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Paramétrages

Paramétrages

1. WO2005066139 - 2-(AMINO-SUBSTITUEES)-4-ARYL PYRAMIDINES ET COMPOSES ASSOCIES UTILES DANS LE TRAITEMENT DE MALADIES INFLAMMATOIRES

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:
R1 and R2 are each independently H, Ci.3 alkyl or C3-5 cycloalkyl;
R3 is H or F;
R4is H, F, -ORA, -C(0)RA, -C(0)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, Cι-3alkyl or C3.5cycloalkyl;
Ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein each R5 is independently selected from halo, CM aliphatic, -CN, -ORB, -SRC, -N(RB)2, -NRBC(0)RB,
-NRBC(0)N(RB)2, -NRBC02Rc, -C02RB, -C(0)RB, -C(0)N(RB)2, -OC(0)N(RB)2, -S(0)2Rc,
-S02N(RB)2, -S(0)Rc, -NRBS02N(RB)2, -NRBS02Rc, or CMaliphatic optionally substituted with halo, -CN, -ORB, -SRC, -N(RB)2, -NRBC(0)RB, -NRBC(0)N(RB)2, -NRBC02Rc, -C02RB, -C(0)RB, -C(0)N(RB)2, -OC(0)N(RB)2, -S(0)2Rc, -S02N(RB)2, -S(0)Rc, -NRBS02N(RB)2, or -NRBS02Rc, wherein each occurrence of RB is is independently H or C 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, O or S; and each occurrence of Rc is independently CM aliphatic;
Cy1 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 Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from -halo, Cι.8 aliphatic, -CN, -ORB, -SRD, -N(RE)2, -NREC(0)RB, -NREC(0)N(RE)2, -NREC02RD, -C02RB, -C(0)RB, -C(0)N(RE)2,
-OC(0)N(RE)2, -S(0)2RD, -S02N(RE)2, -S(0)RD, -NRES02N(RE)2, -NRES02RD, -C(=NH)-N(RE)2, or C,.8 aliphatic optionally substituted with halo, -CN, -ORB, -SRD, -N(RE)2, -NREC(0)RB,
-NREC(0)N(RE)2, -NREC02RD, -C02RB, -C(0)RB, -C(0)N(RE)2, -OC(0)N(RE)2, -S(0)2RD,
-S02N(RE)2, -S(0)RD, -NRES02N(RE)2, -NRES02RD, or -C(=NH)-N(RE)2, wherein each occurrence of RD is Cι_6 aliphatic and each occurrence of RE is independently H, Cι.6 aliphatic, -C(=0)RB, -C(0)ORB or -S02RB; 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, O or S;
W is -R8, V-R8, L R7, V-L,-R7, LrV-R8, or L.-V-LrR7; wherein:
Lj and L2 are each independently an optionally substituted Cι.6 alkylene chain;
V is-CH2-, -0-, -S-, -S(O)-, -S(0)2-, -C(O)-, -C02-, -NRE -, -NRE C(O)-, -NRE C02-, -NRE S02-, -C(0)N(RB)-, -S02N(RB)-, -NRE C(0)N(RB)- or -OC(O)-;
R7 is H, halo, -OH, -N(RF)2, -CN, -ORG, -C(0)RG, -C02H, -C02RG, -SRG, -S(0)RG, -S(0)2RG, -N(RE)C(0)RG, -N(RE)COzRG, -N(RE)S02RG, -C(0)N(RF)2, -S02N(RF)2,
-N(RE)C(0)N(RF)2, -OC(0)RF or an optionally substituted group selected from C1-10 aliphatic, Cβ-ioaryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of RF is independently H, CM aliphatic, C60aryl, 3-14 membered heterocyclyl, 5-14
membered heteroaryl, -C(=0)RB, -C(0)ORB or -S02RB; 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 fromN, O or S; and each occurrence of RG is
aliphatic, Cβ-ioaryl, 3-14 membered
heterocyclyl, or 5-14 membered heteroaryl;
R8 is an optionally substituted group selected from Cι.ι0 aliphatic, C6-ιo aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl;
Q is a bond, CH2 or C(=0);
Cy2 is a C6.ιo 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 CM liphatic, -N(RB)2, halo, N02, -CN, -ORB, -C(0)RA, -C02RA, -SRC, -S(0)Rc, -S(0)2Rc, -OS(0)2Rc-, N(RB)C(0)RA, -N(RB)C02RA, -N(RB)S02RA, -C(0)N(RB)2, -S02N(RB)2, -N(RB)C(0)N(RB)2, -OC(0)RA, or CM aliphatic optionally substituted by -N(RB)2, halo, N02, -CN, -ORB, -C(0)RA, -C02RA, -SRC, -S(0)Rc, -OS(0)2Rc, -S(0)2Rc, -N(RB)C(0)RA, -N(RB)C02RA, -N(RB)S02RA, -C(0)N(RB)2, -S02N(RB)2, -N(RB)C(0)N(RB)2, or -OC(0)RA, and
R10 is selected from phenyl, or a 5-6 membered heterocyclyl or heteroaryl ring, provided that:
1) when Cy1 is phenyl substituted in the meta position with W then:
a) when W is -OMe, R1, R2, R3, 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(0)N(RB)2; and
b) when W is -OMe, R1, R2, R3, and R4 are each hydrogen, and Q is -CH2-, then Cy2 is other than lH-benzimidazol-1-yl;

2) when Cy1 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) -CONHR8, where R8 is an optionally substituted group selected from phenyl, -alkylphenyl, alkyl, or -alkylheterocycle;
iii) -CF3;
iv) - S02Me;
v) -NH2;
vi) -tBu;
vii) -C02H when Cy2 is morpholine;
viii) -O(phenyl) when Cy2 is indole; and
ix) -OMe;
b) when Q is -CH2-, W is other than:
i) -CONH2, when Cy2is optionally substituted imidazole or benzimidazole;
ii) -CONHR8, where R8 is an optionally substituted group selected from phenyl, -alkylphenyl, or -alkylheterocycle;
iii) -CF3;
iv) -S02Me;
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 Cy1 is a 5-membered heteroaryl ring then:
a) when Cy1 is isoxazole, R1, 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 Cy1 is triazolyl, R1, R2, R3, and R4 are each hydrogen, Q is a bond, and W is -(CH2)2N(cyclopentyl)C(0)CH2(naphthyl), then Cy2 is a group other than N-piperidinyl;
c) when Cy1 is imidazolyl, R1, R2, R3, and R4 are each hydrogen, Q is a bond, and W is meta-CF3-phenyl, then R6 is a group other than C(0)OCH2CH3; and
d) when Cy1 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 R1, 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 C6-ιoaryl 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(0)RA, -N(RB)2, halo, C1-4aliphatic optionally substituted by halo, N02, -OS(0)2Rc, -S(0)Rc, -N(RB)S02RA, or -S(0)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 halo or optionally substituted CM aliphatic;
c. Cy1 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 L, is -CHR13-, where R13 is CMalkyl, OH, or OMe, V is
NRE, L, is -(CH2)n-, where n is 1-3, and R7 is -N(RF)2, NRECOORG, NRECORG, NRES02RG, 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 -O- or-COO-, and R8 is Cι.6alkyl; or V is -CH2- or S02, and R8 is an optionally substituted group selected from:



c





k wherein R8 is substituted on one or two carbon atoms with one or two occurrences of CMalkyl, phenyl, heteroaryl, halo, -COOH, -COO(CMalkyl), -CONH2, -CONH(Cι^alkyl), - CON(C1-4alkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -0(Cι^alkyl), -NH(C1-4alkyl), -N(d. alkyl)2, =0, or CMalkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO( .4alkyl), -CONH2, -CONH(Cι_4alkyl), -CON(CMalkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -0(CMalkyl), -NH(CMalkyl), or -N(C1-4alkyl)2; or
iii)-L V-R8, wherein Li is -CH2-, V is -NRE- or -NRECO-, and R8 is an optionally substituted group selected from Cι.6alkyl, or a 5-6-membered heteroaryl or a 3-7-membered heterocyclyl group, wherein R8 is unsubstituted, or R8 is substituted on one or two carbon atoms with one or two occurrences of _4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(Cι_ 4alkyl), -CONH2, -CONH(CMalkyl), -CON(CMalkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), -NH(CMalkyl), -N(Cι- alkyl)2, =0, or Cι.4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(CMalkyl), -CONH2, - CONH(CMalkyl), -CON(CMalkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -0(CMalkyl), - NH(Cι-4alkyl), or -N(CMalkyl)2, and R8 is optionally substituted on one nitrogen atom with - CMalkyl, or -COO(CMalkyl), -S02(Cι.4alkyl), benzyl, or CH2(heteroaryl); and
e) Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from-ORB, CMaliphatic, 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[l,3]dioxolyl, benzo[l,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(0)RΛ, -N(RB)2, halo, CMaliphatic optionally substituted by halo, N02, -OS(0)2Rc, -S(0)Rc, -N(RB)S02RA, or -S(0)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. Cy1 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 Cι-3alkyl, and REis H, Cι-3alkyl, or S02CH3, 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 R11, and at one or more substitutable nitrogen atoms with R12;
ii) -V-R8, wherein V is -CH2- and R8 is a group selected from:



m n



p q r s t or

iϋ)





wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of CMal yl, phenyl, heteroaryl, halo, -COOH, -COO(CMalkyl), -CONH2, -CONH(Cι^alkyl), -CON(Cι^alkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -0(Cι_4fllkyl), -NH(CMalkyl), -N(C1-4alkyl)2, =0, or Q. 4alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, - COOH, -COO(CMalkyl), -CONH2, -CONH(CMalkyl), -CON(C1- alkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), -NHC ^alkyl), or -N(C1-4alkyl)2, and are optionally substituted on one nitrogen atom with -CMalkyl, or -COO(Cι_4alkyl), -S02(Cι.
4alkyl), benzyl, or CH2(heteroaryl); and
e) Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is -OMe, methyl, ethyl, F, or Cl.

6. The compound of claim 1 , wherein Cy ' is phenyl and compounds have the structure:


7. The compound of claim 6, wherein R1, 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. Cy2 is a C6-ιoaryl or a 5-10-membered heteroaryl ring optionally substituted by one to three independent occurrences of R and one occurrence of R , wherein each occurrence of R is independently selected from-ORB, -N(RB)C(0)RA, -N(RB)2, halo, CMaliphatic optionally substituted by halo, N02, -OS(0)2Rc, -S(0)Rc, -N(RB)S02RA, or -S(0)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 halo or optionally substituted CM aliphatic;
c. W is selected from one of:
i) -LrV-L2-R7, wherein L, is -CHR13-, where R13 is C1-3alkyl, OH, or OMe, V is
NRE, La is -(CH2)n-, where n is 1-3, and R7 is -N(RF)2, NRECOORG, NRECORG, NRES02RG, 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 -O- or -COO-, and R8 is
or V is -CH2- or S02, and R8 is an optionally substituted group selected from:





g


wherein R is substituted on one or two carbon atoms with one or two occurrences of C alkyl, phenyl, heteroaryl, halo, -COOH, -COO(C1-4alkyl), -CONH2, -CONH(CMalkyl), - CON(C1-4alkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -OCd^alkyl), -NH(Cι-4alkyl), -N(Cι. 4alkyl)2, =0, or CM lkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(Q.4alkyl), -CONH2, -CONH(CMalkyl), -CON(C,.4alkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), -NH(CMalkyl), or -N(Cι-4alkyl)2; or
iii)-L V-R8, wherein L: is -CH2-, V is -NRE- or -NRECO-, and R8 is an optionally substituted group selected from Ci-βalkyl, or a 5-6-membered heteroaryl or a 3-7 -membered heterocyclyl group, wherein R8 is unsubstituted, or R8 is substituted on one or two carbon atoms with one or two occurrences of CMalkyl, phenyl, heteroaryl, halo, -COOH, -COO(Cι. 4alkyl), -CONH2, -CONH(C1-4alkyl), -CON(CMalkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), -NH(CMalkyl), -N(Cι-4alkyl)2, =0, or CMalkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(CMalkyl), -CONH2, - CONH(CMalkyl), -CON(CMalkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), - NH(CMalkyl), or -N(CMalkyl)2, and R8 is optionally substituted on one nitrogen atom with - CMalkyl, or -COO(Q.4alkyl), -S02(CMalkyl), benzyl, or CH2(heteroaryl); and
d) Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from-ORB, CMaliphatic, or halo.

9. The compound of claim 7, 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[l,3]dioxolyl, benzo[l ,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(0)RA, -N(RB)2, halo, CMaliphatic optionally substituted by halo, N02, -OS(0)2Rc, -S(0)Rc, -N(RB)S02RA, or -S(0)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 CMalkyl, and REis H, CMalkyl, or S02CH3, 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 Rπ, and at one or more substitutable nitrogen atoms with R12;
ii) -V-R8, wherein V is -CH2- and R8 is a group selected from:



m

or

iϋ)





wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of CMalkyl, phenyl, heteroaryl, halo, -COOH, -COO(C1-4alkyl), -CONH2, -CONH(CMalkyl), -CON(d.4alkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -0(d-4alkyl), -NH(CMalkyl), -N(Cι.4alkyl)2, =0, or C,. alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, - COOH, -COO(d-4alkyl), -CONH2, -CONH(d-4alkyl), -CON(CMalkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -CχcMalkyl), -NH(Cι^alkyl), or -N(C,. alkyl)2, and are optionally substituted on one nitrogen atom with -C].4alkyl, or -COO(CMalkyl), -S02(Cι.
alkyl), benzyl, or CH2(heteroaryl); and
d) Cy1 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 Cy1 is optionally substituted thienyl and compounds have the structure:

I-B

11. The compound of claim 10, wherein R1, R2, R3, and R are all hydrogen, and Q is a bond and compounds have the structure:


12. The compound of claim 11, wherein compound variables are selected from one or more, or all of:
a. Cy" is a C6-ιoaryl 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(0)RA, -N(RB)2, halo, d-4aliphatic optionally substituted by halo, N02, -OS(0)2Rc, -S(0)Rc, -N(RB)S02RA, or -S(0)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 halo or optionally substituted CM aliphatic;
c. W is -L V-R8, wherein L, is -CH2-, V is -NRE- or -NRECO-, and R8 is an optionally substituted group selected from Ci-βalkyl, or a 5-6-membered heteroaryl or a 3-7-membered heterocyclyl group, wherein R8 is unsubstituted, or R8 is substituted on one or two carbon atoms with one or two occurrences of d_4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(C1-4alkyl), -CONH2, -CONH(d-4alkyl), -CON(ClJtalkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -0(d-4alkyl), -NH(C,. 4alkyl), -N(d-4alkyl)2, =0, or CM lkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, -COOH, -COO(d.4alkyl), -CONH2, -CONH(C,^alkyl), -CON(C,.4alkyl)2, -CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), -NH(C,.4alkyl), or -N(CMalkyl)2, and R8 is optionally substituted on one nitrogen atom with -d-4alkyl, or -COO(CMalkyl), -S02(d_4alkyl), benzyl, or CH2(heteroaryl); and
d) Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from-ORB, CMaliphatic, or halo.

13. The compound of claim 11 , 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[l,3]dioxolyl, benzo[l,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(0)RA, -N(RB)2, halo, d-4aliphatic optionally substituted by halo, N02, -OS(0)2Rc, -S(0)Rc, -N(RB)S02RA, or -S(0)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:





wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are unsubstituted, or are substituted on one or two carbon atoms with one or two occurrences of d.4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(d-4alkyl), -CONH2, -CONH(d-4alkyl), -CON(CMalkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -0(CMalkyl), -NH(d- alkyl), -N(C,.4alkyl)2, =0, or d. alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, - COOH, -COO(d-4alkyl), -CONH2, -CONH(d-4alkyl), -CON(CMalkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), -NH(CMalkyl), or -N(CMalkyl)2, and are optionally substituted on one nitrogen atom with -CMal yl, or -COO(d.4alkyl), -S02(Cι.
alkyl), benzyl, or CH2(heteroaryl); and
d) Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is -OMe, methyl, ethyl, F, or Cl.

14. A compound of formula I-A-i:


wherein
a. Cy2 is phenyl 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(0)RA, -N(RB)2, halo, d.4aliphatic optionally substituted by halo, N02, -OS(0)2Rc, -S(0)Rc, -N(RB)S02RA, or -S(0)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 d-3alkyl, and REis H, Cι-3alkyl, or S02CH3, 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 R11, and at one or more substitutable nitrogen atoms with R12;
ii) -V-R8, wherein V is -CH2- and R8 is a group selected from:



m n



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 d-4alkyl, phenyl, heteroaryl, halo, -COOH, -COO(d.4alkyl), -CONH2, -COISTH(C1.4a]kyl), -CON(d-4alkyl)2, - CONH ieteroaryl), -CN, -NH2, -OH, -0(d-4alkyl), -NH(CMalkyl), -N(ClJtalkyl)2, =0, or d. alkyl substituted with one or two independent occurrences of phenyl, heteroaryl, halo, - COOH, -COO(C1-4alkyl), -CONH2, -CONH(Cι^alkyl), -CON(CMalkyl)2, - CONH(heteroaryl), -CN, -NH2, -OH, -O(CMalkyl), -NH(d-4alkyl), or -N(C1-4alkyl)2, and are optionally substituted on one nitrogen atom with -d_4alkyl, or -COO(d-4alkyl), -S02(Cι,
4alkyl), benzyl, or CH2(heteroaryl); and
d) Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 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 Cy1 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, d-3 alkyl or C3.5 cycloalkyl;
R3 is H or F;
R4 is H, F, -ORA, -C(0)RA, -C(0)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 RAis independently H, Cι_3alkyl or C3_5cycloalkyl;
Ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein each R5 is independently selected from halo, C1-4 aliphatic, -CN, -ORB, -SRC, -N(RB)2, -NRBC(0)RB,
-NRBC(0)N(RB)2, -NRBC02Rc, -C02RB, -C(0)RB, -C(0)N(RB)2, -OC(0)N(RB)2, -S(0)2Rc,
-S02N(RB)2, -S(0)Rc, -NRBS02N(RB)2, -NRBS02Rc, or CM liphatic optionally substituted with halo, -CN, -ORB, -SRC, -N(RB)2, -NRBC(0)RB, -NRBC(0)N(RB)2, -NRBC02Rc, -C02RB, -C(0)RB, -C(0)N(RB)2, -OC(0)N(RB)2, -S(0)2Rc, -S02N(RB)2, -S(0)Rc, -NRBS02N(RB)2, or-NRBS02Rc, wherein each occurrence of RB is is independently H or CM 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, O or S; and each occurrence of Rc is independently C aliphatic;
Cy1 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 Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from -halo, Cι.8 aliphatic, -CN, -ORB, -SRD, -N(RE)2, -NREC(0)RB, -NREC(0)N(RE)2, -NREC02RD, -C02RB, -C(0)RB, -C(0)N(RE)2,
-OC(0)N(RE)2, -S(0)2RD, -S02N(RE)2, -S(0)RD, -NRES02N(RE)2, -NRES02RD, -C(=NH)-N(RE)2, or Cι-8 aliphatic optionally substituted, with halo, -CN, -ORB, -SRD, -N(RE)2, -NREC(0)RB,
-NREC(0)N(RE)2, -NREC02RD, -C02RB, -C(0)RB, -C(0)N(RE)2, -OC(0)N(RE)2, -S(0)2RD,
-S02N(RE)2, -S(0)RD, -NRES02N(RE)2, -NRES02RD, or -C(=NH)-N(RE)2, wherein each occurrence of RD is Ci-6 aliphatic and each occurrence of RE is independently H, Cι.6 aliphatic, -C(=0)RB,
-C(0)ORB or -S02RB; 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, O or S;
W is -R8, V-R8, L R7, V-Li-R7, L V-R8, or
wherein:
Li and L^ are each independently an optionally substituted Cι_6 alkylene chain;
V is-CH2-, -O-, -S-, -S(O)-, -S(0)2-, -C(O)-, -C02-, -NRE -, -NRE C(O)-, -NRE C02-, -NRE S02-, -C(0)N(RB)-, -S02N(RB)-, -NRE C(0)N(RB)- or -OC(O)-;
R7 is H, halo, -OH, -N(RF)2, -CN, -ORG, -C(0)RG, -C02H, -C02RG, -SRG, -S(0)RG, -S(0)2RG, -N(RE)C(0)RG, -N(RE)C02RG, -N(RE)S02RG, -C(0)N(RF)2, -S02N(RF)2,
-N(RE)C(0)N(RF)2, -OC(0)RF or an optionally substituted group selected from CM0 aliphatic, d-ioaryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of RF is independently H, Cι_6 aliphatic, Cβ-ioaryl, 3-14 membered heterocyclyl, 5-14
membered heteroaryl, -C(=0)RB, -C(0)ORB or -S02RB; 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, O or S; and each occurrence of RG is Cι.6 aliphatic, C6-ιoaryl, 3-14 membered
heterocyclyl, or 5-14 membered heteroaryl;
R8 is an optionally substituted group selected from Cι_ι0 aliphatic, C6.w aryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl;
Q is a bond, CH2 or C(=0);
Cy2 is a Cβ-io ryl, 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 CMaliphatic, -N(RB)2, halo, N02, -CN, -ORB, -C(0)RA, -C02RA, -SRC, -S(0)Rc, -S(0)2Rc, -OS(0)2Rc-, N(RB)C(0)RA, -N(RB)C02RA, -N(RB)S02RA, -C(0)N(RB)2, -S02N(RB)2, -N(RB)C(0)N(RB)2, -OC(0)RA, or CM aliphatic optionally substituted by -N(RB)2, halo, N02, -CN, -ORB, -C(0)RA, -C02RA, -SRC, -S(0)Rc, -OS(0)2Rc, -S(0)2Rc, -N(RB)C(0)RA, -N(RB)C02RA, -N(RB)S02RA, -C(0)N(RB)2, -S02N(RB)2, -N(RB)C(0)N(RB)2, or -OC(0)RA, and R 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:
R1 and R2 are each independently H, CM alkyl or C3.5 cycloalkyl;
R3 is H or F;
R4is H, F, -ORA, -C(0)RA, -C(0)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, CMalkyl or C3.5cycloalkyl;
Ring A is optionally substituted with 1 or 2 independent occurrences of R5, wherein each R5 is independently selected from halo, C aliphatic, -CN, -ORB, -SRC, -N(RB)2, -NRBC(0)RB,
-NRBC(0)N(RB)2, -NRBC02Rc, -C02RB, -C(0)RB, -C(0)N(RB)2, -OC(0)N(RB)2, -S(0)2Rc,
-S02N(RB)2, -S(0)Rc, -NRBS02N(RB)2, -NRBS02Rc, or CMaliphatic optionally substituted with halo, -CN, -ORB, -SRC, -N(RB)2, -NRBC(0)RB, -NRBC(0)N(RB)2, -NRBC02Rc, -C02RB, -C(0)RB, -C(0)N(RB)2, -OC(0)N(RB)2, -S(0)2Rc, -S02N(RB)2, -S(0)Rc, -NRBS02N(RB)2, or-NRBS02Rc, wherein each occurrence of RB is is independently H or d_ 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, O or S; and each occurrence of Rc is independently C aliphatic;
Cy1 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 Cy1 is optionally further substituted by one to three independent occurrences of R6, wherein each occurrence of R6 is independently selected from -halo, d-8 aliphatic, -CN, -ORB, -SRD, -N(RE)2, -NREC(0)RB, -NREC(0)N(RE)2, -NREC02RD, -C02RB, -C(0)RB, -C(0)N(RE)2,
-OC(0)N(RE)2, -S(0)2RD, -S02N(RE)2, -S(0)RD, -NRES02N(RE)2, -NRES02RD, -C(=NH)-N(RE)2, or C1-8 aliphatic optionally substituted with halo, -CN, -ORB, -SRD, -N(RE)2, -NREC(0)RB,
-NREC(0)N(RE)2, -NREC02RD, -C02RB, -C(0)RB, -C(0)N(RE)2, -OC(0)N(RE)2, -S(0)2RD,
-S02N(RE)2, -S(0)RD, -NRES02N(RE)2, -NRES02RD, or -C(=NH)-N(RE)2, wherein each occurrence of RD is Cι-6 aliphatic and each occurrence of RE is independently H, C1-6 aliphatic, -C(=0)RB,
-C(0)ORB or -S02RB; 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, O or S;
W is -R8, V-R8, L R7, V-L R7, LrV-R8, or
wherein:
Li and L^ are each independently an optionally substituted Cι.6 alkylene chain;
V is-CH2-, -0-, -S-, -S(O)-, -S(0)2-, -C(O)-, -C02-, -NRE -, -NRE C(O)-, -NRE C02-, -NRE S02-, -C(0)N(RB)-, -S02N(RB)-, -NRE C(0)N(RB)- or -OC(O)-;
R7 is H, halo, -OH, -N(RF)2, -CN, -ORG, -C(0)RG, -C02H, -C02RG, -SRG, -S(0)RG, -S(0)2RG, -N(RE)C(0)RG, -N(RE)C02RG, -N(RE)S02RG, -C(0)N(RF)2, -S02N(RF)2,
-N(RE)C(0)N(RF)2, -OC(0)RF or an optionally substituted group selected from d.io aliphatic, Cβ-ioaryl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein each occurrence of RF is independently H, Cι_6 aliphatic, Ce-ioaryl, 3-14 membered heterocyclyl, 5-14
membered heteroaryl, -C(=0)RB, -C(0)ORB or -S02RB; 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 fromN, O or S; and each occurrence of RG is Cι.6 aliphatic, C6_ioaryl, 3-14 membered
heterocyclyl, or 5-14 membered heteroaryl;
R8 is an optionally substituted group selected from C .i0 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_ioaryl, 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 CMaliphatic, -N(RB)2, halo, N02) -CN, -ORB, -C(0)RA, -C02RA, -SRC, -S(0)Rc, -S(0)2Rc, -OS(0)2Rc-, N(RB)C(0)RA, -N(RB)C02RA, -N(RB)S02RA, -C(0)N(RB)2, -S02N(RB)2, -N(RB)C(0)N(RB)2, -OC(0)RA, or CM aliphatic optionally substituted by -N(RB)2, halo, N02, -CN, -ORB, -C(0)RA, -C02RA, -SRC, -S(0)Rc, -OS(0)2Rc, -S(0)2Rc, -N(RB)C(0)RA, -N(RB)C02RA, -N(RB)S02RA, -C(0)N(RB)2, -S02N(RB)2, -N(RB)C(0)N(RB)2, or -OC(0)RA, and
R10 is selected from phenyl, or a 5-6 membered heterocyclyl or heteroaryl ring.