http://www.patsnap.com/patents/view/WO2010129053A2.html
1. A compound of formula I:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Z| and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N; X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic; RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R1 is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1, 2, or 3; and n is 0, 1 or 2; wherein if X is S, Z2 is CR5, and R5 is hal, then ring A is not phenyl para-substituted with Ri; or if Y is S, and RA is hal, then ring B is not phenyl para-substituted with R2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
<(>R2<)>S-CBVY-! RIW-CAVXH may be absent.
(Ri
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CH; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least two of Zi, Z2, Z3 or Z4 are N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each Re is independently H or alkyl; ring A is aryl, heteroaryl, or heterocyclic; ring B is aryl, heteroaryl, or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, or NO2;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, or NO2; each R1 is independently NH(R3), N(R3)CO(R4), C(O)R3, C(O)NH(R3), SO2R3, alkyl, haloalkyl, alkoxy, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R2 is independently hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1 , 2, or 3; and n is O, 1 or 2.
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Y is absent, CO, O, S, or NR6;
RO is H or alkyl; ring A is phenyl or pyridyl;
RA is H, Cl, Br, or CF3; each R, is independently NH(R3), N(R3)CO(R4), C(O)R3, C(O)NH(R3), SO2R3, alkyl, haloalkyl, alkoxy, heteroaryl, carbocyclic, or heterocyclic, each of which may be optionally substituted; each R2 is independently alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
R5, for each instance, is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted;
RSA, for each instance, is independently hal or OS(O)PR\ wherein p is 0, 1 or 2 and R' is alkyl or aryl;
W, for each instance, is independently absent, CH2, CH2CH2, (CH2^, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1 , 2, or 3 nitrogens; m is 1, 2, or 3; and n is 1 or 2.
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
X is O, S, or NR6; Y is absent, O, S, or NR6; each R6 is independently H or alkyl; ring B is heterocyclic;
RA is H, Cl, Br, or CF3;
RB is H, hai, OH, NH2, NHR3, haloalkyl, CN, N3, or NO2; each R, is independently NH(R3), N(R3)CO(R4), C(O)R3, C(O)NH(R3), SO2R3, alkyl, haloalkyl, alkoxy, or heterocyclic, each of which may be optionally substituted; each R2 is independently hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR\ wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1, 2, or 3; and n is 1 or 2.
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein, ring A is aryl or heteroaryl; X is O, S, or NR6;
Y is absent, O, S, or NR6; each R6 is independently H or alkyl; each R, is independently NH(R3), N(R3)CO(R4), C(O)R3, C(O)NH(R3), SO2R3, alkyl, haloalkyl, alkoxy, or heterocyclic, each of which may be optionally substituted; each R2 is independently
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be further substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1, 2, or 3; and n is 1 or 2.
<; - ;or> .
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Z5 is N or CH; Ze is N or CH, wherein one of Z5 or Z6 is N; X is O, S, or NR6; Y is absent, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic, or heterocyclic; ring B is aryl, heteroaryl, carbocyclic, or heterocyclic; each Ri is independently N(R3)(R4), N(R3)CO(R4), C(O)R3, alkyl, alkoxy, or heterocyclic, each of which may be optionally substituted; each R2 is independently
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is O, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens;
R8 is H, alky, or aryl, each of which may be optionally substituted; m is 1, 2, or 3; and n is 1 or 2.
.
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
each Re is independently H or alkyl; ring B is aryl, heteroaryl, carbocyclic, or heterocyclic; ring D is aryl, heteroaryl, carbocyclic, or heterocyclic; each R2 is independently
each R7 is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, and carbocyclic, each of which may be optionally substituted; each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be further substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be further substituted; each R5A is independently hal or OS(O)PR', wherein p is O, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; n is 1 or 2; and q is O, l or 2.
H
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi is N or CR6; X iS O5 S1 Or NR6;
Y is O, S, or NR6; each R6 is independently H or alkyl which may be optionally substituted; ring A is aryl, heteroaryl, carbocyclic, or heterocyclic; ring B is aryl, heteroaryl, carbocyclic, or heterocyclic; each Ri is independently N(R3)(R4), N(R3)CO(R4), C(O)R3, alkyl, alkoxy, or heterocyclic, each of which may be optionally substituted; each R2 is independently hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, 5 each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be further substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; 0 each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1 , 2, or 3 nitrogens;
R9 is H or aryl which may be optionally substituted; m is 1 , 2, or 3; and n is 1 or 2; K u - , (R2)n- ( B )-Y- or (R )_/ A \_[chi]_ 5 wherein one of ^^ ^S <<> may be absent.
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Z3 is N or CRB; Z4 is N or CRA; wherein one Of Z3 or Z4 is N; X is O, S, or NR6; Y is O, S, or NR6; each R6 is independently H or alkyl; RA is H, Cl, Br, or CF3;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, or NO2; ring A is aryl, heteroaryl, carbocyclic, or heterocyclic; ring B is aryl, heteroaryl, carbocyclic, or heterocyclic; each Ri is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, and carbocyclic, each of which may be optionally substituted; each R2 is independently hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be further substituted; each Rs is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each RsA is independently hal or OS(O)PR', wherein p is O, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1 , 2, or 3; and n is 1 or 2.
OL <;> OtN<[chi] ;> OtN<[chi] ;or> - H
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Y iS O Or NR6; R6 is H or alkyl; ring A is phenyl or pyridyl; RA is H, Cl, Br, or CF3; each Ri is independently N(R3)CO(R4), C(O)NH(R3), alkyl, haloalkyl, alkoxy, heteroaryl, carbocyclic, or heterocyclic, each of which may be optionally substituted; each R2 is independently alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
R5, for each instance, is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; R5A, for each instance, is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl;
W, for each instance, is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1, 2, or 3; and n is 1 or 2.
78. A compound that covalently modifies Cysteine 797 in EGFR, wherein the compound exhibits greater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, 100-fold, or 1000-fold inhibition of L858R/T790M or Del/T790M EGFR relative to wild-type EGFR.
Table 5 or Table 6.
89. A method of inhibiting a kinase in a subject, comprising administering a compound of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CRs; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Z\, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each Ri is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each Rs is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is O, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1 , 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
(RdHghH (Ri)m-<^-! may be absent
92. A method of inhibiting epidermal growth factor receptor (EGFR) in a subject, comprising administering a compound of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each Ri is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1 , 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
<(R>2<)>H-(J)-Y-I [deg.]
may be absent.
94. A method of treating a disease in a subject comprising administering to the subject a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein, Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6; Y is absent, CO, O, S, or NR6; each Rf, is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R, is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3,
C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1, 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
(R2)
may , be a ,bsen ,t.
HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk.
stroke including ischemic and hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia including stroke and brain ischemia, and ischemia resulting from cardiac/coronary bypass, neurodegenerative disorders, liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, herpes virus, myalgias due to infection, influenza, autoimmune disease, graft vs.
host reaction and allograft rejections, treatment of bone resorption diseases, osteoporosis, multiple sclerosis, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML) and acute promyelocyte leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders,
central nervous system disorders having an inflammatory or apoptotic component, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy, or B- Cell Lymphoma.
105. A method of treating a kinase mediated disorder in a subject comprising: administering to the subject identified as in need thereof a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Z|, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R, is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each Rs is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each RsA is independently hal or OS(O)PR', wherein p is O, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1, 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
(R[Lambda]r-0-vH -
may be absent.
109. A method of treating a disease in a subject, wherein the disease is resistant to an EGFR targeted therapy, comprising administering to the subject a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Z| and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R, is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is O, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1, 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
(R2)n- (R)-Y-| or (Ri)_[phi]-[chi]-| may be absent.
1033, PF00299804, BMS 690514, cetuximab, panitumumab, or matuzumab.
T854A or D761 Y resistance mutation.
1 15. A method of treating cancer in a subject, wherein the cancer comprises EGFR activated tumors, comprising administering to the subject a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
-->
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R1 is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
each R.3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1 , 2, or 3 nitrogens; m is 1, 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
<(>R2<)>KET)-Y-! r
may be absen,
G719C, G719A, L858R, L861Q, an exon 19 deletion mutation or an exon 20 insertion mutation.
1 19. A method of treating cancer in a subject, wherein the subject is identified as being in need of EGFR inhibition for the treatment of cancer, comprising administering to the subject a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein, Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Z|, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each Ri is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
793770 ] 74
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR\ wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1 , 2, or 3 nitrogens; m is 1, 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
(R2)I[Gamma]-( <[kappa]> -B)-Y-|
may . be a .bsen tt.
120. A method of treating cancer in a subject, wherein the cancer comprises ERBB2 activated tumors, comprising administering to the subject a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
793770 175
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Z| and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6; Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R, is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
793770 176
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1 , 2, or 3 nitrogens; m is 1, 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
(R2)F-(B)--| (R1)ST-CA)-X-I . , + ^-^ ^S may be absent.
793770 177
124. A method of treating cancer in a subject, wherein the subject is identified as being in need of ERBB2 inhibition for the treatment of cancer, comprising administering to the subject a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R, is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
793770 178
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1 , 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
may be absent.
125. A method of preventing resistance to gefitinib or erlotinib in a disease, comprising administering to a subject a compound, pharmaceutically acceptable salt, ester or prodrug of formula I
793770 179
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6;
Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R, is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3, C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
793770 180
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1, 2, or 3 nitrogens; m is 1 , 2, or 3; and n is 0, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
<(>R[Lambda][Gamma]H (R1XHS)-XH may be absent.
793770 1 8 J
129. A kit comprising a compound capable of inhibiting EGFR activity selected from one or more compounds of formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein,
Zi and Z2 are each independently N or CR5; Z3 and Z4 are each independently N or C, wherein RA and RB are absent when Z3 or Z4 is N; wherein at least one of Zi, Z2, Z3 or Z4 is N;
X is O, S, or NR6; Y is absent, CO, O, S, or NR6; each R6 is independently H or alkyl; ring A is aryl, heteroaryl, carbocyclic or heterocyclic; ring B is aryl, heteroaryl, carbocyclic or heterocyclic;
RA is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted;
RB is H, hal, OH, NH2, NHR3, haloalkyl, CN, N3, NO2; alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; or RA and RB, together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, each of which may be optionally substituted; each R, is independently NH(R3), N(R3)(R4), N(R3)CO(R4), CO2H, C(O)R3,
C(O)OR3, C(O)NH2, C(O)NH(R3), C(O)N(R3)(R4), SO2R3, SOR3, SR3, alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R2 is independently an optionally substituted alkyl, hal,
793770 J g2
each R3 and R4 is independently H, alkyl, alkenyl, vinyl, heterocyclic, or carbocyclic, each of which may be optionally substituted; each R5 is independently H, alkyl, hal, or haloalkyl, each of which may be optionally substituted; each R5A is independently hal or OS(O)PR', wherein p is 0, 1 or 2 and R' is alkyl or aryl; each W is independently absent, CH2, CH2CH2, (CH2)3, (CH2)4, O, S, or NR3; ring C is a 5-6 membered heterocyclic or heteroaryl having 1 , 2, or 3 nitrogens; m is 1 , 2, or 3; and n is O, 1 or 2; wherein if RA and RB together with the atoms to which each is attached, form a fused aryl, heteroaryl, carbocyclic or heterocyclic, then one of
OUKi)-VH , H may be absent. and instructions for use in treating cancer.
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显身卡
