US2008287410A1PendingUtilityA1
Pyrimidine derivatives useful as inhibitors of pkc-theta
Est. expiryJul 8, 2024(expired)· nominal 20-yr term from priority
Inventors:Antonio J.M. BarbosaSteven Richard BrunetteEugene Richard HickeyJin Mi KimMichael David LawlorRene LemieuxBryan MckibbenMatt Aaron TschantzHui Yu
A61P 43/00A61P 3/10A61P 37/06A61P 37/00A61P 37/08A61P 29/00C07D 239/48A61P 17/00A61P 1/04A61P 17/06C07D 401/12C07D 403/12
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Claims
Abstract
Disclosed are novel compounds of formula (I): wherein X, Y, R 1 , R 2 and R 3 are as defined herein, which are useful as inhibitors of PKC-theta and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC-theta, including immunological disorders and type II diabetes. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
Claims
exact text as granted — not AI-modified1 .- 11 . (canceled)
12 . A method of treating a disease or disorder that is that is mediated or sustained through the activity of inhibiting PKC-theta in a patient comprising administering to said patient a therapeutically effect amount of a compound of the following formula (I):
wherein:
X is C 1-6 alkyl wherein one or two of the methylene units can be replaced by an oxygen or sulfur atom, and wherein the C 1-6 alkyl group is optionally and independently substituted with:
(A) oxo,
(B) C 1-6 alkyl which is optionally substituted with one or more of the following groups:
(i) hydroxyl,
(ii) C 1-3 alkyloxy,
(iii) halogen,
(C) C 1-6 alkyloxy,
(D) C 1-6 alkylthio,
(E) aryl
(F) —COR 6 , wherein R 6 is:
(i) C 1-6 alkyl,
(ii) C 1-6 alkyloxy,
(iii) —NR 7 R 8 , wherein R 7 and R 8 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(iv) —OH,
(G) halogen,
(H) —NR 9 R 10 , wherein R 9 and R 10 are each independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl,
(iii) C 1-6 alkylcarbonyl,
(iv) C 1-6 alkylsulfonyl,
(v) aryl,
(vi) heteroaryl;
Y is —NH—, —O— or —S—;
R 1 is:
(A) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(i) C 1-6 alkyl, which is optionally substituted one or more of the following:
(a) halogen,
(b) NH 2
(ii) C 1-6 alkoxy, which is optionally substituted with halogen,
(iii) C 1-6 alkylthio, which is optionally substituted with halogen,
(iv) C 1-6 alkylsulfonyl,
(v) cyano,
(vi) halogen,
(vii) hydroxyl,
(viii) nitro,
(ix) —COR 11 , wherein R 1 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(d) —NR 12 R 13 , wherein R 12 and R 13 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) aryl,
(IV) heteroaryl,
(x) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
or wherein R 14 and R 15 together constitute an alkylene bridge which together with the nitrogen atom between them forms a five to seven-membered ring,
(xi) arylthio, arylsulfonyl or aryloxy, each optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyl,
(b) C 1-6 alkoxy,
(c) C 1-6 alkylthio,
(d) C 1-6 alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR 16 R 17 , wherein R 16 and R 17 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) C 1-6 alkylcarbonyl,
(IV) C 1-6 alkylsulfonyl,
(B) C 3-6 cycloalkyl which is optionally and independently substituted with one or more of the following groups:
(i) C 1-6 alkyl, which is optionally substituted with halogen,
(ii) C 1-6 alkoxy, which is optionally substituted with halogen,
(iii) C 1-6 alkylthio, which is optionally substituted with halogen,
(iv) C 1-6 alkylsulfonyl,
(v) halogen,
(vi) hydroxyl,
(vii) —NR 18 R 19 , wherein R 18 and R 19 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
(viii) —COR 20 , wherein R 20 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(d) —NR 21 R 22 , wherein R 21 and R 22 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(C) —COR 23 , wherein R 23 is:
(i) C 1-6 alkyloxy,
(ii) —NR 24 R 25 , wherein R 24 and R 25 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
or wherein R 24 and R 25 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four to six-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyloxy,
(b) C 1-6 alkyl, which is optionally substituted with halogen,
(c) hydroxyl,
(d) halogen,
(e) —COR 26 , wherein R 26 is:
(I) C 1-6 alkyloxy,
(II) —NR 27 R 28 , wherein R 27 and R 28 are each independently selected from:
a. hydrogen,
b. C 1-6 alkyl,
c. aryl,
d. heteroaryl,
(D) is:
which is optionally substituted with halogen;
(E) is selected from the following:
R 2 is selected from the following groups:
(A) CF 3 ,
(B) cyano,
(C) halogen,
(D) nitro,
(E) C 1-6 alkylalkynyl,
(F) arylalkynyl which is optionally substituted with one or more of the following groups:
(i) halogen,
(ii) C 1-6 alkyl, which is optionally substituted with halogen,
R 3 is selected from the following groups:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-6 alkyl, optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) C 3-6 cycloalkyl,
(iii) C 1-6 alkyloxy,
(iv) C 1-6 alkylthio,
(v) —COR 29 , wherein R 29 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(vi) —CONR 30 R 31 , wherein R 30 and R 31 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(vii) halogen,
(viii) hydroxyl,
(ix) —NR 32 R 33 , wherein R 32 and R 33 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
(e) aryl,
(f) heteroaryl,
(x) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyl, which is optionally substituted with halogen,
(b) C 1-6 alkoxy, which is optionally substituted with halogen,
(c) C 1-6 alkylthio, which is optionally substituted with halogen,
(d) C 1-6 alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR 34 R 35 , wherein R 34 and R 35 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) C 1-6 alkylcarbonyl,
(IV) C 1-6 alkylsulfonyl,
(i) —COR 36 , wherein R 36 is:
(I) C 1-6 alkyl,
(II) C 1-6 alkyloxy,
(III) —OH,
(j) —CONR 37 R 38 , wherein R 37 and R 38 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) aryl,
(IV) heteroaryl,
(C) C 1-6 alkylsulfonyl,
(D) arylsulfonyl,
(E) aryl-C 1-6 alkylsulfonyl,
(F) heteroarylsulfonyl,
(G) C 1-6 alkylcarbonyl,
(H) arylcarbonyl,
(I) aryl-C 1-6 alkylcarbonyl,
(J) heteroarylcarbonyl,
(K) C 1-6 alkylaminocarbonyl, or
(L) heteroaryl,
or wherein R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(A) C 1-6 alkyl, which is optionally substituted with halogen,
(B) C 1-6 alkoxy, which is optionally substituted with halogen,
(C) C 1-6 alkylthio, which is optionally substituted with halogen,
(D) C 1-6 alkylsulfonyl,
(E) halogen,
(F) —NR 39 R 40 , wherein R 39 and R 40 are each independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl,
(iii) C 1-6 alkylcarbonyl,
(iv) C 1-6 alkylsulfonyl,
(v) arylcarbonyl,
(vi) arylsulfonyl
(vii) heteroarylcarbonyl,
(viii) heteroarylsulfonyl,
(G) —COR 41 , wherein R 1 is:
(i) C 1-6 alkyl,
(ii) C 1-6 alkyloxy,
(iii) —NR 42 R 43 , wherein R 42 and R 43 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(iv) hydroxyl,
(H) —OR 44 , wherein R 44 is selected from:
(i) hydrogen,
(ii) C 1-6 alkylcarbonyl,
(iii) C 1-6 alkylsulfonyl
(I) oxo,
or wherein NR 4 R 5 constitutes a 5-membered heteroaryl ring containing a total of 2 nitrogen hetero atoms in the ring;
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
13 . A method of claim 12 , wherein the compound administered is of formula (I) wherein:
X is C 1-3 alkyl, optionally substituted with oxo,
Y is —NH— or —O—;
R 1 is:
(A) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(i) C 1-3 alkyl, which is optionally and independently substituted with fluorine,
(ii) C 1-3 alkoxy, which is optionally and independently substituted with fluorine,
(iii) C 1-3 alkylthio, which is optionally and independently substituted with fluorine,
(iv) arylthio, which is optionally substituted with —NH 2 ,
(v) halogen,
(vi) hydroxyl,
(vii) C 1-3 alkylsulfonyl,
(viii) CONH 2 ,
(ix) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
or wherein R 14 and R 15 together constitute an alkylene bridge which together with the nitrogen atom between them forms a five to seven-membered ring,
(B) cyclohexyl, which is optionally and independently substituted with:
(i) C 1-3 alkyl,
(ii) hydroxyl;
(c) —COR 23 , wherein R 23 is:
(i) —NR 24 R 25 , wherein R 24 and R 25 are each independently selected from:
(a) C 1-6 alkyl;
or wherein R 24 and R 25 together constitute a alkylene bridge which together with the nitrogen atom between them forms a five to six-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen atom and which ring is optionally and independently substituted with one or more of the following groups:
(ii) hydroxyl,
(iii) —CONH 2 ,
(D) is:
which is optionally substituted with halogen;
(E) is selected from the following:
R 2 is:
(A) CF 3 ,
(B) cyano,
(C) halogen, or
(D) nitro,
R 3 is selected from the following:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-6 alkyl, which is optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) C 3-5 cycloalkyl,
(iii) aryl or heteroaryl, each of which is optionally and independently substituted with one or more of the following groups:
(a) C 1-3 alkyl which is optionally substituted with fluorine,
(b) —CO 2 H
(c) halogen,
(iv) NH 2
(v) hydroxyl,
(vi) —CONH 2 ,
(vii) fluorine,
(viii) NHCOCH 3
or R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an NH or oxygen atom and which ring is optionally and independently substituted with one or more of the following groups:
(A) —CONH 2 ,
(B) NR 39 R 40 wherein R 39 and R 40 are optionally and independently selected from:
(i) C 1-5 alkylcarbonyl
(ii) C 1-5 alkylsulfonyl
(iii) arylcarbonyl
(iv) arylsulfonyl
(C) —OR 4 , wherein R 4 is selected from:
(i) hydrogen,
(ii) C 1-5 alkylcarbonyl
(D) oxo, or
(E) fluorine
or wherein NR 4 R 5 constitute a 5-membered heteroaryl ring containing a total of 2 nitrogen hetero atoms in the ring,
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
14 . A method of claim 12 , wherein the compound administered is of the formula (I) wherein:
X is —CH 2 —, —CH 2 CH 2 — or —CH 2 CO—,
Y is —NH— or —O—;
R 1 is:
(A) phenyl, pyridyl, naphthyl, quinolinyl or benzothienyl, each of which is optionally and independently substituted with one or more of the following groups:
(i) C 1-3 alkyl, which is optionally substituted with fluorine,
(ii) C 1-3 alkoxy, which is optionally substituted with fluorine,
(iii) methylthio, which is optionally substituted with fluorine,
(iv) arylthio, optionally substituted with NH 2 ,
(v) F, Cl or Br,
(vi) hydroxyl,
(vii) NH 2 or N(CH 3 ) 2 ,
(viii) SO 2 CH 3
(B) cyclohexyl, optionally substituted with hydroxyl,
R 2 is:
(A) CF 3 ,
(B) cyano,
(C) F, Cl, Br or
(D) nitro,
R 3 is:
R 4 , R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-4 alkyl, which is optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) cyclopropyl,
(iii) aryl or heteroaryl selected from phenyl, pyridyl, pyrimidyl, pyrazolyl and oxazolyl, each of which is optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyl,
(b) fluorine or chlorine,
(iv) —CONH 2
(v) hydroxyl,
(vi) fluorine,
(vii) NHCOCH 3
or R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an NH, and which ring is optionally and independently substituted with one or more of the following groups:
(A) CONH 2 ,
(B) hydroxyl,
(C) C 1-5 alkylcarbonyloxy,
(D) oxo,
(E) fluorine,
(F) NR 39 R 40 wherein R 39 and R 40 are optionally and independently selected from:
(i) hydrogen
(ii) C 1-5 alkylcarbonyl
(iii) C 1-5 alkylsulfonyl
(iv) phenylcarbonyl, or
(v) phenylsulfonyl,
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
15 . A method of claim 12 , wherein the compound administered is of the formula (I) wherein:
X is —CH 2 —,
Y is —NH—,
R 1 is:
(A) phenyl or pyridyl optionally and independently substituted with one or more of the following groups:
(i) methyl,
(ii) CF 3 ,
(iii) OCF 3 ,
(iv) OCF 2 H
(v) OCH 3 ,
(vi) OCH(CH 3 ) 2
(vii) SCF 3 ,
(viii) arylthio substituted with NH 2 ,
(ix) F or Cl,
(x) N(CH 3 ) 2 ,
(xi) OCH 2 CF 3
(xii) SO 2 CH 3
(B) naphthyl,
R 2 is:
(A) cyano,
(B) Cl, or
(C) nitro;
R 3 is:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-3 alkyl, optionally substituted with one or more of the following groups:
(i) hydroxyl,
(ii) pyridyl,
(iii) 1-methyl-1H-pyrazole,
(iv) 1,5-dimethyl-1H-pyrazole,
(v) —CONH 2 ,
or R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four or five-membered ring, each optionally and independently substituted with one or more of the following:
(A) hydroxyl,
(B) amino
(C) fluorine
(D) oxo
(E) —NHSO 2 CH 3
(F) —NHCOCH 3
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
16 . A method of claim 12 , wherein the compound administered is of the formula (I) wherein:
X is —CH 2 —,
Y is —NH—,
R 1 is:
(A) phenyl, optionally and independently substituted with one or more of the following groups:
(i) methyl,
(ii) CF 3 ,
(iii) OCF 3 ,
(iv) OCH 3 ,
(v) SCF 3 ,
(vi) arylthio substituted with NH 2 ,
(vii) F or Cl;
(B) naphthyl,
R 2 is:
(A) cyano,
(B) Cl, or
(C) nitro;
R 3 is:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-2 alkyl, optionally substituted with one or more of the following groups:
(i) hydroxyl,
(ii) pyridyl,
(iii) 1,5-dimethyl-1H-pyrazole,
(iv) —CONH 2 ,
or R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four or five-membered ring, each optionally and independently substituted with one or more hydroxyl or oxo;
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
17 . A method of treating a disease or disorder associated with the activation of T cells in a patient comprising administering to said patient a therapeutically effective amount of a compound of the following formula (I):
wherein:
X is C 1-6 alkyl wherein one or two of the methylene units can be replaced by an oxygen or sulfur atom, and wherein the C 1-6 alkyl group is optionally and independently substituted with:
(A) oxo,
(B) C 1-6 alkyl which is optionally substituted with one or more of the following groups:
(i) hydroxyl,
(ii) C 1-3 alkyloxy,
(iii) halogen,
(C) C 1-6 alkyloxy,
(D) C 1-6 alkylthio,
(E) aryl
(F) —COR 6 , wherein R 6 is:
(i) C 1-6 alkyl,
(ii) C 1-6 alkyloxy,
(iii) —NR 7 R 8 , wherein R 7 and R 8 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(iv) —OH,
(G) halogen,
(H) —NR 9 R 10 , wherein R 9 and R 10 are each independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl,
(iii) C 1-6 alkylcarbonyl,
(iv) C 1-6 alkylsulfonyl,
(v) aryl,
(vi) heteroaryl;
Y is —NH—, —O— or —S—;
R 1 is:
(A) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(i) C 1-6 alkyl, which is optionally substituted one or more of the following:
(a) halogen,
(b) NH 2
(ii) C 1-6 alkoxy, which is optionally substituted with halogen,
(iii) C 1-6 alkylthio, which is optionally substituted with halogen,
(iv) C 1-6 alkylsulfonyl,
(v) cyano,
(vi) halogen,
(vii) hydroxyl,
(viii) nitro,
(ix) —COR 11 , wherein R 11 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(d) —NR 12 R 13 , wherein R 12 and R 13 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) aryl,
(IV) heteroaryl,
(x) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
or wherein R 14 and R 15 together constitute an alkylene bridge which together with the nitrogen atom between them forms a five to seven-membered ring,
(xi) arylthio, arylsulfonyl or aryloxy, each optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyl,
(b) C 1-6 alkoxy,
(c) C 1-6 alkylthio,
(d) C 1-6 alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR 16 R 17 , wherein R 16 and R 17 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) C 1-6 alkylcarbonyl,
(IV) C 1-6 alkylsulfonyl,
(B) C 3-6 cycloalkyl which is optionally and independently substituted with one or more of the following groups:
(i) C 1-6 alkyl, which is optionally substituted with halogen,
(ii) C 1-6 alkoxy, which is optionally substituted with halogen,
(iii) C 1-6 alkylthio, which is optionally substituted with halogen,
(iv) C 1-6 alkylsulfonyl,
(v) halogen,
(vi) hydroxyl,
(vii) —NR 18 R 19 , wherein R 18 and R 19 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
(viii) —COR 20 , wherein R 20 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(d) —NR 21 R 22 , wherein R 21 and R 22 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(C) —COR 23 , wherein R 23 is:
(i) C 1-6 alkyloxy,
(ii) —NR 24 R 25 , wherein R 24 and R 25 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
or wherein R 24 and R 25 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four to six-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyloxy,
(b) C 1-6 alkyl, which is optionally substituted with halogen,
(c) hydroxyl,
(d) halogen,
(e) —COR 26 , wherein R 26 is:
(I) C 1-6 alkyloxy,
(II) —NR 27 R 28 , wherein R 27 and R 28 are each independently selected from:
a. hydrogen,
b. C 1-6 alkyl,
c. aryl,
d. heteroaryl,
(D) is:
which is optionally substituted with halogen;
(E) is selected from the following:
R 2 is selected from the following groups:
(A) CF 3 ,
(B) cyano,
(C) halogen,
(D) nitro,
(E) C 1-6 alkylalkynyl,
(F) arylalkynyl which is optionally substituted with one or more of the following groups:
(i) halogen,
(ii) C 1-6 alkyl, which is optionally substituted with halogen,
R 3 is selected from the following groups:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-6 alkyl, optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) C 3-6 cycloalkyl,
(iii) C 1-6 alkyloxy,
(iv) C 1-6 alkylthio,
(v) —COR 29 , wherein R 29 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(vi) —CONR 30 R 31 , wherein R 30 and R 31 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(vii) halogen,
(viii) hydroxyl,
(ix) —NR 32 R 33 , wherein R 32 and R 33 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
(e) aryl,
(f) heteroaryl,
(x) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyl, which is optionally substituted with halogen,
(b) C 1-6 alkoxy, which is optionally substituted with halogen,
(c) C 1-6 alkylthio, which is optionally substituted with halogen,
(d) C 1-6 alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR 34 R 35 , wherein R 34 and R 35 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) C 1-6 alkylcarbonyl,
(IV) C 1-6 alkylsulfonyl,
(i) —COR 36 , wherein R 36 is:
(I) C 1-6 alkyl,
(II) C 1-6 alkyloxy,
(III) —OH,
(j) —CONR 37 R 38 , wherein R 37 and R 38 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) aryl,
(IV) heteroaryl,
(C) C 1-6 alkylsulfonyl,
(D) arylsulfonyl,
(E) aryl-C 1-6 alkylsulfonyl,
(F) heteroarylsulfonyl,
(G) C 1-6 alkylcarbonyl,
(H) arylcarbonyl,
(I) aryl-C 1-6 alkylcarbonyl,
(J) heteroarylcarbonyl,
(K) C 1-6 alkylaminocarbonyl, or
(L) heteroaryl,
or wherein R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(A) C 1-6 alkyl, which is optionally substituted with halogen,
(B) C 1-6 alkoxy, which is optionally substituted with halogen,
(C) C 1-6 alkylthio, which is optionally substituted with halogen,
(D) C 1-6 alkylsulfonyl,
(E) halogen,
(F) —NR 39 R 40 , wherein R 39 and R 40 are each independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl,
(iii) C 1-6 alkylcarbonyl,
(iv) C 1-6 alkylsulfonyl,
(v) arylcarbonyl,
(vi) arylsulfonyl
(vii) heteroarylcarbonyl,
(viii) heteroarylsulfonyl,
(G) —COR 41 , wherein R 41 is:
(i) C 1-6 alkyl,
(ii) C 1-6 alkyloxy,
(iii) —NR 42 R 43 , wherein R 42 and R 43 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(iv) hydroxyl,
(H) —OR 44 , wherein R 44 is selected from:
(i) hydrogen,
(ii) C 1-6 alkylcarbonyl,
(iii) C 1-6 alkylsulfonyl
(I) oxo,
or wherein NR 4 R 5 constitutes a 5-membered heteroaryl ring containing a total of 2 nitrogen hetero atoms in the ring;
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
18 . A method of claim 17 , wherein the compound administered is of formula (I) wherein:
X is C 1-3 alkyl, optionally substituted with oxo,
Y is —NH— or —O—;
R 1 is:
(A) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(i) C 1-3 alkyl, which is optionally and independently substituted with fluorine,
(ii) C 1-3 alkoxy, which is optionally and independently substituted with fluorine,
(iii) C 1-3 alkylthio, which is optionally and independently substituted with fluorine,
(iv) arylthio, which is optionally substituted with —NH 2 ,
(v) halogen,
(vi) hydroxyl,
(vii) C 1-3 alkylsulfonyl,
(viii) CONH 2 ,
(ix) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
or wherein R 14 and R 15 together constitute an alkylene bridge which together with the nitrogen atom between them forms a five to seven-membered ring,
(B) cyclohexyl, which is optionally and independently substituted with:
(i) C 1-3 alkyl,
(ii) hydroxyl;
(C) —COR 23 , wherein R 23 is:
(i) —NR 24 R 25 , wherein R 24 and R 25 are each independently selected from:
(a) C 1-6 alkyl;
or wherein R 24 and R 25 together constitute a alkylene bridge which together with the nitrogen atom between them forms a five to six-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen atom and which ring is optionally and independently substituted with one or more of the following groups:
(i) hydroxyl,
(ii) —CONH 2 ,
(D) is:
which is optionally substituted with halogen;
(E) is selected from the following:
R 2 is:
(A) CF 3 ,
(B) cyano,
(C) halogen, or
(D) nitro,
R 3 is selected from the following:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-6 alkyl, which is optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) C 3-5 cycloalkyl,
(iii) aryl or heteroaryl, each of which is optionally and independently substituted with one or more of the following groups:
(a) C 1-3 alkyl which is optionally substituted with fluorine,
(b) —CO 2 H
(c) halogen,
(iv) NH 2
(v) hydroxyl,
(vi) —CONH 2 ,
(vii) fluorine,
(viii) NHCOCH 3
or R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an NH or oxygen atom and which ring is optionally and independently substituted with one or more of the following groups:
(A) —CONH 2 ,
(B) NR 39 R 40 wherein R 39 and R 40 are optionally and independently selected from:
(i) C 1-5 alkylcarbonyl
(ii) C 1-5 alkylsulfonyl
(iii) arylcarbonyl
(iv) arylsulfonyl
(C) —OR 44 , wherein R 44 is selected from:
(i) hydrogen,
(ii) C 1-5 alkylcarbonyl
(D) oxo, or
(E) fluorine
or wherein NR 4 R 5 constitute a 5-membered heteroaryl ring containing a total of 2 nitrogen hetero atoms in the ring,
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
19 . A method of treating an immunological disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of the following formula (I):
wherein:
X is C 1-6 alkyl wherein one or two of the methylene units can be replaced by an oxygen or sulfur atom, and wherein the C 1-6 alkyl group is optionally and independently substituted with:
(A) oxo,
(B) C 1-6 alkyl which is optionally substituted with one or more of the following groups:
(i) hydroxyl,
(ii) C 1-3 alkyloxy,
(iii) halogen,
(C) C 1-6 alkyloxy,
(D) C 1-6 alkylthio,
(E) aryl
(F) —COR 6 , wherein R 6 is:
(i) C 1-6 alkyl,
(ii) C 1-6 alkyloxy,
(iii) —NR 7 R 8 , wherein R 7 and R 8 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(iv) —OH,
(G) halogen,
(H)—NR 9 R 10 , wherein R 9 and R 10 are each independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl,
(iii) C 1-6 alkylcarbonyl,
(iv) C 1-6 alkylsulfonyl,
(v) aryl,
(vi) heteroaryl;
Y is —NH—, —O— or —S—;
R 1 is:
(A) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(i) C 1-6 alkyl, which is optionally substituted one or more of the following:
(a) halogen,
(b) NH 2
(ii) C 1-6 alkoxy, which is optionally substituted with halogen,
(iii) C 1-6 alkylthio, which is optionally substituted with halogen,
(iv) C 1-6 alkylsulfonyl,
(v) cyano,
(vi) halogen,
(vii) hydroxyl,
(viii) nitro,
(ix) —COR 11 , wherein R 11 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(d) —NR 12 R 13 , wherein R 12 and R 13 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) aryl,
(IV) heteroaryl,
(x) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
or wherein R 14 and R 15 together constitute an alkylene bridge which together with the nitrogen atom between them forms a five to seven-membered ring,
(xi) arylthio, arylsulfonyl or aryloxy, each optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyl,
(b) C 1-6 alkoxy,
(c) C 1-6 alkylthio,
(d) C 1-6 alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR 16 R 17 , wherein R 16 and R 17 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) C 1-6 alkylcarbonyl,
(IV) C 1-6 alkylsulfonyl,
(B) C 3-6 cycloalkyl which is optionally and independently substituted with one or more of the following groups:
(i) C 1-6 alkyl, which is optionally substituted with halogen,
(ii) C 1-6 alkoxy, which is optionally substituted with halogen,
(iii) C 1-6 alkylthio, which is optionally substituted with halogen,
(iv) C 1-6 alkylsulfonyl,
(v) halogen,
(vi) hydroxyl,
(vii) —NR 18 R 19 , wherein R 18 and R 19 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
(viii) —COR 20 , wherein R 20 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(d) —NR 21 R 22 , wherein R 21 and R 22 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(C) —COR 23 , wherein R 23 is:
(i) C 1-6 alkyloxy,
(ii) —NR 24 R 25 , wherein R 24 and R 25 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
or wherein R 24 and R 25 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four to six-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyloxy,
(b) C 1-6 alkyl, which is optionally substituted with halogen,
(c) hydroxyl,
(d) halogen,
(e) —COR 26 , wherein R 26 is:
(I) C 1-6 alkyloxy,
(II) —NR 27 R 28 , wherein R 27 and R 28 are each independently selected from:
a. hydrogen,
b. C 1-6 alkyl,
c. aryl,
d. heteroaryl,
(D) is
which is optionally substituted with halogen;
(E) is selected from the following:
R 2 is selected from the following groups:
(A) CF 3 ,
(B) cyano,
(C) halogen,
(D) nitro,
(E) C 1-6 alkylalkynyl,
(F) arylalkynyl which is optionally substituted with one or more of the following groups:
(i) halogen,
(ii) C 1-6 alkyl, which is optionally substituted with halogen,
R 3 is selected from the following groups:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-6 alkyl, optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) C 3-6 cycloalkyl,
(iii) C 1-6 alkyloxy,
(iv) C 1-6 alkylthio,
(v) —COR 29 , wherein R 29 is:
(a) C 1-6 alkyl,
(b) C 1-6 alkyloxy,
(c) —OH,
(vi) —CONR 30 R 31 , wherein R 30 and R 31 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) aryl,
(d) heteroaryl,
(vii) halogen,
(viii) hydroxyl,
(ix) —NR 32 R 33 , wherein R 32 and R 33 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl,
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
(e) aryl,
(f) heteroaryl,
(x) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(a) C 1-6 alkyl, which is optionally substituted with halogen,
(b) C 1-6 alkoxy, which is optionally substituted with halogen,
(c) C 1-6 alkylthio, which is optionally substituted with halogen,
(d) C 1-6 alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR 34 R 35 , wherein R 34 and R 35 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) C 1-6 alkylcarbonyl,
(IV) C 1-6 alkylsulfonyl,
(i) —COR 36 , wherein R 36 is:
(I) C 1-6 alkyl,
(II) C 1-6 alkyloxy,
(III) —OH,
(j) —CONR 37 R 38 , wherein R 37 and R 38 are each independently selected from:
(I) hydrogen,
(II) C 1-6 alkyl,
(III) aryl,
(IV) heteroaryl,
(C) C 1-6 alkylsulfonyl,
(D) arylsulfonyl,
(E) aryl-C 1-6 alkylsulfonyl,
(F) heteroarylsulfonyl,
(G) C 1-6 alkylcarbonyl,
(H) arylcarbonyl,
(I) aryl-C 1-6 alkylcarbonyl,
(J) heteroarylcarbonyl,
(K) C 1-6 alkylaminocarbonyl, or
(L) heteroaryl,
or wherein R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(A) C 1-6 alkyl, which is optionally substituted with halogen,
(B) C 1-6 alkoxy, which is optionally substituted with halogen,
(C) C 1-6 alkylthio, which is optionally substituted with halogen,
(D) C 1-6 alkylsulfonyl,
(E) halogen,
(F) —NR 39 R 40 , wherein R 39 and R 40 are each independently selected from:
(i) hydrogen,
(ii) C 1-6 alkyl,
(iii) C 1-6 alkylcarbonyl,
(iv) C 1-6 alkylsulfonyl,
(v) arylcarbonyl,
(vi) arylsulfonyl,
(vii) heteroarylcarbonyl,
(viii) heteroarylsulfonyl,
(G) —COR 41 , wherein R 1 is:
(i) C 1-6 alkyl,
(ii) C 1-6 alkyloxy,
(iii) —NR 42 R 43 , wherein R 42 and R 43 are each independently selected from:
hydrogen,
(a) C 1-6 alkyl,
(b) aryl,
(c) heteroaryl,
(iv) hydroxyl,
(H) —OR 44 , wherein R 44 is selected from:
(i) hydrogen,
(ii) C 1-6 alkylcarbonyl,
(iii) C 1-6 alkylsulfonyl
(I) oxo,
or wherein NR 4 R 5 constitutes a 5-membered heteroaryl ring containing a total of 2 nitrogen hetero atoms in the ring;
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
20 . A method of claim 19 , wherein the compound administered is of formula (I) wherein:
X is C 1-3 alkyl, optionally substituted with oxo,
Y is —NH— or —O—;
R 1 is:
(A) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(i) C 1-3 alkyl, which is optionally and independently substituted with fluorine,
(ii) C 1-3 alkoxy, which is optionally and independently substituted with fluorine,
(iii) C 1-3 alkylthio, which is optionally and independently substituted with fluorine,
(iv) arylthio, which is optionally substituted with —NH 2 ,
(v) halogen,
(vi) hydroxyl,
(vii) C 1-3 alkylsulfonyl,
(viii) CONH 2 ,
(ix) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl
(c) C 1-6 alkylcarbonyl,
(d) C 1-6 alkylsulfonyl,
or wherein R 14 and R 15 together constitute an alkylene bridge which together with the nitrogen atom between them forms a five to seven-membered ring,
(B) cyclohexyl, which is optionally and independently substituted with:
(i) C 1-3 alkyl,
(ii) hydroxyl;
(c) —COR 23 , wherein R 23 is:
(i) —NR 24 R 25 , wherein R 24 and R 25 are each independently selected from:
(a) C 1-6 alkyl;
or wherein R 24 and R 25 together constitute a alkylene bridge which together with the nitrogen atom between them forms a five to six-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen atom and which ring is optionally and independently substituted with one or more of the following groups:
(ii) hydroxyl,
(iii) —CONH 2 ,
(D) is:
which is optionally substituted with halogen;
(E) is selected from the following:
R 2 is:
(A) CF 3 ,
(B) cyano,
(C) halogen, or
(D) nitro,
R 3 is selected from the following:
R 4 and R 5 are each independently selected from:
(A) hydrogen,
(B) C 1-6 alkyl, which is optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) C 3-5 cycloalkyl,
(iii) aryl or heteroaryl, each of which is optionally and independently substituted with one or more of the following groups:
(a) C 1-3 alkyl which is optionally substituted with fluorine,
(b) —CO 2 H
(c) halogen,
(iv) NH 2
(v) hydroxyl,
(vi) —CONH 2 ,
(vii) fluorine,
(viii) NHCOCH 3
or R 4 and R 5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an NH or oxygen atom and which ring is optionally and independently substituted with one or more of the following groups:
(A) —CONH 2 ,
(B) NR 39 R 40 wherein R 39 and R 40 are optionally and independently selected from:
(i) C 1-5 alkylcarbonyl
(ii) C 1-5 alkylsulfonyl
(iii) arylcarbonyl
(iv) arylsulfonyl
(C) —OR 44 , wherein R 44 is selected from:
(i) hydrogen,
(ii) C 1-5 alkylcarbonyl
(D) oxo, or
(E) fluorine
or wherein NR 4 R 5 constitute a 5-membered heteroaryl ring containing a total of 2 nitrogen hetero atoms in the ring,
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.
21 . The method of claim 19 , wherein the immunological disorder is: an inflammatory disease, an autoimmune disease, organ and bone marrow transplant rejection, acute or chronic inflammation, an allergy, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, graft versus host disease or lupus erythematosus.
22 . The method of claim 20 , wherein the immunological disorder is: an inflammatory disease, an autoimmune disease, organ and bone marrow transplant rejection, acute or chronic inflammation, an allergy, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, graft versus host disease or lupus erythematosus.
23 . The method of claim 12 , wherein the compound of the formula (I) is one of the following compounds:
24 . The method of claim 12 , wherein the compound of the formula (I) is one of the following compounds:
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[2-fluoro-3-(trifluoromethyl)benzyl]-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -(2-chloro-6-fluoro-3-methylbenzyl)-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -(1-naphthylmethyl)-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-5-nitro-N 2 -{2-[(trifluoromethyl)thio]benzyl}pyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-5-chloro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)azetidin-3-one;
N 4 -{[trans-4-(3-aminoazetidin-1-yl)cyclohexyl]methyl}-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine;
N-[1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)azetidin-3-yl]methanesulfonamide;
N-[1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)azetidin-3-yl]acetamide;
N 4 -[(trans-4-aminocyclohexyl)methyl]-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
4-{[(trans-4-aminocyclohexyl)methyl]amino}-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidine-5-carbonitrile;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -{2-[(2-aminophenyl)thio]benzyl}-5-nitropyrimidine-2,4-diamine;
5-nitro-N 4 -[(trans-4-pyrrolidin-1-ylcyclohexyl)methyl]-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)pyrrolidin-3-ol;
N 4 -[(trans-4-azetidin-1-ylcyclohexyl)methyl]-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
N 4 -{[trans-4-(dimethylamino)cyclohexyl]methyl}-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
4-({[trans-4-(dimethylamino)cyclohexyl]methyl}amino)-2-{[2-(trifluoromethoxy)benzyl]-amino}pyrimidine-5-carbonitrile;
5-nitro-N 4 -({trans-4-[(pyridin-3-ylmethyl)amino]cyclohexyl}methyl)-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
5-nitro-N 4 -({trans-4-[(pyridin-4-ylmethyl)amino]cyclohexyl}methyl)-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
2-[(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)amino]ethanol;
1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)azetidin-3-ol;
5-nitro-N 4 -({trans-4-[(pyridin-2-ylmethyl)amino]cyclohexyl}methyl)-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
N 2 -(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}-cyclohexyl)glycinamide;
N 4 -[(trans-4-{[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]amino}cyclohexyl)methyl]-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
N 4 -[(trans-4-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}cyclohexyl)methyl]-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[(2-isopropoxypyridin-3-yl)methyl]-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-5-nitro-N 2 -{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidine-2,4-diamine; N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[(5-fluoro-2-methoxypyridin-3-yl)methyl]-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[2-(difluoromethoxy)benzyl]-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -(2-chlorobenzyl)-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-azetidin-1-ylcyclohexyl)methyl]-5-nitro-N 2 -{[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl}pyrimidine-2,4-diamine;
N 4 -{[trans-4-(3-fluoroazetidin-1-yl)cyclohexyl]methyl}-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
N 4 -{[trans-4-(ethylamino)cyclohexyl]methyl}-5-nitro-N 2 -[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[2-chloro-3-(dimethylamino)benzyl]-5-nitropyrimidine-2,4-diamine;
1-(trans-4-{[(2-{[2-chloro-3-(dimethylamino)benzyl]amino}-5-nitropyrimidin-4-yl)amino]methyl}cyclohexyl)azetidin-3-ol;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -(5-chloro-2-methoxybenzyl)-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -(2-methoxybenzyl)-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[5-chloro-2-(trifluoromethoxy)benzyl]-5-nitropyrimidine-2,4-diamine;
N 2 -[5-chloro-2-(trifluoromethoxy)benzyl]-5-nitro-N 4 -[(trans-4-pyrrolidin-1-ylcyclohexyl)-methyl]pyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[(2-methoxypyridin-3-yl)methyl]-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-5-nitro-N 2 -{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrimidine-2,4-diamine;
N 4 -[(trans-4-aminocyclohexyl)methyl]-N 2 -[5-chloro-2-(methylsulfonyl)benzyl]-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-azetidin-1-ylcyclohexyl)methyl]-N 2 -[(4-chloropyridin-3-yl)methyl]-5-nitropyrimidine-2,4-diamine;
N 4 -[(trans-4-azetidin-1-ylcyclohexyl)methyl]-5-nitro-N 2 -{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrimidine-2,4-diamine;
1-[trans-4-({[5-nitro-2-({[4-(trifluoromethyl)pyridin-3-yl]methyl}amino)pyrimidin-4-yl]amino}methyl)cyclohexyl]azetidin-3-ol;
(2R)-1-[(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)amino]propan-2-ol;
(2S)-1-[(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)amino]propan-2-ol;
3-[(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)amino]propan-1-ol;
(2R)-2-[(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)amino]propan-1-ol; or
(2S)-2-[(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)amino]propan-1-ol.Cited by (0)
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