US 6,982,263 B2 | ||
Nitriles useful as reversible inhibitors of cysteine proteases | ||
Eugene R. Hickey, Danbury, Conn. (US); Younes Bekkali, Danbury, Conn. (US); Usha R. Patel, Brookfield, Conn. (US); Denice Mary Spero, West Redding, Conn. (US); David S. Thomson, Ridgefield, Conn. (US); and Erick Richard Roush Young, Danbury, Conn. (US) | ||
Assigned to Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn. (US) | ||
Filed on Jun. 04, 2002, as Appl. No. 10/163,015. | ||
Claims priority of provisional application 60/296863, filed on Jun. 08, 2001. | ||
Prior Publication US 2003/0119827 A1, Jun. 26, 2003 | ||
Int. Cl. C07D 207/16 (2006.01); C07D 211/66 (2006.01); C07D 217/56 (2006.01); C07D 223/12 (2006.01); C07D 413/12 (2006.01) |
U.S. Cl. 514—235.2 | 22 Claims |
1. A compound of the following formula (I): ![]() wherein: Y is R1, R1O—, R1S—, (R1)2N—;
Each R1 is independently hydrogen, C3-10alkyl, C3-8 cycloalkyl, aryl, benzyl, tetrahydronaphthyl, indenyl, indanyl, C1-10alkylsulfonylC1-10alkyl,
C3-8cycloalkylsulfonylC1-10alkyl, arylsulfonylC1-10alkyl, a heterocyclyl or heteroaryl selected from pyrrolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl,
tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyndinyl, pyrimidinyl, pyrazinyl, pyrazinyl,
tetrazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl,
benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,
tetrahydroquinazolinyl, benzoxazolyl, 2H-benzo[e][1,3]oxazine and quinoxalinyl,
wherein each R1 is optionally substituted by one or more Ra; or R1 is Ra or Rb;
Each Ra is independently hydrogen C3-10 alkyl, C3-8 cycloalkyl, aryl, tetrahydronaphthyl, indenyl, indanyl, a heterocycle or heteroaryl
selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl,
thienyl, pyrrolyl, oxazolyl, dihydro-oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,
benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl, C1-10 alkoxy, C1-10alkanoyl, C1-10alkanoyloxy,
aryloxy, benzyloxy, aroyl, C1-10 alkoxycarbonyl, aryloxycarbonyl, aroyloxy, heterocyclyloxy, heterocyclyl-C1-6alkoxy, heteroaryloxy
or heteroaryl-C1-6alkoxy, wherein the heterocyclyl or heteroaryloxy moiety is selected from those described in this paragraph,
carbamoyl wherein the nitrogen atom may be independently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Ra is C1-10 mono- or dialkyl amino, C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein the sulfur atom may be oxidized
to a sulfoxide or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either
nitrogen atom may be independently substituted by one or more C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,
pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl,
quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Ra is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, heterocyclylcarbonylamino, heteroarylcarbonylamino, C1-10 alkylcarbamoyloxy,
arylcarbamoyloxy, C1-10 alkylsulfonylamino, arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, amino wherein
the nitrogen atom may be independently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl,
benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Ra is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino,
wherein Ra may be further optionally substituted by one or more Rb;
Rb is a C3-6 saturated or unsaturated alkyl group wherein one or more carbon atoms are optionally replaced by O, N, S(O), S(O)2 or S and wherein said alkyl group is optionally independently substituted with one or two oxo groups, and/or one or more:
—NH2, C1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,
dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl;
or Rb is C3-6 cycloalkyl, C1-6 alkoxy, aryl, aryloxy, benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, mono-C1-5alkylamino,
di-C1-5alkylamino, carboxamide, amidino or guanidino;
R2 and R3 are each independently a hydrogen, C3-8 cycloalkyl, arylC1-5alkyl, aryl, or a C1-10 saturated or unsaturated alkyl group wherein
one or more C atoms are optionally replaced by O, NH, S(O), or S and wherein said alkyl group is optionally independently
substituted with one or two oxo groups, and/or one or more: —NH2, C1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
benzoxazolyl or quinoxalinyl; wherein each R2 and R3 is independently optionally substituted by one or more Rc; or R2 and R3 are each independently Rc;
Rc is C1-10 alkyl, C3-4 cycloalkyl, aryl, indanyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,
bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, spiro[2.5]octanyl, cubanyl, tetrahydronaphthyl, decahydronaphthyl, pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl,
tetrahydrothiopyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,
pyrazinyl, indolyl, dihydrobenzofuranyl, octohydrobenzofuranyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzimidazolyl, benzothiazolyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,
C1-10 alkoxy, aryloxy, C1-10 alkanoyl, aroyl, C1-10 alkoxycarbonyl, aryloxycarbonyl, C1-10 alkanoyloxy, aroyloxy, carbamoyl
wherein the nitrogen atom may be independently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl,
benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Rc is C1-10alkanoylamino, aroylamino, C1-10 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, arylthio
wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom may be independently
substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl
or quinoxalinyl,
or Rc is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino, arylsulfonylamino,
C1-10 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono or di-substituted by
C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,
dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Rc is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidino or guanidino;
Each Rc may be further optionally substituted by one or more Rd;
Rd is C1-5 alkyl, C3-4 cycloalkyl, aryl, arylC1-5alkyl, C1-5 alkoxy, aryloxy, arylC1-5alkoxy, aroyl, amino, halogen, hydroxy,
oxo, carboxy, cyano, nitro, amidino or guanidino; or
R2 and R3 together with the carbon they are attached optionally form a nonaromatic 3-10 membered mono- or bicyclic optionally partially
unsaturated cycloalkyl or a 3-10 membered mono- or bicyclic heterocycle each in turn optionally substituted by one or more
Rc as described hereinabove;
R4 and R5 are each independently a hydrogen, or a C1-10 saturated or unsaturated alkyl group wherein one or more C atoms are optionally
replaced by O, NH, S(O), S(O)2 or S and wherein said alkyl group is optionally independently substituted with one or two oxo groups, and/or one or more:
—NH2, C1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
benzoxazolyl or quinoxalinyl;
or R4 and R5 are each independently C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, C1-10alkylthioC1-10alkyl wherein the sulfur atom
may be oxidized to a sulfoxide or sulfone, C3-8 cycloalkyl, aryl, tetrahydronaphthyl, indenyl, indanyl, C3-7cycloalkylsulfonylC1-5alkyl,
arylsulfonylC1-5alkyl, heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,
pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridizinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl, benzofuranyl,
benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, tetrahydroquinolinyl,
isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl, C1-10alkanoyl,
aroyl, C1-10alkoxycarbonyl, arylC1-5alkoxycarbonyl, aryloxycarbonyl, carbamoyl wherein the nitrogen atom may be independently
mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,
benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl,
quinazolinyl or quinoxalinyl,
or R4 and R5 are each independently C1-10 alkanoylamino, aroylamino, C1-10 alkylthio wherein the sulfur atom may be oxidized to a sulfoxide
or sulfone, arylthio wherein the sulfur atom may be oxidized to a sulfoxide or sulfone, ureido wherein either nitrogen atom
may be independently substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,
indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl,
isoquinolinyl, quinazolinyl or quinoxalinyl,
or R4 and R5 are each independently C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,
arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, amino wherein the nitrogen atom may be independently mono
or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl
or quinoxalinyl,
or R4 and R5 are each independently halogen, hydroxy, carboxy, cyano, nitro, carboxamide, amidino or guanidino;
wherein each R4 and R5 may be further optionally independently substituted by one or more Re;
or R4 and R5 together with the carbon they are attached to optionally form a heterocyclic ring said heterocyclic ring being selected from:
azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oxepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl,
azocanyl, oxocanyl, 1,3-diazocanyl, 1,4-diazocanyl, 1,5-diazocanyl, 1,3-dioxocanyl, 1,4-dioxocanyl, 1,5-dioxocanyl, 1,3-oxazocanyl,
1,4-oxazocanyl, 1,5-oxazocanyl, 1,3-diazepanyl, 1,4-diazepanyl, 1,3-dioxepanyl, 1,4-dioxepanyl, 1,3-oxazepanyl, 1,4-oxazepanyl,
1,2-thiazocanyl-1,1-dioxide, 1,2,8-thiadiazocanyl-1,1-dioxide, 1,2-thiazepanyl-1,1-dioxide, 1,2,7-thiadiazepanyl-1,1-dioxide,
tetrahydrothiophenyl, hexahydropyrimidinyl, hexahydropyridazinyl, piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl,
dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl, oxazolidinyl, 1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,
isothiazolidinyl-1,1-dioxide, imidazolidinyl-2,4-dione, imidazolidinyl, morpholinyl, dioxanyl, tetrahydropyridinyl, thiomorpholinyl,
thiazolidinyl, dihydropyranyl, dithianyl, decahydro-quinolinyl, decahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, indolinyl,
octahydro-quinolizinyl, dihydro-indolizinyl, octahydro-indolizinyl, octahydro-indolyl, decahydroquinazolinyl, decahydroquinoxalinyl,
1,2,3,4-tetrahydroquinazolinyl or 1,2,3,4-tetrahydroquinoxalinyl;
or R4 and R5 together with the carbon they are attached to optionally form a C6-C10 bridged bicyclic ring group wherein one or more carbon
atoms are optionally replaced by a heteroatom chosen from N, O, S, S(O) or S(O)2;
or R4 and R5 together with the carbon they are attached to optionally form a carbocyclic ring group, said carbocyclic ring group being
selected from:
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, cyclononanyl, cyclodecanyl, cubanyl,
bicyclo[1.1.0]propanyl, bicyclo[2.1.0]butanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[5.1.0]octanyl, bicyclo[2.2.0]hexanyl,
bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[5.2.0]nonanyl, bicyclo[3.3.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[5.3.0]decanyl,
bicyclo[4.4.0]dccanyl, bicyclo[5.4.0]undecanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.1]octanyl,
bicyclo[5.1.1]nonanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[4.2.1]nonanyl, bicyclo[5.2.1]decanyl, bicyclo[2.2.2]octanyl,
bicyclo[3.2.2]nonanyl, bicyclo[4.2.2]decanyl, bicyclo[5.2.2]undecanyl, bicyclo[3.3.2]decanyl, bicyclo[4.3.2]undecanyl, bicyclo[5.3.2]dodecanyl,
bicyclo[3.3.3]undecanyl, bicyclo[4.3.3]dodecanyl, bicyclo[5.3.3]tridecanyl;
each of the above ring groups formed by the combination of R4 and R5 being optionally substituted with one or more Re; or R4 and R5 are each independently Re;
Re is a C1-10 saturated or unsaturated alkyl group wherein one or more C atoms are optionally replaced by O, NH, S(O), S(O)2 or S and wherein said alkyl group is optionally independently substituted with one or two oxo groups, and/or one or more:
—NH2, C1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
benzoxazolyl or quinoxalinyl;
or Re is a C1-10alkoxy, C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl, C1-10alkylthioC1-10alkyl wherein the sulfur atom may be
oxidized to a sulfoxide or sulfone, C3-8 cycloalkyl, C3-8 cycloalkyloxy, aryl, tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, thiopyranyl, tetrahydrothiopyranyl, pyranyl, tetrahydropyranyl,
tetrahydrofuranyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,
pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10alkanoyl, aroyl, C1-10alkanoyloxy,
aryloxy, benzyloxy, C1-10 alkoxycarbonyl, arylC1-3alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen
atom may be independently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,
pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl,
quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Re is ureido wherein either nitrogen atom may be independently substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,
pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl,
benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Re is amino wherein the nitrogen atom may be independently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Re is halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide, amidino or guanidino,
wherein Re may be further optionally substituted by one or more Rf,
Rf is C1-5 alkyl, C3-6 cycloalkyl, tolylsulfonyl, C1-5 alkoxy, aryl, aryloxy, benzyloxy, halogen, hydroxy, oxo, carboxy, cyano,
nitro, carboxamide, amidino or guanidino;
or Rf is aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl,
dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,
or Rf is amino wherein the nitrogen atom may be independently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,
tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl;
or Rf is a C1-10 saturated or unsaturated alkyl group wherein one or more C atoms are optionally replaced by O, NH, S(O), S(O)2 or S and wherein said alkyl group is optionally independently substituted with one or two oxo groups, and/or one or more:
—NH2, C1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,
benzothienyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
benzoxazolyl or quinoxalinyl;
R6 is hydrogen, hydroxy, C1-3 alkyl, or C3-6 cycloalkyl;
X is O or S; or
a pharmaceutically acceptable acid or salt thereof;
with the proviso that:
when R2 is hydrogen or alkyl; and R3 is hydrogen, alkyl or benzyl; and R4 is hydrogen, alkyl or cycloalkyl; and R5 is hydrogen, alkyl or cycloalkyl; or R4 and R5 together with the carbon atom they are attached to form cylopentanyl, cyclohexanyl or cycloheptanyl; and R6 is hydrogen; then Y is not phenyl substituted by optionally substituted pyrimidinyl.
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