Recherche dans les collections de brevets nationales et internationales
Une partie du contenu de cette demande n'est pas disponible pour le moment.
Si cette situation persiste, contactez-nous auObservations et contact
1. (AU2005204060) 2-(amino-substituted)-4-aryl pyramidines and related compounds useful for treating inflammatory diseases
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique
CLAIMS
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R' and R2 are each independently H, C13 alkyl or C3-s cycloalkyl;
R3 is H or F;
R4 is H, F, -ORA, -C(O)RA, -C(O)ORA or -N(RA)2 ; or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group; wherein each occurrence of RA is independently H, C13alkyl or C3.5cycloalkyl;
Ring A is optionally substituted with 1 or 2 independent occurrences of R, wherein each Rs is independently selected from halo, Ci 4 aliphatic, -CN, -ORB, -SRc, -N(RB)2 , -NR BC(0)RB -NRBC(O)N(R) 2, -WBCO 2RC, -CO2RB, -C(O)RB, -C(O)N(RB)2, -OC(O)N(RB) 2, -S(O)2Rc,
-SO 2 N(RB) 2, -S(O)Rc, -4B S 2 N(R")2 , -NRSO 2Rc, or C14aliphatic optionally substituted with halo, -CN, -ORB, -SRC, -N(RB) 2, PRBC(O)RB, NRBC(O)N(R) 2, -NRWCO 2RC, -CO2RB, -C(O)RB, -C(O)N(Re) 2, -OC(O)N(RB) 2, -S(O)2RC, -SO 2N(RB) 2, -S(O)Rc, _ BSO2 N(RB) 2, or -NRBSO 2Rc, wherein each occurrence of RB is is independently H or C 1.4 aliphatic; or two RB on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S; and each occurrence of Rc is independently C14 aliphatic;
Cyl is selected from:
a) a 6-membered aryl or heteroaryl ring substituted by one occurrence of W at the meta or para position of the ring; or
b) a 5-membered heteroaryl ring substituted by one occurrence of W;
wherein Cy' is optionally further substituted by one to three independent occurrences of R., wherein each occurrence of R6 is independently selected from -halo, C1 s aliphatic, -CN, -ORe, -SRD, -N(RE) 2, ~NREC(O)RB, -NEC(O)N(RE) 2, -NRC02RD, -CO 2RB, -C(O)R, -C(O)N(RE) 2, -OC(O)N(RE) 2, -S(O)2RD, "S02N(RE) 2, -S(O)RD, -NRES0 2N(RE) 2, NR ESO 2RD, -C(=NH)-N(RE) 2, or C18 aliphatic optionally substituted with halo, -CN, -ORB, -SRD, -N(RE) 2, ~ EC(O)R, -NREC(O)N(RE) 2, _ ECO2RD, -C0 2RB, -C(O)RB, -C(O)N(RE) 2, -OC(O)N(RE) 2, -S(O)2RD,
-SO 2N(RE)2, -S(O)RD, -NRES0 2N(RE) 2, ~ IESO2RD, or -C(=NH)-N(RE) 2, wherein each occurrence of RD is C1-6 aliphatic and each occurrence of RE is independently H, C1.6 aliphatic, -C(=O)RB,
-C(O)ORB or -SO 2RB; or two RE on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S;
W is -R, V-R', L1-R7, V-LI-R 7, L1-V-R", or L1-V-L2-R7; wherein:
L1 and L2 are each independently an optionally substituted C1.6 alkylene chain;
V is-CH2-, -0-, -S-, -S(O)-, -S(O) 2-, -C(O)-, -CO2 , -NRE NRE C(O)-, -NRE C02 -, -NRE SO2 , -C(O)N(R)-, -SO 2N(RB)-, -NRE C(O)N(R)- or -OC(O)-;
R is H, halo, -OH, -N(R) 2 , -CN, -ORG, -C(O)RG, -CO 2H, -CO 2RG, -SRG, -S(O)R G -S(O) 2RO, -N(RE)C(O)RG, -N(RE)C0 2RG, -N(RE)SO 2RG, -C(O)N(RF)2, -SO 2N(RF) 2, -N(RE)C(O)N(RF) 2, -OC(O)RF or an optionally substituted group selected from C1-10 aliphatic, C6.10aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of R is independently H, C1.6 aliphatic, C610aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, -C(=O)RB, -C(O)ORB or -SO 2RB; or two RF on the same nitrogen atom taken together with the nitrogen atom form an optionally substituted 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S; and each occurrence of 0 is C1-6 aliphatic, C6 -10aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl;
R8 is an optionally substituted group selected from C1.i 0 aliphatic, C6.10 aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl;
Q is a bond, CH 2 or C(=O);
Cy 2 is a C6.10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl ring, wherein each ring is optionally substituted by one to three independent occurrences of R9 and one occurrence of R 0 ,
wherein each occurrence of R9 is independently selected from Cl-aliphatic, -N(RB) 2, halo, NO2, -CN, -ORB, -C(O)RA, -CO2RA, -SRc, -S(O)RC, -S(O) 2Rc, -OS(O) 2 Rc-, N(RB)C(O)RA, -N(RB)CO 2RA, -N(RB)SO 2RA, -C(O)N(RB) 2, -SO 2N(RB) 2, -N(RB)C(O)N(R) 2, -OC(O)RA, or C-4 aliphatic optionally substituted by -N(RB) 2, halo, NO2, -CN, -OR", -C(O)RA, -CO2RA, -SRc, -S(O)Rc, -OS(O) 2Rc, -S(O)2Rc, -N(RB)C(O)R^, -N(RB)CO2RA, -N(Ra)SO 2RA, -C(O)N(RB) 2, -SO 2N(RB) 2 , -N(RB)C(O)N(RB)2, or -OC(O)RA, and
R'0 is selected from phenyl, or a 5-6 membered heterocyclyl or heteroaryl ring, provided that:
1) when Cy' is phenyl substituted in the meta position with W then:
a) when W is -OMe, R', R2, R, and R4 are each hydrogen, and Q is a bond, then when ring A is futher substituted with R5 , R5 is a group other than -CF3 or -C(O)N(RB)2; and
b) when W is -OMe, R', R 2 , R3, and R4 are each hydrogen, and Q is -CH 2-, then Cy2 is other than 1H-benzimidazol-1-yl;
2)  when Cyl is phenyl substituted in the para position with W, and R1, R2, R3, and R4 are each hydrogen then:
a) when Q is a bond, W is other than:
i) -CONH2;
ii) -CONHR', where R' is an optionally substituted group selected from phenyl, alkylphenyl, alkyl, or -alkylheterocycle;
iii) -CF3;
iv) - SO 2Me;
v) -NH 2;
vi) -tBu;
vii) -CO2H when Cy2 is morpholine;
viii) -O(phenyl) when Cy2 is indole; and
ix) -OMe;
b) when Q is -CH 2-, W is other than:
i) -CONH2, when Cy2 is optionally substituted imidazole or benzimidazole; ii) -CONHR8 , where R is an optionally substituted group selected from phenyl, alkylphenyl, or -alkylheterocycle;
iii) -CF 3;
iv) -SO 2Me;
v) -OH, where Cy2 is a 5-10 membered heterocyclyl ring;
vi) tBu, when Cy2 is a 5-10 membered heterocyclyl ring; and
vii) -OMe; and
3)  when Cyl is a 5-membered heteroaryl ring then:
a) when Cyl is isoxazole, R', R2, R3, and R4 are each hydrogen, Q is a bond, and W is p fluoro-phenyl, then Cy2 is a group other than pyridyl or N-pyrrolidinyl;
b) when Cyl is triazolyl, R', R2, R3, and R4 are each hydrogen, Q is a bond, and W is (CH 2)2N(cyclopentyl)C(O)CH 2(naphthyl), then Cy 2 is a group other than N-piperidinyl;
c) when Cy' is imidazolyl, R', R2 , R3, and R4 are each hydrogen, Q is a bond, and W is neta CF3-phenyl, then R is a group other than C(O)OCH 2CH3; and
d) when Cyl is imidazol-5-yl and W is para-fluoro-phenyl, then R6 is a group other than cyclohexyl.
2.           The compound of claim 1, wherein Q is a bond.
3.           The  compound  of claim 2, wherein R',  R2, R3 and R4 are each hydrogen. 
4.          The compound of claim 3, wherein compound variables are selected from one or more, or all of:
a. Cy2 is a Cr-1 aryl or a 5-10-membered heteroaryl ring optionally substituted by one to three independent occurrences of R9 and one occurrence of R 0, wherein each occurrence of R9 is independently selected from -ORB, -N(RB)C(O)RA, -N(RB)2, halo, C14aliphatic optionally substituted by halo, NO2, -OS(O)2 Rc, -S(O)Rc, -N(RB)SO 2RA, or -S(O) 2N(RB)2;
b. ring A is optionally substituted with 1 or 2 independent occurrences of R, wherein R5 on ring A, when present, is selected from halo or optionally substituted C14 aliphatic;
c. Cyl is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, thienyl, thiadiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, furanyl, or oxadiazolyl;
d. W is selected from one of:
i) -L-V-L2-R7 , wherein L1 is -CHR13-, where R" is C1-3alkyl, OH, or OMe, V is NRE, L2 is -(CH 2)n-, where n is 1-3, and R7 is -N(RF) 2 , NRECOORG ECORG NEs 2 RG an optionally substituted 5-6-membered aryl or heteroaryl group, or an optionally substituted 3-8-membered heterocyclyl group;
ii)-V-R, wherein V is -NH- and RW is optionally substituted group selected from piperidinyl, azetidinyl, or pyrrolidinyl; V is -0- or -COO-, and R8 is C16alkyl; or V is -CH 2 or SO 2 , and R8 is an optionally substituted group selected from:
j                                       k 
wherein R is substituted on one or two carbon atoms with one or two occurrences of Ci 4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(C14akyl), -CONH 2, -CONH(Ci 4alkyl), CON(Ci.4alkyl) 2, -CONH(heteroaryl), -CN, -NH 2, -OH, -O(Ci 4alkyl), -NH(C14alkyl), -N(C 4alkyl) 2, =0, or Ci 4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(C14alkyl), -CONH2, -CONH(Ci 4alkyl), -CON(C14 alkyl) 2, CONH(heteroaryl), -CN, -NH2, -OH, -O(Ci 4 alkyl), -NH(C14 alkyl), or -N(CI.4alkyl)2; or iii)-L 1 -V-Rs, wherein L1 is -CH 2-, V is -NRE- or -NRECO-, and RW is an optionally substituted group selected from C16alkyl, or a 5-6-membered heteroaryl or a 3-7-membered heterocyclyl group, wherein R8 is unsubstituted, or R is substituted on one or two carbon atoms with one or two occurrences of C14alkyl, phenyl, heteroaryl, halo, -COOH, -COO(C 4alkyl), -CONH2, -CONH(Ci4alkyl), -CON(Cl4alkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -O(C,4alkyl), -NH(Ci 4 alkyl), -N(C14 alkyl) 2, =0, or C14 alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(C14alkyl), -CONH 2, CONH(Ci 4alkyl), -CON(Cl4alkyl) 2 , -CONH(heteroaryl), -CN, -NH2, -OH, -O(Ci-alkyl), NH(C14alkyl), or -N(Ci4 alkyl)2, and R8 is optionally substituted on one nitrogen atom with C 14 alkyl, or -COO(Ci 4alkyl), -SO2(C14 alkyl), benzyl, or CH2(heteroaryl); and
e) Cyl is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from-ORB, C13aliphatic, or halo.
5.          The compound of claim 3, wherein compound variables are selected from one or more, or all of:
a. Cy2 is phenyl, pyridyl, naphthyl, thienyl, 2-oxo-2,3-dihydrobenzooxazolyl, benzo[1,3]dioxolyl, benzo[1,3]dioxinyl, indolyl, tetrazole, piperidinyl, piperazinyl, or morpholinyl optionally substituted by one to three independent occurrences of R9 and one occurrence of R10 , wherein each occurrence of R9 is independently selected from -ORB, -N(RB)C(O)RA, -N(RB) 2, halo, C1 4aliphatic optionally substituted by halo, NO2, -OS(O)2Rc, -S(O)Rc, -N(RB)SO 2RA, or S(0)2N(RB)2;
b. ring A is optionally substituted with 1 or 2 independent occurrences of Rs, wherein R5 on ring A, when present, is selected from F, Cl, Br, or methyl;
c. Cyl is selected from phenyl, pyridyl, pyrimidinyl, or thienyl;
d. W is selected from:
i) 
wherein m is 1, 2, or 3, RF is H or C1.3alkyl, and R-is H, C1.3alkyl, or SO 2CH3, and wherein each of the foregoing pyridyl, pyrrolidinyl, piperidinyl, and piperazinyl groups is optionally substituted at one or more carbon atoms with 1, 2, or 3 independent occurrences of R", and at one or more substitutable nitrogen atoms with R12;
ii) -V-R, wherein V is -CH 2- and R8 is a group selected from:
p q r s t or
iii) 
wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of CiAalkyl, phenyl, heteroaryl, halo, -COOH, -COO(C14 alkyl), -CONH2, -CONH(C 14 alkyl), -CON(C14alkyl) 2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(Ci 4 alkyl), -NH(C14 alkyl), -N(C14 alkyl)2, =0, or C1. 4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, COOH, -COO(C14 alkyl), -CONH2, -CONH(C 14 alkyl), -CON(C14 alkyl)2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(C 14 alkyl), -NH(C14 alkyl), or -N(C14 alkyl)2, and are optionally substituted on one nitrogen atom with -C14alkyl, or -COO(C14 alkyl), -S0 2 (C1. 4alkyl), benzyl, or CH 2(heteroaryl); and
e) Cy' is optionally further substituted by one to three independent occurrences of R, wherein each occurrence of R6 is -OMe, methyl, ethyl, F, or Cl.
6.          The compound of claim 1, wherein Cy' is pheny] and compounds have the structure:
I-A.
7.           The compound of claim 6, wherein R', R2, R3, and R4 are all hydrogen, and Q is a bond and compounds have the structure:
I-A-i
8.          The compound of claim 7, wherein compound variables are selected from one or more, or all of:
a. Cy 2 is a C- 10aryl or a 5-10-membered heteroaryl ring optionally substituted by one to three independent occurrences of R9 and one occurrence of R10, wherein each occurrence of R9 is independently selected from -ORB, -N(RB)C(O)RA, -N(RB) 2, halo, C14aliphatic optionally substituted by halo, NO2 , -OS(0)2Rc, -S(O)Rc, -N(RB)SO 2 RA, or -S(O)2N(RD)2;
b. ring A is optionally substituted with 1 or 2 independent occurrences of R, wherein R5 on ring A, when present, is selected from halo or optionally substituted CIA aliphatic;
c. W is selected from one of:
i) -Lr-V-L 2-R7, wherein L1 is -CHR13-, where R13 is C1.3alkyl, OH, or OMe, V is NRE, L2 is -(CH 2).-, where n is 1-3, and R7 is -N(RF) 2 , NRECOORG NECORG NRESO 2RG, an optionally substituted 5-6-membered aryl or heteroaryl group, or an optionally substituted 3-8-membered heterocyclyl group;
ii)-V-R8, wherein V is -NH- and R8 is optionally substituted group selected from piperidinyl, azetidinyl, or pyrrolidinyl; V is -0- or -COO-, and R8 is C1.6alkyl; or V is -CH 2 or SO 2, and R8 is an optionally substituted group selected from:
d                                      e                                      f 
j k
wherein R' is substituted on one or two carbon atoms with one or two occurrences of C14 alkyl, phenyl, heteroaryl, halo, -COOH, -COO(C14alkyl), -CONH42, -CONH(C14 alkyl), CON(C14 alkyl)2 , -CONH(heteroaryl), -CN, -NH 2, -OH, -O(C 14 alkyl), -NH(C14 alkyl), -N(C 4alkyl) 2, =0, or C14 alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(C14 alkyl), -CONH 2, -CONH(C 14 alkyl), -CON(C14 alkyl) 2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(C14alkyl), -NH(C14 alkyl), or -N(C14 alkyl) 2; or iii)-L 1 -V-R8 , wherein Li is -CH 2 -, V is -NRE- or -NRECO-, and R is an optionally substituted group selected from C16alkyl, or a 5-6-membered heteroaryl or a 3-7-membered heterocyclyl group, wherein R' is unsubstituted, or R is substituted on one or two carbon atoms with one or two occurrences of C14 alkyl, phenyl, heteroaryl, halo, -COOH, -COO(Cl. 4alkyl), -CONH 2, -CONH(C14 alkyl), -CON(Cl4alkyl) 2, -CONH(heteroaryl), -CN, -NH 2, -OH, -O(C, 4 alkyl), -NH(C14 alkyl), -N(Cl.4alkyl)2, =O, or C14alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(C14 alkyl), -CONH2, CONH(C14 alkyl), -CON(C14alkyl) 2, -CONH(heteroaryl), -CN, -NH2, -OH, -O(C 14alkyl), NH(C4alkyl), or -N(CI4 alkyl)2, and Rg is optionally substituted on one nitrogen atom with C14alkyl, or -COO(C14 alkyl), -S02(C14 alkyl), benzyl, or CH 2(heteroaryl); and
d) Cy' is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from-ORB, C13aliphatic, or halo.
9.           The compound of claim 7, wherein compound variables are selected from one or more, or all of:
a. Cy 2 is phenyl, pyridyl, naphthyl, thienyl, 2-oxo-2,3-dihydrobenzooxazolyl, benzo[1,3]dioxolyl, benzo[1,3]dioxinyl, indolyl, tetrazole, piperidinyl, piperazinyl, or morpholinyl optionally substituted by one to three independent occurrences of R9 and one occurrence of R10 , wherein each occurrence of R9 is independently selected from -ORB, -N(RB)C(O)RA, -N(R) 2, halo, C14aliphatic optionally substituted by halo, NO 2, -OS(O) 2RC, -S(O)Rc, -N(RB)SO 2R^, or S(O)2N(RB)2;
b. ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein R5 on ring A, when present, is selected from F, Cl, Br, or methyl;
c. W is selected from:
i)
wherein m is 1, 2, or 3, RF is H or C1.3alkyl, and REis H, CI-3alkyl, or SO2 CH 3, and wherein each of the foregoing pyridyl, pyrrolidinyl, piperidinyl, and piperazinyl groups is optionally substituted at one or more carbon atoms with 1, 2, or 3 independent occurrences of R", and at one or more substitutable nitrogen atoms with R12 ;
ii) -V-R', wherein V is -CH 2 - and R8 is a group selected from:
NH NH NH NH
N" 1 N, 4 N N
m                                     n                                      0 
wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of CI.4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(C14 alkyl), -CONH 2, -CONH(C14 alkyl), -CON(C14 alkyl)2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(CI4 alkyl), -NH(C14 alkyl), -N(C14 a]kyl) 2, =0, or C 4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, COOH, -COO(C14alkyl), -CONH2, -CONH(C 14 alkyl), -CON(C14 alkyl)2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(CiAalkyl), -NH(C14 alkyl), or -N(CI4 alkyl)2, and are optionally substituted on one nitrogen atom with -C14 alkyl, or -COO(C 14 alkyl), -S0 2(C1. 4alkyl), benzyl, or CH 2(heteroaryl); and
d) Cyl is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is -OMe, methyl, ethyl, F, or Cl.
10.        The compound of claim 1, wherein Cy' is optionally substituted thienyl and compounds have the structure:
I-B
11. The compound of claim 10, wherein R', R2, R, and R4 are all hydrogen, and Q is a bond and compounds have the structure:
I-B-i
12. The compound of claim 11, wherein compound variables are selected from one or more, or all of:
a. Cy2 is a C6-1oaryl or a 5-10-membered heteroaryl ring optionally substituted by one to three independent occurrences of R9 and one occurrence of R10 , wherein each occurrence of R9 is independently selected from -ORB, -N(R)C(O)RA, -N(RB) 2, halo, Ci 4aliphatic optionally substituted by halo, NO2, -OS(O)2Rc, -S(O)Rc, -N(RB)SO 2RA, or -S(O)2N(R")2;
b. ring A is optionally substituted with 1 or 2 independent occurrences of R, wherein R5 on ring A, when present, is selected from halo or optionally substituted CiA aliphatic;
c. W is -L 1-V-R8 , wherein L, is -CH 2-, V is -NRE- or -NRECO-, and R is an optionally substituted group selected from C1.6alkyl, or a 5-6-membered heteroaryl or a 3-7-membered heterocyclyl group, wherein R is unsubstituted, or R8 is substituted on one or two carbon atoms with one or two occurrences of CI 4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(Ci 4alkyl), -CONH2, CONH(C14alkyl), -CON(Ci 4 alkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -O(Ci-alkyl), -NH(C1 _ 4alkyl), -N(Ci-alkyl)2, =0, or Ciaalkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(Ci 4 a]kyl), -CONH 2, -CONH(Ci 4alkyl), -CON(Ci 4alkyl) 2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(C14 alkyl), -NH(C14alkyl), or -N(C14 alkyl) 2, and Rs is optionally substituted on one nitrogen atom with -C1-4alkyl, or -COO(C14alkyl), -SO2(C 14 alkyl), benzyl, or CH 2(heteroaryl); and
d) Cyl is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from-ORB, C1-3aliphatic, or halo.
13.        The compound of claim 11, wherein compound variables are selected from one or more, or all of:
a. Cy 2 is phenyl, pyridyl, naphthyl, thienyl, 2-oxo-2,3-dihydrobenzooxazolyl, benzo[1,3]dioxolyl, benzo[1,3]dioxinyl, indolyl, tetrazole, piperidinyl, piperazinyl, or morpholinyl optionally substituted by one to three independent occurrences of R 9 and one occurrence of R10, wherein each occurrence of R9 is independently selected from -ORB, -N(RB)C(O)RA, -N(RB)2 , halo, C14 aliphatic optionally substituted by halo, NO2, -OS(O)2 Rc, -S(O)Re, -N(R )SO2RA, or S(O)2N(R B)2;
b. ring A is optionally substituted with 1 or 2 independent occurrences of R5 , wherein Rs on ring A, when present, is selected from F, Cl, Br, or methyl;
c. W is:
wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of Ci.4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(C14 alkyl), -CONH 2, -CONH(C 14 alkyl), -CON(C1.4 alkyl) 2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(C.4alkyl), -NH(C14 alkyl), -N(C14 alkyl)2, =0, or C1. 4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, COOH, -COO(C14alkyl), -CONH2, -CONH(C14 alkyl), -CON(C14 alkyl)2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(C 14alkyl), -NH(C14 alkyl), or -N(C1.4alkyl)2, and are optionally substituted on one nitrogen atom with -C14alkyl, or -COO(Cl.4alkyl), -S02(C 4alkyl), benzyl, or CH 2(heteroaryl); and
d) CyI is optionally further substituted by one to three independent occurrences of R , wherein each occurrence of R is -OMe, methyl, ethyl, F, or Cl.
14. A compound of formula I-A-i:
I-A-i
wherein
a. Cy 2 is phenyl optionally substituted by one to three independent occurrences of R9 and one occurrence of R 10, wherein each occurrence of R9 is independently selected from -ORB, N(RB)C(O)RA, -N(RB) 2, halo, C14aliphatic optionally substituted by halo, NO2, -OS(O)2RC, -S(O)Rc, -N(RB)SO 2RA, or -S(O) 2N(RB) 2 ;
b. ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein R' on ring A, when present, is selected from F, Cl, Br, or methyl;
c. W is selected from:
i)
wherein m is 1, 2, or 3, RF is H or C13alkyl, and RE is H, C1.3alkyl, or SO 2CH 3, and wherein each of the foregoing pyridyl, pyrrolidinyl, piperidinyl, and piperazinyl groups is optionally substituted at one or more carbon atoms with 1, 2, or 3 independent occurrences of R", and at one or more substitutable nitrogen atoms with R12;
ii) -V-R, wherein V is -CH 2- and R8 is a group selected from:
p q r s t or
iii) 
wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of Ci 4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(Ci 4 alkyl), -CONH 2, -CONH(C 14 alkyl), -CON(C14 alkyl)2, CONH(heteroaryl), -CN, -NH 2, -OH, -O(C14alkyl), -NH(C14alkyl), -N(C14 alkyl) 2, =0, or C1. 4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, COOH, -COO(CI 4 alkyl), -CONH 2, -CONH(Cl4alkyl), -CON(Ci 4 alkyl)2 , CONH(heteroaryl), -CN, -NH2, -OH, -O(Ci-alkyl), -NH(C14 alkyl), or -N(Ci 4 alkyl) 2, andare optionally substituted on one nitrogen atom with -C1.4alkyl, or -COO(Ci 4 alkyl), -S0 2(C1. 4alkyl), benzyl, or CH 2(heteroaryl); and
d) Cyl is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R is -OMe, methyl, ethyl, F, or Cl.
15.         The compound of claim 14, wherein Cy2 is optionally further substituted with one or two occurrences of R9, wherein R9 is halo.
16.         The compound of claim 14, wherein ring A is not further substituted by R5.
17.         The compound of claim 14, wherein Cy is optionally further substituted by one occurrence of F or methyl.
18.        A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable excipient or carrier.
19. A pharmaceutical composition comprising:
a) the compound or pharmaceutically acceptable salt according to claim 1,
b) methotrexate or a pharmaceutically acceptable salt thereof, and
c) a pharmaceutically acceptable excipient or carrier.
20. A method for treating an inflammatory or immune-related physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to the patient a compound of formula I:
or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein: R1 and R2 are each independently H, C13 alkyl or C3.5 cycloalkyl;
R3 is H or F;
R4 is H, F, -ORA, -C(O)RA, -C(O)ORA or -N(RA) 2 ; or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group; wherein each occurrence of RA is independently H, C13 alkyl or C3.5cycloalkyl;
Ring A is optionally substituted with 1 or 2 independent occurrences of R5 , wherein each R is independently selected from halo, CI 4 aliphatic, -CN, -ORB, -SRc, -N(RB) 2, -NRBC(O)RB, -NReC(O)N(R) 2, -NBC 2RC, -CO2RB, -C(O)R5 , -C(O)N(RB) 2, -OC(O)N(RB) 2, -S(O) 2Rc,
-SO 2N(RB) 2 , -S(O)Rc, _NRBSO 2N(RB) 2 -NRBSO 2Rc, or C14 aliphatic optionally substituted with halo, -CN, -ORB, -SRc, -N(RB) 2, _ BC(O)RB BC(O)N(RB)2 _ B 2 Rc -CO 2R5 , -C(O)RB, -C(O)N(RB)2, -OC(O)N(R) 2, -S(O)2Rc, -SO2N(RB) 2, -S(O)Rc, _BSO2N(RB) 2 , or -NRBSO 2Rc, wherein each occurrence of RB is is independently H or C14 aliphatic; or two RB on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S; and each occurrence of Rc is independently CIA aliphatic;
Cy' is selected from:
a) a 6-membered aryl or heteroaryl ring substituted by one occurrence of W at the meta or para position of the ring; or
b)   a  5-membered  heteroaryl ring  substituted by  one occurrence of W; 
wherein Cyl is optionally further substituted by one to three independent occurrences of R, wherein each occurrence of R6 is independently selected from -halo, C1 s aliphatic, -CN, -ORB, -SRD -N(RE)2 , -NPEC(O)RB, -NEC(O)N(RE) 2, -NREC0 2RD, -CO2 RB, -C(O)RB, -C(O)N(RE) 2, -OC(O)N(RE) 2, -S(O)2 RD, -S02N(RE)2 , -S(O)RD, -NRESO 2N(RE) 2 , -NRESO2RD, -C(=NH)-N(RE) 2 , or C1 s aliphatic optionally substituted. with halo, -CN, -ORB, -SRD, -N(RE) 2, -NREC(O)RB -NREC(O)N(RE) 2 , -NRECO 2RD, -CO 2RB, -C(O)RB, -C(O)N(R )2 , -OC(O)N(RE) 2, -S(O)2RD,
-SO 2N(RE) 2, -S(O)RD, -NRESO 2N(RE)2, _NRESO 2RD, or -C(=NH)-N(RE) 2, wherein each occurrence of RD is C1-6 aliphatic and each occurrence of RE is independently H, Cs6 aliphatic, -C(=O)R5 , -C(O)OR or -SO 2RB; or two RE on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S;
W is -R, V-R", L-R, V-L1 -R7, L1-V-R8 , or L1-V-L2-R7 ; wherein:
L1 and L2 are each independently an optionally substituted C1 s alkylene chain; V is-CH2-, -0-, -S-, -S(O)-, -S(0) 2-, -C(O)-, -CO2-, -NRE -, -NRE C(O)-, -NRE CO2-, -NRE SO2-, -C(O)N(R5 )-, -SO 2N(RB)-, -NRE C(O)N(RB)- or -OC(O)-;
R7 is H, halo, -OH, -N(RF)2 , -CN, -ORG, -C(O)R, -CO2 H, -CO2 RG, -SRG, -S(O)RG, -S(O) 2RG, -N(RE)C(O)R3, -N(RE)CO 2RG, -N(RE)SO 2RG, -C(O)N(RF)2, -SO 2N(RF) 2 , -N(RE)C(O)N(RF) 2 , -OC(O)Rr or an optionally substituted group selected from C 1i0 aliphatic, C6.10aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of RF is independently H, C1_6 aliphatic, Cs_10aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, -C(=O)RB, -C(O)OR or -SO 2R5 ; or two R on the same nitrogen atom taken together with the nitrogen atom form an optionally substituted 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S; and each occurrence of RG is C16 aliphatic, C6_10aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl;
R8 is an optionally substituted group selected from Cl 10 aliphatic, C6 _10 aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl;
Q is a bond, CH2 or C(=0);
Cy2 is a C6_10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl ring, wherein each ring is optionally substituted by one to three independent occurrences of R9 and one occurrence of R10,
wherein each occurrence of R9 is independently selected from Cl-aliphatic, -N(RB) 2, halo, NO2, -CN, -ORB, -C(O)RA, -CO2RA, -SRc, -S(O)Rc, -S(O) 2Rc, -OS(O)2Rc-, N(RB)C(O)RA, -N(RB)CO2RA, -N(Rs)SO2 RA, -C(O)N(R) 2, -SO2N(RB) 2, -N(RB)C(O)N(RB) 2, -OC(O)RA, or C14 aliphatic optionally substituted by -N(RB) 2, halo, NO2, -CN, -OR", -C(O)RA, -CO2 RA, -SRc, -S(O)Rc, -OS(O) 2Rc, -S(O) 2Rc, -N(RB)C(O)RA, -N(RB)CO 2RA, -N(RB)SO 2RA, -C(O)N(RB) 2, -SO 2N(RB) 2 , -N(RB)C(O)N(R")2, or -OC(O)RA, and
R' 0 is selected from phenyl, or a 5-6 membered heterocyclyl or heteroaryl ring.
21.         The method according to claim 20, where the inflammatory disease is rheumatoid arthritis, asthma, psoriasis, chronic obstructive pulmonary disease, inflammatory bowel disease or multiple sclerosis.
22.         The method according to claim 21, where the inflammatory disease is rheumatoid arthritis.
23.         A method of inhibiting PKC-theta activity in a biological sample or a patient, which method comprises administering to the patient or contacting said biological sample with a compound of formula I:
or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein: R' and R2 are each independently H, C1-3 alkyl or C3.5 cycloalkyl;
R3 is H or F;
RW is H, F, -ORA, -C(O)RA, -C(O)ORA or -N(RA) 2; or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group; wherein each occurrence of RA is independently H, C1-3alkyl or C3.5cycloalkyl;
Ring A is optionally substituted with 1 or 2 independent occurrences of Rs, wherein each R is independently selected from halo, C 14 aliphatic, -CN, -ORB, -SRc, -N(R) 2 , -NRBC(O)RB, -NRC(O)N(RB)2 , NRBCO 2Rc, -CO 2RB, -C(O)R, -C(O)N(RB) 2 , -OC(O)N(RB) 2, -S(O)2Rc,
-SO 2N(R) 2, -S(O)Re, _NRBSO 2N(RB) 2, NR BSO 2Rc, or C14aliphatic optionally substituted with halo, -CN, -ORB, -SRC, -N(RB) 2 , -NRBC(O)RB, -N C(O)N()2, -WCO2Rc, -CO2 RB, -C(O)RB, -C(O)N(RB) 2 , -OC(O)N(RB) 2, -S(O) 2Rc, -SO2N(RB) 2 , -S(O)Rc, _NBSO2N(RB) 2, or -NR BSO 2RC wherein each occurrence of R5 is is independently H or CI 4 aliphatic; or two RB on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S; and each occurrence of Rc is independently C1.4 aliphatic;
Cy' is selected from:
a) a 6-membered aryl or heteroaryl ring substituted by one occurrence of W at the meta or para position of the ring; or
b) a 5-membered heteroaryl ring substituted by one occurrence of W;
wherein Cyl is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from -halo, C1.8 aliphatic, -CN, -ORB, -SRD, -N(RE)2, .NREC(O)RB ,NREC(O)N(RE) 2, -NRECO 2RD, -CO 2RB, C(O)R, -C(O)N(RE) 2 , -OC(O)N(RE) 2, -S(O)2RD, -SO2 N(RE) 2, -S(O)RD, -NRESO 2N(R) 2 , -NRESO 2RD, -C(=NH)-N(RE)2, or C1.s aliphatic optionally substituted with halo, -CN, -ORB, -SRD, -N(RE)2, -NR EC(O)RB -NREC(O)N(RE) 2 -NRECO 2RD, -CO2RB, -C(O)RB, -C(O)N(RE) 2, -OC(O)N(RE) 2 , -S(O) 2RD,
-SO 2N(RE) 2, -S(O)RD, -NRESO 2N(RE)2, -NESO2R0 , or -C(=NH)-N(RE) 2, wherein each occurrence of RD is C1.6 aliphatic and each occurrence of RE is independently H, C1.6 aliphatic, -C(=O)RB, -C(O)ORB or -SO 2RB; or two RE on the same nitrogen atom taken together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S;
W is -R', V-R8, L1-R 7, V-L1-R 7, L,-V-R', or L1-V-L2-R7; wherein:
L, and L2 are each independently an optionally substituted C1.6 alkylene chain; V is-CH2-, -0-, -S-, -S(O)-, -S(O) 2-, -C(O)-, -C02-, -NRE -, -NRE C(O)-, -NRE CO2-, -NRE SO2r, -C(O)N(RE)-, -SO 2N(RB)-, -NRE C(O)N(RB)- or -OC(O)-;
R7 is H, halo, -OH, -N(R) 2, -CN, -ORG, -C(O)RG, -CO 2H, -C02 RG, -SRG, -S(O)RG,
-S(O) 2 RG, -N(RE)C(O)RG, -N(RE)CO 2 RG, -N(RE)SO 2 RG, -C(O)N(RF) 2 , -SO 2N(RF)2, -N(RE)C(O)N(RF) 2, -OC(O)RF or an optionally substituted group selected from C1-10 aliphatic, C-aoaryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of RF is independently H, Ci 6 aliphatic, C6.10aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, -C(=O)RB, -C(O)0RB or -S0 2RB; or two RF on the same nitrogen atom taken together with the nitrogen atom form an optionally substituted 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 ring heteroatoms selected from N, 0 or S; and each occurrence of RG is Ci.6 aliphatic, Co10aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl;
R8 is an optionally substituted group selected from CI. 0 aliphatic, C6.10 aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl;
Q is a bond, CH 2 or C(=O);
Cy2 is a C6.10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl ring, wherein each ring is optionally substituted by one to three independent occurrences of R9 and one occurrence of R10 ,
wherein each occurrence of R9 is independently selected from C, 4 aliphatic, -N(RB) 2, halo, NO2 , -CN, -ORB, -C(O)RA, -CO2 RA, -SRc, -S(O)Rc, -S(O) 2Rc, -OS(O)2 Rc-, N(RD)C(O)RA, -N(RB)CO 2RA, -N(RB)SO2R^, -C(O)N(RB) 2, -SO 2N(RB) 2 , -N(RB)C(O)N(RB) 2 , -OC(O)RA, or Ci 4 aliphatic optionally substituted by -N(RB) 2 , halo, NO2 , -CN, -ORB, -C(O)RA, -CO 2 RA, -SRc, -S(O)Rc, -OS(O) 2Rc, -S(O)2Rc, -N(RB)C(O)RA, -N(RB)CO 2RA, -N(RB)SO2 RA, -C(O)N(RB) 2 , -SO 2N(RB) 2, -N(RB)C(O)N(RB) 2, or -OC(O)RA, and
R10 is selected from phenyl,  or a 5-6 membered  heterocyclyl or heteroaryl  ring.