Pyrazolopyrimidines as CRF antagonists

A compound of formula I:

• or a stereoisomer or pharmaceutically accetable salt thereof, wherein:
• R1 is selected from the group consisting of
• C1-6 alkyl,
• C2-10 alkenyl,
• C2-10 alkynyl,
• C3-6 cycloalkyl,
• C1-6 alkyloxy,
• C1-6 alkylS(O)n,
• —NR1aR1B wherein R1a and R1b are independently selected from H, C1-4 alkyl, —C(O)C1-4alkyl,
• —C(O)NR1aR1b,
• —O—C(O)C1-4alkyl,
• —XR1c wherein R1c is selected from H or —C1-4 alkylaryl, and X is selected from O or S(O)n,
• wherein R1 is substituted with 0-6 substituents selected from halogen, C1-4 alkyl, C1-6 alkyloxy, C1-4 haloalkyl, —NR1aR1b, and XR1c;
• R2 is selected from the group consisting of
• C1-10 alkyl,
• C2-10 alkenyl,
• C2-10 alkynyl,
• C3-8 cycloalkyl,
• C3-6 cycloalkyl C1-6 alkyl,
• C1-10 alkyloxy,
• C1-10 alkyloxyC1-10 alkyl,
• —SO2—C1-10alkyl
• —SO2R2a wherein R2a is aryl,
• —SO2R2b wherein R2b is heteroaryl,
• —NR2CR2D wherein R2c and R2d are independently selected from H, C1-8 alkyl, S(O)nC1-4alkyl, C(O)NR2cR2d, CO2C1-4alkyl, C3-8 cycloalkyl, C1-6 alkyloxyC1-6 alkyl, —C(O)C1-4alkyl or R2c and R2d may join to form a heterocyclic ring having 0-3 heteroatoms selected from O, N or S,
• -halogen, and
• —C(O)L wherein L is selected from C1-6 alkyl, H, —OC1-6 alkyl, O(CH2)mOC1-6alkyl, O(CH2)mNR2cR2d, —OH, aryl, heteroaryl or C(O)OC1-6 alkyl, wherein m is 1-3;
• n is 0, 1 or 2;
• R2 is substituted with 0-3 substituents independently selected from R′, R″, R″′ wherein R′, R″ and R″′ are independently selected from C1-6 alkyl, C3-7 cycloalkyl, hydroxyC1-6 alkyl, C1-6 alkyloxyC1-6 alkyl, C2-6 alkenyl, C1-6 alkyloxy, hydroxy;
• or
• R2 is substituted with 0-3 substitutents independently selected from
• halogen,
• —CN,
• —S(O)nR2e wherein R2e is selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 alkyloxy C1-4 alkyl, C3-6 cycloalkyl;
• —COR2f wherein R2f is selected from H, C1-4alkyl, C1-4 haloalkyl, C1-4 alkyloxy C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkylC1-4 alkyl;
• —CO2R2f,
• —NR2gCOR2f wherein R2g is selected from H, C1-6 alkyl, C3-7 c-alkyl, C3-6 cycloalkyl C1-6 alkyl;
• —N(COR2f)2,
• —NR2gCONR2fR2h wherein R2h is selected from H, C1-6 alkyl, C1-4 haloalkyl, C1-4 alkoxy C1-4 alkyl, C3-6 cycloalkyl and C3-6 cycloalkylC1-6 alkyl;
• —NR2gCO2R2e,
• —CONR2gR2h,
• 1-morpholinyl,
• 1-piperidinyl,
• 1-piperazinyl, and
• C3-8 cycloalkyl wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from —O—, —S(O)n—, —NR2g—, —NCO2R2e, —NCOR2e, and —NSO2R2e;
• and
• wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from R2g, CO2R2e, COR2e and SO2R2e;
• or
• R2 is substituted with the group R2i, R2j, R2k, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, —OR2g, —NR2gR2h, —C1-6 alkylOR2g, and C3-8 cycloalkyl which is substituted with 0-1 R2l and in wich 0-1 carbons of C4-8 cycloalkyl is replaced by —O—, wherein
• R2i is selected from aryl wherein aryl includes phenyl, naphthyl, indanyl and indenyl, each R2i being substituted with 0-1 OR2m and 0-5 substituents independently selected from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, —CN, nitro, —SH, —S(O)nR2n, —COR2m, —OC(O)R2n, —NR2gCOR2m, N(COR2m)2, —NR2gCONR2oR2p, —NR2gCO2R2n, —NR2oR2p and —CONR2oR2p;
• R2j is selected from heteroaryl wherein heteroaryl includes pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-s-oxide, 2,3-dihydro-benzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, —CN, nitro, OR2m, —SH, —S(O)nR2h, —COR2m, —OC(O)R2h, —NR2gCOR2m, —N(COR2m)2, —NR2gCONR2oR2p, —NR2gCO2R2h, —NR2oR2p and —CONR2oR2p and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R2g, CO2R2e, COR2e and SO2R2e;
• R2k is heterocyclyl which is a saturated or partially saturated heteroaryl as defined for R2j, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, —CN, nitro, —OR2m, —SH, —S(O)nR2h, —COR2m, —OC(O)R2h, —NR2gCOR2m, —N(COR2m)2, —NR2gCONR2oR2p, NR2gCO2R2h, —NR2oR2p and —CONR2oR2p and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R2f, CO2R2e, COR2e and SO2R2e;
• wherein
• R2l is H, C1-4 alkyl, C3-6 cycloalky-C1-4 alkyl and C3-8 cycloalkyl;
• R2m is H, C1-6 alkyl, C3-6 cycloalkyl C1-6 alkyl, C1-2 alkyloxy C1-2 alkyl, C1-4 haloalkyl, R2qS(O)n—C1-4 alkyl or R2rR2sN—C2-4 alkyl;
• R2n is H, C1-6 alkyl, C3-10 cyloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkyloxy C1-2 alkyl, and C1-4 haloalkyl;
• R2o and R2p are independently selected at each occurrence from H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl C1-6 alkyl and C1-4 haloalkyl;
• R2q is selected from C1-6 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl), heteroaryl and heleroaryl (C1-4 alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
• R2rR2s taken together with the N form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl wherein N4 in 1-piperiazinyl is substituted with 0-1 substituents selected from the group R2t, CO2R2q, COR2q and SO2R2q;
• R2t is selected from H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl (C1-4 alkyl)-, heteroaryl and heteroaryl (C1-4 alkyl);
• R3 is an aryl or heteroaryl group attached through an unsaturated carbon atom of the heteroaryl group;
• aryl is selected from phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkyloxy-C1-4 alkyloxy, —OR2m, Br, Cl, F, I, C1-4 haloalkyl, —CN, —NO2, —SH, —S(O)nR2n, —COR2m, —CO2R2m, —OC(O)R2n, —NR2gCOR2m, —N(COR2m)2, —NR2gCONR2oR2p, —NR2gCO2R2h, —NR2oR2p and CONR2oR2p and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, —CN, dimethylamino, CF3, C2F5, OCF3, SO2Me and acetyl;
• heteroaryl is selected from the group pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzo-furanyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-benzothienyl-S-oxide, 2,3-dihydrobenzothienyl-s-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, F, I, C1-4 haloalkyl, —CN, NR2gR2h, nitro, —OR2m, —SH, —S(O)nR2n, COR2m, —CO2R2m, —OC(O)R2n, —NR2gCOR2m, —N(COR2m)2, —NR2gCONR2oR2p and each heteroaryl being substituted at any nitrogen atom with 0-1 substituents selected from the group R2g, CO2R3a, COR3a and SO2R3a wherein,
• R3a is selected from the group C1-6 alkyl, C1-4 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
• R4 and R5 are independently selected at each occurrence from H, Br, Cl, F, I, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkyloxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2 amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, —C(O)H, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2 amino and wherein R4 and R5 non-phenyl groups may be substituted with 0-5 substituents selected from OH, halogen, —C(O)H, —OC1-6-alkyl and C1-6 haloalkyl, C1-6 alkyl, and C3-7 c-alkyl;
• with the proviso that the compounds of Formula I with R1, R2, R3, R4 and R5 as specifically defined below are excluded:
• (a) a compound of formula I wherein R1 is unsubstituted, unbranched (linear) C1-3 alkyl and R2 is —C(O)-Ph;
• (b) a compound of formula I, wherein R5 is H or C1-3 alkyl and R3 is pyridyl, pyridyl-N-oxide, thien-3-yl or furan-3-yl or C1-3 alkyl substituted versions thereof and R1 is carboamoyl or unsubstituted, unbranched C1-3 alkyl, R2 is F, Cl, Br, formyl, carboxyl, hydroxymethyl, unsubstituted, unbranched C1-3 alkyl, —C(O)R, —C(O)OR, —CH2OR, —C(O)O(CH2)2OR, —C(O)O(CH2)2NHR, or —C(O)O(CH2)2NR2 wherein R is C1-3 alkyl;
• (c) a compound of formula I, wherein R1 is unsubstituted, unbranched C1-3 alkyl and R2 is halogen, or —C(O)R wherein R is H, C1-3 alkyl or C1-4 alkoxy, R3 is Ph substituted with NR2gC(O)R2m;
• (d) a compound of formula I, R2 is halogen, CO2R with R equal to C1-3 alkyl, unsubstituted, unbranched C1-3 alkyl, C1-3 haloalkyl or CONH2 and R1 is equal to OR, SR wherein R is C1-3 alkyl, C1-4 haloalkyl or C3-4 halocycloalkyl, and R3 is phenyl or substituted phenyl;
• (e) a compound of formula I, wherein R5 is H or C1-3 alkyl;
• R3 is phenyl, ortho-trifluoromethylphenyl, meta-trifluorophenyl or meta-methoxyphenyl;
• R1 is carbamoyl or unsubstituted, unbranched C1-3 alkyl;
• R2 is halogen, formyl, carboxyl, cyano, hydroxymethyl, unsubstituted, unbranched C1-3 alkyl, —C(O)R, —C(O)OR, CH2OR, —C(O)O(CH2)2OR, —C(O)O(CH2)2NHR or —C(O)O(CH2)2NR2 wherein R is C1-3 alkyl;
• (f) in a compound of formula I, R2 is C(O)OEt, R1 is SCH3, R3 is Ph, R4 is SCH3 (or Ph) and R5 is H;
• (g) in a compound of formula I, R1 is N(C(O)CH3)2, R2 is CH2Ph(p-Me, p-Cl), R3 is Ph (p-ClPh), R4 is SCH3 and R5 is H;
• (h) in a compound of formula I, R1 is N(C(O)CH3)2, R2 is CH2Ph(p-OMe), R3 is p-ClPh, R4 is SCH3 and R5 is H;
• (i) in a compound of formula I, R2 is CH3, R1 is CH3, R3 is p-F-Ph, R4 is c-propyl and R5 is —CH2OH;
• (j) in a compound of formula I, R2 is CH3, R1 is CH3, R3 is p-F-Ph, R4 is c-propyl and R5 is —C(O)H;
• (k) in a compound of formula I, R2 is CH3, R1 is CH3, R3 is p-F-Ph, R4 is c-propyl and R5 is —CH═CH—C(O)H;
• (l) in a compound of formula I, R2 is C(O)OMe, R1 is —SCH2-Ph, R3 is Ph, R4 is Me and R5 is H;
• (m) in a compound of formula I, R2 is C(O)OMe, R1 is —SCH2-Ph, R3 is Ph, R4 is H and R5 is H;
• (n) in a compound of formula I, R2 is C(O)Ph, R1 is Me, R3 is pyrid-4-yl, R4 and R5 are H;
• (o) in a compound of formula I, R2 is C(O)Ph, R1 is Me, R3 is m-CF3-Ph, R4 and R5 are H;
• (p) in a compound of formula I, R2 is C(O)Ph, R1 is Me, R3 is pyrid-3-yl, R4 and R5 are H;
• (q) in a compound of formula I, R2 is Cl, R1 is Et, R3 is pyrid-3-yl, R4 and R5 are H;
• (r) in a compound of formula I, R2 is CO2H, R1 is Et, R3 is pyrid-3-yl, R4 and R5 are H;
• (s) in a compound of formula I, R2 is CO2H, R1 is CH3, R3 is pyrid-3-yl, R4 and R5 are H and H Cl salt;
• (t) in a compound of formula I, R2 is C(O)OEt, R1 is CH3, R3 is pyrid-3-yl, R4 and R5 are H;
• (u) in a compound of formula I, R2 is C(O)OEt, R1 is Et, R3 is pyrid-3-yl, R4 and R5 are H;
• (v) in a compound of formula I, R2 is C(O)OMe, R1 is Me, R3 is m-CF3-Ph, R4 and R5 are H;
• (w) in a compound of formula I, R2 is C(O)OEt, R1 is Et, R3 is Ph, R4 and R5 are H;
• (x) in a compound of formula I, R2 is C(O)OEt, R1 is Et, R3 is m-CF3-Ph, R4 and R5 are H.