Claims for Patent: 8,129,374

Summary for Patent: 8,129,374

Title:	Method of using imidazolothiazole compounds for the treatment of disease
Abstract:	Compounds, compositions and methods are provided for modulating the activity of receptor kinases and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by receptor kinases.
Inventor(s):	Shripad Bhagwat, Qi Chao, Robert M. Grotzfeld, Hitesh K. Patel, Kelly G. Sprankle
Assignee:	Ambit Bioscience Corp
Application Number:	US12/850,557
Patent Claims:	1. A method of treating a proliferative disease in a patient comprising administrating to the patient a therapeutically effective amount of a compound, wherein the compound is of formula (I) wherein bond b is a single bond or double bond; X is —S—, —N(R5)— or —O—; Z1 and Z3 are each independently —N(R5)—, —(CH2)q—, —O—, —S—, or a direct bond; Z2 is —C(O)— or —C(S)—; m is an integer from 1 to 2; n is an integer from 1 to 3; each q is independently an integer from 1 to 4; R0 is hydrogen, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy; each R1 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, —R6OR7, —R6SR7, —R6S(O)tR8, —R6N(R7)2, —R6—OR9OR7, —R6CN, —R6C(O)R7, —R6C(S)R7, —R6C(NR7)R7, —R6C(O)OR7, —R6C(S)OR7, —R6C(NR7)OR7, —R6C(O)N(R7)2, —R6C(S)N(R7)2, —R6C(NR7)N(R7)2, —R6C(O)N(R7)R9N(R7)2, —R6C(O)SR8, —R6C(S)SR8, —R6C(NR7)SR8, —R6S(O)tOR7, —R6S(O)tN(R7)2, —R6S(O)tN(R7)N(R7)2, —R6S(O)tN(R7)N═C(R7)2, —R6S(O)tN(R7)C(O)R8, —R6S(O)tN(R7)C(O)N(R7)2, —R6S(O)tN(R7)C(NR7)N(R7)2, —R6N(R7)C(O)R8, —R6N(R7)C(O)OR8, —R6N(R7)C(O)SR8, —R6N(R7)C(NR7)SR8, —R6N(R7)C(S)SR8, —R6N(R7)C(O)N(R7)2, —R6N(R7)C(NR7)N(R7)2, —R6N(R7)C(S)N(R7)2, —R6N(R7)S(O)tR8, —R6OC(O)R8, —R6OC(NR7)R8, —R6OC(S)R8, —R6OC(O)OR8, —R6OC(NR7)OR8, —R6OC(S)OR8, —R6OC(O)SR8, —R6OC(O)N(R)2, —R6OC(NR7)N(R7)2, —R6OC(S)N(R7)2, —R6OR9N(R7)2, —R6SR9N(R7)2, —R6N(R7)R9N(R)2, —R6C(O)R9C(O)R7, —R6C(O)R9C(S)R7, —R6C(O)R9C(NR7)R7, —R6C(O)R9C(O)OR7, —R6C(O)R9C(S)OR7, —R6C(O)R9C(NR7)OR7, —R6C(O)R9C(O)N(R7)2, —R6C(O)R9C(S)N(R7)2, —R6C(O)R9C(NR7)N(R7)2, —R6C(O)R9C(O)SR8, —R6C(O)R9C(S)SR8, —R6C(O)R9C(NR7)SR8, —R6OR9OR7, —R6C(O)R9N(R7)R9N(R7)2, —R6C(O)R9N(R7)R9OR7 and —R6C(O)N(R7)R9OR7; t is 1 or 2; each R2 is independently selected from hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, and —N(R12)S(O)tR13; R3 is hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, or —N(R12)S(O)tR13; R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, and optionally substituted aryl; each R5 is independently hydrogen, or optionally substituted alkyl; each R6 is independently a direct bond, an optionally substituted alkylene chain, or an optionally substituted alkenylene chain; each R7 is independently selected from (i) or (ii) below (i) R7 is selected from a group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or (ii) two R7 groups together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; R8 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; each R9 is independently an optionally substituted alkylene chain or an optionally substituted alkenylene chain; each R12 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; and R13 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; with the proviso that, (i) if —Z1Z2Z3R4 is —NHC(O)Bu then R1 may not be ethoxy; (ii) if —Z1Z2Z3R4 is —C(O)ORp, where Rp is methyl, or ethyl, then R1 may not be hydroxyl, methoxy or methoxycarbonyl; (iii) if —Z1Z2Z3R4 is —NHC(O)C(O)ORp, where Rp is methyl, or ethyl, then R1 may not be methoxy; (iv) if —Z1Z2Z3R4 is —CH2C(O)ORp, where Rp is methyl, or ethyl, then R1 may not be methoxy or ethoxy; (v) if —Z1Z2Z3R4 is —OC(O)CH3, then R1 may not be methyl, methoxy or ethoxy; or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, and wherein the proliferative disease is a solid cancer or blood cancer. 2. The method of claim 1, wherein the disease is a FLT3-mediated disease, KIT-mediated disease, RET-mediated disease, PDGFR-mediated disease, VEGFR-mediated disease or a CSF-1R-mediated disease. 3. A method of inhibiting a FLT3 kinase by contacting a cell with a compound of formula (I): wherein bond b is a single bond or double bond; X is —S—, —N(R5)— or —O—; Z1 and Z3 are each independently —N(R5)—, —(CH2)q—, —O—, —S—, or a direct bond; Z2 is —C(O)— or —C(S)—; m is an integer from 1 to 2; n is an integer from 1 to 3; each q is independently an integer from 1 to 4; R0 is hydrogen, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy; each R1 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, —R6OR7, —R6SR7, —R6S(O)tR8, —R6N(R7)2, —R6—OR9OR7, —R6CN, —R6C(O)R7, —R6C(S)R7, —R6C(NR7)R7, —R6C(O)OR7, —R6C(S)OR7, —R6C(NR7)OR7, —R6C(O)N(R7)2, —R6C(S)N(R7)2, —R6C(NR7)N(R7)2, —R6C(O)N(R7)R9N(R7)2, —R6C(O)SR8, —R6C(S)SR8, —R6C(NR7)SR8, —R6S(O)tOR7, —R6S(O)tN(R7)2, —R6S(O)tN(R7)N(R7)2, —R6S(O)tN(R7)N═C(R7)2, —R6S(O)tN(R7)C(O)R8, —R6S(O)tN(R7)C(O)N(R7)2, —R6S(O)tN(R7)C(NR7)N(R7)2, —R6N(R7)C(O)R8, —R6N(R7)C(O)OR8, —R6N(R7)C(O)SR8, —R6N(R7)C(NR7)SR8, —R6N(R7)C(S)SR8, —R6N(R7)C(O)N(R7)2, —R6N(R7)C(NR7)N(R7)2, —R6N(R7)C(S)N(R7)2, —R6N(R7)S(O)tR8, —R6OC(O)R8, —R6OC(NR7)R8, —R6OC(S)R8, —R6OC(O)OR8, —R6OC(NR7)OR8, —R6OC(S)OR8, —R6OC(O)SR8, —R6OC(O)N(R)2, —R6OC(NR7)N(R7)2, —R6OC(S)N(R7)2, —R6OR9N(R7)2, —R6SR9N(R7)2, —R6N(R7)R9N(R)2, —R6C(O)R9C(O)R7, —R6C(O)R9C(S)R7, —R6C(O)R9C(NR7)R7, —R6C(O)R9C(O)OR7, —R6C(O)R9C(S)OR7, —R6C(O)R9C(NR7)OR7, —R6C(O)R9C(O)N(R7)2, —R6C(O)R9C(S)N(R7)2, —R6C(O)R9C(NR7)N(R7)2, —R6C(O)R9C(O)SR8, —R6C(O)R9C(S)SR8, —R6C(O)R9C(NR)SR8, —R6OR9OR7, —R6C(O)R9N(R7)R9N(R7)2, —R6C(O)R9N(R7)R9OR7 and —R6C(O)N(R7)R9OR7; t is 1 or 2; each R2 is independently selected from hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, and —N(R12)S(O)tR13; R3 is hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, or —N(R12)S(O)tR13; R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, and optionally substituted aryl; each R5 is independently hydrogen, or optionally substituted alkyl; each R6 is independently a direct bond, an optionally substituted alkylene chain, or an optionally substituted alkenylene chain; each R7 is independently selected from (i) or (ii) below (i) R7 is selected from a group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or (ii) two R7 groups together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; R8 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; each R9 is independently an optionally substituted alkylene chain or an optionally substituted alkenylene chain; each R12 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; and R13 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 4. A method of treating leukemia by administering a compound of formula (I): wherein bond b is a single bond or double bond; X is —S—, —N(R5)— or —O—; Z1 and Z3 are each independently —N(R5)—, —(CH2)q—, —O—, —S—, or a direct bond; Z2 is —C(O)— or —C(S)—; m is an integer from 1 to 2; n is an integer from 1 to 3; each q is independently an integer from 1 to 4; R0 is hydrogen, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy; each R1 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heteroaralkyl, optionally substituted heteroaralkenyl, —R6OR7, —R6SR7, —R6S(O)tR8, —R6N(R7)2, —R6—OR9OR7, —R6CN, —R6C(O)R7, —R6C(S)R7, —R6C(NR7)R7, —R6C(O)OR7, —R6C(S)OR7, —R6C(NR7)OR7, —R6C(O)N(R7)2, —R6C(S)N(R7)2, —R6C(NR7)N(R7)2, —R6C(O)N(R7)R9N(R7)2, —R6C(O)SR8, —R6C(S)SR8, —R6C(NR7)SR8, —R6S(O)tOR7, —R6S(O)tN(R7)2, —R6S(O)tN(R7)N(R7)2, —R6S(O)tN(R7)N═C(R7)2, —R6S(O)tN(R7)C(O)R8, —R6S(O)tN(R7)C(O)N(R7)2, —R6S(O)tN(R7)C(NR7)N(R7)2, —R6N(R7)C(O)R8, —R6N(R7)C(O)OR8, —R6N(R7)C(O)SR8, —R6N(R7)C(NR7)SR8, —R6N(R7)C(S)SR8, —R6N(R7)C(O)N(R7)2, —R6N(R7)C(NR7)N(R7)2, —R6N(R7)C(S)N(R7)2, —R6N(R7)S(O)tR8, —R6OC(O)R8, —R6OC(NR7)R8, —R6OC(S)R8, —R6OC(O)OR8, —R6OC(NR7)OR8, —R6OC(S)OR8, —R6OC(O)SR8, —R6OC(O)N(R)2, —R6OC(NR7)N(R7)2, —R6OC(S)N(R7)2, —R6OR9N(R7)2, —R6SR9N(R7)2, —R6N(R7)R9N(R)2, —R6C(O)R9C(O)R7, —R6C(O)R9C(S)R7, —R6C(O)R9C(NR7)R7, —R6C(O)R9C(O)OR7, —R6C(O)R9C(S)OR7, —R6C(O)R9C(NR7)OR7, —R6C(O)R9C(O)N(R7)2, —R6C(O)R9C(S)N(R7)2, —R6C(O)R9C(NR7)N(R7)2, —R6C(O)R9C(O)SR8, —R6C(O)R9C(S)SR8, —R6C(O)R9C(NR7)SR8, —R6OR9OR7, —R6C(O)R9N(R7)R9N(R7)2, —R6C(O)R9N(R7)R9OR7 and —R6C(O)N(R7)R9OR7; t is 1 or 2; each R2 is independently selected from hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, and —N(R12)S(O)tR13; R3 is hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, or —N(R12)S(O)tR13; R4 is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, and optionally substituted aryl; each R5 is independently hydrogen, or optionally substituted alkyl; each R6 is independently a direct bond, an optionally substituted alkylene chain, or an optionally substituted alkenylene chain; each R7 is independently selected from (i) or (ii) below (i) R7 is selected from a group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, or (ii) two R7 groups together with the atom to which they are attached form an optionally substituted heterocyclyl or optionally substituted heteroaryl; R8 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; each R9 is independently an optionally substituted alkylene chain or an optionally substituted alkenylene chain; each R12 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; and R13 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl; or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 5. The method of claim 4, wherein the leukemia is FLT3 kinase modulated leukemia. 6. The method of claim 1, wherein the proliferative disease is thyroid cancer, stomach cancer, gastrointestinal stromal tumor, colorectal cancer, prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, lymphoma or myeloma. 7. The method of claim 1, wherein the proliferative disease is leukemia. 8. The method of claim 4, wherein the leukemia is an acute leukemia. 9. The method of claim 8, wherein the leukemia is acute myeloid leukemia. 10. The method of claim 8, wherein the leukemia is promyelocytic leukemia. 11. The method of claim 7, wherein the leukemia is acute promyelocytic leukemia, myelodysplastic syndrome, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute erythroleukemia, acute monocytic leukemia, acute megakaryoblastic leukemia, myeloproliferative disease, mast cell leukemia, systemic mastocytosis, hypereosinophilic syndrome, chronic eosinophilic leukemia, or acute lymphoblastic leukemia. 12. The method of claim 8, wherein the leukemia is FLT3-mediated acute myeloid leukemia. 13. The method of claim 1, wherein the proliferative disease is a head and neck cancer, lung cancer, esophageal cancer, gastrointestinal tract cancer, liver cancer, renal cancer, bladder cancer, breast cancer, gynecologic cancer, testicular cancer, urinary tract cancer, neurologic tumors, glioma, glioblastoma, melanoma or endocrine neoplasms. 14. The method of claim 1, wherein the compound is a pharmaceutically acceptable salt of the compound of formula (I). 15. The method of claim 1, wherein R4 is optionally substituted heterocyclyl or optionally substituted heteroaryl. 16. The method of claim 1, wherein R4 is wherein R10 is hydrogen, alkyl, haloalkyl or haloaryl. 17. The method of claim 16, wherein R10 is hydrogen, methyl, tert-butyl, trifluoromethyl or p-chlorophenyl. 18. The method of claim 16, wherein R4 is 19. The method of claim 1, wherein R4Z3Z2Z1— is R4N(R5)C(O)— or R4N(R5)C(S)—, and R5 is hydrogen, or optionally substituted alkyl. 20. The method of claim 1, wherein the compound is of formula (II): wherein: X is —S—, —N(R5)— or —O—; X1, X2, X3, X4 are each independently selected from —C(R10)—, —C(R10)2—, —N—, —N(R16)—, —O— and —S—, provided that no more than two of X1, X2, X3 and X4 are heteroatoms and wherein no two adjacent X's are both —O— or —S—; and each R16 is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; and each R16 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 21. The method of claim 20, wherein the compound is of formula (III): wherein: X is —S—, —N(R5)— or —O—; X1 is —C(R10)—, or —N—; X2 is —O— or —S—; where each R10 is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 22. The method of claim 21, wherein the compound is of formula (IV) wherein: K is —(CH2)q—, —C(O), —(CH2)q—, —(CH2)qO(CH2)q—, —(CH2)qC(O)—, —(CH2)qC(O)NH(CH2)q—, —C(O)NH(CH2)q—, —O(CH2)q—, —OC(O)—, —OC(O)(CH2)q— or a direct bond; X is —S—, —N(R5)— or —O—; X1 is —C(R10)—, or —N—; X2 is —O— or —S—; Y is —O—, —S—, —S(O)—, —S(O)2—, —N(R14)—, —C(H)R15—, or —C(O)—; q is an integer from 1 to 4; p is an integer from 0 to 2; R10 is independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aryl; R14 is independently, hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, or —C(O)SR12; R15 is independently, hydrogen, halo, nitro, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, —OR12, —SR12, —N(R12)2, —S(O)tR13, —C(O)R12, —C(O)OR12, —C(O)N(R12)2, —C(O)SR12, or —N(R12)S(O)tR13; t is 1 or 2; and or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 23. The method of claim 22, wherein the compound is of formula (V): wherein K is —O(CH2)q—, —C(O), —C(O)NH(CH2)q—, —(CH2)qO—, or —(CH2)qO(CH2)q—; p is an integer from 0 to 2; each q is independently an integer from 1 to 4; X1 is —N—; X2 is —O—; Y is —O—, —S—, —N(R14)— or —C(H)R15—, m is 0, 1, or 2; R14 is hydrogen, optionally substituted alkyl, —C(O)OR12, —C(O)SR12, —C(O)NR12 or —S(O)tR13; R15 is hydrogen or optionally substituted alkyl; R13 is optionally substituted alkyl; and t is 1 or 2; or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 24. The method of claim 23, wherein the compound is of formula (Va): wherein K is —O(CH2)q—, —(CH2)qO—, —(CH2)q— or —(CH2)qO(CH2)q—; each q is independently 1 to 4; Y is —O—, —S—, or —N(R14)—; R14 is hydrogen, optionally substituted lower alkyl, or —S(O)tR13; R13 is lower alkyl; and t is 1 or 2. 25. The method of claim 1, wherein R1 is fluoro, methyl, ethyl, hydroxy, methoxy, diethylamino or carboxy. 26. The method of claim 1, wherein the compound is selected from the group consisting of: 3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-propionamide; 3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-propionamide; 3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-propionamide; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazin-1-yl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-piperidin-1-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methanesulfonyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea; N-(5-tert-butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-3-oxo-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 3-(5-tert-butyl-isoxazol-3-yl)-1-methyl-1-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-yl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea; N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea; N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[5-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea; 2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-acetamide; 2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-acetamide; 2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide; 1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethyl]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea and 1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-ylmethyl-imidazo[2,1-b][1,3]benzothiazol-2-yl)-phenyl]-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-ethyl-piperazin-1-ylmethyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-piperidin-1-ylmethyl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-morpholin-4-yl-2-oxo-ethyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-morpholin-4-yl-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-piperidin-1-yl-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-urea; 1-(5-tert-butylisoxazol-3-yl)-3-(4-{7-[2-(4-ethyl-piperazin-1-yl)-ethyl]-imidazo[2,1-b][1,3]benzothiazol-2-yl}-phenyl)-urea; N-(5-tert-butylisoxazol-3-yl)-N′-{4-[6-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea; 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acid (2-piperidin-1-yl-ethyl)-amide; 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide; 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acid (2-diethylamino-ethyl)-amide; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-ethyl-piperazine-1-carbonyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(piperazine-1-carbonyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazine-1-carbonyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-hydroxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-methoxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-diethylamino-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea; ethyl {2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}acetate; 3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}acetic acid; pyrrolidine-2-carboxylic acid 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl ester; ethyl 3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoate; 3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoic acid; 3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N,N-diethyl-propionamide; 2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-acetamide; 3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-propionamide; 2-amino-3-methyl-butyric acid 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl ester; 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acid ethyl ester; 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acid; 1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-fluoro-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-methyl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea; 2-benzo[d]isoxazol-3-yl-N-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-acetamide; 2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid {4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide; 2-(4-chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid {4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide; and morpholine-4-carboxylic acid {4-[7-(3-morpholin-4-yl-3-oxo-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide; or a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. 27. The method of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 28. The method of claim 3, wherein R4 is optionally substituted heterocyclyl or optionally substituted heteroaryl. 29. The method of claim 3, wherein R4 is wherein R10 is hydrogen, alkyl, haloalkyl or haloaryl. 30. The method of claim 29, wherein R10 is hydrogen, methyl, tert-butyl, trifluoromethyl or p-chlorophenyl. 31. The method of claim 29, wherein R4 is 32. The method of claim 3, wherein R4Z3Z2Z1— is R4N(R5)C(O)— or R4N(R5)C(S)—, and R5 is hydrogen, or optionally substituted alkyl. 33. The method of claim 3, wherein the compound is: or a pharmaceutically acceptable salt thereof. 34. The method of claim 4, wherein R4 is optionally substituted heterocyclyl or optionally substituted heteroaryl. 35. The method of claim 4, wherein R4 is wherein R10 is hydrogen, alkyl, haloalkyl or haloaryl. 36. The method of claim 35, wherein R10 is hydrogen, methyl, tert-butyl, trifluoromethyl or p-chlorophenyl. 37. The method of claim 35, wherein R4 is 38. The method of claim 4, wherein R4Z3Z2Z1— is R4N(R5)C(O)— or R4N(R5)C(S)—, and R5 is hydrogen, or optionally substituted alkyl. 39. The method of claim 4, wherein the compound is: or a pharmaceutically acceptable salt thereof. 40. The method of claim 2, wherein the disease is mediated by a FLT3 kinase having an internal tandem duplication mutation. 41. The method of claim 3, wherein the FLT3 kinase has an internal tandem duplication mutation. 42. The method of claim 5, wherein the FLT3 kinase has an internal tandem duplication mutation.