1. A compound of formula I:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
ring D is aryl or heteroaryl;
R is H, halo, or -A-B;
A is NRAC(O), O, S(O)m, C(O), C(O)O, C(O)NRA, NRAC(O)NRA, or absent;
B is H, alkyl, alkoxy, cycloalkyl, or aryl, each of which is optionally substituted;
R1 is hydroxyl, alkyl, alkoxy, C(O)ORA, C(O)NRARB, or NRARB, each of which may be optionally substituted; or H or halo;
R\u2032 is absent, or R and R\u2032 together with the atoms to which each is attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, each of which is optionally substituted;
Z is NRA, O, NRAC(O), C(O)NRA, CR3R4 or S(O)m;
R3 is H or alkyl;
R4 is H, alkyl, or absent;
or R3 and R4 together with the carbon to which each is attached form C(O);
ring E is monocyclic or bicyclic heteroaryl;
RZ is NRAR2,
R2 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, C(O)RA, C(O)ORA, C(O)NRARB, C(NRB)RA, or C(NRB)ORA;
R5 is H, halo, alkyl, alkoxy, or thioalkoxy;
R6 is H, NRARB, or ORA;
each RA is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each RB is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
or, for each occurrence of NRARB, RA and RB are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycloalkyl ring;
each m is independently 0, 1, or 2; and
each n is independently 0 or 1.
2. The compound of claim 1, wherein ring D is selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrrolo pyridinyl, thiazolo pyridinyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, indazolyl, indolonyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, and quinoxalinyl.
3. The compound of claim 2, wherein ring D is selected from phenyl, naphthyl, pyrazinyl, pyrimidinyl, pyrrolo pyridinyl, thiazolo pyridinyl, indazolyl, indolonyl, and quinolinyl.
4. The compound of claim 1, wherein ring E is selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiophenyl, furanyl, indazolyl, indolonyl, quinolinyl, isoquinolinyl, quinazolinyl, 1H-pyrrolo2,3-bpyridine, 9H-purine, 7H-pyrrolo2,3-dpyrimidine, 1H-pyrazolo3,4-dpyrimidine, and quinoxalinyl.
5. The compound of claim 4, wherein ring E is selected from phenyl, naphthyl, pyridinyl, pyrazinyl, and pyrimidinyl.
6. The compound of claim 1, of formula II:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
Z is NH or O;
R is H or -A-B;
A is NRAC(O), O, S(O)m, C(O), C(O)O, C(O)NRA, or absent;
B is alkyl, alkoxy, or aryl, each of which is optionally substituted;
R1 is H, alkyl, alkoxy, or halo; each of which may be optionally substituted;
R2 is H, C(O)RA, C(O)ORA, C(O)NRARB, C(NRB)RA, or C(NRB)ORA;
each RA is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each RB is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
7. The compound of claim 6, wherein R2 is H, C(O)RA, C(O)ORA, or C(O)NRARB.
8. The compound of claim 7, wherein each RA is independently H, alkyl, or cycloalkyl, each of which may be optionally substituted; and RB is H.
9. The compound of claim 6, wherein R2 is H,
10. The compound of claim 6, wherein R1 is H, alkyl, alkoxy, or halo.
11. The compound of claim 10, wherein R1 is H, methyl, methoxy, or chloro.
12. The compound of claim 6, wherein R is H or -A-B; A is NRAC(O), C(O), C(O)O, C(O)NRA, or absent; and B is alkyl, alkoxy, or aryl, each of which is optionally substituted.
13. The compound of claim 12, wherein A is NHC(O), C(O)O, C(O)NH, or absent.
14. The compound of claim 12, wherein B is phenyl, methyl, or methoxy; each of which is optionally substituted.
15. The compound of claim 14, wherein B is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or hydroxyl, each of which is optionally substituted.
16. The compound of claim 12, wherein R is selected from H, methyl, methoxy,
17. The compound of claim 1, of formula III:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
ring D is aryl or heteroaryl;
R is H, halo, or -A-B;
A is NRAC(O), O, S(O)m, C(O), C(O)O, C(O)NRA, or absent;
B is H, alkyl, cycloalkyl, or aryl, each of which is optionally substituted;
R1 is H, hydroxyl, alkyl, alkoxy, C(O)ORA, C(O)NRARB, NRARB, or halo; each of which may be optionally substituted;
or R and R\u2032 together with the atoms to which each is attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, each of which is optionally substituted;
R2 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, C(O)RA, C(O)ORA, C(O)NRARB, C(NRB)RA, or C(NRB)ORA;
each RA is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each RB is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
18-27. (canceled)
28. The compound of claim 1, of formula IV:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
R is H or -A-B;
A is NRAC(O), O, S(O)m, C(O), C(O)O, C(O)NRA, or absent;
B is alkyl or aryl, each of which is optionally substituted;
R1 is H, alkyl, alkoxy, or halo; each of which may be optionally substituted;
Z is NRA, O, or S(O)m;
R3 is H or alkyl;
R4 is H or alkyl;
or R3 and R4 together with the carbon to which each is attached form C(O);
R5 is H, halo, alkoxy, or thioalkoxy,
each RA is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
each m is independently 0, 1, or 2.
29-38. (canceled)
39. The compound of claim 1, of formula V:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
R is H or -A-B;
A is NRAC(O), O, S(O)m, C(O), C(O)O, C(O)NRA, or absent;
B is alkyl or aryl, each of which is optionally substituted;
R1 is H, alkyl, alkoxy, or halo; each of which may be optionally substituted;
R5 is H, halo, alkoxy, or thioalkoxy,
each RA is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
40-47. (canceled)
48. The compound of claim 1, of formula VI:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
ring D is aryl or heteroaryl;
R is H, halo, or -A-B;
A is NRAC(O), O, S(O)m, C(O), C(O)O, C(O)NRA, or absent;
B is alkyl, cycloalkyl, or aryl, each of which is optionally substituted;
R1 is H, hydroxyl, alkyl, alkoxy, C(O)ORA, C(O)NRARB, NRARB, or halo; each of which may be optionally substituted;
R6 is H, NRARB, or ORA;
R5 is H, halo, alkoxy, or thioalkoxy,
each RA is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each RB is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
49-58. (canceled)
59. The compound of claim 1, selected from a compound in any one of Tables 1-13.
60. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier.
61. A method of inhibiting a b-raf kinase in a subject, comprising administering to the subject a compound of formula I.
62-63. (canceled)
64. A method of treating a disease related to kinase modulation in a subject comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I;
wherein the kinase is selected from b-raf, Abl, Csf1R, EGFR, EphA8, FGFR,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha, beta, PDGFRalpha, beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2, DDR1, EPHA2, ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr, FLT4, MAP4K2, ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1, Hck, Tnk2, Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1, JNK2, MLK1, MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn, Zak, DDR2, AurC, Lyn, Hpk1, and Gck.
65. (canceled)
66. A method of treating a disease related to b-raf or b-raf mutation modulation in a subject comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I, or
A method of treating a disease related to b-raf or b-raf mutation modulation in a subject comprising: administering to the subject identified as in need thereof a compound or pharmaceutically acceptable salt of formula, or
A method of treating a disease related to b-raf or b-raf mutation modulation in a subject, wherein the disease is resistant to drug resistant mutations in b-raf, comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I,
A method of treating cancer in a subject, wherein the cancer comprises b-raf activated tumors, comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I, or
A method of treating cancer in a subject, cancer comprises b-raf activated tumors, wherein the subject is identified as being in need of b-raf inhibition for the treatment of cancer, comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I.
67-82. (canceled)
83. A kit comprising a compound or pharmaceutically acceptable salt of formula I capable of inhibiting b-raf or b-raf mutation activity; and instructions for use in treating cancer.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A blocked metal silicide resistor structure, comprising:
a silicide blocking region comprising a silicon nitride film arranged over a region of doped polycrystalline silicon or doped silicon, wherein the silicon nitride film has a conformality of greater than about 90%, and is formed by a rapid thermal nitride deposition process at a temperature from about 600\xb0 C. to about 775\xb0 C.;
metal silicide structures adjacent to opposite sides of the silicon nitride film with a contact overlying each of the adjacent silicide structures, wherein the resistor overlies device sourcedrain implants.
2. The resistor structure according to claim 1, wherein the metal silicide is selected from the group consisting of titanium silicide and cobalt silicide.
3. The resistor structure according to claim 1, wherein the silicon nitride film has a thickness of about 100 \u212b or less.
4. The resistor structure according to claim 1, wherein the resistor structure is formed on cobalt silicide based structures.