US2006069264A1PendingUtilityA1
Aza hydroxylated ethyl amine compounds
Est. expiryMay 22, 2021(expired)· nominal 20-yr term from priority
A61P 43/00A61P 25/16C07C 243/28C07C 311/16A61P 25/00C07C 243/32A61P 25/28C07C 311/49
45
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Claims
Abstract
Disclosed are compounds of formula: and pharmaceutically acceptable salts and esters thereof, useful in treating and/or preventing Alzheimer's disease and other similar diseases, wherein R N , R C , R 1 , R 2 and R 20 are defined herein. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer's disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.
Claims
exact text as granted — not AI-modified1 . A compound of the formula II:
or a pharmaceutically acceptable salt thereof, where Rc is
(I) —C 1 -C 10 alkyl optionally substituted with one, two or three groups independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O-phenyl, —NR 1-a R 1-b , —OC═O NR 1-a R 1-b , —S(═O) 0-2 R 1-a , —NR 1-a C═O NR 1-a R 1-b , —C═O NR 1-a R 1-b , and —S(═O) 2 NR 1-a R 1-b wherein
R 1-a and R 1-b at each occurrence are independently H or C 1 -C 6 alkyl,
(II) —(CH 2 ) 0-3 —(C 3 -C 8 ) cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O-phenyl, —CO 2 H, —CO 2 —(C 1 -C 4 alkyl), and —NR 1-a R 1-b
(III) —(CR C-x R C-y ) 0-4 —R C-aryl where R C-x and R C-y are independently selected from the group consisting of
—H,
C 1 -C 4 alkyl optionally substituted with 1 or 2 —OH,
C 1 -C 4 alkoxy optionally substituted with 1, 2, or 3 halogen,
—(CH 2 ) 0-4 —C 3 -C 8 cycloalkyl,
C 2 -C 6 alkenyl containing one or two double bonds,
C 2 -C 6 alkynyl containing one or two triple bonds, and phenyl, or
R C-x and R C-y are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six or seven carbon atoms, where one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO 2 —, —NR N-2 — and R C-aryl , wherein
R C-aryl is phenyl, which is optionally substituted with 1, 2, or 3 groups that are independently:
(1) C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —O≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) —OH,
(3) —NO 2 ,
(4) halogen,
(5) —CO 2 H,
(6) —C≡N,
(7) —(CH 2 ) 0-4 —CO—NR N-2 R N-3 where
R N-2 and R N-3 are independently selected from the group consisting of:
(a) —H,
(b) —C 1 -C 6 alkyl optionally substituted with one substituent selected from the group consisting of:
(i) —OH, and
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —Br, —I, or OH,
(d) —C 3 -C 7 cycloalkyl,
(e) —(C 1 -C 2 alkyl)-(C 3 -C 7 cycloalkyl),
(f) —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl),
(g) —C 2 -C 6 alkenyl
(h) —C 2 -C 6 alkynyl
(i) —C 1 -C 6 alkyl chain with one double bond and one triple bond,
(j) —R 1-aryl wherein R 1-aryl at each occurrence is independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of -F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iv) —F, Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 —F,
(vi) —NR N-2 R N-3 ,
(vii) —OH,
(viii) —C≡N,
(ix) C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) —CO—(C 1 -C 4 alkyl),
(xi) —SO 2 —NR 1-a R 1-b ,
(xii) —CO—NR 1-a R 1-b , or
(xiii) —SO 2 —(C 1 -C 4 alkyl),
(k) —R 1-heteroaryl wherein R 1-heteroaryl at each occurrence is independently selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,
where the R 1-heteroaryl group is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iv) —F, —Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(vi) —(CH 2 ) 0-4 —NR N-2 R N-3 .
(vii) —OH,
(viii) —C≡N,
(ix) (CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) (CH 2 ) 0-4 —CO—(C 1 -C 6 alkyl),
(xi) (CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(xii) (CH 2 ) 0-4 —CO—NR N-2 R N-3 ,
(xiii) (CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl),
(xiv) (CH 2 ) 0-4 —N(R N-2 )—SO 2 —, and
(xv) (CH 2 ) 0-4 —N(R N-2 )—C(O)—,
(8) —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl),
(9) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl),
(10) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl),
(11) —(CH 2 ) 0-4 —CO—(CH 2 ) 0-4 (C 3 -C 7 cycloalkyl),
(12) —(CH 2 ) 0-4 —CO—R 1-aryl ,
(13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,
(14) —(CH 2 ) 0-4 —CO—R 1-heterocycle wherein
R 1-heterocycle at each occurrence is independently selected from the group consisting of morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide, where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(a) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —NR 1-a R 1-b —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(b) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b
(c) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b
(d) halogen,
(e) C 1 -C 6 alkoxy,
(f) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(g) —NR N-2 R N-3 ,
(h) —OH,
(i) —C≡N,
(j) (CH 2 ) 0-4 —(C 3 -C 7 cycloalkyl), optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(k) —(CH 2 ) 0-4 —CO—(C 1 -C 4 alkyl),
(l) —(CH 2 ) 0-4 —SO 2 —NR 1-a R 1-b ,
(m) —(CH 2 ) 0-4 —CO—NR 1-a R 1-b ,
(n) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl), and
(o) ═O,
(p) —(CH 2 ) 0-4 —N(R N-2 )—SO 2 —
(q) —(CH 2 ) 0-4 —N(R N-2 )—C(O)—
(15) —(CH 2 ) 0-4 —CO—R N-4 wherein
R N-4 at each occurrence is independently selected from the group consisting of morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl,
(16) —(CH 2 ) 0-4 —CO 2 —R N-5 where
R N-5 at each occurrence is independently selected from the group consisting of:
(a) C 1 -C 6 alkyl,
(b) —(CH 2 ) 0-2 —(R 1-aryl ),
(c) C 2 -C 6 alkenyl,
(d) C 2 -C 6 alkynyl,
(e) C 3 -C 7 cycloalkyl, and
(f) —(CH 2 ) 0-4 —(R 1-heteroaryl ),
(17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3
(18) —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl),
(19) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12 alkyl),
(20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7 cycloalkyl),
(21) —(CH 2 ) 0-4 —N(H or R N-5 − )—CO 2 —R N-5 ,
(22) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 ,
(23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 ,
(24) —(CH 2 ) 0-4 —N(—H or R N-5 )—CO—R N-2 ,
(25) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(26) —(CH 2 ) 0-4 —R N-4 ,
(27) —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl),
(28) —(CH 2 ) 0-4 —O—P(O)—(OR 100 ) 2 where R 100 is independently H or C 1 -C 4 alkyl,
(29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,
(30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,
(31) —(CH 2 ) 0-4 —O—(R N-5 ),
(32) —(CH 2 ) 0-4 —O—(R N-5 )—COOH,
(33) —(CH 2 ) 0-4 —S—(R N-5 ),
(34) —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl) wherein the alkyl group is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of F, Cl, Br, and I,
(35) —(CH 2 ) 0-4 —(C 3 -C 8 cycloalkyl),
(36) C 2 -C 6 alkenyl optionally substituted with C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(37) C 2 -C 6 alkynyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b , and
(38) —(CH 2 ) 0-4 —N(—H or R N-5 )—SO 2 —R N-2 ;
(IV) —(CR C-x R C-y ) 0-4 -R C-heteroaryl wherein R C-heteroaryl at each occurrence is independently selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzoisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl, quinazolinonyl, pyrazopyridyl, benzooxadiazolyl, dihydropyrimidinonyl, dihydrobenzofuranonyl, where the R C-heteroaryl group is bonded by any atom of the parent R C-heteroaryl group substituted by hydrogen such that the new bond to the R C-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted 1, 2, 3, or 4 groups that are independently:
(1) C 1 -C 6 alkyl, optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) —OH,
(3) —NO 2 ,
(4) —F, —Cl, —Br, —I,
(5) —CO—OH,
(6) —C≡N,
(V) C 2 -C 10 alkenyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O-phenyl, and —NR 1-a R 1-b ,
(VI) C 2 -C 10 alkynyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O-phenyl, and —NR 1-a R 1-b ,
(VII) —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-OH,
(VIII) —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2 ,
(IX) —(CH 2 ) 0-6 —C(═NR 1-a ) (NR 1-a R 1-b );
where R N is
(I) R N-1 —X N — where X N is —CO—, and where R N-1 is selected from the group consisting of:
(A) phenyl, which is optionally substituted with one, two or three of the following substituents which can be the same or different and are:
(1) C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
wherein R 1-a and R 1-b at each occurrence are independently H or C 1 -C 6 alkyl,
(2) —OH,
(3) —NO 2 ,
(4) —F, —Cl, —Br, —I,
(5) —CO 2 H,
(6) —C≡N,
(7) —(CH 2 ) 0-4 —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same or different and are selected from the group consisting of:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one substituent selected from the group consisting of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —Br, or —I,
(d) —C 3 -C 8 cycloalkyl,
(e) —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl),
(f) —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl),
(g) —C 2 -C 6 alkenyl,
(h) —C 2 -C 6 alkynyl,
(i) —C 1 -C 6 alkyl chain with one double bond and one triple bond,
(j) —R 1-aryl , wherein R 1-aryl at each occurrence is independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iv) —F, Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 —F,
(vi) —NR N-2 R N-3 ,
(vii) —OH,
(viii) —C≡N,
(ix) C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) —CO—(C 1 -C 4 alkyl),
(xi) —SO 2 —NR 1-a R 1-b ,
(xii) —CO—NR 1-a R 1-b , or
(xiii) —SO 2 —(C 1 -C 4 alkyl),
(k) —R 1-heteroaryl , wherein R 1-heteroaryl at each occurrence is independently selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,
where the R 1-heteroaryl group is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 3 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(iv) —F, —Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(vi) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(vii) —OH,
(viii) —C≡N,
(ix) (CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) (CH 2 ) 0-4 —CO—(C 1 -C 6 alkyl),
(xi) (CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(xii) (CH 2 ) 0-4 —CO—NR N-2 R N-3 ,
(xiii) (CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl),
(xiv) (CH 2 ) 0-4 —N(R N-2 )—SO 2 —, and
(xv) (CH 2 ) 0-4 —N(R N-2 )—C(O)—,
(l) —R 1-heterocyle , wherein
R 1-heterocycle at each occurrence is independently selected from the group consisting of morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(a) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —NR 1-a R 1-b —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(b) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b
(c) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R -b
(d) halogen,
(e) C 1 -C 6 alkoxy,
(f) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(g) —NR N-2 R N-3 ,
(h) —OH,
(i) —C≡N,
(j) (CH 2 ) 0-4 —(C 3 -C 8 cycloalkyl), optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(k) —(CH 2 ) 0-4 —CO—(C 1 -C 4 alkyl),
(l) —(CH 2 ) 0-4 —SO 2 —NR 1-a R 1-b ,
(m) —(CH 2 ) 0-4 —CO—NR 1-a R 1-b ,
(n) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl), and
(o) ═O,
(p) —(CH 2 ) 0-4 —N(R N-2 )—SO 2 —
(q) —(CH 2 ) 0-4 —N(R N-2 )—C(O)—
(8) —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl),
(9) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl),
(10) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl),
(11) —(CH 2 ) 0-4 —CO—(C 3 -C 8 cycloalkyl),
(12) —(CH 2 ) 0-4 —CO—R 1-aryl ,
(13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,
(14) —(CH 2 ) 0-4 —CO—R 1-heterocycle ,
(15) —(CH 2 ) 0-4 —CO—R N-4 wherein R N-4 is selected from the group consisting of phenyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl, thienyl, pyrazolyl, pyridyl N-oxide, oxazolyl, thiazolyl, imidazolyl, and pyrrolidinyl where each group is optionally substituted with one, two, three, or four groups that are independently C 1 -C 6 alkyl,
(16) —(CH 2 ) 0-4 —CO—O—R N-5 where R N-5 is selected from the group consisting of:
(a) C 1 -C 6 alkyl,
(b) —(CH 2 ) 0-2 —(R 1-aryl ),
(c) C 2 -C 6 alkenyl,
(d) C 2 -C 6 alkynyl,
(e) —(CH 2 ) 0-2 —C 3 -C 8 cycloalkyl,
(f) —(CH 2 ) 0-2 —(R 1-heteroaryl ), and
(g) —(CH 2 ) 0-2 —(R 1-heterocycle ),
(17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(18) —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl),
(19) —(CH 2 ) 0-4 —SO 2 (C 1 -C 12 alkyl),
(20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 8 cycloalkyl),
(21) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—O—R N-5 ,
(22) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 ,
(23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 ,
(24) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—R N-2 ,
(25) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(26) —(CH 2 ) 0-4 —R N-4 ,
(27) —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl),
(28) —(CH 2 ) 0-4 —O—P(O)—(OR 100 ) 2 wherein
R 100 at each occurrence is independently —H or C 1 -C 4 alkyl,
(29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,
(30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,
(31) —(CH 2 ) 0-4 —O—(R N-5 ) ,
(32) —(CH 2 ) 0-4 —O—(R N-5 )—COOH,
(33) —(CH 2 ) 0-4 —S—(R N-5 ),
(34) —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with one, two, three, four, or five of —F),
(35) C 3 -C 8 cycloalkyl,
(36) C 2 -C 6 alkenyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(37) C 2 -C 6 alkynyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(38) —(CH 2 ) 0-4 —N(H or R N-5 )—SO 2 —R N-2 ,
( 39) —(CH 2 ) 1-4 —(C 3 -C 8 cycloalkyl),
(B) —R N-heteroaryl where R N-heteroaryl is selected from the group consisting of pyridinyl, indolyl, indolinyl, isoindolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, indolizinyl and isochromanyl,
where the R N-heteroaryl group is bonded by any atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R N-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four of:
(1) C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) —OH,
(3) —NO 2 ,
(4) —F, —Cl, —Br, —I,
(5) —CO 2 H,
(6) —C≡N,
(7) —(CH 2 ) 0-4 —CO—NR N-2 R N-3 ,
(8) —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl),
(9) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl),
(10) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl),
(11) —(CH 2 ) 0-4 —CO—(C 3 -C 8 cycloalkyl),
(12) —(CH 2 ) 0-4 —CO—R 1-aryl ,
(13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,
(14) —(CH 2 ) 0-4 —CO—R 1-heterocycle ,
(15) —(CH 2 ) 0-4 —CO—R N-4
(16) —(CH 2 ) 0-4 —CO—O—R N-5
(17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(18) —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl),
(19) —(CH 2 ) 0-4 —SO 2— (C 1 -C 12 alkyl),
(20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 8 cycloalkyl),
(21) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—O—R N-5 ,
(22) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 ,
(23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 ,
(24) —(CH 2 ) 0-4 —N(—H or R N-5 )—CO—R N-2 ,
(25) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(26) —(CH 2 ) 0-4 —R N-4 ,
(27) —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl),
(28) —(CH 2 ) 0-4 —O—P(O)—(OR 100 ) 2 ,
(29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,
(30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,
(31) —(CH 2 ) 0-4 —O—(R N-5 ),
(32) —(CH 2 ) 0-4 —O—(R N-5 )—COOH,
(33) —(CH 2 ) 004 —S—(R N-5 ),
(34) —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with one, two, three, four, or five of —F),
(35) C 3 -C 8 cycloalkyl,
(36) C 2 -C 6 alkenyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(37) C 2 -C 6 alkynyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(38) —(CH 2 ) 0-4 —N(—H or R N-5 )—SO 2 —R N-2 ,
(39) —(CH 2 ) 1-4 —C 3 -C 8 cycloalkyl,
(C) R N-aryl —W—R N-aryl ,
(D) R N-aryl —W—R N-heteroaryl ,
(E) R N-aryl —W—R 1-heterocycle ,
(F) R N-heteroaryl —W—R N-aryl ,
(G) R N-heteroaryl —W—R N-heteroaryl ,
(H) R N-heteroaryl —W—R N-1-heterocycle ,
(I) R N-heterocycle —W—R N-aryl ,
(J) R N-heterocycle —W—R N-heteroaryl ,
(K) R N-heterocycle —W—R N-1-heterocycle ,
where W is
(19) —(CH 2 ) 1-4 —,
(20) —O—,
(21) —S(O) 0-2 —,
(22) —N(R N-5 )—,
(23) —CO—; or
(24) a bond;
(II) —CO—(C 1 -C 6 alkyl)-M-(C 1 -C 6 alkyl), where M is S, SO or SO 2 , and wherein each alkyl is unsubstituted or substituted with one, two, or three of substituents independently selected from the group consisting of:
(A) —NH—CO—(C 1 -C 6 alkyl),
(B) —NH—CO—O—R N-8 ,
(C) —NR N-2 R N-3 ;
where R 1 is
—(CH 2 ) n1 -phenyl, where n 1 is zero or one, and which is optionally substituted with one, two, three or four of the following substituents on the phenyl ring:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(B) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(C) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(D) —F, Cl, —Br or —I,
(F) —C 1 -C 6 alkoxy optionally substituted with one, two or three of —F,
(G) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(H) —OH,
(I) —C≡N,
(J) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(K) —CO—(C 1 -C 4 alkyl),
(L) —SO 2 —NR 1-a R 1-b ,
(M) —CO—NR 1-a R 1-b ,
(N) —SO 2 —(C 1 -C 4 alkyl); and
where R 2 is
(I) -(Z)-C 1 -C 6 alkyl, where Z is a bond, —C(O)—, —CO 2 — or —SO 2 —, wherein the alkyl group is optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 7 alkyl (optionally substituted with C 1 -C 3 alkyl and C 1 -C 3 alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, —NR 1-a R 1-b where R 1-a and R 1-b are independently —H or C 1 -C 6 alkyl, and —OC═O NR 1-a R 1-b ,
(II) -(Z)-CH 2 —S(O) 0-2 —(C 1 -C 6 alkyl),
(III) -(Z)-CH 2 —CH 2 —S(O) 0-2 —(C 1 -C 6 alkyl),
(IV) -(Z)-C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(V) -(Z)-C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(VI) -(Z)-(CH 2 ) n1 —(R 1-aryl ), where Z is a bond, CO, CO 2 or SO 2 , where n 1 is zero or one and where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthalyl, or tetralinyl optionally substituted with one, two, three or four of the following substituents on the aryl ring:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(B) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(C) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(D) —F, Cl, —Br or —I,
(F) —C 1 -C 6 alkoxy optionally substituted with one, two or three of —F,
(G) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(H) —OH,
(I) —C≡N,
(J) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(K) —CO—(C 1 -C 4 alkyl),
(L) —SO 2 —NR 1-a R 1-b ,
(M) —CO—NR 1-a R 1-b ,
(N) —SO 2 —(C 1 -C 4 alkyl),
(VII) -(Z)-(CH 2 ) n1 —(R 1-heteroaryl ) where n 1 is as defined above and where R 1-heteroaryl is selected from the group consisting of:
pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,
where the R 1-heteroaryl group is bonded to —(CH 2 ) n1 — by any ring atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three or four of:
(1) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the-group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(3) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(4) —F, Cl, —Br or —I,
(6) —C 1 -C 6 alkoxy optionally substituted with one, two, or three of —F,
(7) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(8) —OH,
(9) —C≡N.
(10) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(11) —CO—(C 1 -C 4 alkyl),
(12) —SO 2 —NR 1-a R 1-b ,
(13) —CO—NR 1-a R 1-b , or
(14) —SO 2 —(C 1 -C 4 alkyl), with the proviso that when n 1 is zero R 1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VIII) -(Z)-(CH 2 ) n1 —(R 1-heterocycle ) where n 1 is as defined above and R 1-heterocycle is selected from the group consisting of:
morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with one, two, three or four:
(1) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(3) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(4) —F, Cl, —Br, or —I,
(5) C 1 -C 6 alkoxy,
(6) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(7) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(8) —OH,
(9) —C≡N,
(10) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(11) —CO—(C 1 -C 4 alkyl),
(12) —SO 2 —NR 1-a R 1-b ,
(13) —CO—NR 1-a R 1-b ,
(14) —SO 2 —(C 1 -C 4 alkyl),
(15) ═O, with the proviso that when n 1 is zero R 1-heterocycle is not bonded to the carbon chain by nitrogen; and
where R 20 is H or C 1-6 alkyl or alkenyl.
2 . A compound according to claim 1 , wherein Rc is —(CR C-x R C-y ) 0-4 —R C-aryl where R C-x and R C-y are independently selected from the group consisting of
—H, C 1 -C 4 alkyl optionally substituted with 1 or 2 —OH, C 1 -C 4 alkoxy optionally substituted with 1, 2, or 3 halogen, —(CH 2 ) 0-4 —C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl containing one or two double bonds, C 2 -C 6 alkynyl containing one or two triple bonds, and phenyl, or R C-x and R C-y are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six or seven carbon atoms, where one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO 2 —, —NR N-2 — and R C-aryl , wherein R C-aryl is phenyl, which is optionally substituted with 1, 2, or 3 groups that are independently:
(1) C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) —OH,
(3) —NO 2 ,
(4) halogen,
(5) —CO 2 H,
(6) —C≡N.
3 . A compound according to claim 1 , wherein Rc is —(CR C-x R C-y ) 0-4 —R C-aryl where R C-x and R C-y are independently selected from the group consisting of
—H, C 1 -C 4 alkyl optionally substituted with 1 or 2 —OH, C 1 -C 4 alkoxy optionally substituted with 1, 2, or 3 halogen, —(CH 2 ) 0-4 —C 3 -C 8 cycloalkyl, C 2 -C 6 alkenyl containing one or two double bonds, C 2 -C 6 alkynyl containing one or two triple bonds, and phenyl, or R C-x and R C-y are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six or seven carbon atoms, where one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO 2 —, —NR N-2 — and R C-aryl , wherein —(CR C-x R C-y ) 0-4 —R C-heteroaryl is selected from the group consisting of pyridinyl, indolyl, indolinyl, isoindolyl, imidazolyl, isoxazolyl., oxazolyl, thiazolyl, indolizinyl and isochromanyl.
4 . A compound according to claim 1 , of the formula:
5 . A compound according to claim 1 , of the formula:
6 . A compound according to claim 1 , of the formula:
7 . A compound according to claim 1 , of the formula:
8 . A compound according to claim 1 , of the formula:
9 . A compound of the formula III:
or a pharmaceutically acceptable salt thereof wherein
R 1 represents phenyl (C 1 -C 6 )alkyl where the phenyl is optionally substituted with up to three groups independently selected from halogen, hydroxy, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, amino, nitro, trifluoromethyl, cyano, mono(C 1 -C 2 )alkylamino and di(C 1 -C 2 )alkylamino;
R a and R b independently represent hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkoxy, halogen, cyano, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, mono- or di(C 1 -C 6 )alkylaminosulfonyl, C 1 -C 6 alkyl sulfonylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, trifluoromethyl, mono(C 1 -C 6 )alkylaminocarbonyl, or di(C 1 -C 6 )alkylaminocarbonyl and provided that not both R a and R b are hydrogen simultaneously;
R c represents hydrogen, or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl each of which is optionally substituted with halogen, hydroxy, amino, cyano, or trifluoromethyl;
R d represents
phenyl optionally substituted with hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkoxy, halogen, cyano, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, mono- or di(C 1 -C 6 )alkylaminosulfonyl, C 1 -C 6 alkyl sulfonylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or
C 1 -C 6 alkyl optionally substituted with hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or trifluoromethyl; and
R 20 represents hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or trifluoromethyl.
10 . A compound according to claim 9 , wherein R 1 is benzyl where the phenyl is optionally substituted.
11 . A compound according to claim 10 , wherein the phenyl is substituted with one or two groups independently selected from halogen, hydroxy, C 1 -C 3 alkyl, amino, and trifluoromethyl.
12 . A compound according to claim 11 , wherein phenyl is substituted with two groups independently selected from halogen, hydroxy, and trifluoromethyl.
13 . A compound according to claim 12 , wherein phenyl is disubstituted with halogen.
14 . A compound according to claim 13 , wherein R 1 is 3,5-difluorobenzyl.
15 . A compound according to claim 12 , wherein R a and R b are different and R b represents mono- or di(C 1 -C 6 )alkylaminocarbonyl.
16 . A compound according to claim 12 , wherein R d is phenyl optionally substituted with C 1 -C 3 alkyl, C 1 -C 3 alkoxy, amino, hydroxy, or halogen.
17 . A compound according to claim 12 , wherein R c is hydrogen or C 1 -C 4 alkyl.
18 . A compound according to claim 17 , wherein R c is C 1 -C 3 alkyl.
19 . A compound according to claim 12 , wherein R d is C 1 -C 6 lower alkyl and R 20 is hydrogen.
20 . A compound according to claim 12 , which has the formula IV:
21 . A compound according to claim 20 , wherein
R 1 is benzyl where the phenyl is disubstituted with chloro or fluoro; R c is C 1 -C 3 alkyl; R d is C 1 -C 6 lower alkyl; R 20 is hydrogen or C 1 -C 6 alkyl; and R b is di(C 1 -C 6 )alkylaminocarbonyl attached to the 3-position of the phenyl group.
22 . A compound of the formula V:
or a pharmaceutically acceptable salt thereof wherein
R 1 represents phenyl (C 1 -C 6 )alkyl where the phenyl is optionally substituted with up to three groups independently selected from halogen, hydroxy, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, amino, nitro, trifluoromethyl, cyano, mono(C 1 -C 2 )alkylamino and di(C 1 -C 2 )alkylamino;
R a and R b independently represent hydrogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkoxy, halogen, cyano, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, mono- or di(C 1 -C 6 )alkylaminosulfonyl, C 1 -C 6 alkyl sulfonylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, trifluoromethyl, mono(C 1 -C 6 )alkylaminocarbonyl, or di(C 1 -C 6 )alkylaminocarbonyl and provided that not both R a and R b are hydrogen simultaneously;
R c represents hydrogen, or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl each of which is optionally substituted with halogen, hydroxy, amino, cyano, or trifluoromethyl;
R d represents
phenyl optionally substituted with hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkyl, C 3 -C 7 cycloalkyl(C 1 -C 6 )alkoxy, halogen, cyano, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, mono- or di(C 1 -C 6 )alkylaminosulfonyl, C 1 -C 6 alkyl sulfonylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or
C 1 -C 6 alkyl optionally substituted with hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, cyano, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or trifluoromethyl; and
R 20 represents hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or trifluoromethyl.
23 . A compound according to claim 22 , wherein R 1 is benzyl where the phenyl is optionally substituted.
24 . A compound according to claim 23 , wherein the phenyl is substituted with one or two groups independently selected from halogen, hydroxy, C 1 -C 3 alkyl, amino, and trifluoromethyl.
25 . A compound according to claim 24 , wherein phenyl is substituted with two groups independently selected from halogen, hydroxy, and trifluoromethyl.
26 . A compound according to claim 25 , wherein phenyl is disubstituted with halogen.
27 . A compound according to claim 26 , wherein R 1 is 3,5-difluorobenzyl.
28 . A compound according to claim 25 , wherein R a and R b are different and R b represents C 1 -C 6 )alkylsulfonylamino.
29 . A compound according to claim 25 , wherein R d is phenyl optionally substituted with C 1 -C 3 alkyl, -C 1 -C 3 alkoxy, amino, hydroxy, or halogen.
30 . A compound according to claim 25 , wherein R c is hydrogen or C 1 -C 4 alkyl.
31 . A compound according to claim 30 , wherein R c is C 1 -C 3 alkyl.
32 . A compound according to claim 25 , wherein R d is C 1 -C 6 lower alkyl and R 20 is hydrogen.
33 . A compound according to claim 25 , which has the formula VI:
34 . A compound according to claim 33 , wherein
R 1 is benzyl where the phenyl is disubstituted with chloro or fluoro; R c is C 1 -C 3 alkyl; R d is C 1 -C 6 lower alkyl; R 20 is hydrogen or C 1 -C 6 alkyl; and R b is alkylsulfonylamino attached to the 2-position of the thiazolyl group.
35 . A compound according to claim 1 , selected from the group consisting of:
36 . A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer's disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of an aza hydroxylated ethyl amine of the formula II:
or a pharmaceutically acceptable salt thereof, where Rc is
(I) —C 1 -C 10 alkyl optionally substituted with one, two or three groups independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O—phenyl, —NR 1-a R 1-b , —OC═O NR 1-a R 1-b , —S(═O) 0-2 R 1-a , —NR 1-a C═O NR 1-a R 1-b , —C═O NR 1-a R 1-b , and —S(═O) 2 NR 1-a R 1-b wherein
R 1-a and R 1-b at each occurrence are independently H or C 1 -C 6 alkyl,
(II) —(CH 2 ) 0-3 —(C 3 -C 8 )cycloalkyl where cycloalkyl can be optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O-phenyl, —CO 2 H, —CO 2 —(C 1 -C 4 alkyl), and —NR 1-a R 1-b
(III) —(CR C-x R C-y ) 0-4 -R C-aryl where R C-x and R C-y are independently selected from the group consisting of
—H,
C 1 -C 4 alkyl optionally substituted with 1 or 2 —OH,
C 1 -C 4 alkoxy optionally substituted with 1, 2, or 3 halogen,
—(CH 2 ) 0-4 —C 3 -C 8 cycloalkyl,
C 2 -C 6 alkenyl containing one or two double bonds,
C 2 -C 6 alkynyl containing one or two triple bonds, and phenyl, or
R C-x and R C-y are taken together with the carbon to which they are attached to form a carbocycle of three, four, five, six or seven carbon atoms, where one carbon atom is optionally replaced by a group selected from —O—, —S—, —SO 2 —, —NR N-2 — and R C-aryl , wherein
R 2-aryl is phenyl, which is optionally substituted with 1, 2, or 3 groups that are independently:
(1) C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) —OH,
(3) —NO 2 ,
(4) halogen,
(5) —CO 2 H,
(6) —C≡N,
(7) —(CH 2 ) 0-4 —CO—NR N-2 R N-3 where
R N-2 and R N-3 are independently selected from the group consisting of:
(a) —H,
(b) —C 1 -C 6 alkyl optionally substituted with one substituent selected from the group consisting of:
(i) —OH, and
(ii) —NH 2 ,
(c) —C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —Br, —I, or OH,
(d) —C 3 -C 7 cycloalkyl,
(e) —(C 1 -C 2 alkyl)-(C 3 -C 7 cycloalkyl),
(f) —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl),
(g) —C 2 -C 6 alkenyl
(h) —C 2 -C 6 alkynyl
(i) —C 1 -C 6 alkyl chain with one double bond and one triple bond,
(j) —R 1-aryl wherein R 1-aryl at each occurrence is independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of. —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iv) —F, Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 —F,
(vi) —NR N-2 R N-3 ,
(vii) —OH,
(viii) —C≡N,
(ix) C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) —CO—(C 1 -C 4 alkyl),
(xi) —SO 2 —NR 1-a R 1-b ,
(xii) —CO—NR 1-a R 1-b , or
(xiii) —SO 2 —(C 1 -C 4 alkyl),
(k) —R 1-heteroaryl wherein R 1-heteroaryl at each occurrence is independently selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,
where the R 1-heteroaryl group is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iv) —F, —Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F.
(vi) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(vii) —OH,
(viii) —C≡N,
(ix) (CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) (CH 2 ) 0-4 —CO—(C 1 -C 6 alkyl),
(xi) (CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(xii) (CH 2 ) 0-4 —CO—NR N-2 R N-3 ,
(xiii) (CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl),
(xiv) (CH 2 ) 0-4 —N(R N-2 )—SO 2 —, and
(xv) (CH 2 ) 0-4 —N(R N-2 )—C(O)—,
(8) —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl),
(9) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl),
(10) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl),
(11) —(CH 2 ) 0-4 —CO—(CH 2 ) 0-4 (C 3 -C 7 cycloalkyl),
(12) —(CH 2 ) 0-4 —CO—R 1-aryl ,
(13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,
(14) —(CH 2 ) 0-4 —CO—R 1-heterocycle wherein
R 1-heterocycle at each occurrence is independently selected from the group consisting of morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(a) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —NR 1-a R 1-b —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(b) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b
(c) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b
(d) halogen,
(e) C 1 -C 6 alkoxy,
(f) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(g) —NR N-2 R N-3 ,
(h) —OH,
(i) —C≡N,
(j) (CH 2 ) 0-4 —(C 3 -C 7 cycloalkyl), optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(k) —(CH 2 ) 0-4 —CO—(C 1 -C 4 alkyl),
(l) —(CH 2 ) 0-4 —SO 2 —NR 1-a R 1-b ,
(m) —(CH 2 ) 0-4 CO—NR 1-a R 1-b ,
(n) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl), and
(o) ═O,
(p) —(CH 2 ) 0-4 —N(R N-2 )—SO 2 —
(q) —(CH 2 ) 0-4 —N(R N-2 )—C(O)—
(15) —(CH 2 ) 0-4 —CO—R N-4 wherein
R N-4 at each occurrence is independently selected from the group consisting of morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with 1, 2, 3, or 4 groups that are independently C 1 -C 6 alkyl,
(16) —(CH 2 ) 0-4 —CO 2 —R N-5 where
R N-5 at each occurrence is independently selected from the group consisting of:
(a) C 1 -C 6 alkyl,
(b) —(CH 2 ) 0-2 —(R 1-aryl ),
(c) C 2 -C 6 alkenyl,
(d) C 2 -C 6 alkynyl,
(e) C 3 -C 7 cycloalkyl, and
(f) —(CH 2 ) 0-4 —(R 1-heteroaryl ),
(17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3
(18) —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl),
(19) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12 alkyl),
(20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7 cycloalkyl),
(21) —(CH 2 ) 0-4 —N(H or R N-5 )—CO 2 —R N-5 ,
(22) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 ,
(23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 ,
(24) —(CH 2 ) 0-4 —N(—H or R N-5 )—CO—R N-2 ,
(25) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(26) —(CH 2 ) 0-4 —R N-4 ,
(27) —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl),
(28) —(CH 2 ) 0-4 —O—P(O)—(OR 100 ) 2 where R 100 is independently H or C 1 -C 4 alkyl,
(29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,
(30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,
(31) —(CH 2 ) 0-4 —O—(R N-5 ),
(32) —(CH 2 ) 0-4 —O—(R N-5 )—COOH,
(33) —(CH 2 ) 0-4 —S—(R N-5 ),
(34) —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl) wherein the alkyl group is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of F, Cl, Br, and I,
(35) —(CH 2 ) 0-4 —(C 3 -C 8 cycloalkyl),
(36) C 2 -C 6 alkenyl optionally substituted with C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(37) C 2 -C 6 alkynyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b , and
(38) —(CH 2 ) 0-4 —N(—H or R N-5 )—SO 2 —R N-2 ;
(IV) —(CR C-x R C-y ) 0-4 —R C-heteroaryl wherein R C-heteroaryl at each occurrence is independently selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzoisothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl, quinazolinonyl, pyrazopyridyl, benzooxadiazolyl, dihydropyrimidinonyl, dihydrobenzofuranonyl,
where the R C-heteroaryl group is bonded by any atom of the parent R C-heteroaryl group substituted by hydrogen such that the new bond to the R C-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted 1, 2, 3, or 4 groups that are independently:
(1) C 1 -C 6 alkyl, optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) —OH,
(3) —NO 2 ,
(4) —F, —Cl, —Br, —I,
(5) —CO—OH,
(6) —C≡N,
(V) C 2 -C 10 alkenyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O-phenyl, and —NR 1-a R 1-b ,
(VI) C 2 -C 10 alkynyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, —O-phenyl, and —NR 1-a R 1-b ,
(VII) —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-OH,
(VIII) —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2 ,
(IX) —(CH 2 ) 0-6 —C(═NR 1-a ) (NR 1-a R 1-b );
where R N is
(I) R N-1 —X N — where X N is —CO—, and where R N-1 is selected from the group consisting of:
(A) phenyl, which is optionally substituted with one, two or three of the following substituents which can be the same or different and are:
(1) C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
wherein R 1-a and R 1-b at each occurrence are independently H or C 1 -C 6 alkyl,
(2) —OH,
(3) —NO 2 ,
(4) —F, —Cl, —Br, —I,
(5) —CO 2 H,
(6) —C≡N,
(7) —(CH 2 ) 0-4 —CO—NR N-2 R N-3 where R N-2 and R N-3 are the same-or different and are selected from the group consisting of:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one substituent selected from the group consisting of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —Br, or —I,
(d) —C 3 -C 8 cycloalkyl,
(e) —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl),
(f) —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl),
(g) —C 2 -C 6 alkenyl,
(h) —C 2 -C 6 alkynyl,
(i) —C 1 -C 6 alkyl chain with one double bond and one triple bond,
(j) —R 1-aryl , wherein R 1-aryl at each occurrence is independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(iv) —F, Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 —F,
(vi) —NR N-2 R N-3 ,
(vii) —OH,
(viii) —C≡N,
(ix) C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) —CO—(C 1 -C 4 alkyl),
(xi) —SO 2 —NR 1-a R 1-b ,
(xii) —CO—NR 1-a R 1-b , or
(xiii) —SO 2 —(C 1 -C 4 alkyl),
(k) —R 1-heteroaryl , wherein R 1-heteroaryl at each occurrence is independently selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide,
where the R 1-heteroaryl group is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(i) C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR 1-a R 1-b , —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(ii) C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(iii) C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 groups that are independently —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(iv) —F, —Cl, —Br and —I,
(v) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(vi) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(vii) —OH,
(viii) —C≡N,
(ix) (CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, optionally substituted with 1, 2, or 3 groups that are independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(x) (CH 2 ) 0-4 —CO—(C 1 -C 6 alkyl),
(xi) (CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(xii) (CH 2 ) 0-4 —CO—NR N-2 R N-3 ,
(xiii) (CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl),
(xiv) (CH 2 ) 0-4 —N(R N-2 )—SO 2 —, and
(xv) (CH 2 ) 0-4 —N(R N-2 )—C(O)—,
(l) —R 1-heterocyle , wherein
R 1-heterocycle at each occurrence is independently selected from the group consisting of morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with 1, 2, 3, or 4 groups that are independently:
(a) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —NR 1-a R 1-b —C≡N, —CF 3 , and C 1 -C 3 alkoxy,
(b) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b
(c) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b
(d) halogen,
(e) C 1 -C 6 alkoxy,
(f) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(g) —NR N-2 R N-3 ,
(h) —OH,
(i) —C≡N,
(j) (CH 2 ) 0-4 —(C 3 -C 8 cycloalkyl), optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(k) —(CH 2 ) 0-4 —CO—(C 1 -C 4 alkyl),
(l) —(CH 2 ) 0-4 —SO 2 —NR 1-a R 1-b ,
(m) —(CH 2 ) 0-4 —CO—NR 1-a R 1-b ,
(n) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 6 alkyl), and
(o) ═O,
(p) —(CH 2 ) 0-4 —N(R N-2 )—SO 2 —
(q) —(CH 2 ) 0-4 —N(R N-2 )—C(O)—
(8) —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl),
(9) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl),
(10) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl),
(11) —(CH 2 ) 0-4 —CO—(C 3 -C 8 cycloalkyl),
(12) —(CH 2 ) 0-4 —CO—R 1-aryl ,
(13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,
(14) —(CH 2 ) 0-4 —CO—R 1-heterocycle ,
(15) —(CH 2 ) 0-4 —CO—R N-4 wherein R N-4 is selected from the group consisting of phenyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl, thienyl, pyrazolyl, pyridyl N-oxide, oxazolyl, thiazolyl, imidazolyl, and pyrrolidinyl where each group is optionally substituted with one, two, three, or four groups that are independently C 1 -C 6 alkyl,
(16) —(CH 2 ) 0-4 —CO—O—R N-5 where R N-5 is selected from the group consisting of:
(a) C 1 -C 6 alkyl,
(b) —(CH 2 ) 0-2 —(R 1-aryl ).
(c) C 2 -C 6 alkenyl,
(d) C 2 -C 6 alkynyl,
(e) —(CH 2 ) 0-2 —C 3 -C 8 cycloalkyl,
(f) —(CH 2 ) 0-2 —(R 1-heteroaryl ), and
(g) —(CH 2 ) 0-2 —(R 1-heterocycle ),
(17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(18) —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl),
(19) —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12 alkyl),
(20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 8 cycloalkyl),
(21) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—O—R N-5 ,
(22) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 ,
(23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 ,
(24) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—R N-2 ,
(25) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(26) —(CH 2 ) 0-4 —R N-4 ,
(27) —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl),
(28) —(CH 2 ) 0-4 —O—P(O)—(OR 100 ) 2 wherein
R 100 at each occurrence is independently —H or C 1 -C 4 alkyl,
(29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,
(30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,
(31) —(CH 2 ) 0-4 —O—(R N-5 ),
(32) —(CH 2 ) 0-4 —O—(R N-5 )—COOH,
(33) —(CH 2 ) 0-4 —S—(R N-5 ),
(34) —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with one, two, three, four, or five of —F),
(35) C 3 -C 8 cycloalkyl,
(36) C 2 -C 6 alkenyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(37) C 2 -C 6 alkynyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(38) —(CH 2 ) 0-4 —N(H or R N-5 )—SO 2 —R N-2 ,
(39) —(CH 2 ) 1-4 —(C 3 -C 8 cycloalkyl),
(B) —R N-heteroaryl where R N-heteroaryl is selected from the group consisting of pyridinyl, indolyl, indolinyl, isoindolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, indolizinyl and isochromanyl,
where the R N-heteroaryl group is bonded by any atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R N-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four of:
(1) C 1 -C 6 alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) —OH,
(3) —NO 2 ,
(4) —F, —Cl, —Br, —I,
(5) —CO 2 H,
(6) —C≡N,
(7) —(CH 2 ) 0-4 —CO—NR N-2 R N-3 ,
(8) —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl),
(9) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl),
(10) —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl),
(11) —(CH 2 ) 0-4 —CO—(C 3 -C 8 cycloalkyl),
(12) —(CH 2 ) 0-4 —CO—NR 1-aryl ,
(13) —(CH 2 ) 0-4 —CO—R 1-heteroaryl ,
(14) —(CH 2 ) 0-4 —CO—R 1-heterocycle ,
(15) —(CH 2 ) 0-4 —CO—R N-4
(16) —(CH 2 ) 0-4 —CO—O—R N-5
(17) —(CH 2 ) 0-4 —SO 2 —NR N-2 R N-3 ,
(18) —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl),
(19) —(CH 2 ) 0-4 —SO 2- (C 1 -C 12 alkyl),
(20) —(CH 2 ) 0-4 —SO 2 —(C 3 -C 8 cycloalkyl),
(21) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—O—R N-5 ,
(22) —(CH 2 ) 0-4 —N(H or R N-5 )—CO—N(R N-5 ) 2 ,
(23) —(CH 2 ) 0-4 —N—CS—N(R N-5 ) 2 ,
(24) —(CH 2 ) 0-4 —N(—H or R N-5 )—CO—R N-2 ,
(25) —(CH 2 ) 0-4 —NR N-2 R N-3 ,
(26) —(CH 2 ) 0-4 —R N-4 ,
(27) —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl),
(28) —(CH 2 ) 0-4 —O—P(O)—(OR 100 ) 2 ,
(29) —(CH 2 ) 0-4 —O—CO—N(R N-5 ) 2 ,
(30) —(CH 2 ) 0-4 —O—CS—N(R N-5 ) 2 ,
(31) —(CH 2 ) 0-4 —O—(R N-5 ),
(32) —(CH 2 ) 0-4 —O—(R N-5 )—COOH,
(33) —(CH 2 ) 0-4 —S—(R N-5 ),
(34) —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with one, two, three, four, or five of —F),
(35) C 3 -C 8 cycloalkyl,
(36) C 2 -C 6 alkenyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(37) C 2 -C 6 alkynyl optionally substituted with C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, or —NR 1-a R 1-b ,
(38) —(CH 2 ) 0-4 —N(—H or R N-5 )—SO 2 —R N-2 ,
(39) —(CH 2 ) 1-4 —C 3 -C 8 cycloalkyl,
(C) R N-aryl —W—R N-aryl ,
(D) R N-aryl —W—R N-heteroaryl ,
(E) R N-aryl —W—R 1-heterocycle ,
(F) R N-heteroaryl —W—R N-aryl ,
(G) R N-heteroaryl —W—R N-heteroaryl ,
(H) R N-heteroaryl —W—R N-1-heterocycle ,
(I) R N-heterocycle —W—R N-aryl ,
(J) R N-heterocycle —W—R N-heteroaryl ,
(K) R N-heterocycle —W—R N-1-heterocycle ,
where W is
(25) —(CH 2 ) 1-4 —,
(26) —O—,
(27) —S(O) 0-2 —,
(28) —N(R N-5 )—,
(29) —CO—; or
(30) a bond;
(II) —CO—(C 1 -C 6 alkyl)-M-(C 1 -C 6 alkyl), where M is S, SO or SO 2 , and wherein each alkyl is unsubstituted or substituted with one, two, or three of substituents independently selected from the group consisting of:
(A) —NH—CO—(C 1 -C 6 alkyl),
(B) —NH—CO—O—R N-8 ,
(C) —NR N-2 R N-3 ;
where R 1 is
(CH 2 ) n1 -phenyl, where n 1 is zero or one, and which is optionally substituted with one, two, three or four of the following substituents on the phenyl ring:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(B) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(C) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(D) —F, Cl, —Br or —I,
(F) —C 1 -C 6 alkoxy optionally substituted with one, two or three of —F,
(G) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(H) —OH,
(I) —C≡N,
(J) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(K) —CO—(C 1 -C 4 alkyl),
(L) —SO 2 —NR 1-a R 1-b ,
(M) —CO—NR 1-a R 1-b ,
(N) —SO 2 —(C 1 -C 4 alkyl); and
where R 2 is
(I) -(Z)-C 1 -C 6 alkyl, where Z is a bond, —C(O)—, —CO 2 — or —SO 2 —, wherein the alkyl group is optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 7 alkyl (optionally substituted with C 1 -C 3 alkyl and C 1 -C 3 alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, —NR 1-a R 1-b where R 1-a and R 1-b are independently —H or C 1 -C 6 alkyl, and —OC═O NR 1-a R 1-b ,
(II) -(Z)-CH 2 —S(O) 0-2 —(C 1 -C 6 alkyl),
(III) -(Z)-CH 2 —CH 2 —S(O) 0-2 —(C 1 -C 6 alkyl),
(IV) -(Z)-C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(V) -(Z)-C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(VI) -(Z)-(CH 2 ) n1 —(R 1-aryl ), where Z is a bond, CO, CO 2 or SO 2 , where n, is zero or one and where R 1-aryl is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthalyl, or tetralinyl optionally substituted with one, two, three or four of the following substituents on the aryl ring:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(B) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(C) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(D) —F, Cl, —Br or —I,
(F) —C 1 -C 6 alkoxy optionally substituted with one, two or three of —F,
(G) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(H) —OH,
(I) —C≡N,
(J) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(K) —CO—(C 1 -C 4 alkyl),
(L) —SO 2 —NR 1-a R 1-b ,
(M) —CO—NR 1-a R 1-b ,
(N) —SO 2 —(C 1 -C 4 alkyl),
(VII) -(Z)-(CH 2 ) n1 —(R 1-heteroaryl ) where n 1 is as defined above and where R 1-heteroaryl is selected from the group consisting of:
pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide,
where the R 1-heteroaryl group is bonded to —(CH 2 ) n1 — by any ring atom of the parent R N-heteroaryl group substituted by hydrogen such that the new bond to the R 1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three or four of:
(1) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(3) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(4) —F, Cl, —Br or —I,
(6) —C 1 -C 6 alkoxy optionally substituted with one, two, or three of —F,
(7) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(8) —OH,
(9) —C≡N,
(10) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(11) —CO—(C 1 -C 4 alkyl),
(12) —SO 2 —NR 1-a R 1-b ,
(13) —CO—NR 1-a R 1-b , or
(14) —SO 2 —(C 1 -C 4 alkyl), with the proviso that when n 1 is zero R -heteroaryl is not bonded to the carbon chain by nitrogen, or
(VIII) -(Z)-(CH 2 ) n1 —(R 1-heterocycle ) where n 1 is as defined above and R 1-heterocycle is selected from the group consisting of:
morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl, homomorpholinyl, homomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,
where the R 1-heterocycle group is bonded by any atom of the parent R 1-heterocycle group substituted by hydrogen such that the new bond to the R 1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is optionally substituted with one, two, three or four:
(1) C 1 -C 6 alkyl optionally substituted with one, two or three substituents selected from the group consisting of C 1 -C 3 alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(2) C 2 -C 6 alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(3) C 2 -C 6 alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(4) —F, Cl, —Br, or —I,
(5) C 1 -C 6 alkoxy,
(6) —C 1 -C 6 alkoxy optionally substituted with one, two, or three —F,
(7) —NR N-2 R N-3 where R N-2 and R N-3 are as defined below,
(8) —OH,
(9) —C≡N,
(10) C 3 -C 7 cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 1-a R 1-b ,
(11) —CO—(C 1 -C 4 alkyl),
(12) —SO 2 —NR 1-a R 1-b ,
(13) —CO—NR 1-a R 1-b ,
(14) —SO 2 —(C 1 -C 4 alkyl),
(15) ═O, with the proviso that when n 1 is zero R 1-heterocycle is not bonded to the carbon chain by nitrogen; and
where R 20 is H or C 1-6 alkyl or alkenyl.Join the waitlist — get patent alerts
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