Claims for Patent: 8,618,289

Summary for Patent: 8,618,289

Title:	RAF kinase modulator compounds and methods of use thereof
Abstract:	Compounds according to formula (I), compositions and methods are provided for modulating the activity of RAF kinases, including BRAF kinase and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by RAF kinases. Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate of hydrate thereof, wherein X is O or S(O).sub.t; R.sup.a is O or S. ##STR00001##
Inventor(s):	Abraham; Sunny (San Diego, CA), Bhagwat; Shripad S. (San Diego, CA), Campbell; Brian T. (Burlington, NJ), Chao; Qi (San Diego, CA), Faraoni; Raffaella (San Diego, CA), Holladay; Mark W. (San Diego, CA), Lai; Andiliy G. (San Diego, CA), Rowbottom; Martin W. (San Diego, CA), Setti; Eduardo (San Mateo, CA), Sprankle; Kelly G. (Vista, CA)
Assignee:	Ambit Biosciences Corporation (San Diego, CA)
Application Number:	12/933,402
Patent Claims:	1. A compound having formula (I): ##STR00496## or a pharmaceutically acceptable salt, solvate, clathrate or hydrate thereof, wherein X is O or S(O).sub.t; R.sup.a is O or S; each R.sup.1 is independently selected from (i) or (ii) below: i) each R.sup.1 is independently selected from a group consisting of halo, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, --R.sup.6OR.sup.7, --R.sup.6SR.sup.7, --R.sup.6S(O).sub.tR.sup.8, --R.sup.6N(R.sup.7).sub.2, --R.sup.6OR.sup.9OR.sup.7, --R.sup.6OR.sup.9SR.sup.7, --R.sup.6OR.sup.9S(O).sub.tR.sup.8, --R.sup.6OR.sup.9S(O).sub.tN(R.sup.7).sub.2, --R.sup.6OR.sup.9N(R.sup.7).sub.2, --R.sup.6SR.sup.9OR.sup.7, --R.sup.6SR.sup.9SR.sup.7, --R.sup.6SR.sup.9N(R.sup.7).sub.2, --R.sup.6N(R.sup.7)R.sup.9N(R.sup.7).sub.2, --R.sup.6N(R.sup.7)R.sup.9OR.sup.7, --R.sup.6N(R.sup.7)R.sup.9SR.sup.7, --R.sup.6CN, --R.sup.6C(O)R.sup.7, --R.sup.6C(O)OR.sup.7, --R.sup.6C(O)OR.sup.9OR.sup.7, --R.sup.6C(O)N(R.sup.7).sub.2, --R.sup.6C(O)N(R.sup.7)OR.sup.7, --R.sup.6C(NR.sup.7)N(R.sup.7).sub.2, --R.sup.6C(O)N(R.sup.7)R.sup.9N(R.sup.7).sub.2, --R.sup.6C(O)N(R.sup.7)R.sup.9OR.sup.7, --R.sup.6C(O)N(R.sup.7)R.sup.9SR.sup.7, --R.sup.6C(O)SR.sup.8, --R.sup.6S(O).sub.tOR.sup.7, --R.sup.6S(O).sub.tN(R.sup.7).sub.2, --R.sup.6S(O).sub.tN(R.sup.7)N(R.sup.7).sub.2, --R.sup.6S(O).sub.tN(R.sup.7)N.dbd.C(R.sup.7).sub.2, --R.sup.6S(O).sub.tN(R.sup.7)C(O)R.sup.8, --R.sup.6S(O).sub.tN(R.sup.7)C(O)N(R.sup.7).sub.2, --R.sup.6S(O).sub.tN(R.sup.7)C(NR.sup.7)N(R.sup.7).sub.2, --R.sup.6N(R.sup.7)C(O)R.sup.8, --R.sup.6N(R.sup.7)C(O)OR.sup.8, --R.sup.6N(R.sup.7)C(O)N(R.sup.7).sub.2, --R.sup.6N(R.sup.7)C(NR.sup.7)N(R.sup.7).sub.2, --R.sup.6N(R.sup.7)C(S)N(R.sup.7).sub.2, and --R.sup.6N(R.sup.7)S(O).sub.tR.sup.8, or ii) any two adjacent R.sup.1 groups together form an alkylenedioxy group; each R.sup.6 is independently a direct bond, alkylene chain or alkenylene chain; each R.sup.7 is independently selected from (i) or (ii) below: (i) each R.sup.7 is selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or (ii) two R.sup.7 groups together with the N atom to which they are attached form a heterocyclyl or heteroaryl; each R.sup.8 is independently selected from a group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl; each R.sup.9 is independently an alkylene chain or an alkenylene chain; R.sup.2 is hydrogen, halo, alkyl, amino or alkylamino; R.sup.3 is halo or alkyl; R.sup.4 and R.sup.5 are selected as follows: a) R.sup.4 and R.sup.5 are each independently hydrogen or alkyl, or b) R.sup.4 and R.sup.5, together with the N atom to which they are attached, form an oxo-substituted heterocyclyl; R.sup.11 is isoxazolyl; m is an integer from 0 to 4; n is an integer from 0 to 4; t is an integer from 0 to 2; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.11 are optionally substituted with one, two or three substituents independently selected from Q.sup.1, wherein Q.sup.1 is nitro, halo, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, --R.sup.uOR.sup.x, --R.sup.uOR.sup.uOR.sup.x, --R.sup.uOR.sup.uN(R.sup.y)(R.sup.z), --R.sup.u N(R.sup.y)(R.sup.z), --R.sup.uSR.sup.x, --R.sup.uC(J)R.sup.x, --R.sup.uC(J)OR.sup.x, --R.sup.uC(J)N(R.sup.y)(R.sup.z), --R.sup.uC(J)SR.sup.x, --R.sup.uS(O).sub.tR.sup.w, --R.sup.uOC(J)R.sup.x, --R.sup.uOC(J)OR.sup.x, --R.sup.uOC(J)N(R.sup.y)(R.sup.z), --R.sup.uOC(J)SR.sup.x, --R.sup.uN(R.sup.x)C(J)R.sup.x, --R.sup.uN(R.sup.x)C(J)OR.sup.x, --R.sup.uN(R.sup.x)C(J)N(R.sup.y)(R.sup.z), --R.sup.uN(R.sup.x)C(J)SR.sup.x, --R.sup.uSi(R.sup.w).sub.3, --R.sup.uN(R.sup.x)S(O).sub.tR.sup.w, --R.sup.uN(R.sup.x)R.sup.uS(O).sub.2R.sup.w, --R.sup.uN(R.sup.x)S(O).sub.2N(R.sup.y)(R.sup.z), --R.sup.uS(O).sub.2N(R.sup.y)(R.sup.z), --R.sup.uP(O)(R.sup.v).sub.2, --R.sup.uOP(O)(R.sup.v).sub.2, --R.sup.uC(J)N(R.sup.x)S(O).sub.2R.sup.w, --R.sup.uC(J)N(R.sup.x)N(R.sup.x)S(O).sub.2R.sup.w, --R.sup.uC(R.sup.x).dbd.N(OR.sup.x) or --R.sup.uC(R.sup.x).dbd.NN(R.sup.y)(R.sup.z); when Q.sup.1 is alkyl, alkenyl or alkynyl, each Q.sup.1 is optionally substituted with halo, cyano, hydroxy or alkoxy; when Q.sup.1 is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q.sup.1 is optionally substituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkoxy or hydroxyl; each R.sup.u is independently alkylene or a direct bond; each R.sup.v is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, --OR.sup.x or --N(R.sup.y)(R.sup.z); R.sup.w is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each R.sup.x is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R.sup.y and R.sup.z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R.sup.y and R.sup.z, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl; and J is O, NR.sup.x or S. 2. The compound of claim 1 having formula (II): ##STR00497## or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein X is O, S, S(O) or SO.sub.2; each R.sup.1 is independently selected from (i) or (ii) below: i) each R.sup.1 is independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, --R.sup.6OR.sup.7, --R.sup.6SR.sup.7, --R.sup.6S(O).sub.tR.sup.8, --R.sup.6N(R.sup.7).sub.2, --R.sup.6OR.sup.9OR.sup.7, --R.sup.6OR.sup.9SR.sup.7, --R.sup.6OR.sup.9S(O).sub.tR.sup.8, --R.sup.6OR.sup.9S(O).sub.tN(R.sup.7).sub.2, --R.sup.6OR.sup.9N(R.sup.7).sub.2, --R.sup.6SR.sup.9OR.sup.7, --R.sup.6SR.sup.9SR.sup.7, --R.sup.6SR.sup.9N(R.sup.7).sub.2, --R.sup.6N(R.sup.7)R.sup.9N(R.sup.7).sub.2, --R.sup.6N(R.sup.7)R.sup.9OR.sup.7, --R.sup.6N(R.sup.7)R.sup.9SR.sup.7, --R.sup.6CN, --R.sup.6C(O)R.sup.7, --R.sup.6C(O)OR.sup.7, --R.sup.6C(O)OR.sup.9OR.sup.7, --R.sup.6C(O)N(R.sup.7).sub.2, --R.sup.6C(O)N(R.sup.7)OR.sup.7, --R.sup.6C(O)N(R.sup.7)R.sup.9OR.sup.7, --R.sup.6C(O)N(R.sup.7)R.sup.9SR.sup.7, --R.sup.6C(O)SR.sup.8, --R.sup.6S(O).sub.tOR.sup.7, and --R.sup.6S(O).sub.tN(R.sup.7).sub.2; or ii) any two adjacent R.sup.1 groups together form an alkylenedioxy group; each R.sup.6 is independently a direct bond, alkylene chain or alkenylene chain; each R.sup.7 is independently selected from (i) or (ii) below: (i) each R.sup.7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or (ii) two R.sup.7 groups together with the N atom to which they are attached form a heterocyclyl or heteroaryl; each R.sup.9 is independently an alkylene chain or an alkenylene chain; R.sup.3 is halo or alkyl; R.sup.4 and R.sup.5 are each independently hydrogen or alkyl; R.sup.11 is isoxazolyl; m is an integer from 0 to 4; n is an integer from 0 to 4, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.11 are optionally substituted with one, two or three substituents independently selected from Q.sup.1, wherein Q.sup.1 is nitro, halo, azido, cyano, oxo, thioxo, imino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, --R.sup.uOR.sup.x, --R.sup.uOR.sup.uOR.sup.x, --R.sup.uOR.sup.uN(R.sup.y)(R.sup.z), --R.sup.uN(R.sup.y)(R.sup.z), --R.sup.uSR.sup.x, --R.sup.uC(J)R.sup.x, --R.sup.uC(J)OR.sup.x, --R.sup.uC(J)N(R.sup.y)(R.sup.z), --R.sup.uC(J)SR.sup.x, --R.sup.uS(O).sub.tR.sup.w, --R.sup.uOC(J)R.sup.x, --R.sup.uOC(J)OR.sup.x, --R.sup.uOC(J)N(R.sup.y)(R.sup.z), --R.sup.uOC(J)SR.sup.x, --R.sup.uN(R.sup.x)C(J)R.sup.x, --R.sup.uN(R.sup.x)C(J)OR.sup.x, --R.sup.uN(R.sup.x)C(J)N(R.sup.y)(R.sup.z), --R.sup.uN(R.sup.x)C(J)SR.sup.x, --R.sup.uSi(R.sup.w).sub.3, --R.sup.uN(R.sup.x)S(O).sub.2R.sup.w, --R.sup.uN(R.sup.x)R.sup.uS(O).sub.2R.sup.w, --R.sup.uN(R.sup.x)S(O).sub.2N(R.sup.y)(R.sup.z), --R.sup.uS(O).sub.2N(R.sup.y)(R.sup.z), --R.sup.uP(O)(R.sup.v).sub.2, --R.sup.uOP(O)(R.sup.v).sub.2, --R.sup.uC(J)N(R.sup.x)S(O).sub.2R.sup.w, --R.sup.uC(J)N(R.sup.x)N(R.sup.x)S(O).sub.2R.sup.w, --R.sup.uC(R.sup.x).dbd.N(OR.sup.x) or --R.sup.uC(R.sup.x).dbd.NN(R.sup.y)(R.sup.z); when Q.sup.1 is alkyl, alkenyl or alkynyl, each Q.sup.1 is optionally substituted with halo, cyano, hydroxy or alkoxy; when Q.sup.1 is cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, each Q.sup.1 is optionally substituted with halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkoxy, hydroxyl, oxo or cyano; each R.sup.u is independently alkylene or a direct bond; each R.sup.v is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, --OR.sup.x or --N(R.sup.y)(R.sup.z); R.sup.w is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; each R.sup.x is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R.sup.y and R.sup.z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R.sup.y and R.sup.z, together with the nitrogen atom to which they are attached, form a heterocycle or heteroaryl; t is an integer from 0 to 2; and J is O, NR.sup.x or S. 3. The compound of claim 1, wherein the compound is a pharmaceutically acceptable salt of the compound of formula (I). 4. The compound of claim 1, wherein the compound is a solvate of the compound of formula (I). 5. The compound of claim 1, wherein the compound is a hydrate of the compound of formula (I). 6. The compound of claim 1, wherein X is O or S. 7. The compound of claim 1, wherein R.sup.3 is methyl, chloro or fluoro. 8. The compound of claim 1, wherein the compound has formula III: ##STR00498## or a pharmaceutically acceptable salt, solvate or hydrate thereof. 9. The compound of claim 1, wherein the compound has formula IV: ##STR00499## or a pharmaceutically acceptable salt, solvate or hydrate thereof. 10. The compound of claim 1, wherein R.sup.11 is selected from the group consisting of: ##STR00500## and each R.sup.10 is independently selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, alkoxyalkoxy, aryl, heterocyclyl, heterocyclylcarbonyl, alkoxycarbonyl and heteroaryl, where the alkyl, aryl, heteroaryl and heterocyclyl groups are optionally substituted with 1 to 5 groups selected from halo, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl, alkylcarbonyl and alkoxycarbonyl. 11. The compound of claim 1, wherein R.sup.11 is ##STR00501## where R.sup.10 is hydrogen, alkyl, hydroxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkoxyalkyl, aryl or heteroaryl. 12. The compound of claim 1, wherein R.sup.11 is ##STR00502## 13. The compound of claim 1, wherein each R.sup.1 is selected as follows: i) each R.sup.1 is independently selected from the group consisting of hydrogen, halo, nitro, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, --R.sup.6OR.sup.7, --R.sup.6SR.sup.7, --R.sup.6N(R.sup.7).sub.2, --R.sup.6OR.sup.9OR.sup.7, --R.sup.6OR.sup.9SR.sup.7, --R.sup.6SR.sup.9OR.sup.7, --R.sup.6SR.sup.9SR.sup.7, --R.sup.6OR.sup.9N(R.sup.7).sub.2, --R.sup.6SR.sup.9N(R.sup.7).sub.2, --R.sup.6CN, --R.sup.6C(O)R.sup.7, --R.sup.6C(O)OR.sup.7, --R.sup.6C(O)OR.sup.9OR.sup.7, --R.sup.6C(O)N(R.sup.7).sub.2 and --R.sup.6N(R.sup.7)C(O)R.sup.8; or ii) any two adjacent R.sup.1 groups together form an alkylenedioxy group; each R.sup.6 is independently a direct bond, alkylene chain or alkenylene chain; each R.sup.7 is independently selected from (i) or (ii) below: (i) each R.sup.7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaralkyl, or (ii) two R.sup.7 groups together with the N atom to which they are attached form a heterocyclyl or heteroaryl; each R.sup.9 is independently an alkylene chain or an alkenylene chain, wherein R.sup.1, R.sup.6, R.sup.7 and R.sup.9 groups are optionally substituted with one, two or three Q.sup.1 groups, wherein each Q.sup.1 is independently haloalkyl, alkyl, --R.sup.uOR.sup.x, --R.sup.uC(J)OR.sup.x, --R.sup.uS(O).sub.2R.sup.w, --R.sup.uN(R.sup.x)S(O).sub.2R.sup.w or --R.sup.uN(R.sup.x)R.sup.uS(O).sub.2R.sup.w, wherein R.sup.u is direct bond or alkylene, R.sup.x is hydrogen or alkyl; R.sup.w is alkyl and J is O, S or NR.sup.x, such that at least one R.sup.1 is other than hydrogen. 14. The compound of claim 1 having formula XII: ##STR00503## or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R.sup.a is O or S; X is O or S; R.sup.1a and R.sup.1b are selected as follows: i) R.sup.1a and R.sup.1b are each independently selected from hydrogen, halo, amino, alkyl, aryl, heteroaryl, alkoxy, hydroxy, alkoxyalkoxy, cycloalkylcarbonylamino and a group of formula: ##STR00504## where each K is independently a direct bond or alkylene; A is N or CR.sup.16; Y is --O, --S, --S(O), --S(O).sub.2, --N(R.sup.14), --C(H)R'.sup.5, or --C(O); p is an integer from 0 to 2; R.sup.14 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heteroarylalkyl, arylalkyl, S(O).sub.tR.sup.13 or --C(O)R.sup.12; R.sup.15 is hydrogen, halo, alkyl, hydroxyalkyl or --OR.sup.12; R.sup.16 is hydrogen or alkyl; t is 1 or 2; each R.sup.12 is independently selected from the group consisting of hydrogen and alkyl; R.sup.13 is alkyl; each K is optionally substituted with one, two or three hydroxy or alkyl groups; or ii) R.sup.1a and R.sup.1b groups together form an alkylenedioxy group. 15. The compound of claim 1 having formula XVII: ##STR00505## or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein X is O or S; R.sup.1a and R.sup.1b are selected as follows: i) R.sup.1a and R.sup.1b are each independently alkoxy, alkoxyalkoxy, alkylsulfonylalkoxy or a group of formula: ##STR00506## where K is a direct bond or alkylene, optionally substituted with a hydroxy group; A is N or CH; Y is --O, --S(O).sub.2, --N(R.sup.14) or --C(H)R.sup.15; p is 0 or 1; R.sup.14 is hydrogen, alkyl, haloalkyl, hydroxyalkyl or S(O).sub.tR.sup.13; R.sup.15 is hydrogen, halo, alkyl, hydroxyalkyl or --OR.sup.12; t is 1 or 2; R.sup.12 is hydrogen or alkyl; and R.sup.13 is alkyl; or ii) R.sup.1a and R.sup.1b groups together form an alkylenedioxy group; and R.sup.10 is hydrogen, halo, alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl or cycloalkylalkyl; where alkyl, aryl, heterocyclyl and heteroaryl groups are optionally substituted with 1-3 groups selected from halo, cyano, hydroxyl and alkoxy. 16. The compound of claim 1 having formula XIX: ##STR00507## or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein X is O or S; R.sup.1a and R.sup.1b are selected as follows: i) R.sup.1a and R.sup.1b are each independently methoxy, methoxyethoxy, methylsulfonylpropyloxy, or a group of formula: ##STR00508## where K is ethylene or propylene, optionally substituted with a hydroxy group; A is N or CH; Y is --O, --S(O).sub.2, --N(R.sup.14) or --C(H)R.sup.15; p is 1; R.sup.14 is hydrogen, methyl, hydroxyethyl, or methylsulfonyl; R.sup.15 is hydrogen, hydroxymethyl, hydroxyethyl or hydroxy; or ii) R.sup.1a and R.sup.1b groups together with the carbon atoms on which they are substituted form an ethylenedioxy group; and R.sup.10 is hydrogen, halo, alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl or cycloalkylalkyl; where alkyl, aryl, heterocyclyl and heteroaryl groups are optionally substituted with 1-3 groups selected from halo, cyano, hydroxyl and alkoxy. 17. The compound of claim 1 selected from 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)pheny- l)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-yloxyphe- nyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-yloxy)- phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoroquinazolin-4-yloxy)phenyl- )urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(5-methylquinazolin-4-yloxy)phen- yl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-- 4-yloxy)phenyl]urea hydrochloride; 1-(5-tert-Butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazol- in-4-yloxy]phenyl}urea hydrochloride; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methylquinazolin-4-yloxy)phenyl)ure- a; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-- fluorophenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-3-(6,7-dimethoxyquinazolin-4-yl oxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)- phenyl)urea; 1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-(5-tert-butyli- soxazol-3-yl)urea hydrochloride; 1-(5-tert-Butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-yloxy)phenyl- ]urea hydrochloride; 1-(5-tert-Butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinaz- olin-4-yloxy)phenyl]urea hydrochloride; 1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-6-(2-methoxyethoxy)quinazol- in-4-yloxy]phenyl}urea hydrochloride; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(piperidin-1-yl)ethoxy- )quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl- )ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-y- l)ethoxy)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-y- l)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quina- zolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methyl piperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-morpholinopropoxy)quin- azolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(piperidin-1-yl)propox- y)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(hydroxymethyl)piperidin-1-yl- )propoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-(methylsulfonyl)pip- erazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-- propoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-morpholinopropoxy)quin- azolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-y- l)propoxy)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-hydroxymethyl)piperidin-1-yl)- propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-y- l)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(3-hydroxy-pyrrolidin-1-yl)-pro- poxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methyl sulfonyl)piperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea; (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)pr- opoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea; (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)pr- opoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quina- zolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methyl piperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{7-[2-(4-hydroxymethyl-piperidin-1-yl- )-ethoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-y- l)ethoxy)-6methoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{7-[2-(1,1-dioxo-116-thiomorpholin-4-- yl)-ethoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-yloxy- )phenyl)urea 1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propox- y)quinazolin-4-ylthio)phenyl)urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-methoxy-6-(3-(methylsulf- onyl)propoxy)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-methoxyethoxy)quinazolin-4-yloxy- )phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propox- y)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-methoxyethoxy)quinazol- in-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phen- yl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-difluoroquinazolin-4-ylth- io)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-ylthio)phenyl)u- rea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-ylthio)phen- yl)urea; 1-(5-tert-Butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-- 4-ylthio)phenyl]urea; 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-ylthio)pheny- l]urea; 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)q- uinazolin-4-ylthio]phenyl}urea hydrochloride; 1-{3-[6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-(5-tert-butyl- isoxazol-3-yl)urea hydrochloride; 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7,8-dihydro-[1,4]dioxino[2,3-g]quinaz- olin-4-ylthio) phenyl]urea hydrochloride; 1-(5-tert-Butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yl- thio)quinazolin-4-yloxy]phenyl}urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio- )phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(piperidin-1-yl)propox- y)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(hydroxymethyl)piperidin-1-yl- )propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-y- l)propoxy) quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-(methylsulfonyl)pip- erazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-(4-(2-hydroxyethyl)piperazin-1-y- l)propoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-- propoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-morpholinopropoxy)quin- azolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propox- y)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(piperidin-1-yl)ethoxy- )quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl- )ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-y- l)ethoxy)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(2-hydroxyethyl)piperazin-1-y- l)ethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-(methylsulfonyl)pip- erazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quina- zolin-4-ylthio)phenyl)urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-- ethoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quina- zolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-y- l)propoxy)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(hydroxylmethyl)piperidin-1-y- l)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(4-(2-hydroxyethyl)piperazin-1-y- l)propoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(piperidin-1-yl)propox- y)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)pip- erazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quina- zolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy- )quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-(methylsulfonyl)pip- erazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-y- l)ethoxy)quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-y- l)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(hydroxymethyl)piperidin-1-yl- )ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-methoxyethoxy)quinazolin-4-ylthi- o)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(methylsulfonyl)ethoxy- )quinazolin-4-ylthio)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yl- thio)phenyl)urea; 1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-- propoxy]-quinazolin-4-ylsulfanyl}-phenyl)-urea; 1-(5-tert-Butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-116-thiomorpholin-4-- yl)-ethoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea; 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-{[2-(methylsulfonyl)ethylamino]m- ethyl}furan-2-yl)quinazolin-4-yloxy]phenyl}urea; 1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yl- oxy)quinazolin-4-yloxy]phenyl}urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy- )phenyl)urea; (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)q- uinazolin-4-yloxy)phenyl)urea; (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(1-methylpyrrolidin-3- -yloxy)quinazolin-4-yloxy)phenyl); urea mono acetate; (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(pyrrolidin-3-yloxy)q- uinazolin-4-yloxy)phenyl)urea; (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(1-methylpyrrolidin-3- -yloxy)quinazolin-4-yloxy)phenyl)urea mono acetate; (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-hydroxy-3-(4-methylpiperazin- -1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(3-tert-Butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(piperidin-4-ylmethoxy)qu- inazolin-4-yloxy)phenyl)urea; 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-((1-methylpiperidin-4-yl)- methoxy)quinazolin-4-yloxy)phenyl)urea; (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)pyrrolidi- n-3-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea; (S)-1-(5-tert-Butylisoxazol-3-yl)-3-(3-{6-methoxy-7-[1-(2,2,2-trifluoroet- hyl)pyrrolidin-3-yloxy]quinazolin-4-yloxy}phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)piperidin-4-y- loxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy- )phenyl)urea; (S)-tert-butyl 3-(4-(3-(3-(5-tert-butylisoxazole-3-yl)ureido)phenoxy)-7-methoxyquinazoli- n-6-yloxy)pyrrolidine-1-carboxylate; (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(1-methylpyrrolidin-3- -yloxy)quinazolin-4-yloxy)phenyl)urea; (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(1-(2,2-difluoroethyl)pyrrolidi- n-3-yloxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea; (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-hydroxy-3-(4-methylpiperazin- -1-yl)propoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea; (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-hydroxy-3-(4-methylpiperazin- -1-yl)propoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)ur- ea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5- -yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(tetrahydro-2- H-pyran-4-yl)isoxazol-5-yl)urea; 1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phen- yl)urea; 1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinaz- olin-4-yloxy)phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)i- soxazol-5-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-methylcyclopropyl)i- soxazol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-hydroxy-2-methylpro- pan-2-yl)isoxazol-3-yl)urea; 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)pheny- l)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-isopropylisoxaz- ol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-isopropylisoxazol-3-y- l)urea; 1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylo- xy)phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-fluoropropan-2-yl)i- soxazol-3-yl)urea; 1-(3-(1,1-difluoroethyl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yl- oxy)phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-(trifluoromethyl)cy- clobutyl)isoxazol-5-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(1-(trifluoromethyl)c- yclobutyl)isoxazol-5-yl)urea; 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4- -ylthio)phenyl)urea; 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxy- quinazolin-4-yloxy]phenyl)urea; 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxy- quinazolin-4-ylthio]phenyl)urea; 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxy- quinazolin-4-yloxy)phenyl]urea; 1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phen- yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoroprop- an-2-yl)isoxazol-5-yl)urea; 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-[3-(6,7-dimethoxy- quinazolin-4-ylthio)phenyl]urea; 1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phe- nyl)urea; 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy- )quinazolin-4-yloxy)phenyl)urea; 1-(3-(6-Methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenyl- isoxazol-3-yl)urea; 1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazoli- n-4-yloxy)phenyl)urea; 1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazo- lin-4-yloxy)phenyl)urea; 1-(3-(1,1-difluoroethyl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy- )quinazolin-4-yloxy)phenyl)urea; 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(- 2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea; 1-(3-cyclopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazo- lin-4-yloxy)phenyl)urea; 1-(3-isopropylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazoli- n-4-yloxy)phenyl)urea; 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(tetra- hydro-2H-pyran-4-yl)isoxazol-5-yl)urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyetho- xy)quinazolin-4-yloxy)phenyl)urea; 1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazo- lin-4-yloxy)phenyl)urea; 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(3-(trifl- uoromethyl)isoxazol-5-yl)urea; 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(- 2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea; 1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazoli- n-4-ylthio)phenyl)urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyetho- xy)quinazolin-4-ylthio)phenyl)urea; 1-(5-cyclopentylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazo- lin-4-ylthio)phenyl)urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-methoxy-6-(4,4-dioxo-3-t- hiomorpholinopropoxy)quinazolin-4-ylthio)phenyl)urea; 1-(3-(6,7-bis(2-Methoxyethoxy)quinazolin-4-ylthio)phenyl)-3-(3-tert-butyl- isoxazol-5-yl)urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-morpholinoe- thoxy)quinazolin-4-ylthio)phenyl)urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-morpholinoe- thoxy)quinazolin-4-yloxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylsulfinyl)- phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)isoxa- zol-5-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1-hydroxy-2-methylpro- pan-2-yl)isoxazol-5-yl)urea; 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(1,1-dioxo-thiomorpholin-4-yl)-- propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(7-hydroxy-6-methoxyquinazo- lin-4-yloxy)phenyl)urea; 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-hydroxy-7-methoxyquinazo- lin-4-yloxy)phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-met- hylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-- 2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-me- thylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro- -2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro- -2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro- -2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(5-(1,1,1-triflu- oro-2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(5-(1,1,1-triflu- oro-2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(1,1,1-trifluoro-2-met- hylpropan-2-yl)isoxazol-5-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(1,1,1-trifluoro-2-me- thylpropan-2-yl)isoxazol-5-yl)urea; and 1-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(3-(2-fluoro- propan-2-yl)isoxazol-5-yl)urea, or a pharmaceutically acceptable salt, solvate or hydrate thereof. 18. The compound of claim 1 selected from 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-- difluorophenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-me- thylphenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)-3-(5-(2-fluoroprop- an-2-yl)isoxazol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(3-(2-fluoroprop- an-2-yl)isoxazol-5-yl)urea; 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxy- quinazolin-4-yloxy)-4-fluorophenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(3-(2-fluoroprop- an-2-yl)isoxazol-5-yl)urea; 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxy- quinazolin-4-yloxy)-2-fluorophenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yl- oxy)phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-methyl-1-morpholino- propan-2-yl)isoxazol-3-yl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yl- oxy)phenyl)urea; 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fl- uorophenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-(trifluoromethyl)cy- clopropyl)isoxazol-3-yl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1-(trifluoromethyl)c- yclopropyl)isoxazol-3-yl)urea; 1-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-y- lthio)phenyl)urea; 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(trifluoromethyl)isox- azol-5-yl)urea; 1-(3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2- -yl)isoxazol-5-yl)urea; 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(7-ethoxy-6-me- thoxyquinazolin-4-yloxy)phenyl)urea; 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(7-ethoxy-6-me- thoxyquinazolin-4-ylthio)phenyl)urea; 1-(3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-- 2-yl)isoxazol-5-yl)urea; 1-(3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2- -yl)isoxazol-5-yl)urea; 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6-ethoxy-7-me- thoxyquinazolin-4-yloxy)phenyl)urea; 1-(3-(6-ethoxy-7-methoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-fluoropropan-- 2-yl)isoxazol-5-yl)urea; or a pharmaceutically acceptable salt, solvate or hydrate thereof. 19. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent. 20. The composition of claim 19 further comprising a second therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent or an immunosuppressive agent. 21. A method of treating a cancer in a patient a therapeutically effective amount of the compound of claim 1 wherein the cancer is melanoma, thyroid carcinoma, colorectal, ovarian, breast cancer, endometrial cancer, liver cancer, sarcoma, stomach cancer, Barret's adenocarcinoma, glioma, small cell lung cancer, non-small cell lung cancer, head and neck cancer, acute lymphoblastic leukemia or non-Hodgkin's lymphoma. 22. A method of treating an inflammatory disease in a patient comprising administrating to the patient a therapeutically effective amount of the compound of claim 1 wherein the inflammatory disease is immune dysfunction, immunodeficiency, immunomodulation, autoimmune disease, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, allergic rhinitis, inflammatory bowel disease, systemic lupus erythematosis, arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma or chronic obstructive pulmonary disease. 23. The method of claim 21 further comprising administering a second therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent or an immunosuppressive agent. 24. The method of claim 23, wherein the second therapeutic agent is selected from an anti-metabolite, a topoisomerase inhibitor and platinum agent. 25. The method of claim 23, wherein the second therapeutic agent is selected from 5-fluoro-uracil, methotrexate, fludarabine, vincristine, vinblastine, paclitaxel, docetaxel, cyclophosphamide, melphalan, carmustine, bischloroethylnitrosurea, hydroxyurea, cisplatin, carboplatin, oxaliplatin, satraplatin, CI-973, doxorubicin, daunorubicin, mitomycin, idarubicin, adriamycin, daunomycin, etoposide, camptothecins, sorafenib, bevacizumab, estramustine phosphate and prednimustine. 26. The method of claim 21, wherein the cancer is papillary thyroid carcinoma.

Details for Patent 8,618,289

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2028-03-17