable position(s). 65 group optionally having substituent(s)” for R include alkyl, When the number of substituents is two or more, the respec cycloalkyl, aryl and the like. Preferable examples thereof tive substituents may be the same or different. Examples of include C- alkyl, Cso cycloalkyl, C-aryland the like. US 8,329,691 B2 35 36 Examples of the “substituent of the “hydrocarbon group atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, optionally having substituent(s)” for R include 1 to 3 sub oxazolyl pyridyl, tetrahydrofuryl), and optionally having stituents selected from a halogen atom; cyano; hydroxy: C 1 to 3 C alkyl, alkoxy optionally having 1 to 3 halogen atoms; mercapto: (2) C-14 aryl, C. alkylthio; C alkylsulfinyl: C. alkylsulfonyl and the (3) Co cycloalkyl, like. (4) Ce alkyl optionally having 1 to 3 Substituents selected Examples of the "heterocyclic group' of the "heterocyclic from Calkoxy and C alkylthio, or group optionally having substituent(s)” for Rinclude a 5- to (5) Calkoxy-carbonyl and the like. 7-membered aromatic heterocyclic group or nonaromatic In the formula (A), R is a 5- or 6-membered aromatic heterocyclic group containing, as a ring-constituting atom 10 group optionally having Substituent(s). besides carbon atom, 1 to 4 heteroatoms selected from an Examples of the “5- or 6-membered aromatic group' of the oxygenatom, a Sulfur atom and a nitrogen atom and the like. “5- or 6-membered aromatic group optionally having Sub Examples of the “aromatic heterocyclic group' include a stituent(s)” for R' include (i) a 5- or 6-membered aromatic 5- or 6-membered aromatic heterocyclic group containing, as 15 heterocyclic group containing, as a ring-constituting atom a ring-constituting atom besides carbon atom, 1 to 4 heteroa besides carbon atom, 1 to 4 heteroatoms selected from an toms selected from an oxygen atom, a Sulfur atom and a oxygen atom, a Sulfur atom and a nitrogen atom, (ii) phenyl nitrogen atom (e.g., furyl, thienyl, pyridyl, pyrimidinyl, and the like. pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl pyrazolyl, thia Examples of the “5- or 6-membered aromatic group' Zolyl, isothiazolyl, oxazolyl, isoxazolyl) and the like. include a 5-membered aromatic heterocyclic group Such as Examples of the “nonaromatic heterocyclic group' include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thie a 5- to 7-membered nonaromatic heterocyclic group contain nyl), pyrrolyl (e.g., 1-pyrrolyl 2-pyrrolyl, 3-pyrrolyl), imida ing, as a ring-constituting atom besides carbon atom, 1 to 4 Zolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imi heteroatoms selected from an oxygenatom, a Sulfur atom and dazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, a nitrogen atom (e.g., pyrrolidinyl, piperidinyl, morpholinyl, 25 4-pyrazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thia thiomorpholinyl, piperazinyl, tetrahydrofuryl) and the like. Zolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, The "heterocyclic group' optionally has substituent(s) 5-isothiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-OX (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable azolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isox position(s). When the number of substituents is two or more, azolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl, 1.3,4-oxa the respective substituents may be the same or different. 30 diazol-2-yl), thiadiazolyl (e.g., 1,2,4-thiadiazol-5-yl, 1.3,4- Examples of the Substituent include groups exemplified as the thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4- substituents of the aforementioned "heterocyclic group triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3- optionally having substituent(s) and the like. triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl) and Preferable examples of the “substituent of the "heterocy the like; and a 6-membered aromatic heterocyclic group Such clic group optionally having substituent(s)” for R include 1 35 as pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl to 3 Substituents selected from (1) a halogen atom; (2) nitro: (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazi (3) cyano; (4) hydroxy; (5) Calkoxy; (6) amino; (7) mono nyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., or di-C alkylamino; (8) C. aralkylamino; (9) C 2-pyrazinyl), triazinyl (e.g., 1,3,5-triazin-2-yl, 1.3.5-triazin alkoxy-carbonylamino; (10) C. alkyl-carbonylamino; (11) 4-yl, 1,2,3-triazin-4-yl, 1,2,4-triazin-3-yl) and the like. Pref Calkyl-carbonyl: (12) carboxy; (13)C alkoxy-carbonyl: 40 erably is a 5-membered aromatic heterocyclic group, more (14) carbamoyl: (15) mono- or di-C alkylcarbamoyl: (16) preferably furyl, thienyl, oxazolyl and the like. mercapto: (17) C. alkylthio; (18) C alkylsulfinyl: (19) Examples of the “substituent of the “5- or 6-membered C. alkylsulfonyl: (20) C. alkyl optionally having 1 to 3 aromatic group optionally having substituent(s)” for R' halogen atoms and the like. include 1 to 3 substituents selected from (1) a halogen atom; Examples of the “acyl” for Rinclude 45 (2) nitro; (3) cyano; (4) hydroxy; (5) Calkoxy; (6) amino; (1) formyl; (7) mono- or di-C alkylamino; (8) C. aralkylamino; (9) (2) carboxy; Calkoxy-carbonylamino: (10) C. alkyl-carbonylamino: (3)C alkyl-carbonyl: (11) Ce alkyl-carbonyl: (12) carboxy; (13)C alkoxy-car (4) Calkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycar bonyl: (14) carbamoyl: (15) mono- or di-C alkylcarbam bonyl, propoxycarbonyl, tert-butoxycarbonyl); 50 oyl: (16) mercapto: (17) C. alkylthio; (18) Calkylsulfi (5) a group represented by the formula: CO NR'R'' nyl; (19) C-alkylsulfonyl: (20) Calkyl optionally having wherein R'' and Rare each a hydrogenatom, a hydrocarbon 1 to 3 halogen atoms and the like. group optionally having Substituent(s) or a heterocyclic As R', preferred is a 5- or 6-membered aromatic hetero group optionally having substituent(s), or R'' and R' cyclic group containing, as a ring-constituting atom besides optionally form, together with the nitrogen atom bonded 55 carbon atom, 1 to 4 heteroatoms selected from an oxygen thereto, a nitrogen-containing heterocycle optionally hav atom, a Sulfur atom and a nitrogenatom (e.g., furyl, oxazolyl, ing Substituent(s) and the like. thienyl, pyridyl), or phenyl. R is preferably As R', more preferred is a 5-membered aromatic hetero (1) a heterocyclic group optionally having Substituent(s), cyclic group containing, as a ring-constituting atom besides (2) Caryl optionally having Substituent(s), 60 carbon atom, 1 to 4 heteroatoms selected from an oxygen (3) Co cycloalkyl optionally having substituent(s), atom, a Sulfur atom and a nitrogenatom (e.g., furyl, oxazolyl, (4) Ce alkyl optionally having Substituent(s), thienyl). (5) Calkoxy-carbonyl and the like. Among these, preferred as R is furyl, thienyl or oxazolyl, R is more preferably each of which optionally has substituent(s), more preferred is (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic 65 furyl, thienyl or oxazolyl optionally having 1 to 3 C alkyl, group containing, as a ring-constituting atom besides car further preferred is furyl optionally having 1 to 3 C alkyl, bon atom, 1 to 4 heteroatoms selected from an oxygen and particularly preferred is unsubstituted furyl. US 8,329,691 B2 37 38 In the formula (B), R is a substituent excluding 2-(4- As R, preferred is phenylpiperazin-1-yl)ethyl optionally having Substituent(s) (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic and biphenyl-4-yl having Substituent(s). group containing, as a ring-constituting atom besides car bon atom, 1 to 4 heteroatoms selected from an oxygen Examples of the “substituent” for R' include a hydrocar atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, bon group optionally having Substituent(s), a heterocyclic oxazolyl pyridyl, tetrahydrofuryl), and optionally having group optionally having Substituent(s), acyl and the like. 1 to 3 C alkyl, Examples of the “hydrocarbon group' of the “hydrocarbon (2) Caryl (e.g., phenyl), group optionally having substituent(s)” for Rinclude alkyl, (3) Cao cycloalkyl (e.g., cyclopropyl), cycloalkyl, aryl and the like. Preferable examples thereof (4) C. alkyl optionally having 1 to 3 substituents selected include C- alkyl, Cao cycloalkyl, C-aryland the like. 10 from Examples of the “substituent of the “hydrocarbon group (a) hydroxy, optionally having substituent(s)” for R' include 1 to 3 sub (b) Coalkoxy, stituents selected from a halogen atom; cyano; hydroxy: C (c) C alkylthio. alkoxy optionally having 1 to 3 halogen atoms; mercapto: (d) Ce alkylsulfinyl, and 15 (e) Calkylsulfonyl, or C. alkylthio; C alkylsulfinyl: C. alkylsulfonyl and the (5) Calkoxy-carbonyl. like. As R, more preferred is Examples of the "heterocyclic group' of the "heterocyclic (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic group optionally having substituent(s)” for Rinclude a 5- to group containing, as a ring-constituting atom besides car 7-membered aromatic heterocyclic group or nonaromatic bon atom, 1 to 4 heteroatoms selected from an oxygen heterocyclic group containing, as a ring-constituting atom atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, besides carbon atom, 1 to 4 heteroatoms selected from an oxazolyl pyridyl, tetrahydrofuryl), and optionally having oxygenatom, a Sulfur atom and a nitrogen atom and the like. 1 to 3 C alkyl, Examples of the “aromatic heterocyclic group' include a (2) C-14 aryl (e.g., phenyl), 5- or 6-membered aromatic heterocyclic group containing, as 25 (3) Cao cycloalkyl (e.g., cyclopropyl), a ring-constituting atom besides carbon atom, 1 to 4 heteroa (4) Ce alkyl optionally having 1 to 3 C alkoxy, toms selected from an oxygen atom, a Sulfur atom and a (5) Calkoxy-carbonyl and the like. nitrogen atom (e.g., furyl, thienyl, pyridyl, pyrimidinyl, As R, more preferred is a 5-membered aromatic group pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl pyrazolyl, thia optionally having substituent(s). Examples of the “5-mem Zolyl, isothiazolyl, oxazolyl, isoxazolyl) and the like. 30 bered aromatic group optionally having Substituent(s)” for Examples of the “nonaromatic heterocyclic group' include Rinclude groups exemplified as the “5-membered aromatic a 5- to 7-membered nonaromatic heterocyclic group contain group optionally having substituent(s)” for R'' and the like. ing, as a ring-constituting atom besides carbon atom, 1 to 4 Among these, preferred as R is furyl, thienyl or oxazolyl, heteroatoms selected from an oxygenatom, a Sulfur atom and each of which optionally has substituent(s), more preferred is a nitrogen atom (e.g., pyrrolidinyl, piperidinyl, morpholinyl, 35 furyl, thienyl or oxazolyl optionally having 1 to 3 C alkyl, thiomorpholinyl, piperazinyl, tetrahydrofuryl) and the like. further preferred is furyl optionally having 1 to 3 C alkyl, The "heterocyclic group' optionally has substituent(s) and particularly preferred is unsubstituted furyl. (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable In the formula (C), R is a substituent. position(s). When the number of substituents is two or more, Examples of the “substituent” for R include a hydrocar the respective substituents may be the same or different. 40 bon group optionally having Substituent(s), a heterocyclic Examples of the Substituent include groups exemplified as the group optionally having Substituent(s), hydroxy optionally substituents of the aforementioned "heterocyclic group having a substituent, mercapto optionally having a substitu optionally having substituent(s) and the like. ent, acyl and the like. Preferable examples of the “substituent of the "heterocy Examples of the “hydrocarbon group' of the “hydrocarbon clic group optionally having substituent(s)” for Rinclude 1 45 group optionally having substituent(s)” for Rinclude alkyl, to 3 Substituents selected from (1) a halogen atom; (2) nitro: cycloalkyl, aryl and the like. Preferred are C alkyl, Co (3) cyano; (4) hydroxy; (5) Calkoxy; (6) amino; (7) mono cycloalkyl, Caryland the like. or di-C alkylamino; (8) C. aralkylamino; (9) C Examples of the “substituent of the “hydrocarbon group alkoxy-carbonylamino: (10) C. alkyl-carbonylamino; (11) optionally having substituent(s)” for R include 1 to 3 sub Calkyl-carbonyl: (12) carboxy; (13)C alkoxy-carbonyl: 50 stituents selected from a halogen atom; cyano; hydroxy: C (14) carbamoyl: (15) mono- or di-C alkylcarbamoyl: (16) alkoxy optionally having 1 to 3 halogen atoms; mercapto: mercapto: (17) C. alkylthio; (18) C. alkylsulfinyl: (19) C. alkylthio and the like. C. alkylsulfonyl: (20) C. alkyl optionally having 1 to 3 Examples of the "heterocyclic group' of the "heterocyclic halogen atoms and the like. group optionally having substituent(s)” for Rinclude a 5- to Examples of the “acyl” for R include 55 7-membered aromatic heterocyclic group or nonaromatic (1) formyl; heterocyclic group containing, as a ring-constituting atom (2) carboxy; besides carbon atom, 1 to 4 heteroatoms selected from an (3)C alkyl-carbonyl: oxygen atom, a Sulfur atom and a nitrogen atom and the like. (4) Calkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycar Examples of the “aromatic heterocyclic group” include a bonyl, propoxycarbonyl, tert-butoxycarbonyl); 60 5- or 6-membered aromatic heterocyclic group containing, as (5) a group represented by the formula: CO NR'R'' a ring-constituting atom besides carbon atom, 1 to 4 heteroa wherein R" and Rare each a hydrogenatom, a hydrocarbon toms selected from an oxygen atom, a Sulfur atom and a group optionally having Substituent(s) or a heterocyclic nitrogen atom (e.g., furyl, thienyl, pyridyl, pyrimidinyl, group optionally having substituent(s), or R" and R' pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl pyrazolyl, thia optionally form, together with the nitrogen atom bonded 65 Zolyl, isothiazolyl, oxazolyl, isoxazolyl) and the like. thereto, a nitrogen-containing heterocycle optionally hav Examples of the “nonaromatic heterocyclic group' include ing Substituent(s) and the like. a 5- to 7-membered nonaromatic heterocyclic group contain US 8,329,691 B2 39 40 ing, as a ring-constituting atom besides carbon atom, 1 to 4 As R, more preferred is heteroatoms selected from an oxygenatom, a Sulfur atom and (1) Calkoxy, a nitrogen atom (e.g., pyrrolidinyl, piperidinyl, morpholinyl, (2) Ce alkylthio and the like. thiomorpholinyl, piperazinyl, tetrahydrofuryl) and the like. In the formula (C), Z is C. alkylene optionally having The "heterocyclic group' optionally has substituent(s) Substituent(s), C- alkenylene optionally having Substi (e.g., 1 to 5, preferably 1 to 3, substituents) at substitutable tuent(s) or C- alkynylene optionally having Substituent(s). position(s). When the number of substituents is two or more, Examples of the “substituent” of the “C. alkylene option the respective substituents may be the same or different. ally having Substituent(s)', 'Coalkenylene optionally hav Examples of the Substituent include groups exemplified as the ing substituent(s) or “C. alkynylene optionally having Sub 10 stituent(s)” for Zinclude 1 to 3 (preferably 1 or 2) substituents substituents of the aforementioned "heterocyclic group selected from oxo; a halogen atom; nitro; cyano; hydroxy: optionally having substituent(s) and the like. Calkoxy optionally having 1 to 3 halogen atoms; amino Preferable examples of the “substituent of the "heterocy and the like. clic group optionally having substituent(s)” for R include 1 As Z. preferred is C alkylene optionally having substitu to 3 Substituents selected from (1) a halogen atom; (2) nitro: 15 ent(s), more preferred is C. alkylene (e.g., ethylene, trim (3) cyano; (4) hydroxy; (5) Calkoxy; (6) amino; (7) mono ethylene) optionally having 1 or 2 substituents selected from or di-C alkylamino; (8) C. aralkylamino; (9) C OXO and hydroxy, and further preferred is C. alkylene (e.g., alkoxy-carbonylamino: (10) C. alkyl-carbonylamino; (11) ethylene, trimethylene). Calkyl-carbonyl: (12) carboxy; (13)C alkoxy-carbonyl: Ring A. Ring Aa, Ring Ab and Ring Ac (14) carbamoyl: (15) mono- or di-C alkylcarbamoyl: (16) In the formula (I), the formula (A) and the formula (C), ring mercapto: (17) C. alkylthio; (18) C alkylsulfinyl: (19) A, ring Aa and ring Ac are each a homocycle or heterocycle C. alkylsulfonyl: (20) C. alkyl optionally having 1 to 3 optionally having Substituent(s). halogen atoms and the like. Examples of the “homocycle or heterocycle' of the Examples of the “hydroxy optionally having a substituent” “homocycle or heterocycle optionally having substituent(s) for R include hydroxy optionally having a substituent 25 for ring A, ring Aa or ring Ac include (i) an aromatic hetero selected from Calkyl optionally having Substituent(s), C cycle or nonaromatic heterocycle containing, as a ring-con alkenyl optionally having Substituent(s), Co cycloalkyl stituting atom besides carbon atom, 1 to 3 heteroatoms optionally having substituent(s), Co cycloalkenyl option selected from an oxygen atom, a Sulfur atom and a nitrogen ally having Substituent(s), Caryl optionally having Sub atom, (ii) cyclic hydrocarbon (homocycle) and the like. stituent(s), Czaralkyl optionally having Substituent(s) and 30 Examples of the “aromatic heterocycle' include a 5- or the like. The aforementioned C. alkyl, Calkenyl, Co 6-membered aromatic heterocycle containing, as a ring-con cycloalkyl, Co cycloalkenyl, Caryl and C7 aralkyl stituting atom besides carbon atom, 1 to 3 heteroatoms optionally have 1 to 3 substituents selected from a halogen selected from an oxygen atom, a Sulfur atom and a nitrogen atom; cyano; hydroxy, Ce alkoxy optionally having 1 to 3 atom (e.g., pyrazole, pyridine, pyrimidine) and the like. Pref halogen atoms; mercapto: C- alkylthio and the like. Prefer 35 erable examples thereof include a 6-membered aromatic het able examples of the “hydroxy optionally having a substitu erocycle containing, as a ring-constituting atom besides car ent” for R include Calkoxy. bon atom, 1 or 2 nitrogen atoms (e.g., pyridine, pyrimidine) Examples of the “mercapto optionally having a Substitu and the like. The “aromatic heterocycle' is optionally fused ent” for R include mercapto optionally having a substituent with Cs-7 cycloalkene (e.g., cyclopentene, cyclohexene, selected from Calkyl optionally having substituent(s), C 40 cycloheptene) or heterocycle (e.g., thiophene). alkenyl optionally having Substituent(s), Co cycloalkyl Examples of the “nonaromatic heterocycle' include a 5- to optionally having substituent(s), Co cycloalkenyl option 9-membered (preferably 5- or 6-membered) nonaromatic het ally having Substituent(s), Caryl optionally having Sub erocycle containing, as a ring-constituting atom besides car stituent(s), C. aralkyl optionally having Substituent(s) and bon atom, 1 to 3 heteroatoms selected from an oxygen atom, the like. The aforementioned C. alkyl, Calkenyl, Co 45 a Sulfur atom and a nitrogen atom and the like. cycloalkyl, Cso cycloalkenyl, C-14 aryl and C7-6 aralkyl Examples of the “cyclic hydrocarbon include 3- to optionally have 1 to 3 substituents selected from a halogen 10-membered (preferably, 5- to 9-membered, more prefer atom; cyano; hydroxy, Ce alkoxy optionally having 1 to 3 ably 5- or 6-membered) cyclic hydrocarbon and the like, with halogen atoms; mercapto: C- alkylthio and the like. Prefer preference given to benzene, Co cycloalkene, Co able examples of the “mercapto optionally having a substitu 50 cycloalkane and the like. ent” for R include Calkylthio. The above-mentioned “homocycle or heterocycle' option Examples of the “acyl” for R include ally has substituent(s) (e.g., 1 to 3, preferably 1 or 2 substitu (1) formyl; ents) at substitutable position(s). When the number of sub (2) carboxy; stituents is two or more, the respective substituents may be the (3)C alkyl-carbonyl: 55 same or different. Examples of the Substituent include groups (4) Calkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycar exemplified as the substituents that the aforementioned bonyl, propoxycarbonyl, tert-butoxycarbonyl); “hydrocarbon group' optionally has and the like. Preferable (5) a group represented by the formula: –CO NR'R'' examples of the substituent include 1 to 3 (preferably 1 or 2) wherein R'' and R'' are each a hydrogen atom, a hydro Substituents selected from (1) a halogen atom, (2) hydroxy, carbon group optionally having Substituent(s) or a hetero 60 (3)C alkoxy, (4) Ce alkyl optionally having 1 to 3 halogen cyclic group optionally having Substituent(s), or R." and atoms, (5) Caryl (e.g., phenyl), (6) Co cycloalkyl (e.g., R” optionally form, together with the nitrogen atom cyclopropyl), (7) a 5- or 6-membered aromatic heterocyclic bonded thereto, a nitrogen-containing heterocycle option group containing, as a ring-constituting atom besides carbon ally having Substituent(s) and the like. atom, 1 to 3 heteroatoms selected from an oxygen atom, a As R, preferred is 65 Sulfur atom and a nitrogen atom (e.g., thienyl), (8) Calky (1) hydroxy optionally having a Substituent, lthio and the like, more preferably 1 to 3 (preferably 1 or 2) (2) mercapto optionally having a substituent and the like. C. alkyl optionally having 1 to 3 halogen atoms. US 8,329,691 B2 41 42 Examples of the "heterocycle of the "heterocycle option As ring Aa, more preferred is a heterocycle represented by ally having Substituent(s)” for ring A, ring Aa or ring Ac the formula include heterocycles represented by the formulas 21 NN N4Y- N21 1. ^ Y N-N-1,H S1 N1,H S1\1,H N N1 N N1 N 1. 10 H H H O O O O

15 21 NN N 1. 1. O H N N1 N N1 H H O O O

21 NN 21 NN These heterocycles optionally have 1 to 3 C alkyl option and ally having 1 to 3 halogen atoms. 25 As ring Aa, more preferred is a ring represented by the N N1 N N1 formula H H

O O R4 30 21 h

These heterocycles optionally have 1 to 3 substituents O selected from N-n1"H N-N-1H (1) a halogen atom, 35 (2) Ce alkyl optionally having 1 to 3 halogen atoms, O O (3) C-14 aryl (e.g., phenyl), As ring Aa, particularly preferred is a ring represented by (4) Cso cycloalkyl (e.g., cyclopropyl), the formula (5) a 5- or 6-membered aromatic heterocyclic group contain 40 ing, as a ring-constituting atom besides carbonatom, 1 to 3 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogen atom (e.g., thienyl), and (6) C. alkylthio. 45 N 1. As ring Aa, preferred is a 5- or 6-membered aromatic N 1. heterocycle optionally having Substituent(s). N Examples of the “5- or 6-membered aromatic heterocycle” of the “5- or 6-membered aromatic heterocycle optionally 50 O having substituent(s) for ring Aa include a 5- or 6-membered aromatic heterocycle containing, as a ring-constituting atom As R in compound (A), preferred is besides carbon atom, 1 to 3 heteroatoms selected from an (1) a hydrocarbon group optionally having Substituent(s), oxygen atom, a Sulfur atom and a nitrogen atom (e.g., pyra (2) a heterocyclic group optionally having Substituent(s), Zole, pyridine, pyrimidine) and the like. Preferable examples 55 (3) mercapto optionally having a substituent and the like. thereof include a 6-membered aromatic heterocycle contain As R in compound (A), more preferred is ing, as a ring-constituting atom besides carbon atom, 1 or 2 (1) Ce alkyl optionally having 1 to 3 halogen atoms, nitrogen atoms (e.g., pyridine, pyrimidine) and the like. (2) C-14 aryl, Examples of the “substituent of the “5- or 6-membered (3) Co cycloalkyl, 60 (4) a 5- or 6-membered aromatic heterocyclic group contain aromatic heterocycle optionally having Substituent(s)” for ing, as a ring-constituting atom besides carbonatom, 1 to 3 ring Aa include heteroatoms selected from an oxygen atom, a Sulfur atom (1) a hydrocarbon group optionally having Substituent(s), and a nitrogen atom (e.g., thienyl), (2) a heterocyclic group optionally having Substituent(s), (5) Calkylthio and the like. 65 As R' in compound (A), further preferred is C, alkyl (3) mercapto optionally having a substituent, optionally having 1 to 3 halogen atoms, and particularly pre (4) acyl and the like. ferred is C alkyl. US 8,329,691 B2 43 44 In the formula (B), X and Y are each C or N, and ring Ab is Ring Ac is more preferably a ring represented by the for a nitrogen-containing 6-membered ring optionally having mula substituent(s) in addition to R. X is preferably C. 5 R4 R4 ring Ab optionally has substituent(s) (preferably 1 or 2 substituents) at substitutable position(s) in addition to R. 21 Examples of the Substituent include a halogenatom, hydroxy, C. alkoxy, C alkyl and the like. Preferable examples of O the substituent include 1 or 2 substituents selected from a 10 N N1 N N1 halogenatom and Calkyl, and more preferred is C alkyl. H H As ring Ab, preferred is a ring represented by the formula O O 15 Ring Ac is further preferably a ring represented by the R4 R4 formula 21 S N1 O N N1 H H 1s, O O N N1 H wherein R is a hydrocarbon group optionally having Sub 25 stituent(s), a heterocyclic group optionally having Substi O tuent(s) excluding a cyclic amino optionally having Substitu ent(s), mercapto optionally having a substituent or acyl. R" in compound (C) is preferably (1) a hydrocarbon group optionally having Substituent(s), In compound (B), R is preferably 30 (2) a heterocyclic group optionally having Substituent(s), (1) a hydrocarbon group optionally having Substituent(s), (3) mercapto optionally having a substituent and the like. (2) an aromatic heterocyclic group optionally having Sub R" in compound (C) is more preferably (1) C alkyl optionally having 1 to 3 halogen atoms, stituent(s), (2) C-14 aryl, (3) mercapto optionally having a substituent and the like. 35 (3) Co cycloalkyl, In compound (B), R is more preferably (4) a 5- or 6-membered aromatic heterocyclic group contain (1) C alkyl optionally having 1 to 3 halogen atoms, ing, as a ring-constituting atom besides carbonatom, 1 to 3 heteroatoms selected from an oxygen atom, a Sulfur atom (2) C-14 aryl, and a nitrogen atom (e.g., thienyl), (3) Co cycloalkyl, 40 (5) C alkylthio and the like. Rincompound (C) is further preferably C-alkyl option (4) a 5- or 6-membered aromatic heterocyclic group contain ally having 1 to 3 halogenatoms, and particularly preferably ing, as a ring-constituting atom besides carbonatom, 1 to 3 C- alkyl. heteroatoms selected from an oxygen atom, a Sulfur atom Preferable examples of compound (1) are as described and a nitrogen atom (e.g., thienyl), 45 below. (5) Calkylthio and the like. Compound I-1 Ring Ac is preferably a 5- or 6-membered aromatic ring A compound represented by the formula (I) optionally having Substituent(s). wherein R' and Rare each (1) Ce alkyl optionally having 1 to 3 Substituents selected Examples of the “5- or 6-membered aromatic ring of the 50 from cyano and hydroxy, “5- or 6-membered aromatic ring optionally having Substitu (2) Co cycloalkyl (e.g., cyclopropyl, cyclohexyl). ent(s) for ring Ac include (i) 5- or 6-membered aromatic (3) Czaralkyl (e.g., benzyl), or heterocycle containing, as a ring-constituting atom besides (4) a group represented by the formula carbon atom, 1 to 3 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogenatom, (ii) benzene and the 55 like. Preferred is a 6-membered aromatic ring containing, as a ring-constituting atom besides carbon atom, 1 or 2 nitrogen -- atoms (e.g., pyridine, pyrimidine) and the like. Examples of the “substituent of the “5- or 6-membered Rb2 aromatic ring optionally having Substituent(s)” for ring Ac 60 include (1) a hydrocarbon group optionally having Substituent(s), (2) a heterocyclic group optionally having Substituent(s), 65 wherein R'' and Rare each (3) mercapto optionally having a substituent, (1) a hydrogen atom, (4) acyl and the like. (2) Ce alkyl optionally having 1 to 3 hydroxy, US 8,329,691 B2 45 46 (3)C alkoxy-carbonyl, or wherein R is (4) a group represented by the formula: CO N(R)(R) (1) C alkyl optionally having 1 to 3 halogen atoms, wherein Rand Rare each a hydrogenatom or Calkyl, or (2) C-14 aryl (e.g., phenyl), Rand Roptionally form, together with the nitrogen atom (3) Co cycloalkyl (e.g., cyclopropyl), (4) a 5- or 6-membered aromatic heterocyclic group contain bonded thereto, a 5- to 7-membered nonaromatic nitrogen ing, as a ring-constituting atom besides carbonatom, 1 to 3 containing heterocycle containing, as a ring-constituting heteroatoms selected from an oxygen atom, a Sulfur atom atom besides carbon atom, one nitrogen atom, and option and a nitrogen atom (e.g., thienyl), or ally further containing 1 or 2 heteroatoms selected from an (5) Calkylthio, and ring A optionally further has 1 or 2 Oxygen atom, a Sulfur atom and a nitrogen atom (e.g., C. alkyl in addition to R', or a salt thereof. pyrrolidine, piperidine, piperazine, morpholine, thiomor 10 Compound I-2 pholine), and optionally having 1 to 3 Substituents selected A compound represented by the formula (I) from hydroxy and Calkyl, or RandR optionally form, wherein R' and Rare each together with the nitrogen atom bonded thereto, a 5- to (1) Ce alkyl optionally having 1 to 3 Substituents selected from 9-membered (preferably 5- to 7-membered, more prefer 15 ably 5- or 6-membered) nonaromatic nitrogen-containing (a) a halogen atom, heterocycle containing, as a ring-constituting atom besides (b) cyano, carbon atom, one nitrogen atom, and optionally further (c) hydroxy, containing 1 or 2 heteroatoms selected from an oxygen (d) amino, atom, a Sulfur atom and a nitrogen atom (e.g., pyrrolidine, (e) Calkoxy-carbonyl, piperidine, piperazine, morpholine, thiomorpholine, (f) carbamoyl, (g) C alkylcarbamoyl optionally having 1 to 3 substitu aZepane, azocane, azonane, 1,4-diazepane), and optionally ents selected from hydroxy and a heterocyclic group (prefer having 1 to 3 substituents selected from ably a 5- or 6-membered heterocyclic group containing, as a (1) C. alkyl optionally having 1 to 3 substituents selected ring-constituting atom besides carbon atom, 1 to 4 heteroat from 25 oms selected from an oxygen atom, a Sulfur atom and a (a) hydroxy, nitrogen atom, e.g., pyridyl, morpholinyl), and (b) Coalkoxy, (h) C. aralkylcarbamoyl (e.g., benzylcarbamoyl), (c) C-14 aryl (e.g., phenyl), (2) Co cycloalkyl (e.g., cyclopropyl, cyclohexyl). (d) amino, (3) Cz-e aralkyl (e.g., benzyl). (e) mono- or di-C alkylamino, 30 (4) Co cycloalkyl-C alkyl (e.g., cyclopropylmethyl), (f) C7-6 aralkylamino (e.g., benzylamino), and (5) a group represented by the formula (g) Calkoxy-carbonylamino (e.g., tert-butoxycarbony lamino), (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen 35 atOmS, (3) Cz-e aralkyl (e.g., benzyl, phenethyl), (4) Co cycloalkyl (e.g., cyclohexyl). (5) amino, (6) hydroxy, (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and 40 (8) carbamoyl: R is (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic group containing, as a ring-constituting atom besides car (6) a group represented by the formula bon atom, 1 to 4 heteroatoms selected from an oxygen 45 atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, Oxazolyl pyridyl, tetrahydrofuryl), and optionally having 1 to 3 C alkyl, -- (2) Caryl (e.g., phenyl), (3) Cao cycloalkyl (e.g., cyclopropyl), 50 (4) C. alkyl optionally having 1 to 3 substituents selected from Calkoxy and C alkylthio, or (5) Calkoxy-carbonyl; and Rb1 ring A is a ring represented by the formula 55 wherein R is a hydrogenatom, and R is (1) a hydrogen atom, (2) cyano, 60 (3) C alkyl optionally having 1 to 3 substituents selected from (a) hydroxy, (b) C alkyl-carbonyloxy, (c) C. alkylthio, and 65 (d) Ce alkylsulfonyl, (4) Co cycloalkyl (e.g., cyclohexyl) optionally having 1 to 3 hydroxy, US 8,329,691 B2 47 48 (5') C. aralkylamino (e.g., phenethylamino) optionally (i) C7-6 aralkyloxy (e.g., benzyloxy), having 1 to 3 hydroxy, (i) C. alkyl-carbonyl, (6') Calkoxy-carbonylamino, (7) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo (k) Caryl-carbonyl (e.g., benzoyl), nylamino), (l) mono- or di-C alkylsulfamoyl, (8) Calkyl-carbonylamino, (9) Clo cycloalkyl-carbonylamino (e.g., cyclohexylcarbo (m) C alkylsulfonyl, and nylamino) optionally having 1 to 3 Substituents selected (n) a 5- or 6-membered heterocyclic group containing, as a from hydroxy and Calkoxy, ring-constituting atom besides carbon atom, 1 to 4 heteroat (10') Calkylsulfonylamino, 10 oms selected from an oxygen atom, a Sulfur atom and a (11') Carylsulfonylamino (e.g., phenylsulfonylamino), nitrogen atom (e.g., pyridyl, thiazolyl), or (12") C. alkylaminocarbonylamino, (13') Carylaminocarbonylamino (e.g., phenylaminocar R'' and R' optionally form, together with the carbon atoms bonylamino), bonded thereto, a benzene ring or a cyclohexane ring, or (14) Ce alkyl-carbonyl, 15 R" and R optionally form, together with the nitrogen atom (15') Co cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl). bonded thereto, a 5- to 9-membered (preferably 5- to (16’) carboxy, 7-membered, more preferably 5- or 6-membered) nonaro (17) a group represented by the formula: W. R. matic nitrogen-containing heterocycle containing, as a wherein W' is a bond, —CH2—, —CHO , NHCO O ring-constituting atom besides carbon atom, one nitrogen —NHSO , and atom, and optionally further containing 1 or 2 heteroatoms R’ is a 5- or 6-membered heterocyclic group containing, as a selected from an oxygenatom, a Sulfur atom and a nitrogen ring-constituting atom besides carbonatom, 1 to 4 heteroa atom (e.g., pyrrolidine, piperidine, piperazine, morpho toms selected from an oxygen atom, a Sulfur atom and a line, thiomorpholine, azepane, azocane, azonane, 1,4-di nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet aZepane), and optionally having 1 to 3 Substituents selected rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- 25 from oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1,2,4-oxa diazolyl, imidazolidinyl, hexahydropyrimidinyl, (1) Ce alkyl optionally having 1 to 3 Substituents selected pyrazolyl), said 5- or 6-membered heterocyclic group from optionally has 1 to 3 substituents selected from (a) hydroxy, (a) oXo, 30 (b) Coalkoxy, (b) C. alkyl optionally having 1 to 3 hydroxy, (c) Co.14 aryl. (c) C-14 aryl (e.g., phenyl), (d) carbamoyl, and (d) amino, (e) Calkoxy-carbonyl, (e) mono- or di-C alkylamino, (18') Calkoxy-carbonyl, or 35 (19') a group represented by the formula: CO N(R)(R) (f) C. aralkylamino (e.g., benzylamino), and wherein RandR are each a hydrogenatom, C-alkyl or (g) Calkoxy-carbonylamino (e.g., tert-butoxycarbony Coalkoxy, or lamino), Rand Roptionally form, together with the nitrogen atom (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen bonded thereto, a 4- to 7-membered nonaromatic nitrogen 40 containing heterocycle containing, as a ring-constituting atoms, atom besides carbon atom, one nitrogen atom, and option (3) Cz-e aralkyl (e.g., benzyl, phenethyl), ally further containing 1 or 2 heteroatoms selected from an (4) Cao cycloalkyl (e.g., cyclohexyl), oxygen atom, a Sulfur atom and a nitrogen atom, said 4- to (5) amino, 7-membered nonaromatic nitrogen-containing heterocycle 45 (6) hydroxy, optionally forms a fused ring with a benzene ring, a cyclo hexane ring or an oxazole ring, or optionally forms a spiro (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and ring with a 1,3-dioxolane ring (e.g., aZetidine, pyrrolidine, (8) carbamoyl: piperidine, piperazine, morpholine, thiomorpholine, 1,4- R is oxazepane, 1.2.3,4-tetrahydroquinoline, 1,2,3,4-tetrahy 50 droisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic 1H-indole, decahydroquinoline, 4,5,6,7-tetrahydro1.3 group containing, as a ring-constituting atom besides car Oxazolo.5,4-bipyridine, 1,4-dioxa-8-azaspiro4.5 decane, bon atom, 1 to 4 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, 1,2,3,6-tetrahydropyridine), said 4- to 7-membered non oxazolyl pyridyl, tetrahydrofuryl), and optionally having aromatic nitrogen-containing heterocycle, a fused ring 55 thereof and a spiro ring thereof optionally have 1 to 3 1 to 3 C alkyl, Substituents selected from (2) C-14 aryl (e.g., phenyl), (a) oXo, (3) Cao cycloalkyl (e.g., cyclopropyl), (b) a halogen atom, (4) Ce alkyl optionally having 1 to 3 Substituents selected (c) C. alkyl optionally having 1 to 3 Substituents selected 60 from hydroxy and Calkoxy, from (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, (a) hydroxy, alkoxy, (b) Coalkoxy, (e) C7-6 aralkyl (e.g., benzyl). (c) C. alkylthio. (f) hydroxy, 65 (g) Coalkoxy, (d) Ce alkylsulfinyl, and (h) C-14 aryloxy (e.g., phenoxy), (e) C. alkylsulfonyl, or US 8,329,691 B2 49 50 (5) Calkoxy-carbonyl; and Compound A-2 ring A is a heterocycle represented by the formula A compound represented by the formula (A) wherein R" is C, alkyl: R" is a 5-membered aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 21 NN 4N N21 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogen atom (e.g., furyl), or phenyl; ring Aa is a ring represented by the formula N-N1,H S1 N1,H S1N1,H

O 10

21 NN N 1. 15 H

O wherein R is C, alkyl; and ring B is a ring represented by the formula 21 NN 21 NN | or | N N1 N N1 H H 25 -- O O Rb2 said heterocycle optionally has 1 to 3 substituents selected 30 from (1) a halogen atom, (2) C alkyl optionally having 1 to 3 halogen atoms, wherein R'' and Rare each (3) C-14 aryl (e.g., phenyl), (1) a hydrogen atom, (4) Cso cycloalkyl (e.g., cyclopropyl), 35 (2) C alkyl optionally having 1 to 3 hydroxy, (5) a 5- or 6-membered aromatic heterocyclic group contain (3)C alkoxy-carbonyl, or ing, as a ring-constituting atom besides carbonatom, 1 to 3 (4) a group represented by the formula: —CO N(R) (R) heteroatoms selected from an oxygen atom, a Sulfur atom wherein RandR are each a hydrogenatom or Calkyl, or and a nitrogen atom (e.g., thienyl), and Rand Roptionally form, together with the nitrogen atom 40 bonded thereto, a 5- to 7-membered nonaromatic nitrogen (6) C. alkylthio, or a salt thereof. containing heterocycle containing, as a ring-constituting Preferable examples of compound (A) are as described atom besides carbonatom, one nitrogen atom, and option below. ally further containing 1 or 2 heteroatoms selected from an Compound A-1 oxygen atom, a Sulfur atom and a nitrogen atom (e.g., A compound of the formula (A) 45 pyrrolidine, piperidine, piperazine, morpholine, thiomor pholine), and optionally having 1 to 3 Substituents selected wherein R' is C alkyl: from hydroxy and C alkyl, or a salt thereof. R" is a 5- or 6-membered aromatic group optionally having Compound A-3 Substituent(s): A compound represented by the formula (A) ring Aa is a 5- or 6-membered aromatic ring optionally having 50 wherein R' is C, alkyl optionally having Co cycloalkyl; Substituent(s); and R" is a 5- or 6-membered aromatic heterocyclic group con ring B is a ring represented by the formula taining, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogen atom (e.g., furyl, oxazolyl, thienyl, 55 pyridyl), or phenyl: -- ring Aa is a heterocycle represented by the formula

60 wherein R'' and R'' are each a hydrogen atom or a substitu ent, or R'' and R' optionally form, together with the 65 carbon atoms bonded thereto, a 5- to 7-membered ring optionally having Substituent(s), or a salt thereof. US 8,329,691 B2 51 52 -continued (a) OXo, (b) C alkyl optionally having 1 to 3 hydroxy, (c) C-14 aryl, and (d) carbamoyl, 21 21 (9) C- alkoxy-carbonyl, or (10) a group represented by the formula: CO N(R)(R) N O N wherein RandR are each a hydrogenatom or Calkyl, or N N R and R optionally form, together with the nitrogen atom bonded thereto, a 4- to 7-membered nonaromatic nitrogen 10 containing heterocycle containing, as a ring-constituting atom besides carbonatom, one nitrogen atom, and option said heterocycle optionally has 1 to 3 C alkyl optionally ally further containing 1 or 2 heteroatoms selected from an having 1 to 3 halogen atoms; and oxygen atom, a Sulfur atom and a nitrogen atom (e.g., ring B is aZetidine, pyrrolidine, piperidine, piperazine, morpholine, (1) a ring represented by the formula 15 thiomorpholine), and optionally having 1 to 3 Substituents selected from hydroxy and C alkyl, or R'' and R' optionally form, together with the carbonatoms bonded thereto, a benzene ring or a cyclohexane ring, or a salt thereof. Compound A-4 A compound represented by the formula (A) wherein R" is C, alkyl: R" is a 5-membered aromatic heterocyclic group containing, H , 25 as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogenatom (e.g., furyl, oxazolyl, thienyl); ring Aa O (2) a ring represented by the formula is a ring represented by the formula

30 R4 R4

-- 21 Rb2 35 N N1 O S N1 H H HN Rb1 O O wherein R’ is a hydrogenatom, and 40 wherein R is C. alkyl optionally having 1 to 3 halogen R is atoms; and (1) a hydrogen atom, ring B is a ring represented by the formula (2) cyano, (3') C alkyl optionally having 1 to 3 substituents selected from 45 (a) hydroxy, (b) C alkyl-carbonyloxy, -- (c) C. alkylthio, and (d) Calkylsulfonyl, (4) Calkoxy-carbonylamino, 50 (5') C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo nylamino), (6') Calkyl-carbonylamino, (7) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo wherein R is a hydrogenatom, and nylamino) optionally having 1 to 3 Substituents selected 55 R is from hydroxy and Calkoxy, (1) a hydrogen atom, (8) a group represented by the formula: W R (2) cyano, wherein W is a bond, —CH2—, —CHO or NHCO , (3)C alkyl optionally having 1 to 3 Substituents selected and from R is a 5- or 6-membered heterocyclic group containing, as a 60 (a) hydroxy, ring-constituting atom besides carbonatom, 1 to 4 heteroa (b) C alkyl-carbonyloxy, toms selected from an oxygen atom, a Sulfur atom and a (c) C. alkylthio, and nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet (d) C alkylsulfonyl, rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- (4) Calkoxy-carbonylamino, oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1,2,4-oxa 65 (5) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo diazolyl), said 5- or 6-membered heterocyclic group nylamino), optionally has 1 to 3 substituents selected from (6) C. alkyl-carbonylamino, US 8,329,691 B2 53 54 (7) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo wherein R’ is a hydrogen atom, and nylamino) optionally having 1 to 3 Substituents selected R’ is a group represented by the formula:—CO N(R)(R) from hydroxy and C alkoxy, wherein Rand Rare each a hydrogenatom or C. alkyl, (8) a group represented by the formula: W R or R and R' optionally form, together with the nitrogen wherein W is a bond, —CH2—, —CHO or NHCO , atom bonded thereto, a 4- to 7-membered nonaromatic and nitrogen-containing heterocycle containing, as a ring-con R is a 5- or 6-membered heterocyclic group containing, as a stituting atom besides carbonatom, one nitrogenatom, and ring-constituting atom besides carbonatom, 1 to 4 heteroa optionally further containing 1 or 2 heteroatoms selected toms selected from an oxygen atom, a Sulfur atom and a from an oxygen atom, a Sulfur atom and a nitrogen atom nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet 10 (e.g., aZetidine, pyrrolidine, piperidine, piperazine, mor rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- pholine, thiomorpholine), and optionally having 1 to 3 oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1,2,4-oxa Substituents selected from hydroxy and C alkyl, or a salt diazolyl), said 5- or 6-membered heterocyclic group thereof. Preferable examples of compound (B) are as described optionally has 1 to 3 substituents selected from 15 (a) oXo, below. (b) C. alkyl optionally having 1 to 3 hydroxy, Compound B-1 (c) C-14 aryl, and A compound represented by the formula (B) (d) carbamoyl, wherein R'' and R' form, together with the nitrogen atom (9) C- alkoxy-carbonyl, or bonded thereto, piperidine optionally having Substituent(s) (10) a group represented by the formula: CO N(R)(R) or piperazine optionally having Substituent(s): wherein RandR are each a hydrogenatom or C-alkyl, or R is furyl, thienyl or oxazolyl, each of which optionally has R and R optionally form, together with the nitrogen atom Substituent(s); and bonded thereto, a 4- to 7-membered nonaromatic nitrogen m ring Ab is a ring represented by the formula containing heterocycle containing, as a ring-constituting 25 atom besides carbon atom, one nitrogen atom, and option ally further containing 1 or 2 heteroatoms selected from an R4 R4 Oxygen atom, a Sulfur atom and a nitrogen atom (e.g., aZetidine, pyrrolidine, piperidine, piperazine, morpholine, 21 thiomorpholine), and optionally having 1 to 3 Substituents 30 Selected from hydroxy and C alkyl, or S N1 O N N1 R'' and R' optionally form, together with the carbonatoms H H bonded thereto, a benzene ring or a cyclohexane ring, or a salt thereof. O O Compound A-5 35 A compound represented by the formula (A) wherein R is a hydrocarbon group optionally having Sub wherein R' is C alkyl: stituent(s) or a heterocyclic group optionally having Sub R" is a 5-membered aromatic heterocyclic group containing, stituent(s), excluding a cyclic amino optionally having as a ring-constituting atom besides carbon atom, 1 to 4 substituent(s), or a salt thereof. heteroatoms selected from an oxygen atom, a Sulfur atom 40 Compound B-2 and a nitrogenatom (e.g., furyl, oxazolyl, thienyl); ring Aa A compound represented by the formula (B) is a ring represented by the formula wherein R'' and Rare each (1) Ce alkyl optionally having 1 to 3 Substituents selected from cyano and hydroxy, 45 (2) Co cycloalkyl (e.g., cyclopropyl, cyclohexyl), or (3) Cz-e aralkyl (e.g., benzyl), or 1. RandR optionally form, together with the nitrogenatom bonded thereto, a 5- to 9-membered (preferably 5- to N 7-membered, more preferably 5- or 6-membered) nonaro N 50 matic nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atom, one nitrogen atom, and optionally further containing 1 or 2 heteroatoms selected from an oxygenatom, a Sulfur atom and a nitrogen wherein R is C, alkyl; and atom (e.g., pyrrolidine, piperidine, piperazine, morpho ring B is a ring represented by the formula 55 line, thiomorpholine, azepane, azocane, azonane, 1,4-di aZepane), and optionally having 1 to 3 Substituents selected from (1) Ce alkyl optionally having 1 to 3 Substituents selected from 60 (a) hydroxy, (b) Calkoxy, (c) C-14 aryl (e.g., phenyl), (d) amino, (e) mono- or di-C alkylamino, Rb1 65 (f) C. aralkylamino (e.g., benzylamino), and (g) C. alkoxy-carbonylamino (e.g., tert-butoxycarbony lamino), US 8,329,691 B2 55 56 (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen O atOmS, (6) a group represented by the formula (3) Cz-e aralkyl (e.g., benzyl, phenethyl), (4) Cso cycloalkyl (e.g., cyclohexyl). (5) amino, (6) hydroxy, -- (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and (8) carbamoyl: R is (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic 10 group containing, as a ring-constituting atom besides car Rb1 bon atom, 1 to 4 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, wherein R’ is a hydrogen atom, and Oxazolyl pyridyl, tetrahydrofuryl), and optionally having R is 1 to 3 C alkyl, 15 (1) a hydrogen atom, (2) Caryl (e.g., phenyl), (2) cyano, (3) Cao cycloalkyl (e.g., cyclopropyl), (3) C alkyl optionally having 1 to 3 substituents selected (4) Ce alkyl optionally having 1 to 3 C alkoxy, or from (5) Calkoxy-carbonyl: (a) hydroxy, R is (b) C. alkyl-carbonyloxy, (c) C. alkylthio, and (1) C alkyl optionally having 1 to 3 halogen atoms, (d) Ce alkylsulfonyl, (2) C-14 aryl (e.g., phenyl), (4) Co cycloalkyl (e.g., cyclohexyl) optionally having 1 to (3) Co cycloalkyl (e.g., cyclopropyl), 3 hydroxy, (4) a 5- or 6-membered aromatic heterocyclic group contain 25 (5') C. aralkylamino (e.g., phenethylamino) optionally ing, as a ring-constituting atom besides carbonatom, 1 to 3 having 1 to 3 hydroxy, heteroatom selected from an oxygen atom, a Sulfur atom (6') Calkoxy-carbonylamino, and a nitrogen atom (e.g., thienyl), or (7) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo (5) Calkylthio: nylamino), X is C; 30 (8) Calkyl-carbonylamino, Y is C or N; and (9) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo ring Ab is a nitrogen-containing 6-membered ring optionally nylamino) optionally having 1 to 3 substituents selected further having 1 or 2 C, alkyl in addition to R', or a salt from hydroxy and C alkoxy, thereof. (10') Calkylsulfonylamino, Compound B-3 35 (11') Carylsulfonylamino (e.g., phenylsulfonylamino), A compound represented by the formula (B) (12") C. alkylaminocarbonylamino, wherein R'' and Rare each (13') Carylaminocarbonylamino (e.g., phenylaminocar (1) C. alkyl optionally having 1 to 3 substituents selected bonylamino), from (14) Ce alkyl-carbonyl, (a) a halogen atom, 40 (15') Co cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl). (b) cyano, (16’) carboxy, (c) hydroxy, (17) a group represented by the formula: W R7 (d) amino, (e) Calkoxy-carbonyl, wherein W' is a bond, —CH2—, —CHO , NHCO O (f) carbamoyl, —NHSO , and 45 R’ is a 5- or 6-membered heterocyclic group containing, as a (g) C. alkylcarbamoyl optionally having 1 to 3 Substitu ring-constituting atom besides carbonatom, 1 to 4 heteroa ents selected from hydroxy and a heterocyclic group (prefer toms selected from an oxygen atom, a Sulfur atom and a ably a 5- or 6-membered heterocyclic group containing, as a nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet ring-constituting atom besides carbon atom, 1 to 4 heteroat rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- oms selected from an oxygen atom, a Sulfur atom and a 50 oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1.2.4Oxa nitrogen atom, e.g., pyridyl, morpholinyl), and diazolyl, imidazolidinyl, hexahydropyrimidinyl, (h) C. aralkylcarbamoyl (e.g., benzylcarbamoyl). pyrazolyl), said 5- or 6-membered heterocyclic group (2) Cao cycloalkyl (e.g., cyclopropyl, cyclohexyl), optionally has 1 to 3 substituents selected from (3) Cz-e aralkyl (e.g., benzyl). (a) OXo, (4) Co cycloalkyl-C alkyl (e.g., cyclopropylmethyl), 55 (b) C. alkyl optionally having 1 to 3 hydroxy, (5) a group represented by the formula (c) C-14 aryl. (d) carbamoyl, and (e) Calkoxy-carbonyl, (18') Calkoxy-carbonyl, or -- s 60 (19') a group represented by the formula: CO N(R)(R) wherein R and Rare each a hydrogen atom, C alkyl or Coalkoxy, or R and R optionally form, together with the nitrogen atom bonded thereto, a 4- to 7-membered nonaromatic nitrogen N 65 containing heterocycle containing, as a ring-constituting atom besides carbonatom, one nitrogen atom, and option ally further containing 1 or 2 heteroatoms selected from an US 8,329,691 B2 57 58 oxygen atom, a Sulfur atom and a nitrogen atom, said 4- to bon atom, 1 to 4 heteroatoms selected from an oxygen 7-membered nonaromatic nitrogen-containing heterocycle atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, optionally forms a fused ring with a benzene ring, a cyclo oxazolyl pyridyl, tetrahydrofuryl), and optionally having hexane ring or an oxazole ring, or optionally forms a spiro 1 to 3 C alkyl, ring with a 1,3-dioxolane ring (e.g., aZetidine, pyrrolidine, 5 (2) Caryl (e.g., phenyl), piperidine, piperazine, morpholine, thiomorpholine, 1,4- (3) Cao cycloalkyl (e.g., cyclopropyl), oxazepane, 1.2.3,4-tetrahydroquinoline, 1,2,3,4-tetrahy (4) Ce alkyl optionally having 1 to 3 Substituents selected droisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro from 1H-indole, decahydroquinoline, 4,5,6,7-tetrahydro1.3 (a) hydroxy, Oxazolo.5,4-bipyridine, 1,4-dioxa-8-azaspiro4.5 decane, 10 (b) Coalkoxy, 1,2,3,6-tetrahydropyridine), said 4- to 7-membered non (c) C alkylthio. aromatic nitrogen-containing heterocycle, a fused ring (d) Ce alkylsulfinyl, and thereof and a spiro ring thereof optionally have 1 to 3 (e) C. alkylsulfonyl, or Substituents selected from (5) Calkoxy-carbonyl: (a) oXo, 15 (b) a halogen atom, R is (c) C. alkyl optionally having 1 to 3 Substituents selected (1) Ce alkyl optionally having 1 to 3 halogen atoms, from hydroxy and C alkoxy, (2) Caryl (e.g., phenyl), (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, (3) Cao cycloalkyl (e.g., cyclopropyl), alkoxy, (4) a 5- or 6-membered aromatic heterocyclic group contain (e) Czaralkyl (e.g., benzyl). ing, as a ring-constituting atom besides carbonatom, 1 to 3 (f) hydroxy, heteroatoms selected from an oxygen atom, a Sulfur atom (g) Coalkoxy, and a nitrogen atom (e.g., thienyl), or (h) C-14 aryloxy (e.g., phenoxy), (5) Calkylthio; (i) C7-16 aralkyloxy (e.g., benzyloxy), 25 X is C; (i) C. alkyl-carbonyl, Y is C or N; and (k) Caryl-carbonyl (e.g., benzoyl), ring Ab is a nitrogen-containing 6-membered ring optionally (l) mono- or di-C alkylsulfamoyl, further having, in addition to R', 1 or 2 substituents selected (m) Co. alkylsulfonyl, and from a halogen atom and C alkyl, or a salt thereof. (n) a 5- or 6-membered heterocyclic group containing, as a 30 Compound B-4 ring-constituting atom besides carbon atom, 1 to 4 heteroat A compound represented by the formula (B) oms selected from an oxygen atom, a sulfur atom and a wherein R' is nitrogen atom (e.g., pyridyl, thiazolyl), or (1) Ce alkyl optionally having 1 to 3 halogen atoms, R'' and R' optionally form, together with the carbon atoms (2) Co cycloalkyl (e.g., cyclopropyl, cyclohexyl). bonded thereto, a benzene ring or a cyclohexane ring, or 35 R'' and Roptionally form, together with the nitrogen atom (3) Czaralkyl (e.g., benzyl), or bonded thereto, a 5- to 9-membered (preferably 5- to (4) Co cycloalkyl-C alkyl (e.g., cyclopropylmethyl); 7-membered, more preferably 5- or 6-membered) nonaro R’ is a group represented by the formula matic nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atom, one nitrogen 40 atom, and optionally further containing 1 or 2 heteroatoms Selected from an oxygenatom, a Sulfur atom and a nitrogen -- atom (e.g., pyrrolidine, piperidine, piperazine, morpho line, thiomorpholine, azepane, azocane, azonane, 1,4-di aZepane), and optionally having 1 to 3 Substituents selected 45 from (1) C. alkyl optionally having 1 to 3 substituents selected from (a) hydroxy, wherein R is a hydrogenatom, and (b) Coalkoxy, 50 (c) C-14 aryl (e.g., phenyl), R is (d) amino, (1) a hydrogen atom, (e) mono- or di-C alkylamino, (2) cyano, (f) Cz aralkylamino (e.g., benzylamino), and (3) C alkyl optionally having 1 to 3 substituents selected (g) Coalkoxy-carbonylamino (e.g., tert-butoxycarbony 55 from lamino), (a) hydroxy, (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen (b) C. alkyl-carbonyloxy, atOmS, (c) Calkylthio, and (3) Cz-e aralkyl (e.g., benzyl, phenethyl), (d) Ce alkylsulfonyl, (4) Cso cycloalkyl (e.g., cyclohexyl). 60 (4) Co cycloalkyl (e.g., cyclohexyl) optionally having 1 to (5) amino, 3 hydroxy, (6) hydroxy, (5') C. aralkylamino (e.g., phenethylamino) optionally (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and having 1 to 3 hydroxy, (8) carbamoyl: (6') Calkoxy-carbonylamino, R is 65 (7) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic nylamino), group containing, as a ring-constituting atom besides car (8) Calkyl-carbonylamino, US 8,329,691 B2 59 60 (9) Co cycloalkyl-carbonylamino (e.g., cyclohexylcarbo (n) a 5- or 6-membered heterocyclic group containing, as a nylamino) optionally having 1 to 3 Substituents selected ring-constituting atom besides carbon atom, 1 to 4 heteroat from hydroxy and C alkoxy, oms selected from an oxygen atom, a Sulfur atom and a (10') Calkylsulfonylamino, nitrogen atom (e.g., pyridyl, thiazolyl), or (11') Carylsulfonylamino (e.g., phenylsulfonylamino), R'' and R' optionally form, together with the carbonatoms (12") C. alkylaminocarbonylamino, bonded thereto, a benzene ring or a cyclohexane ring; (13') Carylaminocarbonylamino (e.g., phenylaminocar R is bonylamino), (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic (14) Ce alkyl-carbonyl, group containing, as a ring-constituting atom besides car (15') Co cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl), 10 bon atom, 1 to 4 heteroatoms selected from an oxygen (16’) carboxy, atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, (17) a group represented by the formula: W. R. oxazolyl pyridyl, tetrahydrofuryl), and optionally having wherein W' is a bond, —CH2—, —CHO , NHCO O 1 to 3 C alkyl, —NHSO. , and (2) C-14 aryl (e.g., phenyl), R’ is a 5- or 6-membered heterocyclic group containing, as a 15 (3) Co cycloalkyl (e.g., cyclopropyl), (4) Ce alkyl optionally having 1 to 3 Substituents selected ring-constituting atom besides carbonatom, 1 to 4 heteroa from toms selected from an oxygen atom, a Sulfur atom and a (a) hydroxy, nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet (b) Coalkoxy, rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- (c) C alkylthio. oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1,2,4-oxa (d) Ce alkylsulfinyl, and diazolyl, imidazolidinyl, hexahydropyrimidinyl, (e) C. alkylsulfonyl, or pyrazolyl), said 5- or 6-membered heterocyclic group (5) Calkoxy-carbonyl: optionally has 1 to 3 substituents selected from R is (a) oXo, 25 (1) C alkyl optionally having 1 to 3 halogen atoms, (b) C. alkyl optionally having 1 to 3 hydroxy, (2) C-14 aryl (e.g., phenyl), or (c) C-14 aryl. (d) carbamoyl, and (3) Co cycloalkyl (e.g., cyclopropyl); and ring Ab is a ring (e) Calkoxy-carbonyl, represented by the formula (18') Calkoxy-carbonyl, or 30 (19') a group represented by the formula: CO N(R)(R) wherein RandR are each a hydrogenatom, C, alkyl or R4 R4 Calkoxy, or Rand Roptionally form, together with the nitrogen atom 21 N21 NN bonded thereto, a 4- to 7-membered nonaromatic nitrogen 35 containing heterocycle containing, as a ring-constituting N N1 O S N1 s atom besides carbon atom, one nitrogen atom, and option H ally further containing 1 or 2 heteroatoms selected from an oxygen atom, a Sulfur atom and a nitrogen atom, said 4- to O 7-membered nonaromatic nitrogen-containing heterocycle 40 optionally forms a fused ring with a benzene ring, a cyclo or a salt thereof. hexane ring or an oxazole ring, or optionally forms a spiro Compound B-5 ring with a 1,3-dioxolane ring (e.g., aZetidine, pyrrolidine, A compound represented by the formula (B) piperidine, piperazine, morpholine, thiomorpholine, 1,4- wherein R'' and R' form, together with the nitrogen atom oxazepane, 1.2.3,4-tetrahydroquinoline, 1,2,3,4-tetrahy 45 bonded thereto, a 5- to 9-membered (preferably 5- to 7-mem droisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro bered, more preferably 5- or 6-membered) nonaromatic nitro 1H-indole, decahydroquinoline, 4,5,6,7-tetrahydro1.3 gen-containing heterocycle containing, as a ring-constituting Oxazolo.5,4-bipyridine, 1,4-dioxa-8-azaspiro4.5 decane, atom besides carbonatom, one nitrogenatom, and optionally 1,2,3,6-tetrahydropyridine), said 4- to 7-membered non further containing 1 or 2 heteroatoms selected from an oxy aromatic nitrogen-containing heterocycle, a fused ring 50 genatom, a Sulfur atom and a nitrogenatom (e.g., pyrrolidine, thereof and a spiro ring thereof optionally have 1 to 3 piperidine, piperazine, morpholine, thiomorpholine, Substituents selected from aZepane, azocane, azonane, 1,4-diazepane), and optionally (a) oXo, having 1 to 3 substituents selected from (b) a halogen atom, (1) C. alkyl optionally having 1 to 3 substituents selected (c) C. alkyl optionally having 1 to 3 Substituents selected 55 from from hydroxy and Calkoxy, (a) hydroxy, (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, (b) Coalkoxy, alkoxy, (c) C-14 aryl (e.g., phenyl), (e) C7-6 aralkyl (e.g., benzyl). (d) amino, (f) hydroxy, 60 (e) mono- or di-C alkylamino, (g) Coalkoxy, (f) C. aralkylamino (e.g., benzylamino), and (h) C-14 aryloxy (e.g., phenoxy), (g) C. alkoxy-carbonylamino (e.g., tert-butoxycarbony (i) C7 aralkyloxy (e.g., benzyloxy), lamino), (i) C. alkyl-carbonyl, (2) Caryl (e.g., phenyl) optionally having 1 to 3 halogen (k) Caryl-carbonyl (e.g., benzoyl), 65 atoms, (1) mono- or di-C alkylsulfamoyl, (3) Cz-e aralkyl (e.g., benzyl, phenethyl), (m) Co. alkylsulfonyl, and (4) Cao cycloalkyl (e.g., cyclohexyl), US 8,329,691 B2 61 62 (5) amino, (6) Calkoxy-carbonylamino, (6) hydroxy, (7) C. aralkyloxy-carbonylamino (e.g., benzyloxycarbo (7) C. alkoxy-carbonyl (e.g., tert-butoxycarbonyl), and nylamino), (8) carbamoyl: (8) Calkyl-carbonylamino, R3 is (9) Clo cycloalkyl-carbonylamino (e.g., cyclohexylcarbo (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic nylamino) optionally having 1 to 3 Substituents selected group containing, as a ring-constituting atom besides car from hydroxy and C alkoxy, bon atom, 1 to 4 heteroatoms selected from an oxygen (10) C. alkylsulfonylamino, atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, (11) Carylsulfonylamino (e.g., phenylsulfonylamino), Oxazolyl pyridyl, tetrahydrofuryl), and optionally having 10 1 to 3 C alkyl, (12) Ce alkylaminocarbonylamino, (2) C-14 aryl (e.g., phenyl), (13)C arylaminocarbonylamino (e.g., phenylaminocar (3) Cao cycloalkyl (e.g., cyclopropyl), bonylamino), (4) C alkyl optionally having 1 to 3 C alkoxy, or (14) Ce alkyl-carbonyl, (5) Calkoxy-carbonyl: 15 (15) Clo cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl), R is (16) carboxy, (1) Ce alkyl optionally having 1 to 3 halogen atoms, (17) a group represented by the formula: W. R. (2) C-14 aryl (e.g., phenyl), or wherein W' is a bond, —CH2—, —CHO , NHCO O (3) Cao cycloalkyl (e.g., cyclopropyl); and —NHSO , and ring Ab is a ring represented by the formula R’ is a 5- or 6-membered heterocyclic group containing, as a ring-constituting atom besides carbonatom, 1 to 4 heteroa toms selected from an oxygen atom, a Sulfur atom and a R4 nitrogen atom (e.g., imidazolyl, morpholinyl, pyridyl, tet rahydropyranyl, piperidinyl, tetrazolyl. 4.5-dihydro-1,2,4- 21 NN ses 25 oxadiazolyl, 1,2,4-triazolyl, 1.3,4-oxadiazolyl, 1.2.4-Oxa diazolyl, imidazolidinyl, hexahydropyrimidinyl, N N1 or 'N N1 pyrazolyl), said 5- or 6-membered heterocyclic group H H optionally has 1 to 3 substituents selected from (a) OXo, O O 30 (b) C. alkyl optionally having 1 to 3 hydroxy, (c) C-14 aryl. or a salt thereof. (d) carbamoyl, and Compound B-6 (e) Calkoxy-carbonyl, A compound represented by the formula (18) Calkoxy-carbonyl, or 35 (19) a group represented by the formula: —CO N(R)(R) wherein R and Rare each a hydrogen atom, C, alkyl or Coalkoxy, or R and R optionally form, together with the nitrogen atom es 40 bonded thereto, a 4- to 7-membered nonaromatic nitrogen N containing heterocycle containing, as a ring-constituting CH atom besides carbonatom, one nitrogen atom, and option H ally further containing 1 or 2 heteroatoms selected from an R S. N1 in R35 oxygen atom, a Sulfur atom and a nitrogen atom (e.g., N O 45 aZetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, 1,4-oxazepane), said 4- to 7-membered Rb2 nonaromatic nitrogen-containing heterocycle optionally has 1 to 3 substituents selected from, Rb1 (a) OXo, 50 (b) a halogen atom, (c) C. alkyl optionally having 1 to 3 Substituents selected wherein R' is C, alkyl optionally having 1 to 3 halogen from hydroxy and C alkoxy, atoms; (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, R’ is a hydrogenatom, alkoxy, R is 55 (e) C7-16 aralkyl (e.g., benzyl). (1) a hydrogen atom, (f) hydroxy, (2) cyano, (g) Coalkoxy, (3)C alkyl optionally having 1 to 3 Substituents selected (h) C-14 aryloxy (e.g., phenoxy), from (i) C7-6 aralkyloxy (e.g., benzyloxy), (a) hydroxy, 60 (i) C. alkyl-carbonyl, (b) C alkyl-carbonyloxy, (k) Caryl-carbonyl (e.g., benzoyl). (c) C. alkylthio, and (1) mono- or di-C alkylsulfamoyl, (d) Calkylsulfonyl, (m) C alkylsulfonyl, and (4) Co cycloalkyl (e.g., cyclohexyl) optionally having 1 to (n) a 5- or 6-membered heterocyclic group containing, as a 3 hydroxy, 65 ring-constituting atom besides carbon atom, 1 to 4 heteroat (5) C7-caralkylamino (e.g., phenethylamino) optionally hav oms selected from an oxygen atom, a Sulfur atom and a ing 1 to 3 hydroxy, nitrogen atom (e.g., pyridyl, thiazolyl); US 8,329,691 B2 63 64 R is bon atom, 1 to 4 heteroatoms selected from an oxygen (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, group containing, as a ring-constituting atom besides car oxazolyl pyridyl, tetrahydrofuryl), and optionally having bon atom, 1 to 4 heteroatoms selected from an oxygen 1 to 3 C alkyl, or atom, a Sulfur atom and a nitrogenatom (e.g., furyl, thienyl, (2) C alkyl optionally having 1 to 3 C alkoxy; and Oxazolyl pyridyl, tetrahydrofuryl), and optionally having R" is C. alkyl optionally having 1 to 3 halogen atoms, or a 1 to 3 C alkyl, or salt thereof. (2) C alkyl optionally having 1 to 3 C alkoxy; and Preferable examples of compound (C) are as described R" is C, alkyl optionally having 1 to 3 halogen atoms, or a below. salt thereof. 10 Compound C-1 Compound B-7 A compound represented by the formula (C) A compound represented by the formula wherein R' is C, alkyl; R is C, alkoxy or C. alkylthio; 15 Z is C. alkylene; ls ring Ac is a ring represented by the formula R4 R4 CH H 21 R S. N1 YR35 NN O N N1 O N N1 Rb2 H H 25 O O Rb1 wherein R is C, alkyl; and ring B is a ring represented by the formula wherein R' is C, alkyl optionally having 1 to 3 halogen 30 atoms; R’ is a hydrogen atom, R'' is a group represented by the formula:—CO N(R)(R) wherein R and Rare each a hydrogen atom, C, alkyl or -- Calkoxy, or 35 Rand Roptionally form, together with the nitrogen atom Rb2 bonded thereto, a 4- to 7-membered nonaromatic nitrogen containing heterocycle containing, as a ring-constituting atom besides carbon atom, one nitrogen atom, and option ally further containing 1 or 2 heteroatoms selected from an 40 Oxygen atom, a Sulfur atom and a nitrogen atom (e.g., wherein R'' and Rare each aZetidine, pyrrolidine, piperidine, piperazine, morpholine, (1) a hydrogen atom, thiomorpholine, 1,4-oxazepane), said 4- to 7-membered (2) C alkyl optionally having 1 to 3 hydroxy, nonaromatic nitrogen-containing heterocycle optionally (3)C alkoxy-carbonyl, or has 1 to 3 substituents selected from 45 (4) a group represented by the formula: —CO N(R)(R) (a) oXo, wherein Rand Rare each a hydrogenatom or C. alkyl, or (b) a halogen atom, Rand Roptionally form, together with the nitrogen atom (c) C. alkyl optionally having 1 to 3 Substituents selected bonded thereto, a 5- to 7-membered nonaromatic nitrogen from hydroxy and Calkoxy, containing heterocycle containing, as a ring-constituting (d) Caryl (e.g., phenyl) optionally having 1 to 3 C, 50 alkoxy, atom besides carbonatom, one nitrogen atom, and option (e) C7-6 aralkyl (e.g., benzyl). ally further containing 1 or 2 heteroatoms selected from an (f) hydroxy, oxygen atom, a Sulfur atom and a nitrogen atom (e.g., (g) Coalkoxy, pyrrolidine, piperidine, piperazine, morpholine, thiomor (h) C-14 aryloxy (e.g., phenoxy), 55 pholine), and optionally having 1 to 3 Substituents selected (i) C7 aralkyloxy (e.g., benzyloxy), from hydroxy and C alkyl, or a salt thereof. (i) C. alkyl-carbonyl, Examples of the salt of compound (1) (including com (k) Caryl-carbonyl (e.g., benzoyl), pound (A), compound (B) and compound (C), hereinafter the (1) mono- or di-C alkylsulfamoyl, same) include metal salts, ammonium salts, salts with organic (m) Co. alkylsulfonyl, and 60 bases, salts withinorganic acids, salts with organic acids, salts (n) a 5- or 6-membered heterocyclic group containing, as a with basic or acidic amino acids, and the like. ring-constituting atom besides carbon atom, 1 to 4 heteroat Preferable examples of the metal salt include alkali metal oms selected from an oxygen atom, a Sulfur atom and a salts such as Sodium salt, potassium salt and the like; alkaline nitrogen atom (e.g., pyridyl, thiazolyl); earth metal salts such as calcium salt, magnesium salt, barium R is 65 salt and the like, aluminum salt and the like. (1) a 5- or 6-membered aromatic or nonaromatic heterocyclic Preferable examples of the salt with organic base include a group containing, as a ring-constituting atom besides car salt with trimethylamine, triethylamine, pyridine, picoline, US 8,329,691 B2 65 66 2.6-lutidine, ethanolamine, diethanolamine, triethanolamine, -continued cyclohexylamine, dicyclohexylamine, N,N-dibenzylethyl enediamine or the like. Preferable examples of the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, Sulfuric acid, phosphoric acid or the like. Preferable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, (I) citric acid. Succinic acid, malic acid, methanesulfonic acid, 10 benzenesulfonic acid, p-toluenesulfonic acid or the like. Compound (I) can be produced by a condensation reaction Preferable examples of the salt with basic amino acid of compound (II) and compound (III). include a salt with arginine, lysine, ornithine or the like. Compound (II) can be produced by a method known perse, Preferable examples of the salt with acidic amino acid 15 for example, the method described in J. Med. Chem., 1993, include a salt with aspartic acid, glutamic acid or the like. vol. 36, pages 2676-2688 and the like, or a method analogous Of these, a pharmaceutically acceptable salt is preferable. thereto. When the compound has an acidic functional group, As compound (III), a commercially available product may examples thereof include inorganic salts such as alkali metal be used, or it can be produced by a method known perse, for salts (e.g., sodium salt, potassium salt, etc.), alkaline earth example, the method described in J. Am. Chem. Soc., 1948, metal salts (e.g., calcium salt, magnesium salt, barium salt, vol. 70, page 4009 and the like, or a method analogous etc.) and the like, ammonium salts, and the like. When the thereto. compound has a basic functional group, examples thereof When Q is a hydrogen atom, the condensation reaction is include salts with inorganic acids such as hydrochloric acid, performed according to a conventional peptide synthesis hydrobromic acid, nitric acid, Sulfuric acid, phosphoric acid 25 technique, for example, an acid chloride method, an acid and the like, and salts with organic acids such as acetic acid, anhydride method, a mixed anhydride method, a method of phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic using N,N'-dicyclohexylcarbodiimide (DCC), an active ester acid, citric acid. Succinic acid, methanesulfonic acid, p-tolu method, a method of using N,N'-carbonyldiimidazole (CDI), enesulfonic acid and the like. a method of using diethyl phosphorocyanidate (DEPC), a The production methods of compound (I) are shown in the 30 method of using N-ethyl-N'-(3-dimethylaminopropyl)carbo following. diimide hydrochloride (WSC.HCl) and 1-hydroxybenzotria Compound (I) is obtained by, for example, a method shown Zole (HOBt), or the like. Compound (III) is used in an amount in the following reaction scheme or a method analogous of about 1 to 2 mol, is preferably about 1.0 to 1.1 mol, per 1 thereto, or the like. 35 mol of compound (II). The reagent for the aforementioned Each of compounds (II)-(LI) shown in the reaction scheme methods is used in an amount of about 1 molto a large excess, may form a salt. Examples of the salt include salts similar to preferably about 1.1 to 5 mol, per 1 mol of compound (II). The the salts of compound (I). reaction temperature is generally -10° C. to 80°C., prefer The compound obtained in each step can also be used for ably 0° C. to 30° C. the next reaction directly as the reaction mixture or as a crude 40 When Q is an alkali metal atom, the condensation reaction product. In addition, it can also be isolated from the reaction is advantageously performed according to a method using mixture according to a conventional method, and can be WSC.HCl and HOBt. Compound (III) is used in an amount of isolated and purified by a known method such as phase trans about 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of fer, concentration, solvent extraction, fractional distillation, compound (II). WSC.HCl is used in an amount of about 1 to pH conversion, crystallization, recrystallization, chromatog 45 4 mol, preferably about 1.5 to 2.5 mol, per 1 mol of compound (II). HOBt is used in an amount of about 1 to 8 mol, preferably raphy and the like. about 2.5 to 5.0 mol, per 1 mol of compound (II). The reaction The schematic drawings of the reaction scheme are shown temperature is generally -10°C. to 100°C., preferably 40°C. in the following. to 70° C. Each symbol of the compounds in the schemes is as defined 50 In all cases, the condensation reaction is preferably per above. R is Calkyl, Q is a hydrogenatom oran alkali metal formed in a solvent. Examples of the solvent to be used atom, LG is a leaving group (e.g., chloro group, bromo group. include halogenated hydrocarbons such as dichloromethane, iodo group etc.), and PG is an N-protecting group (e.g., ben chloroform, carbon tetrachloride, 1,2-dichloroethane and the Zyl, tert-butoxycarbonyl, benzyloxycarbonyl etc.). Ring Bb is like, ethers such as diethyl ether, tetrahydrofuran, dioxane a nitrogen-containing 5- to 7-membered ring optionally hav 55 and the like, amides such as N,N-dimethylformamide, N.N- ing Substituent(s). dimethylacetamide and the like, dimethyl sulfoxide, pyri dine, acetonitrile and a mixed solvent thereof. While the reaction time varies depending on the reagent and solvent to be used, it is generally 30 min to 3 days, 60 preferably 30 minto 15 hr. Compound (I) can also be produced by performing, when condensation desired in addition to the above-mentioned reaction, known hydrolysis reaction, acylation reaction, alkylation reaction, amination reaction, oxidation-reduction reaction, cyclization 65 reaction, carbon chain extension reaction, Substituent exchange reaction and the like, each singly or in combination of multiple operations. US 8,329,691 B2 67 68 When compound (I) is obtained as a free compound, it can example, the method described in Bioorg. Med. Chem. Lett. be converted to an object salt by a method known perse or a 2004, vol. 14, pages 2543-2546 and the like, or a method method analogous thereto. When compound (I) is obtained as analogous thereto. a salt, it can be converted to a free form or other object salt by Compound (VI) can be produced according to a method a method known perse or a method analogous thereto. known per se, for example, the method described in J. Med. Chem., 1993, Vol. 36, pages 2676-2688 and the like, or a method analogous thereto. Reaction 2 This reaction is more advantageously performed in the presence of a base. As the base in this step, tertiary amine Such 10 as triethylamine, diisopropylethylamine and the like, or an CH inorganic base Such as sodium hydrogen carbonate, potas LG + H.N1 SR3a - sium hydrogen carbonate and the like is preferable. The R (V) amount of the base to be used is about 1 mol to a large excess, No O preferably 1 to 5 mol, per 1 mol of compound (IV). (IV) 15 This reaction is advantageously performed using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, for example, solvents 1's hydrolysis Such as alcohols (e.g., 2-propanol and the like), highly polar H solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide R and the like), hydrocarbons (e.g., benzene, toluene, cyclohex No O ane, hexane and the like), ethers (e.g., diethyl ether, tetrahy (VI) drofuran, dioxane and the like) and the like, a mixed solvent Rg thereof and the like are preferable. YNH While the reaction time varies depending on the reagent 25 and solvent to be used, it is generally 30 minto 48 hr, pref ( pi )m erably 30 minto 15 hr. B The reaction temperature is generally 0° C. to 200° C., N preferably 20° C. to 120° C. N -CH2.R3a PG1 Compound (VII) can be produced by a known hydrolysis, H (VIII) Her 30 for example, alkaline hydrolysis or acid hydrolysis to com Qa condensation pound (VI). O O The reaction is more advantageously performed under (VII) alkali conditions. As the alkali in this step, alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, O) N1 CH2 Y R3a deprotec 35 potassium hydroxide and the like is preferable. The amount of H tion the alkali to be used is about 1 mol to a large excess, prefer R ably 1 to 5 mol, per 1 mol of compound (VI). NN O This reaction is advantageously performed using a solvent inert to the reaction. While the solvent is not particularly 40 limited as long as the reaction proceeds, for example, solvents ( pi )m B Such as alcohols (e.g., methanol, ethanol, propanol and the N like), hydrocarbons (e.g., benzene, toluene, cyclohexane, PG1 hexane and the like), halogenated hydrocarbons (e.g., dichlo (IX) romethane, chloroform, carbon tetrachloride, 1,2-dichloroet 45 hane and the like), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane and the like) and the like, a mixed solvent thereofand the like are preferable. While the reaction time varies depending on the reagent and solvent to be used, it is generally 30 minto 24 hr, pref 50 erably 30 minto 8 hr. The reaction temperature is generally 0° C. to 150° C., preferably 20° C. to 80° C. After the reaction, the reaction mixture is neutralized by the addition of a mineral acid (e.g., hydrochloric acid, Sulfuric (A) 55 acid etc.), an organic acid (e.g., acetic acid etc.) or an ion exchange resin to give carboxylic acid (VII) in a free form (in this case, Q is hydrogen atom). Moreover, the reaction mix Compound (VI) can be produced by reacting compound ture may be directly concentrated to give compound (VII) as (IV) with compound (V). an alkali metal salt of carboxylic acid (in this case, Q is alkali As compound (IV), a commercially available product may 60 metal atom such as lithium, sodium, potassium and the like). Compound (IX) can be produced by a condensation reac be used, or it can be produced by a method known perse, for tion of compound (VII) and compound (VIII). example, the method described in Bioorg. Med. Chem. Lett. As compound (VIII), a commercially available product 2000, vol. 10, pages 1645-1648 and the like, or a method may be used, or it can be produced by a method known perse, analogous thereto. 65 for example, the method described in Bioorg. Med. Chem. As compound (V), a commercially available product may Lett., 2005, vol. 15, pages 833-838, or EP1757582 and the be used, or it can be produced by a method known perse, for like, or a method analogous thereto. US 8,329,691 B2 69 70 When Q is a hydrogen atom, the condensation reaction is phenyl group, a halogen atom, a C- alkyl-carbonyl group, a performed according to a conventional peptide synthesis Calkoxy group optionally substituted by halogen atom(s) technique, for example, an acid chloride method, an acid (e.g., methoxy, ethoxy, trifluoromethoxy and the like), a nitro anhydride method, a mixed anhydride method, a method group and the like can be used. The number of the substi using N,N'-dicyclohexylcarbodiimide (DCC), an active ester tuent(s) is 1 to 3. method, a method using N,N'-carbonyldiimidazole (CDI), a method using diethyl phosphorocyanidate (DEPC), a method Examples of the carboxyl-protecting group include a C using N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide alkyl group, an allyl group, a benzyl group, a phenyl group, a hydrochloride (WSC.HCl) and 1-hydroxybenzotriazole trityl group, a trialkylsilyl group, each optionally having Sub (HOBt) and the like. Compound (VIII) is used in an amount 10 stituent(s), and the like. As the Substituent(s), for example, a of about 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol halogenatom, a formyl group, a C- alkyl-carbonyl group, a of compound (VII). The reagent to be used in the above Calkoxy group optionally Substituted by halogen atom(s) mentioned method is used in an amount of about 1 mol to a (e.g., methoxy, ethoxy, trifluoromethoxy and the like), a nitro large excess, preferably about 1.1 to 5 mol, per 1 mol of group and the like can be used. The number of the substi compound (VII). The reaction temperature is generally -10° 15 tuent(s) is 1 to 3. C. to 80° C., preferably 0° C. to 30° C. Examples of the hydroxy-protecting group include a C When Q is an alkali metal atom, the condensation reaction alkyl group, a C-2 aralkyl group (e.g., benzyl, trity1 and the is advantageously performed by a method using WSC.HCl like), a formyl group, a C- alkyl-carbonyl group, a benzoyl and HOBt. Compound (VIII) is used in an amount of about 1 group, a Cz-o aralkyl-carbonyl group (e.g., benzylcarbonyl to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of compound (VII). WSC.HCl is used in an amount of about 1 to and the like), a 2-tetrahydropyranyl group, a tetrahydrofura 4 mol, preferably about 1.5 to 2.5 mol, per 1 mol of compound nyl group, a trialkylsilyl group (e.g., trimethylsilyl, tert-bu (VII). HOBt is used in an amount of about 1 to 8 mol, pref tyldimethylsilyl, diisopropylethylsilyl and the like), each erably about 2.5 to 5.0 mol, per 1 mol of compound (VII). The optionally having Substituent(s), and the like. As the Substitu reaction temperature is generally -10°C. to 100° C., prefer 25 ent(s), for example, a halogen atom, a C- alkyl group, a ably 40° C. to 70° C. phenyl group, a C-caralkyl group (e.g., benzyl and the like), In all cases, the condensation reaction is preferably per a C alkoxy group, a nitro group and the like can be used. formed in a solvent. Examples of the solvent to be used The number of the substituent(s) is 1 to 4. include the above-mentioned halogenated hydrocarbons, the When compound (A) is obtained as a free compound, it can above-mentioned ethers, amides such as N,N-dimethylfor 30 be converted to an object salt by a method known perse or a mamide, N,N-dimethylacetamide, N-methylpyrrolidone and method analogous thereto. When compound (A) is obtained the like, dimethyl sulfoxide, pyridine, acetonitrile and a mixed solvent thereof. as a salt, it can be converted to a free compound or other object While the reaction time varies depending on the reagent salt by a method known perse or a method analogous thereto. and solvent to be used, it is generally 30 min to 3 days, 35 preferably 30 min to 15 hr. Compound (IX) can also be produced by performing, when (Reaction 3) desired in addition to the above-mentioned reaction, known N21N hydrolysis reaction, acylation reaction, alkylation reaction, Aa amination reaction, oxidation-reduction reaction, cyclization 40 He reaction, carbon chain extension reaction, Substituent N O exchange reaction and the like, each singly or in combination R of multiple operations. No O Compound (A) can be produced by removing the N-pro (X) tecting group PG of compound (IX). In addition, in each of 45 the aforementioned reactions, when the starting compound has an amino group, a carboxyl group or a hydroxyl group as a Substituent, a protecting group generally used in peptide chemistry and the like may be introduced into these groups. 50 4N CH By removing the protecting group as necessary after the reac A 1-12 tion, the objective compound can be obtained. Introduction or 8. HN R3a removal of these protective groups may be performed accord N LG (V) ing to a method known per se, for example, the method disclosed in Theodora W. Greene and Peter G. M. Wuts, R “Protective Groups in Organic Synthesis, 3rd Ed., Wiley 55 No O Interscience (1999), or the like. (XI) Examples of the amino-protecting group include a formyl group; a C- alkyl-carbonyl group, a phenylcarbonyl group, a C alkoxy-carbonyl group, an allyloxycarbonyl (Alloc) group, a phenyloxycarbonyl group, a fluorenylmethyloxycar 60 4N bonyl (Fmoc) group, a Cz aralkyl-carbonyl group (e.g., Aa benzylcarbonyl and the like), a Cz-o aralkyloxy-carbonyl N N1 CH in R3a hydrolysisnyarolysis group (e.g., benzyloxycarbonyl (Cbz) and the like), a C H aralkyl group (e.g., benzyl and the like), a trityl group, a R phthaloyl group, a dithiasuccinoyl group, a N,N-dimethy 65 No O laminomethylene group, each optionally having Substi tuent(s), and the like. As the Substituent(s), for example, a US 8,329,691 B2 72 -continued The reaction temperature is generally 0° C. to 150° C., R1 preferably 20° C. to 130° C. n NH Compound (XII) can be produced by reacting compound (XI) with compound (V). ( pi )m As compound (V), a commercially available product may an N B be used, or it can be produced by a method known perse, for Aa PG1 N example, the method described in Bioorg. Med. Chem. Lett. N N -CH2 NR3a (VIII) 2004, vol. 14, pages 2543-2546 and the like, or a method --- analogous thereto. H condensation 10 Q Compound (XII) can be produced by a method known per No O se, for example, the method described in J. Med. Chem. (XIII) 1993, Vol. 36, pages 2676-2688 and the like, or a method 4.Y. analogous thereto. Aa 15 This reaction is more advantageously performed in the N N1 CH2n R3a deprotect presence of a base. As the base in this step, tertiary amine Such H tion as triethylamine, diisopropylethylamine and the like, or an R la inorganic base Such as sodium hydrogen carbonate, potas n N O sium hydrogen carbonate and the like is preferable. The amount of the base to be used is about 1 mol to a large excess, ( pi )m preferably 1 to 5 mol, per 1 mol of compound (XI). B This reaction is advantageously performed using a solvent PG1 N inert to the reaction. While the solvent is not particularly (XIV) limited as long as the reaction proceeds, for example, solvents 4N 25 Such as alcohols (e.g., 2-propanol and the like), amides (e.g., Aa N,N-dimethylformamide, N,N-dimethylacetamide, N-meth CH ylpyrrolidone and the like), hydrocarbons (e.g., benzene, N N 1-2 R3a toluene, cyclohexane, hexane and the like), ethers (e.g., H diethyl ether, tetrahydrofuran, dioxane and the like), dimethyl R1a 30 n N sulfoxide and the like, a mixed solvent thereof and the like are O preferable. While the reaction time varies depending on the reagent ( pi )m B and solvent to be used, it is generally 30 minto 48 hr, pref HN erably 30 minto 15 hr. 35 The reaction temperature is generally 0° C. to 200° C., (A) preferably 20° C. to 120° C. Compound (XIII) can be produced by known hydrolysis, This method is used for the production of compound (A) for example, alkaline hydrolysis or acid hydrolysis to com wherein ring Aa is a pyrimidine ring. 40 pound (XII). As compound (X), a commercially available product may The reaction is more advantageously performed under the be used, or it can be produced by a method known perse, for alkaline conditions. As the alkali in this step, alkali metal example, the method described in J. Med. Chem., 2000, Vol. hydroxide such as lithium hydroxide, sodium hydroxide, 43, pages 3995-4004 and the like, or a method analogous potassium hydroxide and the like is preferable. The amount of thereto. 45 the alkali to be used is about 1 mol to a large excess, prefer As compound (XI) having a Substitutable leaving group ably 1 to 5 mol, per 1 mol of compound (XII). LG, a commercially available product may be used, or it can be produced using compound (X) as a starting material by a This reaction is advantageously performed using a solvent method known per se, for example, the method described in inert to the reaction. While the solvent is not particularly Bioorg. Med. Chem. Lett., 2000, Vol. 10, pages 1645-1648 limited as long as the reaction proceeds, for example, solvents and the like, or a method analogous thereto. Preferable 50 Such as alcohols (e.g., methanol, ethanol, propanol and the examples of the reagent in the step include phosphorus oxy like), hydrocarbons (e.g., benzene, toluene, cyclohexane, chloride, phosphorus oxybromide, thionyl chloride and the hexane and the like), halogenated hydrocarbons (e.g., dichlo like. romethane, chloroform, carbon tetrachloride, 1,2-dichloroet The amount of the reagent to be used is about 1 mol to a hane and the like), ethers (e.g., diethyl ether, tetrahydrofuran, large excess, per 1 mol of compound (X). 55 dioxane and the like) and the like, a mixed solvent thereofand This reaction is advantageously performed using a solvent the like are preferable. inert to the reaction or without solvent. While the solvent is While the reaction time varies depending on the reagent not particularly limited as long as the reaction proceeds, for and solvent to be used, it is generally 30 minto 24 hr, pref example, solvents such as hydrocarbons (e.g., benzene, tolu erably 30 minto 8 hr. ene, cyclohexane, hexane and the like), halogenated hydro 60 The reaction temperature is generally 0° C. to 150° C., carbons (e.g., dichloromethane, chloroform, carbon tetra preferably 20° C. to 80° C. chloride, 1,2-dichloroethane and the like), ethers (e.g., After the reaction, the reaction mixture is neutralized by diethyl ether, tetrahydrofuran, dioxane and the like) and the the addition of a mineral acid (e.g., hydrochloric acid, Sulfuric like, a mixed solvent thereof and the like are preferable. acid etc.), an organic acid (e.g., acetic acid etc.) or an ion While the reaction time varies depending on the reagent to 65 exchange resin to give carboxylic acid (XIII) in a free form (in be used, it is generally 30 minto 24 hr, preferably 30 minto this case, Q is a hydrogen atom). Moreover, the reaction 8 hr. mixture may be directly concentrated to give compound US 8,329,691 B2 73 74 (XIII) as an alkali metal salt of carboxylic acid (in this case, Q Examples of the amino-protecting group include a formyl is an alkali metal atom Such as lithium, Sodium, potassium group; a C- alkyl-carbonyl group, a phenylcarbonyl group, and the like). a C- alkoxy-carbonyl group, an allyloxycarbonyl (Alloc) Compound (XIV) can be produced by a condensation reac group, a phenyloxycarbonyl group, a fluorenylmethyloxycar tion of compound (XIII) and compound (VIII). bonyl (Fmoc) group, a Cz aralkyl-carbonyl group (e.g., As compound (VIII), a commercially available product benzylcarbonyl etc.), a C-caralkyloxy-carbonyl group (e.g., may be used, or it can be produced by a method known perse, benzyloxycarbonyl (Cbz) etc.), a C- aralkyl group (e.g., for example, the method described in Bioorg. Med. Chem. benzyl etc.), a trityl group, a phthaloyl group, a dithiasucci Lett., 2005, vol. 15, pages 833-838, or EP1757582 and the noyl group, a N,N-dimethylaminomethylene group, each of like, or a method analogous thereto. 10 which optionally having Substituent(s), and the like. Here, as When Q is a hydrogen atom, the condensation reaction is the substituent(s), a phenyl group, a halogen atom, a C performed by a conventional peptide synthesis technique, for alkyl-carbonyl group, a C- alkoxy group optionally Substi example, an acid chloride method, an acid anhydride method, tuted by halogen atom(s) (e.g., methoxy, ethoxy, trifluo a mixed anhydride method, a method using N,N'-dicyclo 15 romethoxy etc.), a nitro group and the like can be used. The hexylcarbodiimide (DCC), an active ester method, a method number of the substituent(s) is 1 to 3. using N,N'-carbonyldiimidazole (CDI), a method using Examples of the carboxyl-protecting group include a C diethyl phosphorocyanidate (DEPC), a method using alkyl group, an allyl group, a benzyl group, a phenyl group, a N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydro trityl group, a trialkylsilyl group each of which optionally chloride (WSC.HCl) and 1-hydroxybenzotriazole (HOBt) having Substituent(s), and the like. Here, as the Substituent(s), and the like. Compound (VIII) is used in an amount of about a halogen atom, a formyl group, a C- alkyl-carbonyl group, 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of a Calkoxy group optionally Substituted by halogenatom(s) compound (XIII). The reagent to be used in the above-men (e.g., methoxy, ethoxy, trifluoromethoxy etc.), a nitro group tioned method is used in an amount of about 1 mol to a large and the like can be used. The number of the substituent(s) is excess, preferably about 1.1 to 5 mol, per 1 mol of compound 25 1 to 3. (XIII). The reaction temperature is generally -10°C. to 80° Examples of the hydroxy-protecting group include a C C., preferably 0°C. to 30° C. alkyl group, a C7-20 aralkyl group (e.g., benzyl, trityl etc.), a When Q is an alkali metal atom, the condensation reaction formyl group, a C- alkyl-carbonyl group, a benzoyl group, a is advantageously performed by a method using WSC.HCl C, o aralkyl-carbonyl group (e.g., benzylcarbonyl etc.), a and HOBt. Compound (VIII) is used in an amount of about 1 30 2-tetrahydropyranyl group, a tetrahydrofuranyl group, a tri to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of alkylsilyl group (e.g., trimethylsilyl, tert-butyldimethylsilyl, compound (XIII). WSC.HCl is used in an amount of about 1 to 4 mol, preferably about 1.5 to 2.5 mol, per 1 mol of diisopropylethylsilyl etc.), each of which optionally having compound (XIII). HOBt is used in an amount of about 1 to 8 substituent(s), and the like. Here, as the substituent(s), a halo mol, preferably about 2.5 to 5.0 mol, per 1 mol of compound 35 gen atom, a C- alkyl group, a phenyl group, a C7-oaralkyl (XIII). The reaction temperature is generally -10°C. to 100° group (e.g., benzyl etc.), a C- alkoxy group, a nitro group C., preferably 40°C., to 70° C. and the like can be used. The number of the substituent(s) is In all cases, the condensation reaction is preferably per 1 to 4. formed in a solvent. Examples of the solvent to be used When compound (A) is obtained as a free compound, it can include the above-mentioned halogenated hydrocarbons, the 40 be converted to an object salt by a method known perse or a above-mentioned ethers, amides such as N,N-dimethylfor method analogous thereto. When compound (A) is obtained mamide, N,N-dimethylacetamide, N-methylpyrrolidone and as a salt, it can be converted to a free form or other object salt the like, dimethyl sulfoxide, pyridine, acetonitrile and a by a method known perse or a method analogous thereto. mixed solvent thereof. While the reaction time varies depending on the reagent 45 and solvent to be used, it is generally 30 min to 3 days, (Reaction 4) preferably 30 min to 15 hr. R R Compound (XIV) can also be produced by performing, when desired in addition to the above-mentioned reaction, O O O O known hydrolysis reaction, acylation reaction, alkylation 50 He- -- reaction, amination reaction, oxidation-reduction reaction, N cyclization reaction, carbon chain extension reaction, Sub B stituent exchange reaction and the like, each singly or in N O N O combination of multiple operations. 2 NR PG1 NR Compound (A) is produced by removing the N-protecting 55 group PG of compound (XIV). Moreover, when the starting O O material compound has an amino group, a carboxyl group or (XV) (XVI) a hydroxyl group as a Substituent in each of the above-men O OH O OH tioned reactions, these groups are optionally protected by a protecting group generally used in the peptide chemistry and 60 -- the like. In this case, the object compound can be obtained by removing the protecting group as necessary after the reaction. B B These protecting groups can be introduced or removed by a po1 n po1 "S method known per se, for example, the method described in Theodora W. Greene and Peter G. M. Wuts, “Protective 65 O O Groups in Organic Synthesis, 3" Ed”, Wiley-Interscience (XVII) (XVIII) (1999) and the like. US 8,329,691 B2 76 -continued hydrocarbons such as benzene, toluene, cyclohexane, hexane O OH and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like, esters such as ethyl acetate and the like, highly polar solvent such as N,N-dimethylformamide, N-me He thylpyrrolidone and the like, a mixed solvent thereof and the B N O like are preferable. PG1 NR While the reaction time varies depending on the reagent O and solvent to be used, it is generally 30 minto 60 hr, pref (XVII) or (XVIII) 10 erably 30 minto 30 hr. NH2 The reaction temperature is generally 0° C. to 150° C., preferably 20° C. to 70° C. reductive B alkylation After the reduction reaction, the reaction mixture is neu N O 15 tralized by the addition of an inorganic base (e.g., Sodium PG1 n R hydroxide, potassium carbonate etc.), an organic base (e.g., triethylamine etc.) and the like and the reaction mixture is O directly concentrated, or the reaction mixture is directly con (XIX) centrated and the concentrate is neutralized by the addition of R1 an inorganic base (e.g., Sodium hydroxide, potassium carbon n NH ate etc.), an organic base (e.g., triethylamine etc.) and the like, and then a protecting group (PG group) is introduced, whereby compounds (XVI), (XVII) and (XVIII) can be B respectively produced. The protecting group (PG group) may N O PG1 n R 25 be introduced by a method known per se, for example, the method described in Theodora W. Greene and Peter G. M. Wuts, “Protective Groups in Organic Synthesis, 3" Ed”, (XX) Wiley-Interscience (1999) and the like. Compound (XVII) can be separated from a mixture of This method is used for the production of a compound 30 compounds (XVI), (XVII) and (XVIII) by a known purifica wherein compound (VIII) has a structure shown by com tion method, for example, silica gel column chromatography, pound (XX). recrystallization, high pressure liquid chromatography and Compound (XV) can be produced by a method known per the like. se, for example, U.S. Pat. No. 6,018,046 and the like, or a 35 Compound (XVII) can also be produced by a method method analogous thereto. known per se, for example, the method described in WO97/ Compounds (XVI), (XVII) and (XVIII) can be each pro 18813 and the like, or a method analogous thereto. duced by Subjecting compound (XV) to a known reduction Compound (XIX) is produced by a rearrangement reaction reaction, for example, catalytic hydrogen reduction reaction (e.g., Curtius rearrangement and the like) of compound in the presence of a metal catalyst and the like, and Succes 40 sively introducing the PG group (protecting group) by a (XVII) or compound (XVIII). known reaction. Compound (XIX) can be produced by a method known per The catalytic hydrogen reduction reaction and the Subse se, for example, the method described in U.S. Pat. No. 5,817, quent introduction of the protecting group (PG group) can be 678 and the like, or a method analogous thereto. performed by a known method, for example, the method 45 Compound (XX) can be produced by a reaction to intro described in Tetrahedron Lett., 1994, Vol. 35, pages 4515 4518, or Tetrahedron: Asymmetry., 2003, vol. 14, pages duce Substituent R' into the amino group of compound 1541-1545, or Tetrahedron Lett., 2003, Vol. 44, pages 1611 (XIX) (e.g., reductive alkylation). 1614 and the like, or a method analogous thereto. Compound (XX) can be produced by a known method, for The catalytic hydrogen reduction reaction is more advan 50 example, Bioorg. Med. Chem. Lett., 2005, Vol. 15, pages tageously performed under the acidic conditions. As the acid 833-838, or a method analogus thereto. in this step, a mineral acid such as hydrochloric acid and the like, an organic acid such as acetic acid etc., and the like are preferable. The amount of the acid to be used is about 1 mol to a large excess, per 1 mol of compound (XV). 55 As the metal catalyst to be used in the catalytic hydrogen (Reaction 5) reduction reaction, for example, rhodium carbon, platinum oxide, palladium-carbon, rhodium-platinum oxide alloy and R4 the like are preferable. The amount of the catalyst to be used CH2 is about 0.01 g to 1 g, preferably about 0.05 g to 0.3 g, per 1 60 Y als, HN1 NR 35 g of compound (XV). | Ab (XXII) X n The catalytic hydrogen reduction reaction is advanta LG geously performed using a solventinert to the reaction. While R the solvent is not particularly limited as long as the reaction No O proceeds, for example, organic acids such as acetic acid and 65 the like, mineral acids such as hydrochloric acid and the like, (XXI) alcohols such as methanol, ethanol, propanol and the like, US 8,329,691 B2 78 -continued Compound (XXIV) can be produced by a known method, R4 for example, the method described in Heterocycles, 1994, vol. 38, pages 529-540 and the like, or a method analogous als thereto. Y Ab N hydrolysis X CH N N 1-2 R3b H (Reaction 7) R No O R4 (XXIII) 10 1. RI condensa R4 Y Ab N -- n H - " - X CH 1. N Sa N1 2n R3b R2b Ab H (XXVI) X CH 15 Q N N 1-2 R3b No O H (XXIV) Q No O R4 (XXIV) als N Ab X CH Compound (XXIII) can be produced by reacting com S. N 1-2 R3b pound (XXI) with compound (XXII). H R Compound (XXIII) can be produced under the conditions 25 similar to those used for the production of compound (VI) and O according to a method known perse, for example, the method R2b described in J. Med. Chem., 1993, vol. 36, pages 2676-2688 (B) and the like, or a method analogous thereto. Compound (XXIV) can be produced by subjecting com 30 pound (XXIII) to known hydrolysis, for example, alkaline Compound (B) can be produced by a condensation reaction hydrolysis or acid hydrolysis. of compound (XXIV) with compound (XXVI). Compound (XXIV) can be produced under the conditions As compound (XXVI), a commercially available product may be used, or it can be produced by a method known perse, similar to those used for the production of compound (XIII) 35 and by performing known hydrolysis, for example, alkaline for example, the method described in J. Am. Chem. Soc., hydrolysis or acid hydrolysis. 1948, vol. 70, page 4009 and the like, or a method analogous thereto. The condensation reaction can be performed by a method (Reaction 6) 40 according to the conditions used in compound (I). R4 Compound (B) can also be produced by performing, when 1-2CH desired in addition to the above-mentioned reaction, known 1.21 NN HN2 R3b hydrolysis reaction, acylation reaction, alkylation reaction,

| Ab He(XXII) amination reaction, oxidation-reduction reaction, cyclization X n 45 reaction, carbon chain extension reaction, Substituent LG exchange reaction and the like, each singly or in combination H of multiple operations. No O When compound (B) is obtained as a free compound, it can (XXV) 50 be converted to an object salt by a method known perse or a R4 method analogous thereto. When compound (B) is obtained als N as a salt, it can be converted to a free form or other object salt Ab by a method known perse or a method analogous thereto. X CH N N 1-12 R3b 55 H (Reaction 8) Q No O R4 (XXIV) 60 1. Ab NH hydrolysis He Compound (XXIV) can be produced by reacting com X pound (XXV) with compound (XXII). N O As compound (XXV), a commercially available product R may be used, or it can be produced by a method known perse, 65 No O for example, the method described in U.S. Pat. No. 3,928,366 (XXVII) and the like, or a method analogous thereto. US 8,329,691 B2

-continued R (Reaction 9) n NH R4 O OH 5 optical resolution y1 YNH (XXVI) - He Ab condensa X tion B N O PG1 N O NR Q 10 No O O (XXVIII) (XVII) O OH O N1 OH R4 CH 15 -- s 1. HN1 "YR35 B B NH (XXII) N O N '' O X N O PG1 n R PG1 r a. R O O R O (XXX) (XXXI) O OH R2b (XXIX) 25 B R4 PG1 N O NR

N O Ab 30 X CH (XXX) N N 1-2 R3b NH H R reductive O B alkylationky 35 R2b N O PG1 n R (B) O (XXXII) Compound (XXVIII) can be produced by subjecting com 40 Rig pound (XXVII) to known hydrolysis, for example, alkaline n NH hydrolysis or acid hydrolysis. For example, the reaction can be performed by a method according to hydrolysis conditions similar to those employed for compound (VI). B Compound (XXIX) can be produced by a condensation 45 N O reaction of compound (XXVIII) with compound (XXVI). For PG1 NR example, the reaction can be performed by a method accord O ing to conditions similar to those employed for the production (XXXIII) of compound (I). Compound (B) can be produced by reacting compound 50 (XXIX) with (XXII) according to the method described in This method is used for the production of a compound Org. Lett., 2006, vol. 11, pages 2425-2428 and the like, or a wherein compound (VIII) has a structure shown by com method analogous thereto. pound (XXXIII). Compound (B) can also be produced by performing, when 55 Compound (XXX) can be separated from compound desired in addition to the above-mentioned reaction, known (XVII), which is a mixture of compounds (XXX) and hydrolysis reaction, acylation reaction, alkylation reaction, (XXXI), according to a known purification method, for amination reaction, oxidation-reduction reaction, cyclization example, diastereomeric salt method, optically active column reaction, carbon chain extension reaction, Substituent chromatography and the like. exchange reaction and the like, each singly or in combination 60 Compound (XXX) can also be produced by a method of multiple operations. known perse, for example, the method described in Tetrahe When compound (B) is obtained as a free compound, it can dron Lett., 2003, Vol. 44, pages 1611-1614 and the like, or a be converted to an object salt by a method known perse or a method analogous thereto. method analogous thereto. When compound (B) is obtained 65 Compound (XXXII) is produced by a rearrangement reac as a salt, it can be converted to a free form or other object salt tion (e.g., Curtius rearrangement and the like) of compound by a method known perse or a method analogous thereto. (XXX). US 8,329,691 B2 81 82 Compound (XXXII) can be produced by a known method, -continued for example, the method described in Tetrahedron Lett., 2003, Vol. 44, pages 1611-1614 and the like, or a method analogous thereto. N. Compound (XXXIII) can be produced by a reaction to introduce substituent R' into the amino group of compound (XXXII) (e.g., reductive alkylation). Compound (XXXIII) can be produced by a known method, for example, Bioorg. Med. Chem. Lett., 2005, Vol. 15, pages 10 833-838, or a method analogous thereto. (A) (Reaction 10) N21SN N21NN 15 This method is used for the production of compound (A) Aa Aa wherein ring Aa is a pyrimidine ring. N O hydrolysis N O Compound (XXXIV) can be produced by subjecting com pound (X) to known hydrolysis, for example, alkaline R Q hydrolysis or acid hydrolysis. For example, the reaction can No O No O be performed by a method according to hydrolysis conditions (X) (XXXIV) similar to those employed for hydrolysis of compound (XII). Compound (XXXV) having a substitutable leaving group LG can be produced by using compound (XXXIV) as a start Rile 25 ing material and according to a method known per se, for YNH example, the method described in J. Med. Chem., 2000, Vol. 43, pages 3995-4004 and the like, or a method analogous thereto. As the reagent in this step, phosphorus oxychloride, ( pi )m B phosphorus oxybromide, thionyl chloride and the like are 4N -N 30 preferable. Aa PG The amount of the reagent to be used is about 1 mol to a N - YVIII) - large excess, per 1 mol of compound (XXXIV). LG condensa tion This reaction is advantageously performed using a solvent inert to the reaction or without solvent. While the solvent is 35 LG O not particularly limited as long as the reaction proceeds, for (XXXV) example, Solvents such as hydrocarbons (e.g., benzene, tolu ene, cyclohexane, hexane and the like), halogenated hydro carbons (e.g., dichloromethane, chloroform, carbon tetra 40 chloride, 1,2-dichloroethane and the like), ethers (e.g., 4\ diethyl ether, tetrahydrofuran, dioxane and the like) and the Aa like, a mixed solvent thereof and the like are preferable. S LG -CH2 While the reaction time varies depending on the reagent to la HN R3a be used, it is generally 30 minto 24 hr, preferably 30 minto R n N O (V)V 45 8 hr. The reaction temperature is generally 0° C. to 150° C., preferably 20° C. to 130° C. ( pi m B Compound (XXXVI) can be produced by a condensation N reaction of compound (XXXV) with compound (VIII). For PG1 50 example, the reaction can be performed by a method accord (XXXVI) ing to conditions similar to those employed for the production of compound (IX). Compound (XIV) can be produced by reacting compound (XXXVI) with compound (V) and by a method according to 4N 55 conditions similar to those employed for the production of Aa compound (XII). N -CH2 3a deprotec N R tion Compound (A) is produced by removing the N-protecting R1 group PG of compound (XIV). Moreover, when the starting NN O 60 material compound has an amino group, a carboxyl group or a hydroxyl group as a Substituent in each of the above-men tioned reactions, these groups are optionally protected by a ( pi )m B protecting group generally used in the peptide chemistry and N the like. In this case, the object compound can be obtained by PG1 65 removing the protecting group as necessary after the reaction. (XIV) These protecting groups can be introduced or removed by a method known per se, for example, the method described in US 8,329,691 B2 83 84 Theodora W. Greene and Peter G. M. Wuts, “Protective Groups in Organic Synthesis, 3" Ed”, Wiley-Interscience -continued (1999) and the like. When compound (A) is obtained as a free compound, it can be converted to an object salt by a method known perse or a method analogous thereto. When compound (A) is obtained as a salt, it can be converted to a free form or other object salt by a method known perse or a method analogous thereto. 10

(Reaction 11) R4 15 (B) 1.Ab CH X n -- HN1 ns. -- LG This method is used for the production of compound (B) (XXXVIII) wherein R’ is a nitrogen-containing 5- to 7-membered ring R optionally having Substituent(s). No O Compound (XXXIX) can be produced by reacting com (XXXVII) pound (XXXVII) with compound (XXXVIII) and by a method according to conditions similar to those employed for the production of compound (VI). 25 R4 As compound (XXXVII), a commercially available prod uct may be used, or it can be produced by a method known per ves, se, for example, the method described in Bioorg. Med. Chem. Lett., 2000, vol. 10, pages 1645-1648 and the like, or a X| NAb -CH2 hydrolysis N NR35 30 method analogous thereto. H As compound (XXXVIII), a commercially available prod R No O uct may be used, or it can be produced by a method known per se, for example, the method described in J. Org. Chem., 1970, (XXXIX) Vol. 35, pages 340-344 and the like, or a method analogous 35 thereto. Compound (XL) can be produced by Subjecting compound R (XXXIX) to known hydrolysis, for example, alkaline 4 YNH hydrolysis or acid hydrolysis. For example, the reaction can R 40 be performed by a method according to hydrolysis conditions 1. (1 ) similar to those employed for compound (VI). 1.Ab N Bb Compound (XLII) can be produced by a condensation 1. reaction of compound (XL) with compound (XLI). For X n N -CH2N 3. PG example, the reaction can be performed by a method accord H R (XLI) 45 Q condensa ing to conditions similar to those employed for the production No O tion of compound (IX). As compound (XLI), a commercially available product (XL) may be used, or it can produced by a method according to conditions similar to those employed for the production of 50 compound (VIII). R4 Compound (B) is produced by removing the N-protecting group PG of compound (XLII). Moreover, when the starting material compound has an amino group, a carboxyl group or ves, a hydroxyl group as a Substituent in each of the above-men | Ab d epro 55 X n 1's 3 tection tioned reactions, these groups are optionally protected by a H R He protecting group generally used in the peptide chemistry and R the like. In this case, the object compound can be obtained by N O removing the protecting group as necessary after the reaction. 60 These protecting groups can be introduced or removed by a method according to conditions similar to those employed for ( pi )m Bb the production of compound (A). N When compound (B) is obtained as a free compound, it can PG1 be converted to an object salt by a method known perse or a (XLII) 65 method analogous thereto. When compound (B) is obtained as a salt, it can be converted to a free form or other object salt by a method known perse or a method analogous thereto. US 8,329,691 B2 86 -continued Reaction 12 R4 5 N25NNH R4 Ab N als, N O -- Ab 10 S no O (XLIII) R NN O

( pi )m 1. 15 Bb Na NN -CH2 HN Ab HN NR35 (B) N LG (XXXVIII)

R No O (XLIV) 25 This method is used for the production of compound (B) wherein ring Ab is a pyrimidine ring and R’ is a nitrogen R4 containing 5- to 7-membered ring optionally having Substitu es ent(s). Ab 30 As compound (XLIV), a commercially available product CH may be used, or it can be produced using compound (XLIII) N N1H Yss Herhydrolysis as starting material and by a method according to conditions R similar to those employed for the production of compound No O (XI). (XLV) 35 Compound (XLV) can be produced by reacting compound (XLIV) with compound (XXXVIII) and by a method accord ing to conditions similar to those employed for the production of compound (XII). R R4 YNH 40 Compound (XLVI) can be produced by Subjecting com pound (XLV) to known hydrolysis, for example, alkaline hydrolysis or acid hydrolysis. For example, the reaction can sts (1, )m be performed by a method according to hydrolysis conditions Ab N Bb CH similar to those employed for compound (XII). S. 1' N,R PG1 45 Compound (XLVII) can be produced by a condensation Q H (XLI) reaction of compound (XLVI) with compound (XLI). For n condensa O O tion example, the reaction can be performed by a method accord (XLVI) ing to conditions similar to those employed for the production 50 of compound (IX). Compound (B) is produced by removing the N-protecting group PG of compound (XLVII). Moreover, when the starting R4 material compound has an amino group, a carboxyl group or a hydroxyl group as a Substituent in each of the above-men y 21 NN 55 tioned reactions, these groups are optionally protected by a Ab deprotec X CH luck protecting group generally used in the peptide chemistry and N N1 NR35 tion the like. In this case, the object compound can be obtained by removing the protecting group as necessary after the reaction. R. n These protecting groups can be introduced or removed by a N O 60 method according to conditions similar to those employed for the production of compound (A). ( pi )m Bb When compound (B) is obtained as a free compound, it can N be converted to an object salt by a method known perse or a PG1 65 method analogous thereto. When compound (B) is obtained (XLVII) as a salt, it can be converted to a free form or other object salt by a method known perse or a method analogous thereto. US 8,329,691 B2 87 88 -continued Reaction 13 R4

N 1. N Ab S 1. CH2 hydrolysis

10

(XLIII)

R4 15 (B) N211. NNH This method is used for the production of compound (B) Ab wherein ring Ab is a pyrimidine ring and R’ is a nitrogen N O -> containing 5- to 7-membered ring optionally having Substitu ent(s). Q Compound (XLVIII) can be produced by subjecting com No O pound (XLIII) to known hydrolysis, for example, alkaline hydrolysis or acid hydrolysis. For example, the reaction can (XLVIII) be performed by a method according to hydrolysis conditions 25 similar to those employed for compound (XII). R4 l Compound (XLIX) having a Substitutable leaving group R LG can be produced by using compound (XLVIII) as a start N 2n it ing material and by a method according to conditions similar Ab to those employed for the production of compound (XXXV). N Bb 30 Compound (L) can be produced by a condensation reaction LG N of compound (XLIX) with compound (XLI). For example, PG1 the reaction can be performed by a method according to conditions similar to those employed for the production of LG O (XLI) compound (IX). (XLIX) condensa Compound (XLVII) can be produced by reacting com tion 35 pound (L) with compound (XXXVIII) and by a method according to conditions similar to those employed for the production of compound (XII). Compound (B) is produced by removing the N-protecting group PG of compound (XLVII). Moreover, when the starting 1. N CH2 40 N Ab HN1 in R3 material compound has an amino group, a carboxyl group or (XXXVIII) a hydroxyl group as a Substituent in each of the above-men N -- tioned reactions, these groups are optionally protected by a LG protecting group generally used in the peptide chemistry and R the like. In this case, the object compound can be obtained by NN O 45 removing the protecting group as necessary after the reaction. These protecting groups can be introduced or removed by a ( pi method according to conditions similar to those employed for Bb the production of compound (A). N When compound (B) is obtained as a free compound, it can PG1 50 be converted to an object salt by a method known perse or a (L method analogous thereto. When compound (B) is obtained 4 as a salt, it can be converted to a free form or other object salt by a method known perse or a method analogous thereto. N21 NN 55 Ab deprotec (Reaction 14) CH N N 1 n R3b tion R NN O 60 ( )m N OH N O Bb PG1 N (XLVII) 65 US 8,329,691 B2 89 90 Compound (LI) can also be produced by a method known per se, for example, the method described in Tetrahedron Reaction 16 Lett., 2003, Vol. 44, pages 1611-1614 and the like, or a method analogous thereto. N21NNH Compound (XXX) can be produced by a known asymmet- Ac ric esterification reaction and using compound (LI). N O He Compound (XXX) can also be produced by a known method, for example, the method described in J. Am. Chem. RN Soc., 2000, vol. 122, pages 9542-9543 and the like, or a O O method analogous thereto. (XLIII-C) N 2N. N Z (Reaction 15) Ac HN1TYR3c S LG (XXXVIII-C) 15 Z R LG + HN1TYR3c —- No O R (V) (XLIV-C) N O 2O N an (XXXVII-C) Ac

O Z hydrolysis N H 17N R3c -e-hydrolysis N 1 N3R - -- H R R 25 O O No O (XLV-C) (XXXIX-C) R R'Slc NH N 2^n N NH Ac 30 N N1 Zn R3C (1, )m (1, )m H Bc Bc N Q 1.

O Z PG-N No O PG (XLI-C) N1 YR3c (XLI-C) 35 (XLVI-C) condensa H condensa- tion QS tion O O N21 n (XL-C) Ac Z deprotec 40 N N1TYR3c on - Zn H N R3C Re H deprotecepile NN1so R'S He N O 45 (1, )m ( ) Bb pi iii. N Bc PG1 PG1 N (XLVII-C) (XLII-C) 50 N an N Ac O N1 n S N 17 n. R3C H H lc Re R NN O 55 NN O

( pi )m ( pi )m Bc Bb HN HN 60 (C) (C)

This method is used for the production of compound (C). This method is used for the production of compound (C) The reaction in each step can be performed according to 65 whereinring Ac is a pyrimidinering. The reaction in each step conditions similar to those employed for the production of can be performed according to conditions similar to those compound (B) in reaction 11. employed for the production of compound (B) in reaction 12. US 8,329,691 B2 91 92 This method is used for the production of compound (C) Reaction 17 whereinring Ac is a pyrimidinering. The reaction in each step can be performed according to conditions similar to those 4NN employed for the production of compound (B) in reaction 13. Ac Compound (I) (including compound (A), compound (B) N O hydrolysis and compound (C), hereinafter the same) may be used as a prodrug. A prodrug of compound (I) means a compound which is converted to compound (I) with a reaction due to an O O enzyme, gastric acid, etc. under the physiological condition in (XLIII-C) 10 the living body, that is, a compound which is converted to compound (I) with oxidation, reduction, hydrolysis, etc. N21NNH according to an enzyme; a compound which is converted to Ac compound (I) by hydrolysis etc. due to gastric acid, etc. S. O He Examples of a prodrug of compound (I) include a com 15 pound wherein an amino group of compound (I) is acylated, Q alkylated orphosphorylated (e.g., compound wherein amino No O group of compound (I) is eicosanoylated, alanylated, penty (XLVIII-C) laminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylm Nay R& NH ethylated, pivaloyloxymethylated or tert-butylated, and the Ac like); a compound wherein a hydroxy group of compound (I) S. LG (1, )m is acylated, alkylated, phosphorylated or borated (e.g., a com Bc pound wherein a hydroxy group of compound (I) is acety N 1 lated, palmitoylated, propanoylated, pivaloylated. Succiny LG O PG 25 lated, fumarylated, alanylated O (XLIX-C) (XLI-C) dimethylaminomethylcarbonylated, and the like); a com condensa pound wherein a carboxyl group of compound (I) is esterified tion or amidated (e.g., a compound wherein a carboxyl group of N21NN compound (I) is ethyl esterified, phenyl esterified, carboxym Ac 30 ethyl esterified, dimethylaminomethyl esterified, pivaloy N Z loxymethyl esterified, ethoxycarbonyloxyethyl esterified, LG 1n phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) HN R3C methyl esterified, cyclohexyloxycarbonylethyl esterified or ReNN O (X XXVIII-C) methylamidated, and the like) and the like. These compounds 35 can be produced from compound (I) by a method known per SC. ( pi )m Bc A prodrug of compound (I) may also be one which is N converted into compound (I) under a physiological condition, PG1 such as those described in IYAKUHIN no KAIHATSU (De (L-C) 40 velopment of Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990). 4\ When compound (I) has an isomer Such as optical isomer, Ac Stereoisomer, positional isomer, rotational isomer and the Sn N1 Z NR3c deprotec like, any isomers and a mixture thereof are encompassed in H -e- 45 compound (I). For example, when compound (I) has an opti Re cal isomer, an optical isomer resolved from a racemate is also NN O encompassed in compound (I). Such isomer can be obtained as a single product by a synthesis method, a separation ( pi )m method (e.g., concentration, solvent extraction, column chro Bc 50 matography, recrystallization etc.), optical resolution method N (e.g., fractional recrystallization, chiral column method, dias PG1 tereomer method etc.) and the like known perse. (XLVII-C) Compound (I) may be a crystal, and both a single crystal an and crystal mixtures are encompassed in compound (I). Crys Ac 55 tals can be produced by crystallization according to crystal lization methods known perse. Compound (I) may be a Solvate (e.g., hydrate etc.) or a Re non-Solvate (e.g., non-hydrate etc.), both of which are encom NN O passed in compound (I). 60 A compound labeled with an isotope (e.g., H. C. S. 'I and the like) and the like is also encompassed in com ( pi )m pound (I). Bc Deuterium-converted compound wherein H has been con HN verted to H(D) are also encompassed in the compound (I). (C) 65 Compound (I) or its prodrug, or salts thereof (hereinafter, Sometimes to be abbreviated to as a compound of the present invention) exhibit superior renin inhibitory activity. They US 8,329,691 B2 93 94 have low toxicity (e.g., acute toxicity, chronic toxicity, inflammatory diseases (e.g., arthritis Such as rheumatoid genetic toxicity, reproductive toxicity, cardiac toxicity, drug arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc.; interaction, carcinogenicity, etc.) and high water-solubility, inflammation after operation or injury; remission of Swelling; and are excellent in the aspects of stability, pharmacokinetics pharyngitis; cystitis; pneumonia; atopic dermatitis; inflam (absorption, distribution, metabolism, excretion, etc.) and matory intestinal diseases such as Crohn's disease, ulcerative efficacy, thus being useful as medicine. colitis etc.; meningitis; inflammatory ocular disease; inflam The compound of the present invention acts as a renin matory pulmonary diseases such as pneumonia, pulmonary inhibitory drug in mammals (e.g., mouse, rat, hamster, rabbit, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis cat, dog, cattle, sheep, monkey, human, etc.), and is useful as etc.), allergic diseases (e.g., allergic rhinitis, conjunctivitis, a drug inhibiting the RA system by inhibiting the biosynthesis 10 gastrointestinal allergy, pollinosis, anaphylaxis etc.), chronic of AII, and is useful as an agent for the prophylaxis or treat obstructive pulmonary disease, interstitial pneumonia, pneu ment of various diseases caused by the RA System. mocystis carinni pneumonia, collagen diseases (e.g., sys Examples of Such diseases include hypertension (e.g., temic lupus erythematodes, Scleroderma, polyarteritis etc.), essential hypertension, renal vascular hypertension, reno hepatic diseases (e.g., hepatitis including chronic hepatitis, parenchymal hypertension, primary aldosteronism, Cush 15 hepatic cirrhosis etc.), portal hypertension, digestive system ing's syndrome etc.), blood pressure circadian rhythm abnor disorders (e.g., gastritis, gastric ulcer, gastric cancer, gastric mality, heart diseases (e.g., cardiac hypertrophy, acute heart disorder after operation, dyspepsia, esophageal ulcer, pancre failure, chronic heart failure including congestive heart fail atitis, colon polyp, cholelithiasis, hemorrhoidal disease, ure, failure of expansion, cardiac myopathy, angina pectoris, Varices ruptures of esophagusandstomach etc.), blood and/or myocarditis, atrial fibrillation, arrhythmia, tachycardia, car myelopoietic diseases (e.g., erythrocytosis, vascular purpura, diac infraction etc.), cerebrovascular disorders (e.g., asymp autoimmune hemolytic anemia, disseminated intravascular tomatic cerebrovascular disorder, transient ischemic attack, coagulation syndrome, multiple myelopathy etc.), bone dis apoplexy, cerebrovascular dementia, hypertensive encephal eases (e.g., fracture, refracture, osteoporosis, osteomalacia, opathy, cerebral infarction etc.), cerebral edema, cerebral cir Paget’s disease of bone, Sclerosing myelitis, rheumatoid culatory disorder, recurrence and sequela of cerebrovascular 25 arthritis, joint tissue dysfunction and the like caused by disorders (e.g., neurotic symptom, psychic symptom, Subjec osteoarthritis of the knee and diseases similar to these), solid tive symptom, disorder in daily living activities etc.), tumor, tumors (e.g., malignant melanoma, malignant lym ischemic peripheral circulation disorder, myocardial phoma, cancer of digestive organs (e.g., stomach, intestine ischemia, Venous insufficiency, progression of cardiac insuf etc.) etc.), cancer and cachexia following cancer, metastasis ficiency after myocardial infarction, renal diseases (e.g., 30 cancer, endocrinopathy (e.g., Addison's disease, pheochro nephritis, glomerulonephritis, glomerulosclerosis, renal fail mocytoma etc.), urinary organ and/or male genital diseases ure, nephrotic syndrome, thrombotic vasculopathy, compli (e.g., cystitis, benign prostatic hyperplasia, prostatic cancer, cation of dialysis, organ damage including nephropathy by sex infectious disease etc.), female disorders (e.g., climac radiation irradiation etc.), arteriosclerosis including athero teric disorder, gestosis, endometriosis, hysteromyoma, ova Sclerosis (e.g., aneurysm, coronary Sclerosis, cerebral arterio 35 rian disease, breast disease, sex infectious disease etc.), dis Sclerosis, peripheral arterial Sclerosis etc.), Vascular hypertro ease relating to environment and occupational factors (e.g., phy, vascular hypertrophy or obliteration and organ damages radiation hazard, hazard by ultraviolet, infrared or laser beam, after intervention (e.g., percutaneous transluminal coronary altitude sickness etc.), respiratory diseases (e.g., cold Syn angioplasty, Stenting, coronary angioscopy, intravascular drome, pneumonia, asthma, pulmonary hypertension, pulmo ultrasound, dounce thrombolytic therapy etc.), vascular re 40 nary thrombosis and pulmonary embolism etc.), infectious obliteration and restenosis after bypass Surgery, poly diseases (e.g., viral infectious diseases with cytomegalovirus, cythemia, hypertension, organ damage and vascular hyper influenza virus, herpes virus etc., rickettsiosis, bacterial trophy after transplantation, rejection after transplantation, infectious disease etc.), toxemias (e.g., sepsis, septic shock, ocular diseases (e.g., glaucoma, ocular hypertension etc.), endotoxin shock, Gram-negative sepsis, toxic shock Syn thrombosis, multiple organ disorder, endothelial dysfunction, 45 drome etc.), otorhinolaryngological diseases (e.g., Meniere's hypertensive tinnitus, other cardiovascular diseases (e.g., syndrome, tinnitus, dysgeusia, Vertigo, disequilibrium, dys deep vein thrombosis, obstructive peripheral circulatory dis phagia etc.), skin diseases (e.g., keloid, hemangioma, psoria order, arteriosclerosis obliterans, thromboangiitis obliterans, sis etc.), intradialytic hypotension, myasthenia gravis, sys ischemic cerebral circulatory disorder, Raynaud's disease, temic diseases such as chronic fatigue syndrome and the like. Buerger's disease etc.), metabolic and/or nutritional disor 50 The compound of the present invention can be used in ders (e.g., diabetes, impaired glucose tolerance, insulin resis combination with an existing hypertension therapeutic drug tance, hyperinsulinemia, diabetic nephropathy, diabetic ret Such as an ACE inhibitor (captopril, enalapril maleate, alace inopathy, diabetic neuropathy, obesity, hyperlipidemia, pril, delapril hydrochloride, imidapril hydrochloride, hypercholesterolemia, hyperuricacidemia, hyperkalemia, quinapril hydrochloride, cilaZapril, temocapril hydrochlo hypernatremia etc.), metabolic syndrome, nerve degenera 55 ride, trandolapril, benazepril hydrochloride, perindopril, lisi tion diseases (e.g., Alzheimer's disease, Parkinson's disease, nopril, etc.), ARB (losartan potassium, candesartan cilexetil, Creutzfeldt-Jakob disease, multiple sclerosis, amyotrophic Valsartan, TAK-536, TAK-491, irbesartan, telmisartan, epro lateral Sclerosis, AIDS encephalopathy etc.), central nervous Sartan, olmesartan medoxomil, etc.), an aldosterone receptor system disorders (e.g., damages such as cerebral hemorrhage antagonist (spironolactone, eplerenone, etc.), a Ca-ion chan and cerebral infarction, and sequela and complication 60 nel inhibitor (Verapamil hydrochloride, diltiazem hydrochlo thereof, head injury, spinal injury, cerebral edema, sensory ride, nifedipine, amlodipine hydrochloride, azelnidipine, malfunction, sensory functional disorder, autonomic nervous aranidipine, efonidipine hydrochloride, cilnidipine, nicar system disorder, autonomic nervous system malfunction dipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, etc.), dementia, migraine, defects of memory, disorder of barnidipine hydrochloride, felodipine, benidipine hydrochlo consciousness, amnesia, anxiety symptom, catatonic symp 65 ride, manidipine hydrochloride, etc.), diuretic (trichlormethi tom, discomfort mental state, sleep disorder, insomnia, psy azide, hydrochlorothiazide, benzylhydrochlorothiazide, chopathies (e.g., depression, epilepsy, alcoholism etc.), indapamide, tripamide, meticrane, mefruside, furosemide, US 8,329,691 B2 95 96 triamterene, chlorthalidone etc.), a B-blocker (propranolol through different administration routes of two preparations hydrochloride, atenolol, metoprolol tartrate, bisoprolol fuma obtained by separately formulating the compound of the rate, etc.), an O.B-blocker (carvedilol, etc.), and the like. present invention and the combination drug (e.g., administra Moreover, the compound of the present invention can be tion in order of the compound of the present invention and also used in combination with an antithrombotic drug Such as then the combination drug, or administration in the reverse heparin Sodium, heparin calcium, warfarin calcium (War order), or the like. The amount of the combination drug to be farin), a blood coagulation factor Xa inhibitor, drug having a administered can be appropriately selected with reference to function of balance correction in the coagulation-fibrinolysis the clinically used dosage. The mixing ratio of the compound system, an oral thrombin inhibitor, a thrombolytic drug (tPA, of the present invention and the combination drug can be urokinase, etc.), an antiplatelet drug aspirin, Sulfinpyrazone 10 (Anturane), dipyridamol (Persantine), ticlopidine hydrochlo appropriately selected in accordance with the Subject of ride (Panaldine), clopidogrel, cilostazol (Pletal), GPIb/IIIa administration, administration route, disease to be treated, antagonist (ReoPro, etc.), and the like. Also, the compound symptoms, combination, and the like. can be used in combination with a lipid lowering drug or a The compound of the present invention can be also used in cholesterol lowering drug. Examples thereof include a 15 combination with, for example, gene therapy involving squalene synthase inhibitor (lapaquistat acetate etc.), fibrates VEGF, TNFC. or the like, or therapeutic methods involving (clofibrate, benzafibrate, gemfibrozil, etc.), nicotinic acid, its various antibody medicines or the like. derivatives and analogs (acipimox, probucol, etc.), a bile acid The compound of the present invention can be safely binding resin (cholestyramine, colestipol, etc.), an omega-3 administered individually, or according to ordinary methods polyunsaturated fatty acid (EPA (eicosapentaenoic acid), (e.g., methods described in the Japanese Pharmacopeia, etc.), DHA (docosahexaenoic acid), or a mixture thereof etc.), a as a pharmaceutical composition mixed with pharmaceuti compound inhibiting cholesterol absorption (sitosterol, neo cally acceptable carriers, for example, a tablet (including a mycin, etc.), and a squalene epoxidase inhibitor (NB-598 and Sugar-coated tablet and a film-coated tablet), a film, a powder, its analogs, etc.). Furthermore, other possible combination a granule, a capsule, a liquid, an emulsion, a Suspension, an components are an oxidosqualene-lanosterol cyclase, for 25 injectable preparation, a Suppository, a Sustained release example, a decalin derivative, an azadecalin derivative, an preparation, a patch and the like, either orally or parenterally indane derivative and the like. Combination with a HMG (e.g., topical, rectal, intravenous administration, etc.). CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A The dosage form of the aforementioned pharmaceutical reductase) inhibitor (atorvastatin calcium hydrate, pravasta preparation may be exemplified by oral preparations such as tin Sodium, simvastatin, itavastatin, lovastatin, fluvastatin, 30 a tablet (including a Sublingual tablet and a buccal disintegra etc.) is also possible. tion tablet), a film (including a buccal disintegration film), a The compound of the present invention can also be used in capsule (including a soft capsule and a microcapsule), a gran combination with a therapeutic drug for diabetes or a thera ule, a powder, atroche, a syrup, an emulsion, a suspension and peutic drug for diabetic complications. For example, the com the like; and parenteral preparations such as an injectable pound of the present invention can be used in combination 35 preparation (e.g., a Subcutaneous injectable preparation, an with an insulin preparation, an insulin sensitizer pioglita intravenous injectable preparation, intramuscular injectable Zone hydrochloride, rosiglitaZone, etc., an O-glucosidase preparation, intraperitoneal injectable preparation, a drip inhibitor Voglibose, acarbose, miglitol, emiglitate etc., infusion), external preparation (e.g., a percutaneous prepara biguanide phenformin, metformin, buformine etc., insulin tion, an ointment), a Suppository (e.g., a rectal Suppository, a secretagogue tolbutamide, glibenclamide, gliclazide, nateg 40 vaginal Suppository), a pellet, a transnasal preparation, a linide, mitiglinide, glimepiride etc., a dipeptidylpeptidase transpulmonary preparation (inhalant), an eye drop and the IV inhibitor Alogliptin benzoate, Vidagliptin (LAF237), like. P32/98, Saxagliptin (BMS-477118) etc.), Kinedak, Penfill, These preparations may be controlled release preparations Humulin, Euglucon, Glimicron, Daonil, Novolin, Monotard, Such as a rapid release preparation, a Sustained release prepa Glucobay, Dimelin, Rastinon, Bacilcon, Deamelin S, Iszilin 45 ration and the like (e.g., a Sustained release microcapsule). family, or the like. The content of the compound of the present invention in the In addition, the compound can be also used together with pharmaceutical composition is about 0.01 to 100% by weight other pharmaceutical components, including a bone disease of the entire composition. medicine, a myocardial protective drug, a coronary artery The amount of administration of the compound of the disease medicine, a chronic cardiac failure medicine, a 50 present invention may vary depending on the Subject of hypothyroidism medicine, a nephrotic syndrome medicine, a administration, administration route, Subject disease or the chronic renal failure medicine, a gynecological disease medi like; however, in the case of administering orally to an adult as cine, an infection medicine, or the like. a hypertension medicine, the amount of administration is The administration mode may be exemplified by (1) about 0.0005 to 2 mg/kg of body weight, preferably about administration of a single preparation obtained by simulta 55 0.001 to 1 mg/kg of body weight, and more preferably about neously formulating the compound of the present invention 0.001 to 0.5 mg/kg of body weight, in terms of compound (I), and the combination drug, (2) simultaneous administration the active ingredient, possibly once to several times a day. through the same administration route of two preparations The aforementioned pharmaceutically acceptable carrier obtained by separately formulating the compound of the may be exemplified by various organic or inorganic carrier present invention and the combination drug, (3) administra 60 materials that are conventionally used as preparation materi tion with a time interval through the same administration als, for example, excipient, lubricant, binding agent and dis route of two preparations obtained by separately formulating integrant for Solid preparations; or solvent, solubilizing the compound of the present invention and the combination agent, Suspending agent, isotonic agent, buffering agent, drug, (4) simultaneous administration through different Soothing agent and the like for liquid preparations. Further, if administration routes of two preparations obtained by sepa 65 necessary, additives such as preservative, antioxidant, colo rately formulating the compound of the present invention and rant, Sweetening agent, adsorbing agent, Wetting agent and the combination drug, (5) administration with a time interval the like can be also used. US 8,329,691 B2 97 98 Examples of the excipient include lactose, white Sugar, LC/MS spectra were measured under the following condi D-mannitol, Starch, corn starch, crystalline cellulose, light tions. anhydrous silicic acid and the like. Equipment: Agilent 1100 HPLC (Gilson 215 autosampler)/ Examples of the lubricant include magnesium Stearate, Waters ZQ, or Waters 2795/ZQ calcium Stearate, talc, colloidal silica and the like. 5 Column: Capcell Pak C18 UG120 (1.5 mmIDX35 mL, S-3 Examples of the binding agent include crystalline cellu um), manufactured by Shiseido Co., Ltd. lose, white Sugar, D-mannitol, dextrin, hydroxypropylcellu Solvent: Solution A (0.05% trifluoroacetic acid-containing lose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, water), Solution B (0.04% trifluoroacetic acid-containing starch, Sucrose, gelatin, methylcellulose, carboxymethylcel water) lulose sodium and the like. 10 Gradient cycle: 0.00 min (A/B=90/10), 2.00 min (A/B=5/95), Examples of the disintegrant include starch, carboxymeth 2.75 min (A/B=5/95), 2.76 min (A/B=90/10), 3.45 min ylcellulose, carboxymethylcellulose calcium, carboxymeth (A/B=90/10) ylstarch sodium, L-hydroxypropylcellulose and the like. Flow rate: 0.5 ml/min Examples of the solvent include water for injection, alco Detection: UV (220 nm) hol, propylene glycol, Macrogol, Sesame oil, corn oil, olive 15 Mass spectrum: electrospray ionization (ESI) oil and the like. Reverse-phase preparative HPLC was performed on a Examples of the Solubilizing agent include polyethylene YMC CombiPrep ODS-A (20 mmIDx50 mL, S-5 um) col glycol, propylene glycol, D-mannitol, benzylbenzoate, etha umn using a Gilson UniPoint system, and eluted with 0.1% nol, trisaminomethane, cholesterol, triethanolamine, sodium trifluoroacetic acid-containing acetonitrile/water (10:90-100: carbonate, sodium citrate and the like. 2O O) at a flow rate of 25 ml/min. Examples of the Suspending agent include Surfactants such The microwave reactor used was Discover of CEM. as Stearyl triethanolamine, Sodium lauryl Sulfate, laurylami Other symbols used in the present text indicate the follow nopropionic acid, lecithin, benzalkonium chloride, benzeto ing meanings. nium chloride, glycerin monostearate and the like; hydro s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, philic polymers such as polyvinyl alcohol, 25 dt: double triplet, td: triple doublet, dd: double quartet, td: polyvinylpyrrolidone, carboxymethylcellulose Sodium, triple quartet, ddd: double double doublet, dddd: double methylcellulose, hydroxymethylcellulose, hydroxyethylcel double double doublet, m: multiplet, br: broad. lulose, hydroxypropylcellulose and the like; and the like. DMF: N,N-dimethylformamide, DMSO: dimethylsulfoxide, Examples of the isotonic agent include glucose, D-Sorbitol, THF: tetrahydrofuran, DMA: N,N-dimethylacetamide. Sodium chloride, glycerin, D-mannitol and the like. 30 HOBt: 1-hydroxybenzotriazole monohydrate, WSC.HCl: Examples of the buffering agent include buffer solutions 1-ethyl-3-3-(dimethylamino)propylcarbodiimide hydro such as phosphates, acetates, carbonates, citrates and the like. chloride, BOP reagent: benzotriazol-1-yloxytris(dimethy Examples of the Soothing agent include benzyl alcohol and lamino)phosphonium hexafluorophosphate, Z-chloride: the like. benzyloxycarbonyl chloride, Examples of the preservative include parahydroxybenzoic 35 TFA: trifluoroacetic acid. acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, Boc: tert-butoxycarbonyl. dehydroacetic acid, Sorbic acid and the like. When relative configuration is known but absolute con Examples of the antioxidant include Sulfites, ascorbic acid, figuration is not, the chiral atom is shown by R*, S*. C-tocopherol and the like. Examples of the colorant include water-soluble Food coal 40 Reference Example 1 tar dyes (e.g., Food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, and ethyl 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5- the like), water-insoluble lake dyes (e.g., aluminum salts of carboxylate the aforementioned water-soluble Food coaltar dyes), natural dyes (e.g., B-carotene, chlorophyll, ferric oxide red) and the 45 like. Examples of the Sweetening agent include Saccharin Sodium, dipotassium glycyrrhizinate, aspartame, Stevia and the like. 50 EXAMPLES N 21 NH The present invention is explained in detail in the following S. O by referring to Reference Examples. Examples, Preparation Examples and Experimental Examples, which are not to be 55 construed as limitative. Of the synthesis starting materials O O used in Reference Examples and Examples, synthesis meth ods of known compounds are omitted. “Room temperature' in the following Reference Examples and Examples represents a temperature of about 10° C. to 60 To a solution of diethyl 2,2-dimethylpropanimidamide about 35°C., and “6” represents weight% unless otherwise hydrochloride (1.36 g) and (ethoxymethylene)malonate stated. Provided that, yield represents mol/mol%. (2.16 g) in ethanol (100 ml) was added 20% sodium ethoxide H-NMR spectra were measured with a Varian MER ethanol solution (6.8 g) under ice-cooling, and the mixture CURY 300 (300 MHz) spectrometer or a BRUKER was stirred at 80° C. for 5 hr. The reaction mixture was ADVANCE 300 (300 MHz) spectrometer using tetramethyl- 65 concentrated under reduced pressure, 1 M hydrochloric acid silane as an internal standard. All of the Ö values are repre (10 ml) was added under ice-cooling, and the mixture was sented in ppm. extracted with ethyl acetate. The extract was concentrated US 8,329,691 B2 99 100 under reduced pressure, hexane was added to the residue, and Reference Example 4 the precipitate was collected by filtration to give the object compound (1.65 g) as a powder. ethyl MS (ESI+, m/e) 225 (M+1) 6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate 'H-NMR (CDC1) & 1.33-1.41 (3H, m), 1.43 (9H, s), 4.32 4.41 (2H, m), 8.72 (1H, s). By a method similar to that of Reference Example 1, the following compounds (Reference Examples 2 to 7) were obtained. 10

Reference Example 2

ethyl 2-isopropyl-6-oxo-1,6-dihydropyrimidine-5- 15 carboxylate

'H-NMR (DMSO-d) & 1.29 (3H, t), 4.26 (2H, q), 7.52 7.70 (3H, m), 8.17 (2H, d), 8.64 (1H, s), 13.20 (1H, brs). 25 Reference Example 5 N NH ethyl N O 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate 30

O O

35

40

MS (ESI+, m/e) 211 (M+1) 'H-NMR (DMSO-d) & 1.25 (3H, t), 2.34 (3H, s), 4.21 (2H, Reference Example 3 45 q), 8.41 (1H, s), 12.94 (1H, brs). Reference Example 6 ethyl 2-cyclopropyl-6-oxo-,6-dihydropyrimidine-5- carboxylate ethyl 50 2-ethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate

55

N NH

N O 60 O O

65 H-NMR (DMSO-d) & 1.18 (3H, t), 1.25 (3H, t), 2.60 (2H, MS (ESI+, m/e) 209 (M+1) q), 4.21 (2H, q), 8.45 (1H, s), 12.90 (1H, brs). US 8,329,691 B2 101 102 Reference Example 7 cooled to room temperature, and water was added. The aque ous layer was separated, adjusted to pH 3 with 1 M hydro ethyl 6-oxo-2-(2-thienyl)-1,6-dihydropyrimidine-5- chloric acid, and extracted with ethyl acetate. The extract was carboxylate washed with saturated brine, dried over anhydrous sodium Sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chroma tography to give the object compound (313 mg) as a powder. 'H-NMR (CDC1) & 1.49 (3H, t), 2.85 (3H, s), 4.22-4.42 10 (1H, m), 4.55 (2H, q). Reference Example 9

15 2-(2-furylmethyl)amino-6-methylnicotinic acid

NN

21 N O

25 HO O MS (ESI+, m/e) 251 (M+1) Reference Example 8 30 2-Chloro-6-methylnicotinic acid (1.72 g) and furfury ethyl 4-methyl-6-oxo-2-(trifluoromethyl)-1,6-dihy lamine (1.94 g) were dissolved in 1-methylpyrrolidin-2-one dropyrimidine-5-carboxylate (25 ml), and the mixture was stirred at 150° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatog 35 raphy. The fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure, and the precipitate was collected by filtration to give the object compound (838 F mg) as a powder.

F F 'H-NMR (CDC1,)ö 245(3H, s), 4.78 (2H, s), 6.26(1H,d), 40 6.32(1H, dd), 6.46 (1H, d), 7.33-7.40 (1H, m), 8.05-8.14 (2H, N1 NNH m). By a method similar to that of Reference Example 9, the N O following compounds (Reference Examples 10 and 11) were 45 obtained.

O O Reference Example 10

50 6-methyl-2-((5-methyl-2-furyl)methyl aminonicotinic acid

Trifluoroacetamidine (2.47 g) and diethyl ethylidenema lonate (3.64 ml) were dissolved in ethanol (50 ml) and the 55 mixture was stirred at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was NN dissolved in water. The mixture was adjusted to pH 4 with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over 60 1N O anhydrous sodium Sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel HO O column chromatography, and the obtained oil (570 mg) was dissolved in carbon tetrachloride (45 ml). N-Bromosuccin imide (381 mg), 2,2'-azobis(2-methylpropionitrile) (16 mg) 65 and potassium carbonate (2.90 g) were added and the mixture 'H-NMR (CDC1) & 2.28 (3H, s), 2.44 (3H, s), 4.71 (2H, s), was heated under reflux for 30 min. The reaction mixture was 5.89 (1H, d), 6.13 (1H, d), 6.45 (1H, d), 7.97-8.07 (2H, m). US 8,329,691 B2 103 104 Reference Example 11 Reference Example 13

6-methyl-2-(2-thienylmethyl)aminonicotinic acid 4-(benzylamino)-2-(methylthio)pyrimidine-5-car boxylic acid

s1 NN 10 2 N S s 21 N 15 H HO O HO O

H-NMR (CDC1) & 2.47 (3H, s), 4.94 (2H, d), 6.47 (1H, 'H-NMR (DMSO-d) & 2.40 (3H, s), 4.71 (2H, d), 7.23 d), 6.94 (1H, dd), 7.03 (1H,d), 7.19 (1H,d), 8.05 (1H,d), 8.13 7.28 (1H, m), 7.30-7.35 (4H, m), 8.53 (1H, s), 8.90 (1H, t), (s, 1H) 13.28 (1H, s). Reference Example 12 Reference Example 14 25 4-(2-furylmethyl)amino-2-(methylthio)pyrimidine 4-(2-furylmethyl)amino-2-(trifluoromethyl)pyrimi 5-carboxylic acid dine-5-carboxylic acid

30

s1 F F 35 s s 2 N O 21 N O

40 HO O HO O

MS (ESI+, m/e) 288 (M+1) To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine 45 5-carboxylate (1.71 g) in 2-propanol (10 ml) were added furfurylamine (714 mg) and diisopropylethylamine (950 Reference Example 15 mg), and the mixture was stirred at room temperature for 10 min. The reaction mixture was poured into 2% aqueous 4-(benzylamino)-2-(trifluoromethyl)pyrimidine-5- Sodium hydrogen carbonate, and the mixture was extracted 50 carboxylic acid with ethyl acetate. The extract was dried over anhydrous magnesium Sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was collected by filtration. The precipitate was F dissolved in ethanol (10 ml), 2 Maqueous sodium hydroxide 55 solution (10 ml) was added and the mixture was stirred at F F room temperature for 5 hr. The reaction mixture was adjusted to pH 3 with 1 M hydrochloric acid, and the precipitated N1 NN crystals were collected by filtration to give the object com pound (1.75 g) as a powder. 60 2 N 'H-NMR (DMSO-d) & 2.48 (3H, s), 4.72 (2H, d), 6.30 H (1H, d), 6.39-6.45 (1H, m), 7.60 (1H, d), 8.54 (1H, s), 8.74 (1H, t), 13.34 (1H, s). HO O By a method similar to that of Reference Example 12, the 65 following compounds (Reference Examples 13 to 20) were H-NMR (CDC1) & 4.82 (2H, d), 7.28-7.41 (5H, m), 8.65 obtained. (1H, brs), 9.01 (1H, s).

US 8,329,691 B2 107 108 Ethyl 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-car 'H-NMR (DMSO-d) & 1.08-1.29 (4H, m), 2.16-2.29 (1H, boxylate (2.90 g) was Suspended in phosphorus oxychloride m), 4.73 (2H, d), 6.31 (1H, d), 6.42(1H, t), 7.60 (1H, t), 8.67 (9.6 g), and the suspension was stirred at 100° C. for 2 hr. Phosphorus oxychloride was evaporated under reduced pres (1H, s), 9.40 (1H, s). sure, and the mixture was cooled to 0°C. and neutralized with saturated aqueous Sodium hydrogen carbonate and water. The Reference Example 24 mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium Sulfate, and concentrated under reduced pressure. The 4-(2-furylmethyl)amino-2-phenylpyrimidine-5- obtained residue was dissolved in 2-propanol (10 ml), and carboxylic acid furfurylamine (1.20 ml) and diisopropylethylamine (2.26 ml) 10 were added. The mixture was stirred at 100° C. for 15 hr and concentrated under reduced pressure. Saturated aqueous Sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and 15 concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, and the fraction eluted with ethyl acetate-hexane (1:5) was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (15 ml) and THF (5 ml), 2 M aqueous sodium s hydroxide solution (15 ml) was added and the mixture was Yn O stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure and the aqueous layer was adjusted to pH 3 with 1 M hydrochloric acid. The HO. O. precipitate was collected by filtration and washed with water to give the object compound (3.30 g) as a powder. 25 'H-NMR (DMSO-d) & 1.32 (9H, s), 4.77 (2H, d), 6.32 'H-NMR (CDC1) & 4.86 (2H, d), 6.36-6.42 (2H, m), 7.48 (1H, s), 6.40 (1H, s), 7.60 (1H, s), 8.68 (1H, s), 8.99 (1H, s). 7.61 (4H, m), 8.42 (2H, dd), 8.72 (1H, s), 8.86 (1H, s). By a method similar to that of Reference Example 21, the following compounds (Reference Examples 22 to 32) were Reference Example 25 obtained. 30 Reference Example 22 4-(2-furylmethyl)amino-2-methylpyrimidine-5- 4-(2-furylmethyl)amino-2-isopropylpyrimidine-5- carboxylic acid carboxylic acid 35 ol, 40 21 N O

HO O 45 MS (ESI+, m/e) 234 (M+1) 'H-NMR (DMSO-d) & 1.23 (6H, d), 2.94-3.09 (1H, m), 4.78 (2H, d), 6.33 (1H, d), 6.41 (1H, s), 7.60 (1H, s), 8.70 (1H, s), 9.09 (1H, s). Reference Example 26 50 Reference Example 23 2-ethyl-4-(2-furylmethyl)aminolpyrimidine-5-car 2-cyclopropyl-4-(2-furylmethyl)aminolpyrimidine boxylic acid 5-carboxylic acid 55

60

1. O HO O l/ 65 HO O MS (ESI+, m/e) 248 (M+1)

US 8,329,691 B2 111 112 Reference Example 33 due was purified by silica gel column chromatography. The fraction eluted with hexane-ethyl acetate (7:1-1:4) was con dimethylpyridine-3,5-dicarboxylate centrated under reduced pressure. The residue was diluted with ethyl acetate, and the precipitate was collected by filtra tion and washed with ethyl acetate to give the object com pound (15.6 g) as a powder. 'H-NMR (CDC1) & 1.47 (9H, s), 1.72 (1H, d), 2.41-2.63 (3H, m), 2.72 (2H, brs), 3.71 (3H, s), 4.38 (2H, d). 10 Reference Example 35 1-tert-butyl 3-methyl 3R,5S)-5-aminorineridine-1,3-dicarboxvils -5-aminoplperidine-l.3-dicarboxylate

15

NH Pyridine-3,5-dicarboxylic acid (100 g) was suspended in methanol (1000 ml), and thionyl chloride (130 ml) was added dropwise at room temperature. The reaction mixture was stirred with heating to reflux for 3 hr. The mixture was allowed to cool to room temperature, and concentrated under reduced pressure. The residue was diluted with water, and the x'sO O mixture was extracted with ethyl acetate. The aqueous layer 25 was neutralized with 8 Maqueous sodium hydroxide solu (3R,5S)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl) tion, and the mixture was extracted with ethyl acetate. The piperidine-3-carboxylic acid (575 mg) was suspended intolu extract was washed Successively with Saturated aqueous ene (10 ml), diphenylphosphoryl azide (0.52 ml) and triethy Sodium hydrogen carbonate Solution and saturated brine, and lamine (0.34 ml) were added and the mixture was stirred at dried over anhydrous sodium sulfate. The solvent was evapo 30 80° C. for 2 hr. The reaction mixture was cooled to room rated under reduced pressure to give the object compound temperature, benzyl alcohol (0.52 ml) and triethylamine (117 g) as a powder. (0.34 ml) were added and the mixture was stirred at 80° C. for 'H-NMR (CDC1) & 4.00 (6H, s), 8.88 (1H, t), 9.37 (2H, d). 2 hr. The reaction mixture was washed with water, 5% aque ous citric acid solution, Saturated aqueous sodium hydrogen Reference Example 34 35 carbonate and saturated brine in this order, and dried over anhydrous sodium sulfate, and the solvent was evaporated (3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycar under reduced pressure. The residue was purified by silica gel bonyl)piperidine-3-carboxylic acid column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pres 40 sure. The obtained residue was dissolved in methanol (5 ml), 10% palladium-carbon (50% containing water) (70 mg) was added, and the mixture was Subjected to catalytic reduction at ambient temperature under a hydrogen atmosphere (1 atm) for 12 hr. The catalyst was filtered off, and the filtrate was 45 concentrated under reduced pressure to give the object com pound (370 mg) as an oil. 'H-NMR (CDC1) & 1.22-1.43 (4H, m), 1.46 (9H, s), 2.27 Xr ON 2.79 (4H, m), 3.70 (3H, s), 4.13 (2H, brs). O 50 Reference Example 36 Dimethylpyridine-3,5-dicarboxylate (55 g) was dissolved 1-tert-butyl 3-methyl (3R*,5S)-5-(isobutylamino) in methanol (500 ml) and 6 M hydrochloric acid (70 ml), and piperidine-1,3-dicarboxylate rhodium-carbon (5.5 g) was added. The reaction mixture was stirred under pressurized hydrogen atmosphere (5 atm) at room temperature for 3 hr and then at 50° C. for 12 hr. The 55 mixture was allowed to cool to room temperature, the rhodium catalyst was filtered off, and the filtrate was concen trated under reduced pressure. The residue was dissolved in ethanol (300 ml), and triethylamine (60 ml) and di-t-butyl 60 dicarbonate (68 g) were successively added under ice-cool ing. The reaction mixture was stirred at room temperature for 12 hr., and concentrated under reduced pressure. The residue X-r O On was dissolved in 0.5 M hydrochloric acid, and the mixture 's was extracted with ethyl acetate. The extract was washed with 65 saturated brine, and dried over anhydrous sodium sulfate. The 1-tert-Butyl 3-methyl (3R*,5S)-5-aminopiperidine-1,3- Solvent was evaporated under reduced pressure and the resi dicarboxylate (370 mg) was dissolved in methanol (10 ml), US 8,329,691 B2 113 114 isobutyraldehyde (0.137 ml), acetic acid (85 ul) and sodium Reference Example 38 triacetoxyborohydride (75.9 mg) were added and the mixture was stirred at room temperature for 1 hr. The reaction mixture (3R*,5S)-1-(tert-butoxycarbonyl)-5-[(2-tert-butyl was concentrated under reduced pressure, and the concen 4-(2-furylmethyl)aminolpyrimidin-5-yl)carbonyl) trated Solution was basified with aqueous Sodium hydrogen 5 (isobutyl)aminolpiperidine-3-carboxylic acid carbonate and extracted with ethyl acetate. The extract was dried over anhydrous Sodium sulfate, and the solvent was evaporated under reduced pressure to give the object com pound (439 mg) as an oil. 10 H-NMR (CDC1) & 0.90 (6H, d), 1.17-141 (3H, m), 1.46 (9H, s), 1.69 (1H, dt), 2.30 (2H, dd), 2.47 (2H, d), 2.52 (1H, dt), 2.74 (1H, brs), 3.69 (3H, s), 4.26 (2H, brs). 2 Reference Example 37 15 y 1-tert-butyl 3-methyl (3R*,5S)-5-[(2-tert-butyl-4- (2-furylmethyl)aminolpyrimidin-5-yl)carbonyl) (isobutyl)aminolpiperidine-1,3-dicarboxylate Xr O OH 25 1-tert-Butyl 3-methyl (3R*,5S)-5-[(2-tert-butyl-4-(2- furylmethyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) N1 NN aminolpiperidine-1,3-dicarboxylate (250mg) was dissolved 30 in 2 Maqueous sodium hydroxide solution (1 ml) and metha 2 nol (2 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water. The mixture was adjusted to pH 3 with 1 M hydrochloric acid, and 35 the precipitate was collected by filtration to give the object compound (205 mg) as a powder. MS (ESI+, m/e) 558 (M+1) Reference Example 39 40 tert-butyl (3R*,5S)-3-(aminocarbonyl)-5-[(2-tert butyl-4-(2-furylmethyl)aminolpyrimidin-5- yl)carbonyl)(isobutyl)aminolpiperidine-1-carboxy late 2-tert-Butyl-4-(2-furylmethyl)aminolpyrimidine-5-car 45 boxylic acid (385 mg) was suspended in toluene (10 ml), thionyl chloride (0.255 ml) and DMF (1 drop) were added and the mixture was stirred at 80°C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure, and the residue was Subjected to azeotropic 50 distillation with toluene. The obtained residue was dissolved N1 NN in acetonitrile (5 ml), the mixture was added to a solution of 1-tert-butyl 3-methyl (3R,5S)-5-(isobutylamino)piperi 21 dine-1,3-dicarboxylate (440 mg) and triethylamine (0.488 55 ml) in acetonitrile (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and diluted with water, and the mix r O ture was extracted with ethyl acetate. The extract was washed with Saturated aqueous Sodium hydrogen carbonate and Satu 60 rated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue xy was purified by Silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:20-1:4) was con centrated under reduced pressure to give the object compound 65 A solution of (3R*.5S*)-1-(tert-butoxycarbonyl)-5-[(2- (363 mg). tert-butyl-4-(2-furylmethyl)aminolpyrimidin-5-yl carbo MS (ESI+, m/e) 572 (M+1) nyl)(isobutyl)aminolpiperidine-3-carboxylic acid (1.03 g). US 8,329,691 B2 115 116 1H-1,2,3-benzotriazol-1-ol ammoniate (420 mg), WSC.HCl Reference Example 41 (530mg) and triethylamine (520 ul) in 1,2-dichloroethane (16 ml) was stirred at room temperature for 24 hr. The mixture tert-butyl (3R*,5S)-3-((2-tert-butyl-4-(2-furylm was poured into water and the mixture was extracted with ethyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) ethyl acetate. The extract was washed with saturated brine, amino-5-(1-hydroxy-1-methylethyl)piperidine-1- and dried over anhydrous magnesium sulfate. The solvent carboxylate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (944 10 mg). MS (ESI+, m/e) 557 (M+1) Reference Example 40 15 tert-butyl (3R*,5S)-3-((2-tert-butyl-4-(2-furylm ethyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) amino-5-(4-hydroxy-4-methylpiperidin-1-yl)carbo nylpiperidine-1-carboxylate

OH 25

1-tert-Butyl 3-methyl (3R*,5S)-5-[(2-tert-butyl-4-(2- furylmethyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) 30 aminolpiperidine-1,3-dicarboxylate (280 mg) was dissolved in THF (5 ml), 1 M methylmagnesium bromide in THF solu tion (2.45 ml) was added and the mixture was stirred at room temperature for 15 hr. Aqueous ammonium chloride Solution was added to the reaction mixture, and the mixture was 35 extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous Sodium sulfate, and concentrated under reduced pressure. The residue was puri fied by silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:2) was concentrated 40 under reduced pressure to give the object compound (280 mg). MS (ESI+, m/e) 572 (M+1)

45 Reference Example 42 (3S.5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbo nyl)piperidine-3-carboxylic acid

(3R*,5S)-1-(tert-Butoxycarbonyl)-5-[(2-tert-butyl-4- 50 (2-furylmethyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) aminolpiperidine-3-carboxylic acid (100 mg), HOBt (41 mg) and WSC.HCl (52 mg) were dissolved in acetonitrile (3 ml), 4-methylpiperidin-4-ol monohydrochloride (27 mg) and tri 55 ethylamine (75ul) were added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was con centrated, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with Xr On saturated brine, and dried over anhydrous sodium sulfate. The 60 Solvent was evaporated under reduced pressure and the resi due was purified by silica gel column chromatography. The A mixture of (3R,5S)-1-(tert-butoxycarbonyl)-5-(meth fraction eluted with ethyl acetate-hexane (1:5-3:1) was con oxycarbonyl)piperidine-3-carboxylic acid (6.16 g), (S)-(-)- centrated under reduced pressure to give the object compound 1-phenylethylamine (2.60 g) and ethanol (24 ml) was dis 65 solved by heating to 70° C. and recrystallization was (110 mg). conducted. The precipitated crystals were collected by filtra MS (ESI+, m/e) 655 (M+1) tion, dissolved again in ethanol (7 ml) and recrystallization US 8,329,691 B2 117 118 was carried out. The precipitated crystals were collected by Reference Example 44 filtration, and Suspended in water. The Suspension was acidi fied with Saturated aqueous potassium hydrogen Sulfate Solu 1-tert-butyl 3-methyl (3R,5S)-5-(isobutylamino)pip tion, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine, and eridine-1,3-dicarboxylate dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object com pound (91.5 mg) as a powder.

specific optical rotation C.I.':-6.2° (after drying, 2012 10 mg, methanol. 2 ml, 100 mm) 'H-NMR (DMSO-d) 81.39 (9H, s), 1.52 (1H, q), 2.18 2.54 (3H, m), 2.55-2.78 (2H, m), 3.63 (3H, s), 4.03-4.23 (2H, m), 12.51 (1H, brs). 15 Xr sO On Reference Example 43 1-tert-Butyl 3-methyl (3R,5S)-5-aminopiperidine-1,3-di 1-tert-butyl 3-methyl carboxylate (1.83 g), isobutyraldehyde (0.78 ml) and acetic (3R,5S)-5-aminopiperidine-1,3-dicarboxylate acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced 25 pressure, the concentrated solution was basified with aqueous Sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. NH The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:1) to ethyl acetate 100% to ethyl acetate-methanol (9:1) was concen trated under reduced pressure to give the object compound 35 (1.42 g) as an oil. 'H-NMR (CDC1) & 0.90 (6H, d), 1.22-1.38 (3H, m), 1.46 (9H, s), 1.69 (1H, dt), 2.23-2.39 (2H, m), 2.44-2.59 (1H, m), 2.47 (2H, d), 2.74 (1H, brs), 3.69 (3H, s), 4.18-4.34 (2H, m). 40 Reference Example 45

(3S,5R)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)pi 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-carboxy peridine-3-carboxylic acid (2.83 g) was suspended in toluene lic acid (36 ml), diphenylphosphoryl azide (2.60 ml) and triethy 45 lamine (1.70 ml) were added and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) were added and the mixture was stirred at 80°C. for 3 hr. The reaction mixture was concentrated, and the residue 50 was dissolved in ethyl acetate. The mixture was washed with N21 NH water, 0.5 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and Saturated brine in this order, and N O dried over anhydrous magnesium sulfate. The solvent was 55 evaporated under reduced pressure and the residue was puri fied by silica gel column chromatography. The fraction eluted HO O with ethyl acetate-hexane (1:3-3:1) was concentrated under reduced pressure. The obtained residue was dissolved in Ethyl 2-tert-butyl-6-oxo-1,6-dihydropyrimidine-5-car methanol (60 ml), 10% palladium-carbon (50% containing 60 boxylate (43.9 g) was dissolved in ethanol (200 ml), 2 M water) (150mg) was added, and the mixture was subjected to aqueous sodium hydroxide solution (330 ml) was added and catalytic reduction at ambient temperature under a hydron the mixture was stirred at room temperature for 40 hr. The atmosphere (1 atm) for 5 hr. The catalyst was filtered off, and reaction mixture was concentrated under reduced pressure, the filtrate was concentrated under reduced pressure to give and the aqueous layer was adjusted to pH 8 with 6 M hydro the object compound (1.83 g) as an oil. 65 chloric acid. The mixture was concentrated under reduced 'H-NMR (CDC1) & 1.22-1.43 (4H, m), 1.46 (9H, s), 2.27 pressure, and Subjected to azeotropic distillation with 2-pro 2.79 (4H, m), 3.70 (3H, s), 4.13 (2H, brs). panol. The residue was suspended in acetone, and insoluble US 8,329,691 B2 119 120 powder was collected by filtration. The obtained powder was Reference Example 47 Suspended in 1 M hydrochloric acid and the Suspension was adjusted to pH 3. The Suspesion was concentrated under 1-tert-butyl 3-methyl (3R*,5S)-5-[(2-tert-butyl-4- reduced pressure. The residue was Subjected to azeotropic chloropyrimidin-5-yl)carbonyl(isobutyl) distillation with 2-propanol, and Suspended in acetone. The amino)piperidine-1,3-dicarboxylate insoluble material was filtered off and the filtrate was con centrated under reduced pressure to give the object compound (32.8 g) as a powder. 'H-NMR (DMSO-d) & 1.45 (9H, s), 8.99 (1H, s), 10.59 (1H, brs), 12.47 (1H, brs). 10 Reference Example 46 N1SN 1-tert-butyl 3-methyl (3R,5S)-5-[(2-tert-butyl-4- 2 chloropyrimidin-5-yl)carbonyl(isobutyl) 15 amino)piperidine-1,3-dicarboxylate

Xy O ON

25 MS (ESI+, m/e) 511 (M+1) N1 NN Reference Example 48

2 30 1-tert-butyl 3-methyl (3R,5S)-5-[(2-tert-butyl-4-(3- methoxypropyl)aminolpyrimidin-5-yl)carbonyl) (isobutyl)aminolpiperidine-1,3-dicarboxylate

Xy O On N NN 40 2 1N1-1 H

N O 2-tert-Butyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic 45 acid (3.25 g) was dissolved in THF (60 ml), thionyl chloride r (4.3 ml) and DMF (5 drops) were added and the mixture was stirred with heating to reflux for 2.5 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure, and the residue was Subjected to azeotropic 50 xy distillation with toluene. The obtained residue was suspended in THF (50 ml), a solution of 1-tert-butyl 3-methyl (3R,5S)- To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-((2-tert 5-(isobutylamino)piperidine-1,3-dicarboxylate (4.13 g) and butyl-4-chloropyrimidin-5-yl)carbonyl(isobutyl) diisopropylethylamine (9.15 ml) in THF (50 ml) was added 55 amino)piperidine-1,3-dicarboxylate (2.98 g) and diisopropy and the mixture was stirred at room temperature for 8 hr. The lethylamine (3.0 ml) in DMF (60 ml) was added reaction mixture was concentrated under reduced pressure, 3-methoxypropylamine (1.19 ml), and the mixture was and diluted with water, and the mixture was extracted with stirred at 80°C. for 1.5 hr. The reaction mixture was concen ethyl acetate. The extract was washed with saturated brine, trated under reduced pressure, Saturated aqueous sodium and dried over anhydrous magnesium sulfate. The solvent 60 hydrogen carbonate was added, and the mixture was was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried over anhy purified by silica gel column chromatography. The fraction drous magnesium Sulfate, and concentrated under reduced eluted with ethyl acetate-hexane (1:19-2:3) was concentrated pressure. The obtained residue was purified by silica gel under reduced pressure to give the object compound (6.29 g). chromatography, and the fraction eluted with hexane to ethyl MS (ESI+, m/e) 511 (M+1) 65 acetate-hexane (1:2) was concentrated under reduced pres By a method similar to that of Reference Example 46, the Sure to give the object compound (3.15 g). following compound (Reference Example 47) was obtained. MS (ESI+, m/e) 564 (M+1) US 8,329,691 B2 121 122 Reference Example 49 (3R,5S)-1-(tert-Butoxycarbonyl)-5-[(2-tert-butyl-4-(3- methoxypropyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) (3R,5S)-1-(tert-butoxycarbonyl)-5-[(2-tert-butyl-4- aminolpiperidine-3-carboxylic acid (110 mg), morpholine (3-methoxypropyl)aminolpyrimidin-5-yl)carbonyl) (52 ul) and diisopropylethylamine (140 ul) were dissolved in (isobutyl)aminolpiperidine-3-carboxylic acid DMF (8 ml), BOP reagent (265 mg) was added and the mixture was stirred at room temperature for 1.5 hr. The reac tion mixture was diluted with Saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium 10 Sulfate, and the Solvent was evaporated under reduced pres Sure. The residue was purified by Silica gel column chroma N NN tography, and the fraction eluted with ethyl acetate-hexane (1:9) to ethyl acetate was concentrated under reduced pres Sure to give the object compound (105 mg). 2 1)N-1\1 15 H MS (ESI+, m/e) 619 (M+1) r N O Example 1 Method A xy 3-(2-ethylpiperidin-1-yl)carbonyl-N-(2-furylm 25 ethyl)-6-methylpyridin-2-amine 1-tert-Butyl 3-methyl (3R,5S)-5-[(2-tert-butyl-4-(3- methoxypropyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) aminolpiperidine-1,3-dicarboxylate (1.08 g) was dissolved in methanol (25 ml) and THF (12 ml), 2 M aqueous sodium 30 hydroxide solution (4.79 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with Saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was 35 dried over anhydrous magnesium Sulfate, and concentrated n under reduced pressure to give the object compound (1.05 g). MS (ESI+, m/e) 550 (M+1) 1. O 40 Reference Example 50 N NO tert-butyl (3S.5R)-3-(2-tert-butyl-4-(3-methox ypropyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl) amino-5-(morpholin-4-ylcarbonyl)piperidine-1- 45 carboxylate

To a solution of 2-(2-furylmethyl)aminol-6-methylnico tinic acid (65.0 mg) and 2-ethylpiperidine (47.5 mg) in DMF (2.8 ml) were added HOBt (45.9 mg) and WSC.HCl (65.2 mg), and the mixture was stirred at room temperature over night. The reaction mixture was poured into 2% aqueous Sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel 60 column chromatography, and the fraction eluted with ethyl acetate-hexane (0:1-3:7) was concentrated under reduced pressure to give the object compound (81.8 mg). 'H-NMR (CDC1) & 0.81 (3H, s), 1.38-1.62 (4H, m), 1.65 65 1.80 (4H, m), 2.41 (3H, s), 2.83-2.97 (3H, m), 4.65 (2H, d), 5.80 (1H, s), 6.22 (1H, d), 6.26-6.34 (1H, m), 6.43 (1H, d), 7.19 (1H, d), 7.33 (1H, s). US 8,329,691 B2 123 124 Example 2 the extract was concentrated by a nitrogen gas blower. The residue was subjected to reversed-phase preparative HPLC, Method B and the object fraction was passed through MP-CO3 resin (manufactured by Polymer Laboratories) to remove trifluo N-(2-furylmethyl)-3-(2R)-2-(methoxymethyl)pyr 5 roacetic acid. The obtained solution was concentrated by a rolidin-1-yl)carbonyl-6-methylpyridin-2-amine trif nitrogen gas blower to give the object compound (10.6 mg). luoroacetate MS (ESI+, m/e) 468 (M+1)

10 Example 4

Method D

15 5-(2-ethylpiperazin-1-yl)carbonyl-N-(2-furylm ethyl)-2-isopropylpyrimidin-4-amine dihydrochlo ride

To a solution of 2-(2-furylmethyl)amino-6-methylnico tinic acid (13.9 mg) and (2R)-2-(methoxymethyl)pyrrolidine (8.3 mg) in DMF (1.0 ml) was added a solution of HOBt (9.7 25 mg) and WSC.HCl (13.8 mg) in DMF (0.5 ml), and the mixture was stirred at room temperature overnight. The reac 2 N O tion mixture was poured into 2% aqueous Sodium hydrogen 2HC carbonate, the mixture was extracted with ethyl acetate, and / the extract was concentrated by a nitrogen gas blower. The N O residue was subjected to reversed-phase preparative HPLC, 30 and the object fraction was concentrated by a nitrogen gas is blower to give the object compound (12.2 mg). MS (ESI+, m/e) 330 (M+1) tert-Butyl 3-ethyl-4-(4-(2-furylmethyl)amino-2-iso Example 3 35 propylpyrimidin-5-yl)carbonyl)piperazine-1-carboxylate (100 mg) was dissolved in 4 M hydrogen chloride-ethyl Method C acetate solution (3 ml), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated (2R)-1-(2-(2-furylmethyl)aminol-6-methylpyri under reduced pressure, ethyl acetate was added and the pre din-3-yl)carbonyl)pyrrolidin-2-yl)(diphenyl)metha 40 cipitate was collected by filtration to give the object com nol pound (74 mg). MS (ESI+, m/e) 358 (M+1) 45 Example 5 NN Method E 2 N O 50 5-(3-aminopyrrolidin-1-yl)carbonyl-N-(2-furylm ethyl)-2-(methylthio)pyrimidin-4-amine N O

OH 55 (CSO 60 To a solution of 2-(2-furylmethyl)amino-6-methylnico tinic acid (13.9 mg) and diphenyl(pyrrolidin-2-yl)methanol (18.2 mg) in DMF (1.0 ml) was added a solution of HOBt (9.7 mg) and WSC.HCl (13.8 mg) in DMF (0.5 ml), and the mixture was stirred at room temperature overnight. The reac 65 tion mixture was poured into 2% aqueous Sodium hydrogen carbonate, the mixture was extracted with ethyl acetate, and US 8,329,691 B2 125 126 To a solution of 4-(2-furylmethyl)amino-2-(methylthio) extracted with ethyl acetate, and the extract was concentrated pyrimidine-5-carboxylic acid (19.1 mg) and tert-butyl pyrro by a nitrogen gas blower. The residue was purified by lidin-3-ylcarbamate (13.4 mg) in DMF (1.0 ml) was added a reversed-phase preparative HPLC, and the object fraction solution of HOBt (9.7 mg) and WSC.HCl (13.8 mg) in DMF was concentrated by a nitrogen gas blower to give the object (0.5 ml), and the mixture was stirred at room temperature compound (15.8 mg). overnight. The reaction mixture was poured into 2% aqueous MS (ESI+, m/e) 331 (M+1) Sodium hydrogen carbonate, the mixture was extracted with By a method similar to that of the above-mentioned ethyl acetate, and the extract was concentrated by a nitrogen Example 1 (Method A) to Example 6 (Method F), the com gas blower. The residue was purified by reversed-phase pre pounds of Examples 7 to 92 below were obtained. The respec parative HPLC, and the object fraction was concentrated by a 10 tive compounds were isolated and purified as necessary by a nitrogen gas blower. The residue was dissolved in trifluoro known means such as phase transfer, pH conversion, Solvent acetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the extraction, silica gel column chromatography, reversed mixture was stirred at room temperature for 3 hr. The reaction phase preparative HPLC and the like. The final products were mixture was passed through a column of MP-TsOH resin isolated as a free form as in Method A and the like, or as (manufactured by Argonaut) to fix the object compound on 15 trifluoroacetate by concentrating the object fraction of the resin, and the resin was washed with methanol (6 ml). 2 M reversed-phase preparative HPLC as in Method B and the Ammonia-methanol solution (6 ml) was passed through the like, or as hydrochloride by treating with 4 M hydrogen column, and the eluate was concentrated by a nitrogen gas chloride-ethyl acetate solution as in Method D and the like. blower to give the object compound (6.3 mg). MS (ESI+, m/e) 334 (M+1) Example 7 Example 6 3-(azepan-1-ylcarbonyl)-N-(2-furylmethyl)-6-meth ylpyridin-2-amine Method F 25 N-(cyclopropylmethyl)-5-[(2-ethylpiperidin-1-yl) carbonyl-2-isopropylpyrimidin-4-amine trifluoroac etate 30 NN

21 N O

35 N O

H 40 N O 'H-NMR (CDC1) & 1.55-1.86 (8H, m), 2.41 (3H, s), 3.52 (4H, s), 4.65 (2H, d), 5.81 (1H, t), 6.23 (1H,d), 6.27-6.34 (1H, m), 6.43 (1H, d), 7.22 (1H, d), 7.34 (1H, d).

To ethyl 2-isopropyl-6-oxo-1,6-dihydropyrimidine-5-car 45 Example 8 boxylate (250mg) was added 6 M hydrochloric acid (5 ml), and the mixture was stirred at room temperature for 3 hr. The N-(2-furylmethyl)-2-phenyl-5-(piperidin-1-ylcarbo reaction mixture was concentrated under reduced pressure nyl)pyrimidin-4-amine and the obtained residue was dissolved in DMF (5 ml). Tri ethylamine (146 mg), 2-ethylpiperidine (163 mg), HOBt (194 50 mg) and WSC.HCl (275 mg) were added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2% aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was Sub 55 jected to silica gel column chromatography, and the fraction eluted with methanol-ethyl acetate (0:1-1:9) was concen trated under reduced pressure. The residue was dissolved in acetonitrile (10 ml). A solution of benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (35.0 60 1. O mg) in acetonitrile (0.5 ml) and a solution of triethylamine (9.1 mg) in acetonitrile (0.5 ml) were added to the solution N O (0.5 ml), and the mixture was stirred at room temperature for 20 min. A Solution of 1-cyclopropylmethanamine (6.4 mg) in acetonitrile (0.5 ml) was added and the mixture was stirred at 65 70° C. overnight. The reaction mixture was poured into 2% aqueous Sodium hydrogen carbonate, the mixture was MS (ESI+, m/e) 363 (M+1)

US 8,329,691 B2 157 158 Example 94 Example 96 Method H methyl (3R,5S)-5-[(2-tert-butyl-4-(3-methoxypro 2-tert-butyl-4-(2-furylmethyl)amino-N-((3R*, pyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl)aminol 5S)-5-(4-hydroxy-4-methylpiperidin-1-yl)carbo 5 piperidine-3-carboxylate dihydrochloride nylpiperidin-3-yl)-N-isobutylpyrimidine-5-carboxa mide dihydrochloride

10

15 2 1n-1\-1 H r O

HN ON

O tert-Butyl (3R*,5S*)-3-((2-tert-butyl-4-(2-furylmethyl) 25 aminolpyrimidin-5-yl)carbonyl)(isobutyl)amino-5-(4-hy droxy-4-methylpiperidin-1-yl)carbonylpiperidine-1-car boxylate (110 mg) was dissolved in 2 M hydrogen chloride MS (ESI+, m/e) 464 (M+1) ethyl acetate (2 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 30 ethyl acetate-hexane was added and the precipitate was col Example 97 lected by filtration and washed with ethyl acetate-hexane to give the object compound (104 mg). MS (ESI+, m/e) 555 (M+1) 2-tert-butyl-4-(3-methoxypropyl)amino-N-(2-me By a method similar to that of the above-mentioned 35 thylpropyl)-N-(3S.5R)-5-(morpholin-4-ylcarbonyl) Example 93 (Method G) and Example 94 (Method H), the piperidin-3-ylpyrimidine-5-carboxamide dihydro compounds of Examples 95 and 96 below were obtained. The chloride respective compounds were isolated and purified as necessary by a known means such as phase transfer, pH conversion, Solvent extraction, silica gel column chromatography, reversed-phase preparative HPLC and the like. The final 40 products were isolated as hydrochloride as in Method G and Method H by treating with a hydrogen chloride-ethyl acetate Solution. Example 95 45 2 1N1So1 2-tert-butyl-4-(2-furylmethyl)amino-N-(3R,5S)- H 5-(1-hydroxy-1-methylethyl)piperidin-3-yl)-N- isobutylpyrimidine-5-carboxamide dihydrochlorde 50 r N O

N NN 55

CityH / tert-Butyl (3S.5R)-3-(2-tert-butyl-4-(3-methoxypro r O 60 pyl)aminolpyrimidin-5-yl)carbonyl)(isobutyl)amino-5- (morpholin-4-ylcarbonyl)piperidine-1-carboxylate (105 mg) is was dissolved in 1 M hydrogen chloride-ethyl acetate (6 ml), and the mixture was stirred at room temperature for 13 hr. The reaction mixture was concentrated to give the object OH 65 compound (93 mg). MS (ESI+, m/e) 472 (M+1) MS (ESI+, m/e) 519 (M+1) US 8,329,691 B2 159 160 Example 98 Example 99 Method I methyl (3R*,5S)-5-[{4-(benzylamino)-2-tert-bu methyl (3R*,5S)-5-[(2-tert-butyl-4-3-(meth- 5 tylpyrimidin-5 -: ty. (hyl)aminolpiperi ylthio)propylaminopyrimidin-5-yl)carbonyl 1ne-3-carboxylate (isobutyl)aminolpiperidine-3-carboxylate

10

H N1 NN r CroO

--- 2O HN O r O N 25

HN O N MS (ESI+, m/e) 482 (M+1) 30 Reference Example 51

(3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycar bonyl)piperidine-3-carboxylic acid, (3R,5R)-1- (tert-butoxycarbonyl)-5-(methoxycarbonyl)piperi 35 dine-3-carboxylic acid and 1-tert-butyl 3,5-dimethyl piperidine-1,3,5-tricarboxlate To a solution of 1-tert-butyl 3-methyl (3R*,5S)-5-[(2- tert-butyl-4-chloropyrimidin-5-yl)carbonyl(isobutyl) amino)piperidine-1,3-dicarboxylate (51.1% mg) and diiso- 40 propylethylamine (38 mg) in DMF (0.5 ml) was added a solution of 3-methylthiopropylamine (21 mg) in DMF (0.5 ml), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added 2% aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate, 45 O N O and the extract was concentrated by a nitrogen gas blower. N The residue was purified by reversed-phase preparative X HPLC, and the object fraction was concentrated by a nitrogen O O gas blower. The residue was dissolved in trifluoroacetic acid/ 's-1 OH acetonitrile solution (20% (V/V), 1.0 ml), and the mixture 50 was stirred at room temperature for 6 hr. The reaction mixture was concentrated by a nitrogen gas blower. The residue was neutralized with triethylamine (1 ml), Saturated aqueous O N O Sodium hydrogen carbonate was added, and the mixture was N extracted with ethyl acetate. The extract was concentrated by 55 X r a nitrogen gas blower. The residue was purified by reversed O O phase preparative HPLC, and the object fraction was concen trated by a nitrogen gas blower to give the object compound O O (6.4 mg). MS (ESI+, m/e) 480 (M+1) 60 By a method similar to that of the above-mentioned Example 98 (Method I), the compound of Example 99 below was obtained. The compounds were isolated and purified as x" N On necessary by a known means such as phase transfer, pH conversion, solvent extraction, silica gel column chromatog- 65 O raphy, reversed-phase preparative HPLC and the like. The final products were isolated as a free form. US 8,329,691 B2 161 162 Dimethylpyridine-3,5-dicarboxylate (55 g) was dissolved and the mixture was stirred under pressurized hydrogen in methanol (500 ml) and 6 M hydrochloric acid (70 ml), and atmosphere (5 atm) at 50° C. for 15 hr. The reaction mixture rhodium-carbon (5.5 g) was added. The reaction mixture was was allowed to cool to room temperature, the rhodium cata stirred under pressurized hydrogen atmosphere (5 atm) at lyst was filtered off, and the filtrate was concentrated under room temperature for 3 hr, and thereafter at 50° C. for 12 hr. reduced pressure. The residue was dissolved in ethanol (300 The mixture was allowed to cool to room temperature, the ml) and, under ice-cooling, triethylamine (107 ml) and di rhodium catalyst was filtered off, and the filtrate was concen tert-butyl dicarbonate (67 g) were successively added. The trated under reduced pressure. The residue was dissolved in reaction mixture was stirred at room temperature for 15 hr, ethanol (300 ml) and, under ice-cooling, triethylamine (60 and concentrated under reduced pressure. The residue was ml) and di-tert-butyl dicarbonate (68 g) were successively 10 dissolved in water, and the mixture was adjusted to pH 3 with added. The reaction mixture was stirred at room temperature 6 M hydrochloric acid. The mixture was extracted with ethyl for 12 hr., and concentrated under reduced pressure. The resi acetate. The ethyl acetate extract layer was washed with satu due was dissolved in 0.5M hydrochloric acid, and the mixture rated brine, and dried over anhydrous sodium sulfate. The was extracted with ethyl acetate. The extract was washed with 15 solvent was evaporated under reduced pressure. The residue saturated brine, and dried over anhydrous sodium sulfate. The was dissolved in methanol (250 ml), and 8 Naqueous sodium Solvent was evaporated under reduced pressure and the resi hydroxide solution (128 ml) was added dropwise at room due was purified by silica gel column chromatography. The temperature. The reaction mixture was stirred at room tem fraction eluted with hexane-ethyl acetate (7:1-1:4) was perature for 24 hr, and methanol was evaporated under obtained. The less polar fraction was concentrated under reduced pressure. The concentrated solution was diluted with reduced pressure to give 1-tert-butyl 3,5-dimethylpiperidine saturated aqueous Sodium hydrogen carbonate Solution (100 1,3,5-tricarboxylate (22.2 g). The more polar fraction was ml) and washed twice with diethyl ether. The basic aqueous concentrated under reduced pressure, and the residue was layer was acidified (pH 3) with 6 M hydrochloric acid. The diluted with ethyl acetate. The precipitate was collected by precipitated powder was collected by filtration, washed with filtration and washed with ethyl acetate to give (3R,5S)-1- water, and air-dried. The obtained powder (55 g) was dis (tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3- 25 solved in methanol (200 ml) by heating and the mixture was carboxylic acid (15.6 g) as a powder. The filtrate was concen concentrated under reduced pressure until the amount of trated under reduced pressure to give a mixture (8.9 g) of methanol became half. Water (50 ml) was added, and the (3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pi mixture was stood at room temperature overnight. The pre peridine-3-carboxylic acid and (3R,5R)-1-(tert-butoxycar cipitated white powder was collected by filtration, washed bonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid. 30 with cold methanol/water 2/1 (200 ml) and air-dried to give (3R*,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pi the object compound (38 g) as a powder. peridine-3-carboxylic acid 'H-NMR (CDC1) & 1.47 (9H, s), 1.72 (1H, d), 2.41-2.63 'H-NMR (CDC1) & 1.47 (9H, s), 1.72 (1H, d), 2.41-2.63 (3H, m), 2.72 (2H, brs), 3.71 (3H, s), 4.38 (2H, d). (3H, m), 2.72 (2H, brs), 3.71 (3H, s), 4.38 (2H, d). Mixture of (3R*,5S)-1-(tert-butoxycarbonyl)-5-(methoxy 35 Reference Example 53 carbonyl)piperidine-3-carboxylic acid and (3R,5R)-1- (tert-butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3- (3S.5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbo carboxylic acid nyl)piperidine-3-carboxylic acid 'H-NMR (CDC1) & 1.33-1.50 (9H, m), 1.60-182 (1H, m), 40 1.96-2.22 (1H, m), 2.41-2.58 (2H, m), 2.62–2.91 (2H, m), 3.34-3.91 (1H, m), 3.71 (3H, s), 4.37 (1H, brs), 7.55-8.47 (1H, m). 1-tert-butyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate 'H-NMR (CDC1) & 1.36-1.50 (2H, m), 1.46 (7H, m), 45 1.62-1.76 (1H, m), 1.99-2.16 (1H, m), 2.38-2.55 (2H, m), 2.61-2.75 (1H, m), 2.81 (1H, t), 3.39-3.60(1H, m), 3.64-3.81 (6H, m), 4.35 (1H, brs).

Xr O On Reference Example 52 50 (3R,5S)-1-(tert-butoxycarbonyl)piperidine-3,5-dicar (3R,5S)-1-(tert-Butoxycarbonyl)piperidine-3,5-dicar boxylic acid boxylic acid (222 g) was suspended in acetic anhydride (2L), and the suspension was heated under reflux for 3 hr. The 55 reaction mixture was concentrated under reduced pressure. Toluene (200 ml) was added and the mixture was concen trated under reduced pressure. This operation was repeated twice. The obtained residue and quinidine (142 g) were dis solved in THF (900 ml), and the mixture was cooled to -40° 60 C. A solution of methanol (161 ml) in THF (100 ml) was added dropwise over 30 min, and the mixture was stirred at xy OH the same temperature for 7 hr. THF (about 700 ml) was evaporated under reduced pressure, ethyl acetate was added, O O and the mixture was washed with 2 N hydrochloric acid. The 65 aqueous layer was extracted with ethyl acetate, the organic Dimethylpyridine-3,5-dicarboxylate (50 g) was dissolved layer was combined and the mixture was washed Successively in acetic acid (300 ml), 5% rhodium carbon (5 g) was added, with 2N hydrochloric acid and saturated brine, and dried over US 8,329,691 B2 163 164 anhydrous magnesium sulfate. The solvent was concentrated Reference Example 55 under reduced pressure and the obtained residue (106 g) was suspended in ethanol (410 ml). (R)-(+)-1-Phenylethylamine 1-tert-butyl 3-methyl (45 g) was added, and the mixture was dissolved by heating to 5-aminopiperidine-1,3-dicarboxylate 75°C. The hot ethanol solution was rapidly filtered, and the filtrate was allowed to stand at room temperature for 12 hr. The resulting colorless crystals were collected by filtration, washed with ethyl acetate-hexane, and then with hexane and NH2 air-dried. The obtained solid was suspended in water (490 ml). Saturated aqueous potassium hydrogen Sulfate Solution 10 (490 ml) was added and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with Satu rated brine, dried over anhydrous magnesium Sulfate and concentrated to dryness to give the object compound (148 g) O O 15 eror as a Solid. 'H-NMR (DMSO-d) & 1.39 (9H, s), 1.52 (1H, q), 2.18 'H-NMR (CDC1) & 1.19-141 (3H, m), 1.4.6-1.50 (9H, m), 2.54 (3H, m), 2.55-2.78 (2H, m), 3.63 (3H, s), 4.03-4.23 (2H, 1.82-2.78 (4H, m), 3.49 (1H, m), 3.64-3.73 (3H, m), 4.15 (2H, m), 12.51 (1H, brs). brs). By a method similar to that of Reference Example 44, the Reference Example 54 following compound (Reference Example 56) was obtained. 1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)piperi Reference Example 56 dine-3-carboxyl acid 25 1-tert-butyl 3-methyl 5-(2-methylpropyl)amino piperidine-1,3-dicarboxylate

30

35 X-r ,O On 40 'H-NMR (CDC1) & 0.93-1.09 (2H, m), 1.02 (4H, d), 1.45 (9H, d), 2.05 (3H, s), 2.65-2.79 (2H, m), 2.83-2.98 (1H, m), 3.25 (1H, dd), 3.49 (2H, s), 3.58-3.75 (3H, m), 3.94 (1H, d). 45 Reference Example 57 1-tert-butyl 3-methyl (3R,5S)-5-(benzyloxy)carbo 1-tert-Butyl 3,5-dimethyl piperidine-1,3,5-tricarboxylate nyl)amino)piperidine-1,3-dicarboxylate (75 g) was dissolved in methanol (375 ml), and 2 Maqueous sodium hydroxide solution (125 ml) was added dropwise at 50 room temperature. The reaction mixture was stirred at room temperature for 14 hr, and methanol was evaporated under reduced pressure. The concentrated solution was diluted with saturated aqueous sodium hydrogen carbonate solution (100 ml) and washed twice with ethyl acetate. The basic aqueous 55 1. layer was acidified (pH2) with 6 Mhydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium Sulfate, and the solvent was evaporated under reduced pressure to give the object com pound (71 g). 60 X-r O On 'H-NMR (CDC1,) & 1.33-1.50 (9H, m), 1.60-1.82(1H, m), 'C 1.96-2.22 (1H, m), 2.41-2.58 (2H, m), 2.62–2.91 (2H, m), 3.34-3.91 (1H, m), 3.71 (3H, s), 4.37 (1H, brs), 7.55-8.47 (3S,5R)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)pi (1H, m). 65 peridine-3-carboxylic acid (2.83 g) was suspended in toluene By a method similar to that of Reference Example 43, the (36 ml), diphenylphosphoryl azide (2.60 ml) and triethy following compound (Reference Example 55) was obtained. lamine (1.70 ml) were added, and the mixture was stirred at US 8,329,691 B2 165 166 100° C. for 1 hr. The reaction mixture was cooled to room (3R,5S)-5-[(Benzyloxy)carbonyl)amino-1-(tert-bu temperature, benzyl alcohol (1.53 ml) and triethylamine toxycarbonyl)piperidine-3-carboxylic acid (49.2g), morpho (7.00 ml) were added and the mixture was stirred at 80°C. for line (11.4 ml), 1 H-benzotriazol-1-ol (10.0 g) and triethy 3 hr. The reaction mixture was concentrated, and the residue lamine (40 ml) were dissolved in DMF (250 ml), WSC.HCl was dissolved in ethyl acetate, washed with water, 0.5 M hydrochloric acid, Saturated aqueous Sodium hydrogen car (30.0 g) was added and the mixture was stirred at room bonate and saturated brine in this order, and dried over anhy temperature for 4 days. The reaction mixture was poured into drous magnesium Sulfate. The solvent was evaporated under water, and the mixture was extracted with ethyl acetate. The reduced pressure. The residue was subjected to silica gel extract was washed Successively with Saturated aqueous Sodium hydrogen carbonate Solution and saturated brine, and column chromatography, and the fraction eluted with ethyl 10 acetate-hexane (1:3-3:1) was concentrated under reduced dried over anhydrous magnesium sulfate. The solvent was pressure to give the object compound (2.78 g) as an oil. evaporated under reduced pressure to give the object com MS (ESI+, m/e) 393 (M+1) pound (62.9 g). H-NMR (CDC1) & 1.46 (9H, s), 1.69 (2H, brs), 2.04 (1H, Reference Example 58 15 s), 2.73 (2H, brs), 2.79-2.96 (1H, m), 3.52-3.65 (6H, m), 3.69 (3R,5S)-5-[(benzyloxy)carbonyl)amino-1-(tert (2H, d), 3.67 (1H, brs), 4.04 (1H, d), 5.09 (2H, s), 5.40 (1H, butoxycarbonyl)piperidine-3-carboxylic acid brs), 7.25-7.41 (5H, m). Reference Example 60

tert-butyl (3S.5R)-3-(2-methylpropyl)amino-5- -- (morpholin-4-ylcarbonyl)piperidine-1 arboxylate 25

X-r O OH o 30 r To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-(benzy loxy)carbonyl)amino piperidine-1,3-dicarboxylate (115 g) r in methanol (700 ml) was added 1 Maqueous sodium hydrox 35 ide solution (350 ml) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture also was concentrated under reduced pressure to about 1/3 vol ume, and the residualaqueous solution was washed with ethyl acetate-hexane (1:1, 600 ml). The aqueous layer was neutral 40 ized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with tert-Butyl (3S.5R)-3-(benzyloxy)carbonylamino-5- saturated brine, and dried over anhydrous magnesium Sulfate. (morpholin-4-ylcarbonyl)piperidine-1-carboxylate (58 g) The solvent was evaporated under reduced pressure to give and palladium(II) hydroxide-carbon (5 g) were Suspended in the object compound (98.5 g). methanol (400 ml), and the Suspension was stirred under a 'H-NMR (DMSO-d) & 1.33 (1H, brs), 1.40 (9H, s), 2.09 45 hydrogen atmosphere (1 atm) at room temperature for 16 hr. (1H, d), 2.36-2.52 (3H, m), 3.93-4.09 (2H, m), 5.03 (2H, s), The palladium catalyst was filtered off, and the filtrate was 7.28-7.43 (5H, m), 12.52 (1H, brs). concentrated under reduced pressure. The obtained residue and acetic acid (8.8 ml) were dissolved in methanol (400 ml), Reference Example 59 2-methylpropanal (14.0 ml) was added and the mixture was 50 stirred at room temperature for 1 hr. Sodium triacetoxyboro tert-butyl (3S.5R)-3-(benzyloxy)carbonyl)amino hydride (40.4 g) was added to the reaction mixture, and the 5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the con 55 centrated solution was basified with 3.5 Maqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The Sol vent was evaporated under reduced pressure. The residue was - - ) Subjected to silica gel column chromatography, and the frac tion eluted with ethyl acetate-hexane (1:5) to ethyl acetate 100% to ethyl acetate-methanol (9:1) was concentrated under r reduced pressure to give the object compound (33.3 g). 'H-NMR (CDC1) & 0.90 (6H, d), 1.46 (9H, s), 1.54 (1H, Xr Nu 65 d), 1.69 (1H, dt), 1.96-2.12 (2H, m), 2.23-2.37 (1H, m), 2.47 (3H, d), 2.66 (1H, d), 3.61 (1H, brs), 3.55 (2H, d), 3.69 (5H, ddd), 4.01-4.46 (2H, m). US 8,329,691 B2 167 168 Reference Example 61 Reference Example 63

tert-butyl (3S)-3-(2-methylpropyl)aminolpiperidine tert-butyl 1-carboxylate 5 3-(2-methylpropyl)aminolpyrrolidine-1-carboxylate

r 10 NH Xr

'H-NMR (CDC1) & 0.77-1.15 (8H, m), 1.16-1.37 (1H, m), tert-Butyl (3S)-3-aminopiperidine-1-carboxylate (5.0 g). 1.36-1.56 (9H, m), 1.61-1.81 (2H, m), 1.83-2.02 (1H, m), isobutyraldehyde (2.66 ml) and acetic acid (1.72 ml) were 2.34-2.59 (3H, m), 2.76-3.00 (1H, m), 3.70-3.95 (1H, m). dissolved in methanol (100 ml), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was 25 added sodium triacetoxyborohydride (13.2g) and the mixture Reference Example 64 was stirred at room temperature for 30 min. The reaction mixture was basified with aqueous Sodium hydrogen carbon tert-butyl 3-(propylamino)piperidine-1-carboxylate ate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhy 30 drous magnesium Sulfate. The solvent was evaporated under reduced pressure. A part of the residue was Subjected to silica N-1NN gel column chromatography, and the fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object compound (3.04 g) as an oil. 35 'H-NMR (CDC1,) & 0.79-1.15 (8H, m), 1.16-1.36 (1H, m), 1.36-1.56 (11H, m), 1.58-1.80 (2H, m), 1.80-2.00 (1H, m), 2.35-2.60 (3H, m), 2.74-2.99 (1H, m), 3.68-3.91 (1H, m). Xr MS (ESI+, m/e) 257 (M+1) 40 By a method similar to that of Reference Example 61, the tert-Butyl 3-piperidone-1-carboxylate (1.99 g), propy following compounds (Reference Examples 62 and 63) were lamine (0.82 ml) and acetic acid (0.57 ml) were dissolved in obtained. methanol (50 ml), and the mixture was stirred at room tem 45 perature for 1 hr. To the reaction mixture was added sodium Reference Example 62 triacetoxyborohydride (4.23 g) and the mixture was stirred at room temperature for 15 hr. The reaction mixture was basified with aqueous Sodium hydrogen carbonate, and the mixture tert-butyl (3R)-3-(2-methylpropyl)aminolpiperi was extracted with ethyl acetate. The extract was washed with dine-1-carboxylate 50 saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in THF (20 ml), 2 Maqueous sodium hydrox ide solution (3 ml) was added, Z-chloride (2.86 ml) was added dropwise, and the mixture was stirred at room temperature for S 55 15 hr. To the reaction mixture was added ethyl acetate, and the organic layer was separated, washed with water and Saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was Subjected to silica gel column chromatography, the fraction Xy 60 eluted with ethyl acetate-hexane (1:9-1:4) was concentrated under reduced pressure and the obtained residue was dis solved in ethanol (30 ml). 10% Palladium carbon (50% con taining water, 0.20 g) was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 'H-NMR (CDC1) & 0.79-1.15 (8H, m), 1.16-1.36 (1H, m), 65 16 hr. The palladium catalyst was filtered off, and the filtrate 1.36-1.56 (11H, m), 1.58-1.80 (2H, m), 1.80-2.00 (1H, m), was concentrated under reduced pressure to give the object 2.35-2.60 (3H, m), 2.74-2.99 (1H, m), 3.68-3.91 (1H, m). compound (2.42 g) as an oil. US 8,329,691 B2 169 170 'H-NMR (CDC1) & 0.92 (3H, t), 1.26 (1H, dd), 1.37-1.58 By a method similar to that of Example 1, the following (2H, m), 1.46 (9H, s), 1.67 (1H, td), 1.78 (1H, brs), 1.91 (1H, compounds (Reference Examples 68 and 69) were obtained. dd), 2.44-2.76 (4H, m), 2.87 (1H, brs), 3.79 (2H, d). By a method similar to that of Reference Example 64, the following compounds (Reference Examples 65 to 67) were is Reference Example 68 obtained. tert-butyl 3-(2-tert-butyl-4-(furan-2-ylmethyl) Reference Example 65 aminolpyrimidin-5-yl)carbonyl)(propyl)aminolpip tert-butyl eridine-1-carboxylate 3-(cyclopropylmethylamino)piperidine-1-carboxylate 10

v- 15 xy- 2O --- O uCC) 'H-NMR (CDC1,) & 0.06-0.17 (2H, m), 0.41-0.54 (2H, m), 0.94 (1H, dddd), 128 (1H, dd), 1.46 (9H, s), 1.60-177 (3H, m), 1.91 (1H, dd), 2.45-2.78 (3H, m), 2.77-3.08 (1H, m), 3.78 (1H, dt), 4.00 (1H, brs). x" N Reference Example 66 tert-butyl 30 O 3-(2-methylpropyl)aminopiperidine-1-carboxylate

MS (ESI+, m/e) 500 (M+1) NH Reference Example 69 O r N 40 aminolpyrimidin-5-yl)carbonyl)(cyclopropylmethyl)tert-butyl 3-(2-tert-butyl-4-(furan-2-ylmethyl) aminolpiperidine-1-carboxylate O H-NMR (CDC1) & 0.90 (6H, d), 1.22-1.40 (3H, m), 1.46 as (9H, s), 1.55-1.78 (2H, m), 1.90 (1H, d), 2.45 (3H, dd), 2.87 (1H, brs), 3.54-4.24 (2H, m). Reference Example 67 tert-butyl 3-(butylamino)piperidine-1-carboxylate 50 NN

1N1 NH 55 v1. O

X O. N. 60 X O. N. O O H-NMR (CDC1) & 0.91 (3H, t), 1.20-1.42 (4H, m), 1.42 1.52 (3H, m), 1.46 (9H, s), 1.67 (1H, td), 1.78–2.04 (1H, m), 65 2.47-2.79 (3H, m), 2.87 (1H, brs), 3.79 (1H, d), 4.04 (1H, br S). MS (ESI+, m/e) 512 (M+1) US 8,329,691 B2 171 172 By a method similar to that of Reference Example 37, the Reference Example 72 following compounds (Reference Examples 70 to 74) were obtained. tert-butyl (3R)-3-(2-tert-butyl-4-(furan-2-ylm 5 ethyl)aminolpyrimidin-5-yl)carbonyl)(2-methylpro Reference Example 70 pyl)aminolpiperidine-1-carboxyate tert-butyl 3-(2-tert-butyl-4-(furan-2-ylmethyl) aminolpyrimidin-5-yl)carbonyl)(2-methylpropyl) aminolpiperidine-1-carboxylate 10

15 n N 21 N

O

r O xy 30

is MS (ESI+, m/e) 514 (M+1) MS (ESI+, m/e) 514 (M+1) Reference Example 73

Reference Example 71 40 tert-butyl (3S)-3-((2-tert-butyl-4-(furan-2-ylm tert-butyl 3-butyl({2-tert-butyl-4-(furan-2-ylm- ethyl)aminolpyrimidin-5-yl)carbonyl)(2-methylpro ethyl)aminolpyrimidin-5-yl)carbonyl)aminolpiperi- pyl)aminolpiperidine-1-carboxylate dine-1-carboxylate 45

Xr 65 MS (ESI+, m/e) 514 (M+1) MS (ESI+, m/e) 514 (M+1) US 8,329,691 B2 173 174 Reference Example 74 Reference Example 76 tert-butyl 3-(2-tert-butyl-4-(furan-2-ylmethyl) (3R,5S)-1-(tert-butoxycarbonyl)-5-[(2-tert-butyl-4- aminolpyrimidin-5-yl)carbonyl)(2-methylpropyl) (1.3-oxazol-2-ylmethyl)aminolpyrimidin-5- aminolpyrrolidine-1-carboxylate y1}carbonyl)(2-methylpropyl)aminolpiperidine-3- carboxylic acid

10

N NN 15 2 H reIX r N O

x's O

25 xy MS (ESI+, m/e) 500 (M+1) Reference Example 75 1-tert-Butyl 3-methyl (3R,5S)-5-[(2-tert-butyl-4-(1,3- oxazol-2-ylmethyl)aminolpyrimidin-5-yl)carbonyl) (2-me 1-tert-butyl 3-methyl (3R,5S)-5-[(2-tert-butyl-4-(1, thylpropyl)aminolpiperidine-1,3-dicarboxylate (0.26 g) was 3-oxazol-2-ylmethyl)aminolpyrimidin-5- 30 y1}carbonyl)(2-methylpropyl)aminolpiperidine-1,3- dissolved in methanol (3 ml), 2 Maqueous sodium hydroxide dicarboxylate solution (1.0 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concen trated under reduced pressure, the residue was diluted with saturated aqueous ammonium chloride Solution, and the mix 35 ture was extracted with ethyl acetate. The extract was dried over anhydrous Sodium Sulfate and concentrated under reduced pressure to give the object compound (0.25 g). MS (ESI+, m/e) 559 (M+1) N NN 40 Reference Example 77 2 H re ly tert-butyl (3S.5R)-3-((2-tert-butyl-4-(1,3-oxazol-2- N O ylmethyl)aminolpyrimidin-5-yl)carbonyl)(2-methyl r 45 propyl)amino-5-(morpholin-4-ylcarbonyl)piperi xy dine-1-carboxylate To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-[(2-tert butyl-4-chloropyrimidin-5-yl)carbonyl(isobutyl) amino)piperidine-1,3-dicarboxylate (0.55g) and diisopropy 55 lethylamine (0.87 ml) in 2-propanol (5 ml) was added 2-oxazolylmethylamine hydrochloride (0.34g), and the mix ture was stirred at 80°C. for 15 hr. The reaction mixture was concentrated under reduced pressure, Saturated aqueous Sodium hydrogen carbonate was added, and the mixture was 60 extracted with ethyl acetate. The extract was dried over anhy drous Sodium Sulfate and concentrated under reduced pres sure. The obtained residue was subjected to silica gel chro matography, and the fraction eluted with hexane to ethyl acetate-hexane (1:2) was concentrated under reduced pres 65 Sure to give the object compound (525 mg). MS (ESI+, m/e) 573 (M+1) US 8,329,691 B2 175 176 (3R,5S)-1-(tert-Butoxycarbonyl)-5-[(2-tert-butyl-4-(1, Reference Example 80 3-oxazol-2-ylmethyl)aminolpyrimidin-5-yl)carbonyl)(2- methylpropyl)aminolpiperidine-3-carboxylic acid (125 mg), HOBt (52 mg) and WSC.HCl (64 mg) were dissolved in tert-butyl (3S.5R)-3-(4-(benzylamino)-2-tert-bu acetonitrile (3 ml), morpholine (20 ul) and triethylamine (94 5 tylpyrimidin-5-yl)carbonyl-(2-methylpropyl)aminol ul) were added and the mixture was stirred at room tempera 5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate ture for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The Solvent was evaporated under reduced pressure and the resi 10 due was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:9) to ethyl acetate was concentrated under reduced pressure to give the object compound (110 mg). MS (ESI+, m/e) 628 (M+1) 15 By a method similar to that of Reference Example 75, the following compound (Reference Example 78) was obtained. Cl, Reference Example 78 1-tert-butyl 3-methyl (3R,5S)-5-(4-(benzy lamino)-2-tert-butylpyrimidin-5-yl)carbonyl}(2-me thylpropyl)aminolpiperidine-1,3-dicarboxylate C 25 alsoO N NN MS (ESI+, m/e) 637 (M+1) By a method similar to that of the above-mentioned 30 H Example 93 (Method G) and Example 94 (Method H), the 21 ro compounds of Examples 100 to 107 below were obtained. N O The respective compounds were isolated and purified as nec essary by a known means such as phase transfer, pH conver Nr. Sion, Solvent extraction, silica gel column chromatography, 35 reversed-phase preparative HPLC and the like. The final products were isolated as hydrochloride as in Method G and Method H by treating with a hydrogen chloride-ethyl acetate xy Solution. MS (ESI+, m/e) 582 (M+1) 40 By a method similar to that of Reference Example 76, the Example 100 following compound (Reference Example 79) was obtained. Reference Example 79 2-tert-butyl-4-(furan-2-ylmethyl)amino-N-piperi (3R,5S)-5-[{4-(benzylamino)-2-tert-butylpyrimidin 45 din-3-yl-N-propylpyrimidine-5-carboxamide dihy 5-yl)carbonyl-(2-methylpropyl)amino-1-(tert-bu drochloride toxycarbonyl)piperidine-3-carboxylic acid

50

N NN l N 55 2 roH 2 N O N O r N-1a O 60 xy 2HC MS (ESI+, m/e) 568 (M+1) 65 By a method similar to that of Reference Example 77, the following compound (Reference Example 80) was obtained. MS (ESI+, m/e) 473 (M+1)

US 8,329,691 B2 181 182 Example 109 By a method similar to that of Reference Example 81, the following compound (Reference Example 82) was obtained. 2-tert-butyl-N-(2-methylpropyl)-N-(3S.5R)-5-(mor pholin-4-ylcarbonyl)piperidin-3-yl)-4-(1,3-oxazol Reference Example 82 2-ylmethyl)aminolpyrimidine-5-carboxamide sulfate Sodium 3.3-dimethyl-2-oxocyclopentylidenemethanolate

10

ONa

15

'H-NMR (DO) & 0.91 (6H, s), 1.58 (2H, t), 2.25 (2H, t), 8.63 (1H, s). HN NO H2SO4 Reference Example 83 25 8a-hydroxy-2-oxo-1,2,3,5,6,7,8,8a-octahydroquino tert-Butyl (3S.5R)-3-((2-tert-butyl-4-(1,3-oxazol-2-yl line-3-carbonitrile methyl)aminolpyrimidin-5-yl)carbonyl)(2-methylpropyl) amino-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxy late (108 mg) was dissolved in 2 M hydrogen chloride-ethyl 30 acetate (2 ml), and the mixture was stirred at room tempera CN ture for 16 hr. The reaction mixture was basified with satu rated sodium hydrogen carbonate Solution, and the mixture was extracted with ethyl acetate. The extract was dried over Sodium sulfate and concentrated under reduced pressure. The 35 HO residue was dissolved in ethanol (3 ml), concentrated sulfuric acid (10 ul) was added and the mixture was concentrated under reduced pressure. Ethyl acetate (5 ml) and ethanol (0.1 ml) were added to the residue and the mixture was heated to Sodium 2-oxocyclohexylidenemethanolate (15 g), 2-cy 90° C. Ethanol was added and a homogeneous solution was 40 anoacetamide (4.3 g) and piperidine (1.0 ml) were suspended cooled to room temperature. The precipitate was collected by in water (35 ml), and the mixture was stirred at 40°C. for 4 filtration to give the object compound (40 mg). days. Insoluble material was filtered off, and the filtrate was MS (ESI+, m/e) 528 (M+1) concentrated under reduced pressure. The residue was Sus pended in methanol, and insoluble material was filtered off. 45 The filtrate was concentrated under reduced pressure to give Reference Example 81 the object compound (21.4 g). MS (ESI+, m/e) 193 (M+1) Sodium 2-oxocyclohexylidenemethanolate By a method similar to that of Reference Example 83, the 50 following compound (Reference Example 84) was obtained.

Reference Example 84

55 7a-hydroxy-7,7-dimethyl-2-oxo-2,3,5,6,7,7a-hexahy dro-1H-cyclopentabpyridine-3-carbonitrile

Cyclohexanone (30 ml) and ethyl formate (24 ml) were 60 dissolved in diethyl ether (150 ml), sodium ethoxide (21 g) CN was added under ice-cooling, and the reaction mixture was stirred at room temperature for 10 hr. Insoluble material was collected by filtration, and washed with diethyl ether to give HO the object compound (49.2 g) as a solid. 65 'H-NMR (DO) & 1.47-1.61 (4H, m), 2.06-2.16 (2H, m), 2.10 (2H, d), 8.98 (1H, s). MS (ESI+, m/e) 207 (M+1) US 8,329,691 B2 183 184 Reference Example 85 acetate. The extract was washed successively with 1 Maque ous sodium hydroxide solution and Saturated brine, and dried 2-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylic over anhydrous magnesium Sulfate. The solvent was evapo acid rated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (50:50-85:15) was concentrated under reduced pressure to give the object compound (3.45 g). O 'H-NMR (CDC1) & 1.38 (3H, t), 1.79 (4H, dd), 2.55 (2H, 21 OH 10 t), 2.77 (2H, t), 4.36 (2H, q), 7.99 (1H, s). By a method similar to that of Reference Example 87, the N following compound (Reference Example 88) was obtained. N OH H

15 Reference Example 88 8a-Hydroxy-2-oxo-1,2,3,5,6,7,8,8a-octahydroquinoline 3-carbonitrile (20.5 g) was suspended in concentrated hydro ethyl 2-hydroxy-7,7-dimethyl-6,7-dihydro-5H-cyclo chloric acid (100 ml), and the mixture was stirred with heat pentabpyridine-3-carboxylate ing to reflux for 12 hr. The reaction mixture was cooled to room temperature, and insoluble material was filtered off. The filtrate was applied to DIAION (registered trademark) HP-20 (manufactured by Mitsubishi Chemical Corporation), and washed with water and the fraction eluted with acetone was concentrated under reduced pressure to give the object compound (11.5 g). 25 MS (ESI+, m/e) 222 (M+1) By a method similar to that of Reference Example 85, the OH following compound (Reference Example 86) was obtained. Reference Example 86 30 2-hydroxy-7,7-dimethyl-6,7-dihydro-5H-cyclopenta 'H-NMR (CDC1,) & 1.30 (6H, s), 1.40 (3H, t), 1.98 (2H, t), bipyridine-3-carboxylic acid 2.78 (1H, t), 4.12 (1H, d), 4.40 (2H, q), 8.01 (1H, s). MS (ESI+, m/e) 236 (M+1) 35 Reference Example 89

21 OH ethyl 40 2-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylate N OH

MS (ESI+, m/e) 208 (M+1) 45 Reference Example 87

ethyl 2-hydroxy-5,6,7,8-tetrahydroquinoline-3-car C boxylate 50

Ethyl 2-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxy O late (3.40 g) was dissolved in phosphorus oxychloride (30 55 ml), and the mixture was stirred with heating to reflux for 10 21 1N hr. The reaction mixture was concentrated under reduced pressure, Saturated aqueous sodium hydrogen carbonate solu N N OH tion was added to the residue, and the mixture was extracted 60 with ethyl acetate. The extract was washed with saturated 2-Hydroxy-7,7-dimethyl-6,7-dihydro-5H-cyclopentab brine, and dried over anhydrous magnesium sulfate. The Sol pyridine-3-carboxylic acid (11.0 g) was dissolved in ethanol vent was evaporated under reduced pressure. The residue was (100 ml), sulfuric acid (3.4 ml) was added and the mixture Subjected to silica gel column chromatography, and the frac was stirred with heating to reflux for 12 hr. The reaction tion eluted with ethyl acetate-hexane (50:50-100:0) was con mixture was concentrated under reduced pressure to a half 65 centrated under reduced pressure to give the object compound volume, the residue was basified with 8 Maqueous sodium (3.68 g). hydroxide solution, and the mixture was extracted with ethyl MS (ESI+, m/e) 240 (M+1) US 8,329,691 B2 185 186 By a method similar to that of Reference Example 89, the Reference Example 93 following compound (Reference Example 90) was obtained. 2-(furan-2-ylmethyl)amino-5,6,7,8-tetrahydro Reference Example 90 quinoline-3-carboxyli acid ethyl 2-chloro-7,7-dimethyl-6,7-dihydro-5H-cyclo pentabpyridine-3-carboxylate

10

21 OH 15 N O N C

MS (ESI+, m/e) 254 (M+1) Reference Example 91 ethyl 2-(furan-2-ylmethyl)amino-5,6,7,8-tetrahyd roquinoline-3-carboxylate 25 To a solution of ethyl 2-(furan-2-ylmethyl)amino-5,6,7, 8-tetrahydroquinoline-3-carboxylate (600mg) in ethanol (4 ml)-water (4 ml) was added 8 Maqueous sodium hydroxide O 30 solution (1.25 ml), and the mixture was stirred at 80°C. for 10 hr. The reaction mixture was concentrated under reduced 21 1N pressure to about 1/3 volume, and neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl N N O acetate. The extract was washed with saturated brine and H dried over anhydrous magnesium sulfate. The solvent was 35 evaporated under reduced pressure to give the object com pound (522 mg). MS (ESI+, m/e) 273 (M+1) A mixture of ethyl 2-chloro-5,6,7,8-tetrahydroquinoline By a method similar to that of Reference Example 93, the 3-carboxylate (500 mg) and furfurylamine (3.0, ml) was 40 following compound (Reference Example 94) was obtained. stirred in a sealed tube at 130° C. for 12 hr. The reaction mixture was Subjected to silica gel column chromatography, Reference Example 94 and the fraction eluted with ethyl acetate-hexane (10:90-50: 50) was concentrated under reduced pressure to give the 2-(furan-2-ylmethyl)amino-7,7-dimethyl-6,7-dihy dro-5H-cyclopentabpyridine-3-carboxylic acid object compound (683 mg). 45 MS (ESI+, m/e) 301 (M+1) By a method similar to that of Reference Example 91, the following compound (Reference Example 92) was obtained. Reference Example 92 50 ethyl 2-(furan-2-ylmethyl)amino-7,7-dimethyl-6,7- dihydro-5H-cyclopentabpyridine-3-carboxylate 21 OH 55 N

O

21 1N 60

N O N N H

65 MS (ESI+, m/e) 315 (M+1) MS (ESI+, m/e) 287 (M+1) US 8,329,691 B2 187 188 Reference Example 95 2-(Furan-2-ylmethyl)amino-7,7-dimethyl-6,7-dihydro 5 H-cyclopentabpyridine-3-carboxylic acid (390 mg), tert tert-butyl 3-(2-(furan-2-ylmethyl)amino-5,6,7,8- butyl 3-(2-methylpropyl)aminolpiperidine-1-carboxylate tetrahydroquinolin-3-yl)carbonyl)(2-methylpropyl) (350 mg) and N,N-diisopropylethylamine (1.2 ml) were dis aminolpiperidine-1-carboxylate solved in 1,2-dichloroethane (10 ml), chloro-N.N.N',N'-tet ramethylformamidinium hexafluorophosphate (540 mg) was added and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with Saturated aqueous NN Sodium hydrogen carbonate Solution and the mixture was extracted with ethyl acetate. The extract was washed with 10 saturated brine and dried over anhydrous magnesium sulfate. 2 O The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-100: 10) was concentrated under reduced pressure to give the r O 15 object compound (123 mg). MS (ESI+, m/e) 525 (M+1) Reference Example 97 2-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydroquinoline NYO 3-carboxylic acid 2-(Furan-2-ylmethyl)amino-5,6,7,8-tetrahydroquino line-3-carboxylic acid (520 mg) was suspended in toluene (5 ml), thionyl chloride (0.42 ml) and DMF (5 drops) were added and the mixture was stirred at 80° C. for 30 min. The reaction mixture was cooled to room temperature, and con 25 centrated under reduced pressure, and the residue was Sub 21 OH jected to azeotropic distillation with toluene. The obtained residue was suspended in THF (5 ml), a solution of tert-butyl N 3-(2-methylpropyl)aminolpiperidine-1-carboxylate (490 mg) and triethylamine (1.5 ml) in THF (2 ml) was added, and 30 the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, 2,2-Dimethylcyclohexanone (3.0 g) and ethyl formate (24 and diluted with 10% aqueous citric acid solution, and the ml) were dissolved in diethyl ether (20 ml), sodium ethoxide mixture was extracted with ethyl acetate. The extract was (1.75 g) was added under ice-cooling, and the reaction mix washed with Saturated brine, and dried over anhydrous mag 35 ture was stirred at room temperature for 3 days, and concen nesium sulfate. The solvent was evaporated under reduced trated under reduced pressure. The residue was dissolved in pressure. The residue was subjected to silica gel column water (50 ml), 2-cyanoacetamide (1.80 g) and piperidine chromatography, and the fraction eluted with ethyl acetate (0.20 ml) were added, and the mixture was stirred at 40°C. for hexane (10:90-80:20) was concentrated under reduced pres 16 hr. Insoluble material was filtered off, and the filtrate was Sure to give the object compound (29 mg). 40 concentrated under reduced pressure. The residue was Sus MS (ESI+, m/e) 459 (M+1) pended in 4 Maqueous sodium hydroxide solution (100 ml), Reference Example 96 and the suspension was stirred at 90° C. for 14hr. The reaction mixture was ice-cooled, neutralized with 6 M hydrochloric tert-butyl 3-(2-(furan-2-ylmethyl)amino-7,7-dim acid, and concentrated under reduced pressure. The residue ethyl-6,7-dihydro-5H-cyclopentabpyridin-3- 45 was suspended in ethanol, insoluble material was filtered off, y1}carbonyl)(2-methylpropyl)aminolpiperidine-1- and the filtrate was concentrated under reduced pressure to carboxylate give the object compound (2.47 g). MS (ESI+, m/e) 222 (M+1) By a method similar to that of Reference Example 97, the following compounds (Reference Examples 98 and 99) were obtained. Reference Example 98 2-hydroxy-5.5,7-trimethyl-6,7-dihydro-5H-cyclo r pentabpyridine-3-carboxylic acid 2 N O / r O 60 21 OH N s 65 O MS (ESI+, m/e) 222 (M+1) US 8,329,691 B2 189 190 Reference Example 99 Reference Example 102 2-hydroxy-6,7,8,9-tetrahydro-5H-cycloheptabpyri- ethyl 2-hydroxy-6,7,8,9-tetrahydro-SH-cycloheptabl dine-3-carboxylic acid 5 pyridine-3-carboxylate

10 O O 21 1N 21 OH N 15 s OH N OH

' MS (ESI+, m/e) 236 (M+1) MS (ESI+, m/e) 208 (M+1) By a method similar to that of Reference Example 89, the By a method similar to that of Reference Example 87, the following compounds (Reference Examples 103 to 105) were following compounds (Reference Examples 100 to 102) were obtained. obtained. 25 Reference Example 103 Reference Example 100 ethyl 2-chloro-8,8-dimethyl-5,6,7,8-tetrahydroquino ethyl 2-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro- 30 line-3-carboxylate quinoline-3-carboxylate

35 O

O 21 1N 21 1N N 40 N C N N OH

45 MS (ESI+, m/e) 268 (M+1) MS (ESI-,(ESI+, m/e) 250 (M+1)(M-1 Reference Example 104 50 Reference Example 101 ethyl 2-chloro-5,5,7-trimethyl-6,7-dihydro-5H-cy clopentabpyridine-3-carboxylate ethyl 2-hydroxy-5.5,7-trimethyl-6,7-dihydro-5H cyclopentabpyridine-3-carboxylate 55

O O 60 21 1N 21 1S N N OH s C

65 MS (ESI+, m/e) 250 (M+1) MS (ESI+, m/e) 268 (M+1) US 8,329,691 B2 191 192 Reference Example 105 Reference Example 108 ethyl 2-chloro-6,7,8,9-tetrahydro-5H-cycloheptab pyridine-3-carboxylate ethyl 2-(furan-2-ylmethyl)amino-6,7,8,9-tetrahy 5 dro-5H-cycloheptabpyridine-3-carboxylate

O O 10 21 1N 21 O 1\ O N s N O N C 15 H /

MS (ESI+, m/e) 254 (M+1) 2O f f a method ityR of Ret E. the MS (ESI+, m/e) 315 (M+1) E. compounds (Reference Examples o 108) were By a method similar to that of Reference Example 93, the following compounds (Reference Examples 109 to 111) were Reference Example 106 2s obtained. ethyl 2-(furan-2-ylmethyl)amino-8,8-dimethyl-5.6, Reference Example 109 7,8-tetrahydroquinoline-3-carboxylate 30 2-(furan-2-ylmethyl)amino-8,8-dimethyl-5,6,7,8- tetrahydroquinoline-3-carboxylic acid

O 35 O 21 1N 21 OH n N O H 40 N O / N N

45 MS (ESI+, m/e) 329 (M+1) MS (ESI+, m/e) 301 (M+1) Reference Example 107 ethyl 2-(furan-2-ylmethyl)amino-5,5,7-trimethyl-6, 50 Reference Example 110 7-dihydro-5H-cyclopentabpyridine-3-carboxylate 2-(furan-2-ylmethyl)amino-5,5,7-trimethyl-6,7- dihydro-5H-cyclopentabpyridine-3-carboxylic acid 55

O O

21 1N 60 21 OH

N O s N O N N H

65 MS (ESI+, m/e) 329 (M+1) MS (ESI+, m/e) 301 (M+1) US 8,329,691 B2 193 194 Reference xample 111 Reference Example 113 2-(furan-2-ylmethyl)amino-6,7,8,9-tetrahydro-5H- tert-butyl 3-(2-(furan-2-ylmethyl)amino-5,5,7- cycloheptabpyridine-3-carboxylic acid 5 trimethyl-6,7-dihydro-5H-cyclopentabpyridin-3- y1}carbonyl)(2-methylpropyl)aminolpiperidine-1- carboxylate

10 O

21 OH N O) 15 r 21 N O 2O / Sr. O

25 O N MS (ESI+, m/e) 287 (M+1) r By a method similar to that of Reference Example 96, the O following compounds (Reference Examples 112 to 114) were obtained. 30

Reference Example 112 MS (ESI+, m/e) 539 (M+1) tert-butyl 3-(2-(furan-2-ylmethyl)amino-8,8-dim- 35 ethyl-5,6,7,8-tetrahydroquinolin-3-yl)carbonyl)(2- Reference Example 114 methylpropyl)aminolpiperidine-1-carboxylate tert-butyl 3-(2-(furan-2-ylmethyl)amino-6,7,8,9- tetrahydro-5H-cycloheptablpyridin-3-yl)carbonyl) 40 (2-methylpropyl)aminolpiperidine-1-carboxylate

45 r 2 O n N 50 N

N O

O N 55 r

60 r

65 MS (ESI+, m/e) 539 (M+1) MS (ESI+, m/e) 525 (M+1) US 8,329,691 B2 195 196 Reference Example 115 saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The 1-tert-butyl 3-methyl 5-(benzyloxy)carbonyl(2- residue was subjected to silica gel column chromatography, methylpropyl)amino)piperidine-1,3-dicarboxylate and the fraction eluted with ethyl acetate-hexane (5:95-80: 20) was concentrated under reduced pressure to give the object compound (8.04 g). MS (ESI+, m/e) 421 (M+1)

10 Reference Example 117 tert-butyl 3-(acetyloxy)methyl-5-(benzyloxy) carbonyl (2-methylpropyl)amino)piperidine-1-car 15 boxylate

1-tert-Butyl 3-methyl 5-(2-methylpropyl)aminolpiperi dine-1,3-dicarboxylate (13.7g) was dissolved in ethyl acetate (250 ml)-1 M aqueous sodium hydroxide solution (55 ml)- water (200 ml), benzyl chlorocarbonate (7.5 ml) was added 25 under ice-cooling, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was 30 evaporated under reduced pressure. The residue was sub jected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (5:95-50:50) was concen trated under reduced pressure to give the object compound To a solution oftert-butyl 3-(benzyloxy)carbonyl(2-me (9.87 g). 35 thylpropyl)amino-5-(hydroxymethyl)piperidine-1-car MS (ESI+, m/e) 449 (M+1) boxylate (4.6 g) and triethylamine (2.3 ml) in ethyl acetate (25 ml) was added acetyl chloride (0.94 ml) under ice-cooling, Reference Example 116 and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with Saturated aqueous sodium tert-butyl 3-(benzyloxy)carbonyl(2-methylpropyl) 40 hydrogen carbonate Solution, and the mixture was extracted amino-5-(hydroxymethyl)piperidine-1-carboxylate with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium Sulfate, and the Solvent was evaporated under reduced pressure to give the object compound (5.09 g). 45 MS (ESI+, m/e) 463 (M+1)

Reference Example 118

50 tert-butyl 3-(acetyloxy)methyl-5-(2-methylpropyl) aminolpiperidine-1-carboxylate

55

A solution of 1-tert-butyl 3-methyl 5-(benzyloxy)carbo nyl (2-methylpropyl)amino)piperidine-1,3-dicarboxylate 60 (13.0 g) in THF (100 ml) was added to a solution of calcium chloride (6.5 g) and sodium borohydride (4.5 g) in ethanol (100 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with 10% aqueous citric acid solution, and concen 65 trated under reduced pressure to a half volume. The residue was extracted with ethyl acetate. The extract was washed with