Pyrrolopyridazine vegfr tyrosine kinase inhibitors

Abstract

Provided are compounds of formula (I) and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are VEGFR inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat cancer and related diseases and conditions, comprising administering a compound of Formula I to a patient in need thereof.

Description

PYRROLOPYRID AZINE VEGFR TYROSINE KINASE INHIBITORSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Nos. 63 / 673,428, filed July 19, 2024; which is incorporated by reference herein in its entirely.INCORPORATION BY REFERENCE

[0002] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, and as if set forth in their entireties.BACKGROUND

[0003] Protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl group of specific tyrosine, serine, or threonine residues in proteins. Typically, such phosphorylation dramatically perturbs the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. Of the many different cellular functions in which the activity of protein kinases is know n to be required, some processes represent attractive targets for therapeutic intervention for certain disease states. Tw o examples are angiogenesis and cell-cycle control, in which protein kinases play a pivotal role; these processes are essential for the growth of solid tumors as well as for other diseases.SUMMARY

[0004] The present disclosure is directed to compounds having structural Formula I:As well as pharmaceutically acceptable salts, esters, and prodrugs thereof, which are VEGFR modulators. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, methods of using these compounds for thepotential prevention or treatment of a VEGF-associated disease or disorder and the use of compounds of Formula I for the potential prevention or treatment of a VEGF-associated disease or disorder.DETAILED DESCRIPTION

[0005] The present disclosure is directed to compounds having structural Formula I:or a pharmaceutically acceptable salt thereof wherein:X is selected from -O-, -NH-, -N-C1-6alkyl-, and -S-; ring A is selected from:(1) aryl,(2) cycloalkyl,(3) heteroaryl, and(4) heterocyclyl; n is 0, 1, 2, or 3;R1is independently selected from:(1) -C1-6alkyl,(2) halo,(3) -C0-6alkyl-C(0)NHRa,(4) -NHC(O)NHRa,(5) -NHC(O)Ra,(6) -C0-6alkyl-ORa,(7) -C0-6alkyl-C(0)ORa,(8) -C0-6alkyl-C(0)Ra,(9) -C0-6alkyl-cyano,(10) -C0-6alkyl-NHRa,(11) -C0-6alkyl-aryl, wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from Ra,(12) -C0-6alkyl-(5-6 membered heteroaryl) wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N. O, and S. and is unsubstituted or substituted with 1 -3 substituents independently selected from Ra,(13) -C3-6cycloalkyl. unsubstituted or substituted with 1-3 substituents selected fromRa,(14) -C0-6alkyl-C(0)NR3R4,(15) -Co-ealky l-NHS(O)2NHRa,(16) -C0-6alkyl-S(0)2NHRa,(17) C2-6alkynyl,(18) =0, and(19) hydrogen; when present, Rais selected from:(1) hydrogen;(2) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, -NR3R4, -cyano, -C1-6alkyl, -O-Co-ealkyl, and -C1-6haloalkyl;(3) -C0-6alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo; -OH; =0; -NH-Cs-ecycloalkyl; -C0-6alkyl-NR3R4; -Co- ealkyl-cyano; -C1-6alkyl; -O-Co-ealkyl; -C(0)-C1-6alkyl; -C(O)NH-C5-6aryl, wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from -Ci- ealkyl, -OH, and halo; and -C1-6haloalkyl;(4) -C0-6alkyl-aryl, unsubstituted or substituted with 1-3 substituents independently selected from halo, =0, and -NH-cyclopropyl, -OH, -C0-6alkyl-NR3R4, -C0-6alkyl-cyano, - C1-6alkyl, -O-Co-ealkyl, and -C1-6haloalkyl;(5) -O-C1-6alkyl;(6) -Co-ealky l-(5-6 membered monocyclic heteroaryl) wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O. and S, and is unsubstituted or substituted with 1-3 substituents independently selected from halo, =0, -NH-cyclopropyl, -OH, - C0-6alkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl, -C(O)OC1-6alkyl, -C1-6alkyl-Cs- ocycloalkyl, -0-Co-6alkyl, and -C1-6haloalkyl;(7) -C1-6alkyl-S-C1-6alkyl;(8) -C3-6 monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, - C0-6alkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl, -OCo-ealkyl, -Ci- ehaloalkyl, and =0;(9) 5-10 membered spiro bicyclic or tricyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, -C0-6alkyl-NR3R4, -Co- ealkyl-cyano, -C1-6alkyl, -OCo-ealkyl, -C1-6haloalkyl, and =0;(10) 5-10 membered spiro bicyclic or tricyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, -C0-6alkyl-NR3R4, -Co- 6alkyl-cyano, -C1-6alkyl, -OCo-6alkyl, -C1-6haloalkyl. and =0;(11) 5-6 membered bridged bicyclic cycloalkyl, unsubstituted or substituted with one substituent selected from -OH, halo and haloalkyl;(12) halo;(13) -C(0)0-C1-6alkyl;(14) -NH2; and(15) -C=C; when present, each of R3and R4is independently selected from(1) hydrogen,(2) -C0-6alkyl- 3-6 membered heterocyclyl having 1-3 heteroatoms selected from N, O, and S. wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rb,(4) -C1-6 alkyl-O-C1-6alkyl. unsubstituted or substituted with 1-3 substituents independently selected from Rb,(5) -Co ealkyl- Cs ecycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1 -3 substituents independently selected from Rb, and(6) 5-10 membered bicyclic or tricyclic cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb; when present, Rbis selected from(1) -C1-6alkyl,(2) halo,(3) -NH2.(4) =0, and(5) -OH; or alternatively, R3and R4together with the nitrogen to which they are attached form a 3-10 membered heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S. in addition to the nitrogen to which R3and R4are attached, wherein the heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from Rc; when present, Rcis selected from(1) -C0-6alkyl-OH,(2) -C1-6alkyl, unsubstituted or substituted with 1-3 -OH substituents,(3) -C0-6alkyl-cyano,(4) -C0-6alkyl-0-Ci-3alkyl,(5) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1-3 Ci -ealky I substituents,(6) halo,(7) -C1-6haloalkyl,(8) C0-6alkyl-aryl, wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from C i-ehaloalkyl and halo,(9) -C3-6Cycloalkyl,(10) -C0-6alkyl-N(Rg)2, wherein each R8is independently selected from hydrogen and C1-6alkyl.(11) -NH-C(O)C1-6alkyl,(12) -Co-3alkyl-(3-6 membered monocyclic heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1 =0 substituent,(13) -O-C1-6haloalkyl,(14) =0,(15) hydrogen, and(16) -C(0)0C1-6alkyl;<,XR5NR2is 'R6, each of R5and R6is independently selected from(1) hydrogen,(2) -C0-6alkyl-(3-6 membered heterocyclyl), wherein the heteroyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1 -3 substituents independently selected from Rd,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rd,(4) -C1-6 alkyl -O-Ci ealkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rd,(5) -C0-6alkyl- C3-6 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1 -3 substituents independently selected from Rd, and(6) 5-10 membered bicyclic or tricyclic cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from Rd; when present, Rdis selected from(1) -C1-6alkyl,(2) halo,(3) -NH2,(4) =0. and(5) -OH; or alternatively, R5and R6together with the nitrogen to which they are attached form 4-10 membered heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S, in addition to the nitrogen to which R5and R6are attached, wherein the heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from Re, when present, Reis selected from(1) -C0-6alkyl-OH,(2) -C1-6alkyl, unsubstituted or substituted with 1-3 -OH substituents,(3) -C0-6alkyl-cyano,(4) -C0-6alkyl-0-Ci-3alkyl,(5) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1-3 -C1-6alkyl substituents,(6) halo.(7) -C1-6haloalkyl,(8) -C0-6alkyl-aryl, wherein the ary l is unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl. and halo.(9) -C3-6cycloalkyl,(10) -C0-6alkyl-N(Rf)2, wherein each Rfis independently selected from hydrogen and C1-6alkyl, or two Rftogether form =OC1-6alkyl,(11) -NHC(O)C1-6alkyl,(12) -Co-3alkyl-(3-7 membered monocyclic heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1 -3 =0 substituents,(13) -O-C1-6haloalkyl,(14) =0.(15) hydrogen,(16) -C(O)OC1-6alkyl,(17) -N(CH3)-C3-6cycloalkyl, wherein the cycloalkyl is substituted with one -OH substituent.(18) -N(CH3)-(3-7 membered monocyclic heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one -Ci-3alkyl substituent,(19) -C(0)C1-6alkyl. and(20) 5-8 membered bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with 1-3 substituents independently selected from -C1-6alkyl, -C1-6alkyl-OH. and hydrogen.R10is selected from:(1) hydrogen,(2) -C1-6alkyl,(3) -Cs-ecycloalkyl,(4) -C1-6haloalkyl,(5) -C1-6alkyl-O-C1-6alkyl, and(6) -C1-6alkyl-OH;

[0006] In Embodiment 2 of this disclosure are compounds of Formula I, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is(1) -Ce-ioaryl,(2) -Ce-iocycloalkyl,(3) 5-10 membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, or(4) 5-10 membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O. and S.

[0007] In Embodiment 3 of this disclosure are compounds of Formula I, or Embodiments 1 or2, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is(1) phenyl or naphthyl,(2) tetrahydronaphthalenyl,(3) indazolyL indolizinyl, quinolinyl, isoquinolinyL pyrrolo[l,2-b]pyridazinyl, benzo[<7]thiazolyl, benzo[d]isothiazolyl, dihydrobenzo[d]isothiazolyl, benzofuranyl,pyrrolo[2,3-b]pyridinyl, dihydroisobenzofuranyl, benzo[c][l,2,5]thiadiazolyl, isoxazolyl. benzo[d]oxazolyl, or oxadiazolyl, or(4) dihydro-quinolinyl, dihydrobenzo[b][l,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, dihydrobenzo |b|| l .4| dioxinyl, dihydro-pyrrolo|2.3- / ?|pyridinyl.

[0008] In Embodiment 4 of this disclosure are compounds of Formula I. or Embodiments 1 to 3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is(1) C1-6alkyl,(2) halo,(3) -Ci-3alkyl-(0)NH-(Co-3alkyl-cyclobutanyl), wherein the cyclobutanyl is unsubstituted or substituted with 1-3 fluoro substituents; -Ci-3alkyl-(0)NH-(Co-3alkyl- bicyclo[l. l. l]pentanyl); -Ci-3alkyl-(0)NH-(C0-6alkyl- cyclopropanyl); -Ci-3alkyl-(0)NH-(Co- salkyl phenyl), wherein the phenyl is unsubstituted or substituted with 1 -3 substituents independently selected from methyl and -F; -C1-6alkyl-(0)NH-(Co-3alkyl thiazolyl) wherein the thiazolyl is unsubstituted or substituted with one methyl substituent; -Ci-3alkyl-(O)NH-Ci-3alkyl; or -Ci-3alkyl-(0)NH-(Co-3alkyl cyclopentenyl),(4) -NHC(O)NH-C3-6Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from -OCH3 and halo; -NHC(O)NH-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one -Ci-3alkyl substituent; - NHC(O)NH-C1-6alkyl; or -NHC(0)NH-Co-3alkyl-aryl, wherein the alkyl-aryl is unsubstituted or substituted with 1 -3 halo substituents,(5) -NHC(O)-aryl, wherein the aryl is substituted with one -OH substituent; - NHC(O)-heteroaryL wherein the heteroaryl is unsubstituted or substituted with 1-3 -C1-6alkyl substituents; -NHC(O)C1-6alkyl, wherein the alkyl is unsubstituted or substituted with one cycloalkyl substituent; -NHC(O)O-C1-6alkyl; -NHC(O)-C1-6alkyl; or -NHC(O)CH2S-C1-6alkyl,(6) -Co-3alkyl-OH, -Co-3alkyl-0-C1-6alkyl, or -Co-3alkyl-0-aryl-0-C1-6alky,(7) -Co-3alkyl-C(0)0-Ci-3alkyl, wherein the -Co-3alkyl is unsubstituted or substituted wi th one -NH2 substituent,(8) -Co-3alkyl-cyano,(9) -Co-3alkyl-NH2; or -Co-3alkyl-NH-phenyl,(10) -Co-3alkyl-phenyl, wherein the phenyl is unsubstituted or substituted with 1-3 halo substituents,(11) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1 -3 ring heteroatoms independently selected fromN, O, and S,(12) -NH-C3-6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1- 3 substituents independently selected from =0 and -NH-cyclopropyl,(13) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected fromN, O, and S, and is unsubstituted or substituted with 1-3 substituents independently selected from -C(0)0C1-6alkyl, -C1-6alkyl. -NH2, and -Ci- 6alkyl-C3-6cycloalkyL(14) -C3-6Cycloalkyl, unsubstituted or substituted with one -C(O)OC1-6alkyl substituent,(15) =0,(16) hydrogen,(17) -Ci-3haloalkyl,(18) -C=C,(19) -NHC(O)-C3-6Cycloalkyl, unsubstituted or substituted with -C(O)NH-C5-6aryl, wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from -C1-6alkyl, -OH, and halo, or(20) -NHS(=O)2NH(-Ci-3alkyl) or -NHS(=O)2NH(-C3-6Cycloalkyl).In a subclass of Embodiment 4, R1is(1) C1-6alkyl,(2) halo,(3) -Ci-3alkyl-(0)NH-(Co-3alkyl-cyclobutanyl), wherein the cyclobutanyl is unsubstituted or substituted with 1-3 fluoro substituents; -Ci-3alkyl-(0)NH-(Co-3alkyl- bicyclofl. 1. l]pentanyl); -Ci-3alkyl-(0)NH-(Co-3alkyl- cyclopropanyl); -Ci-3alkyl-(0)NH-(Co- salkyl phenyl), wherein the phenyl is unsubstituted or substituted with 1-3 substituents independently selected from methyl and -F; -Ci-3alkyl-(0)NH-(Co-3alkyl thiazolyl) wherein the thiazolyl is unsubstituted or substituted with one methyl substituent; or -Ci-3alkyl-(0)NH-(Co- salkyl cyclopentenyl),(4) -NHC(O)NH-C3-6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from -OCH3 and halo; -NHC(O)NH-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one -C1-6alkyl substituent; -NHC(O)NH-Ci-3alkyl; or -NHC(0)NH-Co-3alkyl-aryl, wherein the alkyl-aryl is unsubstituted or substituted with 1-3 halo substituents,(5) -NHC(O)-aryl, wherein the aryl is substituted with one -OH substituent; - NHC(O)-heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1-3 -C1-6alkylsubstituents; -NHC(0)C1-6alkyL wherein the alkyl is unsubstituted or substituted with one cycloalkyl substituent; -NHC(O)O-C1-6alkyl; -NHC(O)-C1-6alkyl; or -NHC(O)CH2S-C1-6alkyl,(6) -Co-3alkyl-OH, -Co-3alkyl-0-C1-6alkyl, or -Co-3alkyl-0-aiyl-0-C1-6alky,(7) -Co-3alkyl-C(0)0-Ci-3alkyl, wherein the -Co-3alkyl is unsubstituted or substituted with one -NH2 substituent.(8) -Co-3alkyl-cyano,(9) -Co-3alkyl-NH2; or -C0-6alkyl-NH-phenyl,(10) -C0-6alkyl-phenyl. wherein the phenyl is unsubstituted or substituted with1-3 halo substituents.(1 1) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S,(12) -NH-C3-6Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from =O and -NH-cyclopropyl,(13) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1-3 substituents independently selected from -C(O)OC1-6alkyl, -C1-6alkyl, -NH2, and -C1-6alkyl-Cs-ecycloalkyl,(14) -C3-6cycloalkyl. unsubstituted or substituted with one -C(O)OC1-6alkyl substituent,(15) =0,(16) hydrogen,(17) -C1-6haloalkyl,(18) -C=C. or(19) -NHS(=O)2NH(-Ci-3alkyl) or -NHS(=O)2NH(-C3-6Cycloalkyl).

[0009] In Embodiment 5 of this disclosure are compounds of Formula I, or Embodiments 1 to4, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is(1) -Ci-3alkyl,(2) -F or -Cl,(3) -C(0)NH-(Co-ialkyl-cyclobutanyl), wherein the cyclobutanyl is unsubstituted or substituted with 1-2 substituents independently selected from -OCH3 and -F; -C(O)NH- (bicyclo[l. l. l]pentanyl); -C(0)NH-(Co-ialkyl-cyclopropanyl); -C(0)NH-(Co-ialkyl- phenyl), wherein the phenyl is unsubstituted or substituted with one substituent selected from methyl or -F; -C(O)NH-thiazolyl, wherein the thiazolyl is substituted with onemethyl substituent; -C(O)NH-(Ci-?alkyl); -CH2C(O)NHCH3; or -C(0)NH-(Co-ialkyl- cyclopentanyl),(4) -NHC(O)NH-cyclopropanyl, wherein the cyclopropanyl is unsubstituted or substituted with 1-2 -F substituents; -NHC(O)NH-isoxazolyl, wherein the isoxazolyl is substituted with one methyl substituent; -N(CH3)(O)NH-cyclopropyl; or -NHC(O)NH- phenyl, wherein the phenyl is unsubstituted or substituted with one -F substituent,(5) -NHC(O)-phenyl, wherein the phenyl is substituted with one -OH substituent; - NHC(O)-thiophenyl, wherein the thiophenyl is unsubstituted or substituted with one methyl substituent; -NHC(O)OCH(CH3)2; -NHC(O)CH2CH2CH3; -NHC(O)CH3; - NHC(O)CH2SCH3, -NHC(O)OCH3, -NHC(O)CH2-cycloproanyl; or -NHC(O)OCH2CH3,(6) -CH2CH2OH, -OCHs, or -O-phenyl-OCH3,(7) -CH2CH2C(O)OCH2CH3, -CH2CH(NH2)C(O)OCH3, -C(O)OCH3, or CH2CH2C(O)OCH3,(8) cyano or -CH2-cyano,(9) -NH2or -CH2NH-phenyl,(10) -Co-ialkyl-phenyl, substituted with 1-2 substituents independently selected from - Cl and -F; or -CH(CH3)-phenyl,(11) -CH2-pyrrolyl,(12) -NH-cyclobutenyl, wherein the cyclobutenyl is substituted with 3 substituents independently selected from =0 and -NH-cyclopropyl,(13) dihydrooxazolyl, substituted with one -C(O)OCH2CH3 substituent; oxadiazole substituted with one substituent selected from methyl or -CH2CH2-cyclopentyl; oxazole; isoxazolyl substituted with -C(O)OCH3; thiazolyl substituted with methyl; triazolyl substituted with -NH2; or -CH2-pyrrolyl,(14) cyclobutanyl substituted with one -C(O)OCHs substituent; or cyclopropanyl,(15) =0,(16) hydrogen,(17) -CF3, or -CHF2,(18) C=C,(19) -NHC(O)-cyclopropyl, substituted with -C(O)NH-phenyl, wherein the phenyl is substituted with -F. or(20) -NHS(=O)2NH-CH3or -NHS(=O)2NH-cyclopropyl.In a subclass of Embodiment 5, R1is(1) -Ci-3alkyl,(2) -F or -CL(3) -C(0)NH-(Co-ialkyl-cyclobutanyl), wherein the cyclobutanyl is unsubstituted or substituted with 1-2 substituents independently selected from -OCHs and -F; -C(O)NH- (bicyclo[l. l. l]pentanyl); -C(0)NH-(Co-ialkyl-cyclopropanyl); -C(0)NH-(Co-ialkyl-phenyl), wherein the phenyl is unsubstituted or substituted with one substituent selected from methyl or - F; -C(O)NH-thiazolyl, wherein the thiazolyl is substituted with one methyl substituent; - C(O)NH-(Ci-3alkyl); -CH2C(O)NHCH3; or -C(0)NH-(Co-ialkyl-cyclopentanyl),(4) -NHC(O)NH-cyclopropanyl, wherein the cyclopropanyl is unsubstituted or substituted with 1-2 -F substituents; -NHC(O)NH-isoxazolyl, wherein the isoxazolyl is substituted with one methyl substituent; -N(CH3)(O)NH-cyclopropyl; or -NHC(O)NH-phenyl, wherein the phenyl is unsubstituted or substituted with one -F substituent,(5) -NHC(O)-phenyl, wherein the phenyl is substituted with one -OH substituent; - NHC(O)-thiophenyl. wherein the thiophenyl is unsubstituted or substituted with one methyl substituent; -NHC(O)OCH(CH3)2; -NHC(O)CH2CH2CH ; -NHC(O)CH3; -NHC(O)CH2SCH3. - NHC(O)OCH3, -NHC(O)CH2-cycloproanyl; or -NHC(O)OCH2CH3,(6) -CH2CH2OH, -OCHs, or -O-phenyl-OCHs,(7) -CH2CH2C(O)OCH2CH3, -CH2CH(NH2)C(O)OCH3, -C(O)OCH3. or CH2CH2C(O)OCH3,(8) cyano or -CH2-cyano,(9) -NH2 or -CH NH-phenyl,(10) -Co-ialkyl-phenyl, substituted with 1-2 substituents independently selected from - Cl and -F; or -CH(CH3)-phenyl,(11) -CH2-pyrrolyl,(12) -NH-cyclobutenyl, wherein the cyclobutenyl is substituted with 3 substituents independently selected from =0 and -NH-cyclopropyl,(13) dihydrooxazolyl, substituted with one -C(O)OCH2CH3 substituent; oxadiazole substituted with one substituent selected from methyl or -CH2CH2-cyclopentyl; oxazole; isoxazolyl substituted with -C(O)OCH3; thiazolyl substituted with methyl; triazolyl substituted with -NH2; or -CH2-pyrrolyl,(14) cyclobutanyl substituted with one -C(O)OCH3 substituent; or cyclopropanyl,(15) =0.(16) hydrogen,(17) -CF3, or -CHF2,(18) C=C. or(19) -NHS(=O)2NH-CH3 or -NHS(=O)2NH-cyclopropyl.

[0010] In Embodiment 6 of this disclosure are compounds of Formula I, or Embodiments 1 to5, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -Ci-3alkyl, -H, -F, -

[0012] In Embodiment 7 of the disclosure are compounds of Formula I, or Embodiments 1 to 6, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is(1) 3-7 membered monocyclic heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S, in addition to the nitrogen to which R3and R4are attached, wherein the monocyclic heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from:(a) -Co ealkyl-OH,(b) -C i -ealky 1,(c) -C0-6alkyl-cyano,(d) -C0-6alkyl-0-Ci-3alkyl,(e) -NHC(O)Ci-3alkyl,(f) 3-7 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with one =0 substituent,(g) -Ci-3haloalkyl, and(h) halo,(2) -N(CH3)-C3-6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one -OH or -C1-6alkyl substituent,(3) -N(CH3)-(3-7 membered monocyclic heterocyclyl), wherein the heterocyclyl has one nitrogen and 0-3 additional ring heteroatoms independently selected from N, O. and S, and is unsubstituted or substituted with one -Ci-3alkyl substituent,(4) 5-8 membered bridged bicyclic heterocyclyl having one nitrogen ring atom and 0- 3 additional ring heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from -C(O)CH3. -Ci-3alkyl, and -C1-6alkyl-OH.(5) 7-10 membered fused bicyclic heterocyclyl having one nitrogen ring atom and 0-3 additional ring heteroatoms independently selected from N, O, and S, or(6) 7-10 membered spiro bicyclic heterocyclyl having one nitrogen ring atom and 0-3 additional ring heteroatoms independently selected from N, O. and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from -H, =0, -Ci-3alkyl, and -OH.

[0013] In a subclass of Embodiment 7, R2is(1) 3-7 membered monocyclic heterocyclyl having 0-3 ring heteroatoms independently selected from N, O. and S, in addition to the nitrogen to which R3and R4are attached, wherein the monocyclic heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from:(a) -C0-6alkyl-OH,(b) -C1-6alkyl,(c) -C0-6alkyl-cyano,(d) -C0-6alkyl-0-Ci-3alkyd,(e) -NHC(O)Ci-3alkyl,(1) 3-7 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with one =0 substituent,(g) -C1-6haloalkyl, and(h) halo,(2) -N(CH3)-C3-6Cycloalkyl, wherein the cycloalkyl is substituted with one -OH substituent,(3) -N(CH3)-(3-7 membered monocyclic heterocyclyl), wherein the heterocyclyl has one nitrogen and 0-3 additional ring heteroatoms independently selected from N, O. and S, and is unsubstituted or substituted with one -Ci-3alkyl substituent, or(4) 5-8 membered bridged bicyclic heterocyclyl having one nitrogen ring atom and 0- 3 additional ring heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from -Ci-3alkyl, and -Ci-3alkyl-OH.

[0014] In Embodiment 8 of the disclosure are compounds of Formula I, or Embodiments 1 to 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is(1) pyrrolidinyl, substituted with 1-2 substituents independently selected from: -OH; - CH2OCH3; -C1-6alkyl-OH; -Cwalkyl; or -NHC(O)CHs;(2) azetidinyl, substituted with 1-2 substituents independently selected from: methyl; cyano; -OCH3; -Co-ialkyl-OH; -NHC(O)CH3; cyclopropyl; -CF3; -CHF2; -F; piperidinyl, substituted with -CH2CH3; and pyrrolidinyl, substituted with one =0 substituent; and methyl.(3) -N(CH3)-cyclobutanyl substituted with one -OH substituent,(4) -N(CH3)-azetidinyl, substituted with one methyl substituent; or -N(CH3)- pyrrolidinyl. substituted with 1 methyl substituent.(5) azabicyclo[2. 1. l]hexanyl, unsubstituted or substituted with one substituent selected from methyl, -OH, -CH2OH and hydrogen; and diazabicyclo[2.2.1]heptanyl, substituted with 1 -C(O)CH3 substituent,(6) oxa-azabicyclo[3.2.0]heptanyl. or(7) diazaspiro[3.4]octanonyl, substituted withl-2 substituents independently selected from =0, methyl and -H; oxaazaspiro[3.4]octanyl, unsubstituted or substituted with -OH.

[0015] In a subclass of Embodiment 8, R2is(1) pyrrolidinyl, substituted with 1-2 substituents independently selected from: -OH; - CH2OCH3; -C1-6alkyl-OH; -Ci-4alkyl; or -NHC(O)CH3;(2) azetidinyl, substituted with 1-2 substituents independently selected from: methyl; cyano; -OCHs; -Co-ialkyl-OH; -NHC(O)CHs; cyclopropyl; -CF3; -CHF2; -F; and pyrrolidinyl, substituted with one =0 substituent; and methyl.(3) -N(CH3)-cyclobutanyl substituted with one -OH substituent.(4) -N(CH3)-azetidinyl, substituted with one methyl substituent; or -N(CHs)- pyrrolidinyl, substituted with 1 methyl substituent, or(5) azabicyclo[2. 1. l]hexanyl, unsubstituted or substituted with one substituent selected from methyl, -OH, -CH2OH and hydrogen.

[0016] In Embodiment 9 of the disclosure are compounds of Formula I, or Embodiments 1 to8, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -OCH3 or - OCH2CH3.

[0017] In Embodiment 10 of the disclosure are compounds of Formula I, or Embodiments 1 to9, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is

[0018] In a subclass of Embodiment 10, R2is

[0019] In Embodiment 11 of this disclosure are compounds of Formula I, or Embodiments 1 to 10, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is -O-, -NH-, -N- C1-6alkyl-, or -S-.

[0020] In Embodiment 12 of this disclosure are compounds of Formula I, or Embodiments 1 to 11, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is -O-, -NH-, or - N-C1-6alkyl-.

[0021] In Embodiment 13 of the disclosure, the compound of Formula I, or Embodiments 1 topharmaceutically acceptable salt of any of the foregoing.

[0022] In Embodiment 14 of this disclosure, the compound of Formula I, or Embodiments 1-13 is:7-({6-[(36')-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-7>]pyridazin- 4-yl}oxy)-tV,2-dimethylindolizine-3-carboxamide,7-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)-H,2-dimethylindolizine-3-carboxamide,7-({6-[(2R.3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2-£]pyridazin-4-yl}oxy)-A 2-dimethylindolizine-3-carboxamide,7-({6-[(2R,4S)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-3-carboxamide,7-({6-[(2R,31?)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- / )|pyndazin-4-yl}oxy)- 2-dimethylindolizine-3-carboxamide.7-({6-[(2R,3R)-3-methoxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-3-carboxamide,N -(c / \s-3-fluorocyclobutyl)-7-({6-[(2R.3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[1.2-6]pyridazin-4-yl}oxy)-2-methylindolizine-3-carboxamide,N-(3,3-difluorocyclobutj l)-7-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[l,2-Z>]pyridazin-4-yl}oxy)-2-methylindolizine-3-carboxamide,8-fluoro-7-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-A|pyndazin-4-yl}oxy)- / V.2-dirnethylindolizine-3-carboxamide.8-fluoro-7-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-3-carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-6] pyridazin-4-yl} oxy )- N.2-dimethylindolizine- 1 -carboxamide,6-({6-[(3 ’)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo [ 1.2-bp ]yridazin- 4-yl } oxy )-;V.2-dimelhylindolizine- 1 -carboxamide.6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-6] pyridazin-4-yl} oxy )- N,2-dimethylindolizine-l -carboxamide,6-[(6-{(36>3-[acetyl(methyl)amino]pyrrolidine-l-carbonyl}-5-methylpyrrolo[l,2- 6]pyridazin-4-yl)oxy] - , 2-dimethylindolizine- 1 -carboxamide,6- [(6- {(3R)-3-|acety l(methyl)amino] pyrrolidine- 1 -carbonyl} -5 -methylpyrrolo[ 1 ,2- 6]pyridazin-4-yl)oxy]- N.2-dimethylindolizine-l-carboxamide,6-({6-[(2R,45)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- 2-dimethylindolizine-l-carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-6 |pyridazm-4-yl }oxy)-A''.2-dimcthylindolizine- 1 -carboxamide.6-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-l-carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- 6|pyridazin-4-yl}oxy)-N-methyl-26 / -mdazole-3-carboxamide.6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo [ 1.2-bp ]yridazin- 4-yl} oxy )- / V-methyl- 1.2-benzolhiazole-3-carboxamide.6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N-methyl-l,2-benzothiazole-3-carboxamide,N-cyclobutyl-6-( {6-|(2R.4S)-4-hy droxy-2-methylpy rrolidine- 1 -carbonyl] -5- methylpyrrolo [ 1.2-b p ]y n dazin-4-y I } oxy )naphthalene- 1 -carboxamide,N-cyclobutyl-6-({6-[(2 .3^)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6 ] py ri dazin-4-y 1 } oxy )naphthalene- 1 -carboxamide,N-cyclopropyl-7-({6-[(2R,3S)-3-fluoro-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6] pyridazin-4-yl } oxy )-2.3 -dihy dro-4 / 7- 1 ,4-benzoxazine-4-carboxamide,N-[2-chloro-4-({6-[(3S)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[ 1,2- 6]pyridazin-4-yl}oxy)phenyl]- N-cyclopropylurea,N-[2-chloro-4-({6-[(3R)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- 6] py ridazin-4-y 1 } oxy)pheny 1] -N'-cy clopropylurea, (R)- N-[2-chloro-4-({6-[3-(2-hydroxypropan-2-yl)pyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl} oxy )phenyl|- / V-cy clopropylurea, ( )- N-[2-chloro-4-({6-[3-(2-hydroxypropan-2-yl)pyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-cyclopropylurea,N-(2-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[1.2-6]pyridazin-4- y 1] oxy } phenyl)- N-cy clopropylurea,N-[2-chloro-4-({6-[(3S)-3-methoxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy)pheny 1] - N-cy clopropylurea,N -[2-chloro-4-({6-f(3R)-3-methoxypyrrolidine-l-carbonyll-5-methylpyrrolo[1.2-£>]pyridazin-4-yl}oxy)phenyl]- N-cy clopropylurea,N-(2-chloro-4-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4- y 1] oxy } pheny l)- N-methy lurea,N-[2-chloro-4-({6-[(2R,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-methylurea,N-[4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-A>|pyndazin-4-yl}oxy)-2-methylphenyl |-,V-methylurca.N-cyclopropyl- N-[4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[1.2-d]pyridazin-4-yl}oxy)-2-(trifluoromethyl)phenyl]urea,N-cyclopropyl- N’-[3-fluoro-4-({6-[(31S’)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpy rrolo [ 1 ,2-b ] py ri dazin-4-y 1 } oxy)phenyl] urea,N -cyclopropyl- N-[3-fluoro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[ 1.2-b} pyridazin-4-yl } oxy )phenyl] urea.Ncyclopropyl- N'-|3-fluoro-4-( {6-|('2R.3R)-3-hydro.xy-2-methylazetidine-l -carbonyl|-5- methylpyrrolo [ 1 ,2-b ] py ri dazin-4-y 1 } oxy)phenyl] urea,N-cyclopropyl- N-[2-fluoro-4-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2 -b] pyridazin-4-yl } oxy )pheny 1] urea.N-cyclopropyl- N-[2-fluoro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b} pyridazin-4-yl } oxy )phenyl] urea,N-cyclopropyl- N-[2-fluoro-4-({6-[(2i?,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b} pyridazin-4-yl } oxy)pheny 1] urea,N-cyclopropyl- N-[2-cyclopropyl-4-({6-f(2R,3A)-3-hydroxy-2-methylazetidine-l- carbonyl]-5-methylpyrrolo[l,2-Z?]pyridazin-4-yl}oxy)phenyl]urea,N-cyclopropyl- N-[3-fluoro-4-({6-[(2R,41S)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-&]pyridazin-4-yl}oxy)-2-methylphenyl]urea,N-cyclopropyl- N'-[3-fluoro-4-({6-[(2.R,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methyl pyrrolo| 1.2-A | pynda / jn-4-yl} oxy )-2-methylphenyl |urea.N-[2-fluoro-4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-(5-methyl-l,2-oxazol-3-yl)urea,N-ethyl-5-({6-[(2A,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- h | py ridazin-4-y 1 } oxy )- 1 H-indazol e- 1 -carboxamide, H-ethyl-4-fluoro-5-( {6-| (2R.3R)-3-hydroxy-2-methylazetidine- 1 -carbonyl |-5- methylpyrrolo| 1.2- / ;> |pyridazin-4-yl} oxy)- 1 H-indazole- 1 -carboxamide.2-[4-({6-[(2R,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- b\ py ridazin-4-y 1 } oxy)pheny 1] - N-methyl acetamide,2-[4-({6-[(2A,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl}oxy)phenyl]- N-(4-methyl-l,3-thiazol-2-yl)acetamide,2- [4-( {6-[(2R,3A)-3-hydroxy-2-methylazetidine-l -carbonyl]-5-methylpyrrolo[ 1 ,2-7>]pyridazin-4-yl}oxy)phenyl]- N-(5-methyl-l,2-oxazol-3-yl)acetamide, (1S)- N-ethyl-7-((6-(3-hydroxy-3-methylpyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2- &]pyridazin-4-yl)oxy)-2-methylindolizine-3-carboxamide, 7-((6-(3-hydroxy-2,2-dimethylazetidine-l-carbonyl)-5-methylpyrrolo[l,2-d]pyridazin-4- yl)oxy)- N,2-dimethylindolizine-3-carboxamide.7-((6-((2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl)oxy)- N,2,8-trimethylindolizine-3-carboxamide, (R)- N-ethyl-2-methyl-7-((5-methyl-6-(3-( N-methylacetamido)pyrrolidine-l- carbonyl)pyrrolo [ 1.2-bp ]yridazin-4-yl)oxy)indolizine-3-carboxamide,,N,5-dimethyl-4-((2-methyl-3-(methylcarbamoyl)indolizin-7-yl)oxy)- N-(l-methylazetidin-3-yl)pyrrolo[l,2-Z>]pyridazine-6-carboxamide, ,V-( / ra / 7s-3-hydroxycyclobutyl)-H.5-dimethyl-4- ||2-methyl-3- (methylcarbamoyl)indolizin-7-yl]oxy}pyrrolo[l,2-d]pyridazine-6-carboxamide,N-(cz5-3-hydroxycyclobutyl)- N,5-dimethyl-4-{[2-methyl-3-(methylcarbamoyl)indolizin- 7-yl]oxy}pyrrolo[l,2-£]pyridazine-6-carboxamide,N ,5-dimethyl-4-{[2-methyl-3-(methylcarbamoyl)indolizin-7-yl]oxy}-N-[(3R)-l- methylpyrrolidin-3-yl |pyrrolo| l.2- / ?|pyndazine-6-carboxamide. / V.5-dimethyl-4- {[2-methyl-3-(methylcarbamoyl)indolizin-7-yl]oxy } -N-| (3.S-)- 1 - methylpyrrolidin-3-yl]pyrrolo[l,2-£]pyridazine-6-carboxamide, 7-({6-[3-(acetylamino)azetidine-l-carbonyl]-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-N,2-dimethylindolizine-3-carboxamide, 7-{[6-(3-hydroxyazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl]oxy}- N,2- dimethylindolizine-3-carboxamide, 7-{[6-(3-hydroxy-3-methylazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl] oxy }-H.2-dimethy I indoli zine-3 -carboxamide,7-({6-[3-hydroxy-3-(hydroxymethyl)azetidine-l-carbonyl]-5-methylpyrrolo[1.2- &]pyridazin-4-yl}oxy)-lV,2-dimethylindolizine-3-carboxamide, H.2-di methyl -7-( { 5-methyl-6-[3 -(2-oxopyrrolidin- 1 -y l)azetidine- 1 -carbony 1] py rrolo [ 1,2- d]pyridazin-4-yl}oxy)indolizine-3-carboxamide,7-({6-[ (2R.3S’)-3-hydroxy-2-(trifluoromethyl)azetidine- l-carbonyl]-5-methylpyrrolo[ 1.2- £>]pyridazin-4-yl}oxy)-. / V,2-dimethylindolizine-3-carboxamide,7- [(6- {(3R)-3-[acety l(methyl)amino] pyrrolidine- 1 -carbonyl} -5 -methylpyrrolo[ 1 ,2- &]pyridazin-4-yl)oxy]-lV.2-dimethylindolizine-3-carboxamide,7- { [6-(4-hydroxy-2-azabicyclo[2. 1.1 ]hexane-2-carbonyl)-5-methylpyrrolo[l .2- / )|pyridazin-4-yl |oxy}- 2-dimethylindolizine-3-carboxamide. lV,2-dimethyl-7-{[5-methyl-6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl)pyrrolo[l,2- A | py ri dazin-4-y 11 oxyj indoli zine-3 -carboxamide.N ,2-dimethyl-7-({5-methyl-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carbonyl]pyrrolo[ 1 ,2-7>]pyridazin-4-yl } oxy)indolizine-3-carboxamide,N,2-dimethyl-7-({5-methyl-6-[(llS',4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carbonyl]pyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)indolizine-3-carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2- 6]pyridazin-4-yl}oxy)-AU-dimethyl-lH-indazole-3-carboxamide,6-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)-AU-dimethyl-1H-indazole-3-carboxamide,6-({6-[(2R,4S)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-Z)]pyridazin-4-yl}oxy)- N,2-dimethyl-2H-indazole-3-carboxamide,6-({6-[(3 ’)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-7>]pyridazin-4-yl}oxy)-;V.2-dimelhyl-2H-mdazole-3-carboxamide.6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyridazin-4-yl}oxy)- N,2-dimethyl-2H-indazole-3-carboxamide,6- { [6-(3-methoxyazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-&]pyridazin-4-yl}oxy}- N- methylnaphthalene- 1 -carboxamide,6-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl]oxy}- N- methylnaphthalene- 1 -carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2- i>]pyridazin-4-yl}oxy)- N-methylnaphthalene-l-carboxamide,6-({6-[(2S',35)-3-hydroxy-2-methylazeti dine- 1 -carbonyl] -5-methylpyrrolo[ 1,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(26'.3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- A|pyridazm-4-yl }oxy)-A''-methy Inaphthalene- 1 -carboxamide.6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b\ py ridazin-4-y 1 } oxy )-H-methy Inaphthalene- 1 -carboxamide,6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-Z>]pyridazin- 4-yl } oxy)- / V-methylnaphthalene- 1 -carboxamide.6-({6-[(2R,45)-4-hydroxy-2-methylpyrrolidine- 1 -carbonyl] -5-methylpyrrolo[ 1.2- A |pyndazin-4-yl}oxy)-H-methylnaphth al ene- 1 -carboxamide.6-({6-[(2R,4R)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )-A,'-mcthy Inaphthalene- 1 -carboxamide,6-({6-[(25',41?)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b\ py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(2S',45)-4-hydroxy-2-methylpyrrolidine- 1 -carbonyl] -5-methylpyrrolo[ 1 ,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(2R,35)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- / V-methy Inaphthalene- 1 -carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- A'-methy Inaphthalene- 1 -carboxamide,6-( {6-[(2S,35)-3-hydroxy-2-methylpyrrolidine- 1 -carbonyl] -5-methylpyrrolo[ 1 ,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(26'.3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[1.2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(2S)-2-(methoxymethyl)pyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-A]pyridazin- 4-yl}oxy)-jV-methylnaphthalene-l-carboxamide,N-cyclobutyl-6-({6-[(2A.3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| l .2-h|pyndazin-4-yl}oxy)naphthalene- l -carboxamide,N-cyclobutyl-6-({6-[(2S',3iS -3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b ] py ri dazin-4-y 1 } oxy)naphthalene- 1 -carboxamide,N-cyclobutyl-6-({6-[(25'.3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolol 1.2-A|pyndazin-4-yl } oxy )naphthalene- 1 -carboxamide.N-cyclobutyl-6-({6-[(2R,31S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 , 2-b ] py ri dazin-4-y 1 } oxy)naphthalene- 1 -carboxamide,5-fluoro-6- {[6-(3-methoxy azetidine- 1 -carbonyl)-5-methylpyrrolo[l .2-61 pyndazin-4- yl] oxy } - N-methy Inaphthalene- 1 -carboxamide,6-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}-5- fluoro- N-methy Inaphthalene- 1 -carboxamide,5-fluoro-6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyll-5-methylpyrrolo[1.2- b\ py ridazin-4-y 1 } oxy )-H-methy Inaphthalene- 1 -carboxamide,5-fluoro-6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,7-({6-[(2S,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- 6|pyndazin-4-yl}oxy)-N-methylnaphthalene-2-carboxamide.7-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy J-N'-mcthy lnaphthalene-2-carboxamide,7-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-61 py ridazin-4-y 1 } oxy )- N-methy Inaphthal ene-2-carboxamide.7-{[6-(3-hydroxyazetidine-l-carbonyl)-5-methylpyrrolo[l,2-b]pyridazin-4-yl]oxy}-. / V- methylnaphthal ene-2-carboxamide,7-{[6-(3-hydroxy-3-methylazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } - N-methylnaphthalene-2-carboxamide,6- { [6-(3-cyanoazetidine- 1 -carbonyl)-5-methylpyrrolo[l .2-61 pyridazm-4-yl |oxy } -N- cyclopropyl-5-fluoro-3,4-dihydroquinoline- 1 (2H)-carboxamide,N-cyclopropyl-5-fluoro-6-({6-[(3R’)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[1.2-6]pyridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-cyclopropyl-5-fluoro-6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,Ncyclopropyl-5-riiioro-6-( {6-|(2R.3R)-3-hydroxy-2-rnethylazetidine- 1 -carbonyl |-5- methylpyrrolo| 1.2-6 |pyridazin-4-yl}oxy)-3.4-dihydroquinoline-l(2H)-carboxamide. N-cyclopropyl-5-fluoro-6-({6-f(2S,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[ 1.2-6 |pyridazin-4-yl| oxy)-3,4-dihydroquinoline-l (2H)-carboxamide, N-cyclopropyl-5-fluoro-6-({6-[(2R,31S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,Ncyclopropyl-5-fluoro-6-({6-[(2S,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide, N-ethyl-5-fluoro-6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-ethyl-5-fluoro-6-( {6-|(26'.36')-3-hydroxy-2-methylazetidine-l -carbonyl |-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-ethyl-5-fluoro-6-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| l .2-6|pyridazin-4-yl [oxy)-3.4-dihydroquinoline- l (2 / 7)-carboxamide.N-ethyl-5-fluoro-6-({6-[(2S’,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[ 1.2-6 |pyridazin-4-yl | oxy)-3,4-dihydroquinoline-l (2H)-carboxamide,N-cyclopropyl-6-({6-[(2R,36’)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-cyclopropyl-6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinohne-l(2H)-carboxamide, cyclopropyl-7 - { [6-(3-methoxy azetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin- 4-yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,7-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}-H- cyclopropyl-2.3-dihydro-4 / 7- l .4-benzoxazine-4-carboxamide.N-cyclopropyl-7 -( { 6-[(2R,3S)-3-hy droxy-2-methylazetidine- 1 -carbonyl] -5- methylpyrrolo] l .2-6|pyndazin-4-yl] oxy)-2.3-dihydro-4 / 7- 1 .4-benzoxazine-4-carboxamide.N -cyclopropyl-7-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| l .2-6|pyndazin-4-yl }oxy)-2.3-dihydro-4 / 7- l .4-benzoxazine-4-carboxamide.N-cyclopropyl-7-({5-methyl-6-[2-(propan-2-yl)azetidine-l-carbonyl]pyrrolo[l,2- 6]pyridazin-4-yl}oxy)-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-cy clopropyl-7- { [6-(2-cy clopropylazetidine- 1 -carbony l)-5-methy Ipy rrolo[ 1 ,2- 6]pyridazin-4-yl]oxy}-2.3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N -cy clopropy 1-7 -( { 5-methy l-6-[(2S)-2-(trifluoromethyl)azetidine- 1 -carbonyl] py rrolo[ 1,2- 6]pyridazin-4-yl}oxy)-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N -cyclopropyl-7-({6-[(2S)-2-(difluoromethyl)azetidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyri dazin-4-yl}oxy)-2.3 -dihydro-4H-1, 4-benzoxazine-4-carboxamide,N-cyclopropyl-7-({6-f(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[ 1.2-6 |pyndazin-4-yl} oxy )-2.3-dihydro-4H- 1 ,4-benzoxazine-4-carboxamide,A-cyclopropyl-7-( {6-| (3, S')-3-hy droxy-3-methylpyrrolidine- 1 -carbonyl |-5- methylpyrrolo| 1.2-6 |pyndazin-4-yl} oxy)-2.3-dihy dro-4 / / - 1.4-benzoxazine-4-carboxamide.7-{[6-(2-azabicyclo[2.1.1]hexane-2-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl] oxy } - N-cy clopropyl-2,3-dihy dro-4H- 1 ,4-benzoxazine-4-carboxamide,N-cyclopropyl-7-{[6-(4-hydroxy-2-azabicyclo[2.1.1]hexane-2-carbonyl)-5- methylpyrrolo [ 1 ,2-6]pyridazin-4-yl] oxy } -2,3 -dihydro-4H- 1 ,4-benzoxazine-4-carboxamide,N-cyclopropyl-7-{[5-methyl-6-(l-methyl-2-azabicyclo[2.1.1]hexane-2- carbonyl)pyrrolo[l,2- / i]pyridazin-4-yl]oxy}-2,3-dihydro-47f-l,4-benzoxazine-4-carboxamide,N -cyclopropyl-7-({6-[l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carbonyl]-5- methylpyrrolo [ 1 ,2-b] pyridazin-4-yl } oxy )-2.3 -dihydro-47 / - 1 ,4-benzoxazine-4-carboxamide,N-cyclobutyl-7-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo[1.2-6]pyridazin-4- yl]oxy}-2,3-dihydro-4H-l?4-benzoxazine-4-carboxamide,7-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl]oxy}- N- cyclobutyl-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N -cyclobutyl-7-({6-[(3A)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo| l.2- / >|pyndazin-4-yl}oxy)-2.3-dihydro-4H-l .4-benzoxazine-4-carboxarriide. / V-cyclobutyl-7-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-7> | pyridazin-4-yl } oxy )-2.3 -dihy dro-47 / - 1 ,4-benzoxazine-4-carboxamide,N -cyclobutyl-7-({6-[(25',3S’)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| 1.2-7 |pyndazin-4-yl} oxy )-2.3-dihy dro-47 / - 1.4-benzoxazine-4-carboxamide.N-cyclobutyl-7-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- melhylpyrrolo| 1.2-7 |pyndazin-4-yl joxy)-2.3-dihy dro-4H- 1 .4-benzoxazine-4-carboxamide.N -ethyl-7-({6-[(2A,35)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-7]pyridazin-4-yl}oxy)-2.3-dihydro-47f-l,4-benzoxazine-4-carboxamide,N-ethyl-7-({6-[(2S,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-7]pyridazin-4-yl}oxy)-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,(4-{[3-(2.6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo[l,2-7]pyridazin-6- yl)(3-hydroxy-3-methylazetidin-l-yl)methanone,(4-{[3-(2.6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo[l,2- / >]pyridazin-6- yl)(3 -methoxy azetidin- 1 -yl)methanone, l-(4-{[3-(2,6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carbonyl)azetidine-3-carbonitrile,(4-{[3-(2?6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolofl,2- / >]pyridazin-6- yl)[(3A)-3-hydroxy-3-methylpyrrolidin- 1 -yl]methanone,(4-{[3-(2.6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo[l,2-Z>]pyridazin-6- yl)[(35)-3-hydroxy-3-methylpyrrolidin-l-yl]methanone,N -[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[l,2- / >]pyridazin-4-yl}oxy)phenyl]- N-((R or S)-2,2-difluorocyclopropyl)urea,N-[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-((<S' or R)-2,2-difluorocyclopropyl)urea,N-cyclopropyl- N-[4-({6-[(2^.3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-b p ]y n da / in-4-y I } oxy )phenyl] - Mmethy I urea.N-cyclopropyl- N-[4-({6-[(2R,3S)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b\ pyridazin-4-yl } oxy)pheny 1] - / V-methy I urea.N-cy cl op ropy 1- N- [ 4-( { 6- [ (2R,4R)-4-hydroxy-2-methy Ipyrrolidine- 1 -carbonyl] -5- methylpyrrolo [ 1.2-b ] pyridazin-4-y 1 } oxy )phenyl] -.V-methy 1 urea.N-cyclopropyl- N-[4-({6-[(2R,4S)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6] pyridazin-4-yl } oxy)phenyl] - V-methy I urea.N-cyclopropyl- N-[4-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-methylurea,N-cyclopropyl- N-[4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6] pyridazin-4-yl } oxy)phenyl] -V-methy I urea.N -cyclopropyl- N-[4-({6-[(2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[1.2-6]pyridazin-4-yl}oxy)-2-methylphenyl]urea.N-cy clopropy I - / V - [4-( { 6- | (2R.36')-3-hy droxy-2-methy Ipyrrolidine- 1 -carbonyl] -5 - methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-2-methylphenyl]urea,N -cyclopropyl- N-[4-({6-[(2R,4R)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[1.2-6]pyridazin-4-yl}oxy)-2-methylphenyl]urea.N-cy clopropy I - N- [4-( { 6- [(2R,4S)-4-hy droxy-2-methy Ipyrrolidine- 1 -carbonyl] -5 - methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy)-2-methylphenyl]urea,N-cyclopropyl- N-[4-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[1.2-6]pyridazin-4-yl}oxy)-2-methylphenyl]urea.N -cyclopropyl- N-[4-({6-[(27<3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-2-methylphenyl]urea,N-[2-chloro-4-({6-[(2i?,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6] pyridazin-4-yl } oxy)pheny 1] -N-cy clopropylurea,N-[2-chloro-4-({6-[(2R,3S)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[ 1 ,2-6]pyridazin-4-yl] oxy )phenyl]- N’-cy clopropylurea,N-[2-chloro-4-({6-[(2i?,4R)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]-jV-cyclopropylurea,N-[2-chloro-4-({6-[(2R,4S)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl} oxy )phenyl|- / V-cy clopropylurea,N-(2-chloro-4-{[6-(3-methoxy azetidine- l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl] oxy } phenyl)- N-cy clopropy lurea,N-[2-chloro-4-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]-A"-cyclopropylurea,M|2-chloro-4-( {(S-l (2R.3R)-3-hydroxy-2-rnetliylazetidine- 1 -carbonyl |-5- methylpyrrolo [ 1.2-7> | py ri dazi n-4-y I } oxy)pheny 1] - N-cy clopropylurea,N-(2-chloro-4-{[6-(4-hydroxy-2-azabicyclo[2.1.1]hexane-2-carbonyl)-5- methylpyrrolo| l.2-6|pyndazin-4-yl|oxy}phenyl)- N’-cyclopropylurea.N-cyclopropyl- N-(2-cyclopropyl-4-{[6-(4-hydroxy-2-azabicyclo[2.1.1]hexane-2- carbonyl)-5-methylpyrrolo| 1.2- / ?|pyridazin-4-yl |o.xy} phenyl )urea.N-cyclopropyl- N-[2-cyclopropyl-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l- carbonyl]-5-methylpyrrolo[l,2-Z?]pyndazin-4-yl}oxy)phenyl]urea,N-cyclopropyl-An-[4-{[6-(4-hydroxy-2-azabicyclo[2.1.1]hexane-2-carbonyl)-5- methylpyrrolo [ 1 , 2-b ] py ri dazin-4-y 1 ] oxy } -2-(trifluoromethy l)pheny 1] urea,N-cyclopropyl-A'"-|4-( |6-|(3R)-3-hy droxy-3-methy Ipy rrolidine- 1 -carbonyl |-5- methylpyrrolo[1.2-d]pyridazin-4-yl}oxy)-2-(trifluoromethyl)phenyl]urea,N -cyclopropyl- N-[2-(difluoromethyl)-4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l- carbonyl] -5-methylpyrrolo [ 1 ,2-b ] pyri dazi n-4-y 1 } oxy )phenyl] urea,N -(4-fluorophenyl)- N-(4-((6-((2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl)-5- methylpyrrolo| l.2-A|pyndazin-4-yl)oxy)phenyl)cyclopropane- 1,1 -dicarboxamide, 7-((6-((1R,4R)-5-acetyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-5-methylpyrrolo[l,2- 6]pyridazin-4-yl)oxy)- N,2-dimethylindolizine-3-carboxamide,(R)-7-((6-(3-acetamidopyrrolidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl)oxy)- N,2-dimethylindolizine-3-carboxamide.7-((6-(3-hydroxy-3-(hydroxymethyl)pyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2- Z>]pyridazin-4-yl)oxy)- N,2-dimethylindolizine-3-carboxamide,7-((6-(2-oxa-6-azabicyclo[3.2.0]heptane-6-carbonyl)-5-methylpyrrolo[l,2-b]pyridazin-4- yl)oxy)- N,2-dimethylindolizine-3-carboxamide,7-((6-((2S’,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl)-5-methylpyrrolo[ 1,2- £]pyridazin-4-yl)oxy)- N,2-dimethylindolizine-3-carboxamide,N,2-dimethyl-7-((5-methyl-6-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)pyrrolo[l,2- &]pyridazin-4-yl)oxy)indolizine-3-carboxamide,(R)-N-(l-acetylpyrrolidin-3-yl)- N,5-dimethyl-4-((2-methyl-3-(methylcarbamoyl)indolizin-7-yl)oxy)pyrrolo[l,2-i>]pyridazine-6-carboxamide,N-(l-ethylpiperidin-4-yl)- N,5-dimethyl-4-((2-methyl-3-(methylcarbamoyl)indolizin-7- yl)oxy)pyrrolo [ 1.2-bp ]yridazine-6-carboxamide,N,2-dimethyl-7-((5-methyl-6-(6-oxa-l-azaspiro[3.4]octane-l-carbonyl)pyrrolo[1.2- &]pyridazin-4-yl)oxy)indolizine-3-carboxamide, 7-((6-(7-hydroxy-2-oxa-5-azaspiro[3.4]octane-5-carbonyl)-5-methylpyrrolo[l,2- d]pyridazin-4-yl)oxy)-Ar.2-dimethylindolizine-3-carboxamide, l-(3-((6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-ft]pyridazin-4- yl)oxy)phenyl)-3-(4-fluorophenyl)urea, ethyl 2-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-b]pyridazin-4- yl]oxy}phenyl)-l,3-oxazole-4-carboxylate, l-{4-[(3-fluoroquinolin-6-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{4-[(l-benzofuran-7-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carbonyl}azetidine-3- carbonitrile,N-(4- { [6-(3-cy anoazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-Z>]pyridazin-4- yl] oxy } pheny l)benzamide. l-{4-[(l -chloronaphthal en-2-yl)oxy]-5-methylpyrrolo[l,2-Z?]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{5-methyl-4-[(quinolin-3-yl)oxy]pyrrolo[l,2- >]pyridazine-6-carbonyl} azetidine-3- carbonitrile, l-[4-(3-chloro-2-fluorophenoxy)-5-methylpyrrolo[l,2-Z?]pyridazine-6-carbonyl]azetidine- 3-carbonitrile, l-{5-methyl-4-[(2-methyl-l,3-benzothiazol-5-yl)oxy]pyrrolo[l,2-Z>]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{5-methyl-4-[(2-methylquinolin-6-yl)oxy]pyrrolo[l,2-7>]pyridazine-6- carbonyl } azetidine-3 -carbonitrile,N-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } pheny l)butanamide, l-{4-[(8-aminonaphthalen-2-yl)oxy]-5-methylpyrrolo[l,2-7>]pyridazine-6- carbonyl } azetidine-3-carbonitrile, l-{4-[(1H-indazol-5-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carbonyl} azetidine-3- carbonitrile,1 - {4- [( 1 -fluoronaphthal en-2-y l)oxy] -5-methy Ipy rrolo[ 1 ,2-6]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-[4-(3-chloro-4-methylphenoxy)-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl]azetidine-3-carbonitrile,1- { 5-methyl-4-[(naphthalen-2-yl)oxy]pyrrolo[ 1.2-d]pyridazine-6-carbonyl} azetidine-3- carbonitrile, ethyl 3-(2-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin- 4-yl] oxy } phenyl)propanoate,N-(3-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[ l,2-6]pyridazin-4- yl] oxy } pheny l)acetamide, l-|4-(4-ethylphenoxy)-5-methylpyrrolo| l.2- / )|pyndazine-6-carbonyl |azetidine-3- carbonitrile, l-{4-[3-fluoro-4-(2-hydroxyethyl)phenoxy]-5-methylpyrrolo[1.2-6]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{4-[(2,3-dihydro-l,4-benzodioxin-6-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile, methyl 3-(4- { [6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[ 1 ,2- >]pyridazin-4- yl] oxy } pheny l)propanoate, l-{4-[(3-chloroisoquinolin-7-yl)oxy]-5-methylpyrrolo[l,2- / )]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{5-methyl-4-[4-(5-methyl-l,2,4-oxadiazol-3-yl)phenoxy]pyrrolo[l,2-&]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-[4-(4-benzylphenoxy)-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carbonyl]azetidine-3- carbonitrile, l-{5-methyl-4-[4-(l,3-oxazol-4-yl)phenoxy]pyrrolo[l,2-d]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{5-methyl-4-[(quinohn-6-yl)oxy]pyrrolo[l,2-ft]pyridazine-6-carbonyl}azetidine-3- carbonitrile, l-{4-[(l,2-benzothiazol-5-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile, l-{4-|X5-cyanonaphthalen-2-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{5-methyl-4-[(3-methylquinolin-6-yl)oxy]pyrrolo[l,2-Z>]pyridazine-6- carbony 1 } azetidine-3-carbonitrile, methyl 3-(4- { [6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin-4- yl] oxy } pheny l)cy clobutane- 1 -carboxylate, methyl 5-(3- { [6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy]phenyl)-l,2-oxazole-3-carboxylate,l-{5-methyl-4-[(8-methylquinolin-4-yl)oxy]pyrrolo[l,2-h]pyridazine-6- carbonyl } azeti dine-3 -carbonitrile, l-{4-[2-fluoro-4-(2-methyl-l,3-thiazol-4-yl)phenoxy]-5-methylpyrrolo[l,2- >]pyridazine- 6-carbonyl}azetidine-3-carbonitrile,3- { [6-(3-cyanoazetidine- l-carbonyl)-5-methylpyrrolo[l,2-h]pyridazin-4-yl]oxy } - N-(4- methylphenyl)benzamide, propan-2-yl (3-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2- b ] py ridazin-4-yl] oxy } pheny l)carbamate, l-[5-methyl-4-(4-propylphenoxy)pyrrolo[l,2-h]pyridazine-6-carbonyl]azetidine-3- carbonitrile,N-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } pheny l)acetami de, l-{4-[(isoquinolin-3-yl)oxy]-5-methylpyrrolo[l,2-d]pyridazine-6-carbonyl}azetidine-3- carbonitrile, l-{5-methyl-4-[(l-oxo-l,2-dihydroisoquinolin-7-yl)oxy]pyrrolo[l,2-i]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[4-(5-amino-1H-l,2,4-triazol-3-yl)phenoxy]-5-methylpyrrolo[l,2-&]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[(4-fluoronaphthalen-2-yl)oxy]-5-methylpyrrolo[l,2-£]pyridazine-6- carbony 1 } azeti dine-3 -carbonitril e,3-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}- N- phenylbenzamide, l-{4-[(8-fluoroquinolin-3-yl)oxy]-5-methylpyrrolo[1.2-b]pyridazine-6- carbonyl } azeti dine-3 -carbonitrile, methyl <9-[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]-Z-tyrosinate, l-{5-methyl-4-[(3-methylnaphthalen-2-yl)oxy]pyrrolo[l,2-ft]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[(8-methoxyquinolin-3-yl)oxy]-5-methylpyrrolo[l,2-h]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-[4-(2-fluoro-3-methylphenoxy)-5-methylpyrrolo[l,2-b]pyridazine-6- carbonyl]azetidine-3-carbonitrile, ethyl (4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2- ]pyridazin-4- y 1] oxy } pheny l)carbamate,N-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[1.2-6]pyridazin-4- y 1] oxy } pheny l)thiophene-3-carboxamide,N-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } pheny l)-3 -methy lthiophene-2-carboxamide, l-{4-[4-(cyanomethyl)-2-methylphenoxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl } azetidine-3 -carbonitrile,N-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } pheny l)- N-phenylurea,N-(4- {[6-(3-cyanoazeti dine- l-carbonyl)-5-methylpyrrolo[ 1.2-6] pyridazin-4- yl]oxy}phenyl)-2-(methylsulfanyl)acetamide, l-(4- {4-[5-(2-cyclopentylethyl)- 1 ,2,4-oxadiazol-3-yl]phenoxy } -5-methylpyrrolo[l ,2-6]pyridazine-6-carbonyl)azetidine-3-carbonitrile, l-{5-methyl-4-[(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]pyrrolo[l,2-b]pyridazine-6-carbonyl} azetidine-3 -carbonitrile. l-{5-methyl-4-[(5-methylnaphthalen-l-yl)oxy]pyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile,3- { |6-(3-cyanoazetidine- 1 -carbonyl )-5-methylpyrrolo| 1.2-6 |pyndazin-4-yl |oxy }- '-(4- fluorophenyl)benzamide, l-[4-(2,3-difluoro-4-methylphenoxy)-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl]azetidine-3-carbonitrile, l-(5-methyl-4-{4-[(phenylamino)methyl]phenoxy}pyrrolo [ 1.2-bp ]yridazine-6- carbonyl)azetidine-3-carbonitrile, l-{5-methyl-4-[(6-methylnaphthalen-2-yl)oxy]pyrrolo[1.2-6]pyridazine-6- carbonyl } azetidine-3-carbonitrile, methyl 7 - { [6-(3-cy anoazetidine-1 -carbonyl)-5-methylpyrrolo[ 12-b ] pyridazin-4-yl ] oxy } -1 -benzofuran-4-carboxy late,1 - {5-methy l-4-[4-( 1 -pheny lethyl)phenoxy ]pyrrolo[ 1 ,2-6]pyridazine-6- carbonyl } azetidine-3-carbonitrile, l-{4-[(2,3-dihydro-16f-pyrrolo[2,3-b]pyridin-5-yl)oxy]-5-methylpyrrolo[l,2-6] pyridazine-6-carbonyl} azetidine-3 -carbonitrile, methyl (4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl] oxy } pheny l)carbamate, l-{4-[4-(5-amino-4H-l,2,4-triazol-3-yl)-2-chlorophenoxy]-5-methylpyrrolo[l,2-6] pyridazine-6-carbonyl} azetidine-3 -carbonitrile,l-{4-[(2-amino-l,3-benzothiazol-5-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{4-[(8-chloroquinolin-4-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile, l-(5-methyl-4-((2-methyl-1H-pyrrolo[2.3-6]pyridin-5-yl)oxy)pyrrolo [ 1.2-bp ]yridazine-6- carbonyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate,1-{5-methyl-4-[(3-methyl-1H-indazol-6-yl)oxy]pyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile,6-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}- N- methyl-2H-indazole-3-carboxamide,7- { [6-(3 -methoxy azeti dine- 1 -carbonyl)-5-methylpyrrolo[l ,2-6] pyridazin-4-yl] oxy } - N,2- dimethylindolizine-3-carboxamide,6-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}- N- methyl-27 / -indazole-3-carboxamide. methyl 5-( [6-| (3R)-3-hydroxy-3-methyl yrrolidine- 1 -carbonyl |-5-methylpyrrolo| 1 .2-6] pyridazin-4-yl } oxy )naphthalene- 1 -carboxylate,2-cyclopropyl- N-[3-fluoro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpy rrolo[l.2-6] pyridazin-4-yl} oxy )phenyl] acetamide.N -cyclobutyl-6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6]pyridazin-4-yl } oxy)naphthalene- 1 -carboxamide,N-(bicyclo[l.l.l]pentan-l-yl)-6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[1.2-6]pyridazin-4-yl]oxy)naphthalene-l -carboxamide,7-({6-[(3A)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N-methylnaphthalene-2-carboxamide,N-[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6] pyridazin-4-yl } oxy)pheny 1] -N'-cy clopropy lurea,6-( { 6- [ (2R.3R)-3-hydroxy-2-methylazetidine- 1 -carbonyl]-5-methylpyrrolo[ 1.2-6]pyridazin-4-yl}oxy)-A-(cz '-3-methoxycyclobutyl)naphthalene-l-carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-6] pyridazin-4-yl } oxy )-A^tra«.s-3 -methoxy cy cl obutyl)naphthal ene- 1 -carboxamide. l-(4-((6-methoxy- 1,2,3, 4-tetrahydronaphthalen-2-yl)oxy)-5-methylpyrrolo[ 1.2- 6]pyridazine-6-carbonyl)azetidine-3-carbonitrile,7-((6-((2R,3S)-3-hydroxy-2,3-dimethylazetidine-l-carbonyl)-5-methylpyrrolo[l,2-6]pyridazin-4-yl)oxy)- N,2-dimethylindolizine-3-carboxamide,7-((6-((2^.3^)-3-hydroxy-2.3-dimethylazetidine-l-carbonyl)-5-methylpyrrolo[1.2- &]pyridazin-4-yl)oxy)- N,2-dimethylindolizine-3-carboxamide, l-(5-methyl-4-((2-methyl-1H-pyrrolo[2,3-Z>]pyridin-5-yl)amino)pyrrolo [ 1.2-bp ]yridazine-6-carbonyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate, l-(4-{[3-fluoro-4-(3-methoxyphenoxy)phenyl]amino}-5-methylpyrrolo[l,2-d]pyridazine-6-carbonyl)azetidine-3-carbonitrile, l-{4-[(2,3-dimethyl-2 / 7-indazol-6-yl)amino]-5-methylpyrrolo[l,2-Z)]pyridazine-6- carbony 1 } azetidine-3-carbonitrile,N-[3-({[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]amino}methyl)phenyl]-A -cyclopropylurea, l-{4-[(l,2-benzothiazol-5-yl)amino]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3 -carbonitrile,1-(4-{[3-(2-chlorophenyl)-l,2,4-oxadiazol-5-yl]amino}-5-methylpyrrolo[1.2-6]pyridazine-6-carbonyl)azetidine-3-carbonitrile,2-(4- { [6-(3-cyanoazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin-4- y 1] amino } phenyl )-A'r-(4-methy I - 1 ,3 -thiazol-2-yl)acetamide, l- [4-|(5-hydroxynaphthalen-2-yl)amino|-5-methylpyrrolo| l.2- / ?|pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[(2,l,3-benzothiadiazol-5-yl)amino]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile, l-(4-{[5-(4-fluorophenyl)-l,2-oxazol-3-yl]amino}-5-methylpyrrolo[l,2-d]pyridazine-6- carbonyl)azetidine-3-carbonitrile, l-[5-methyl-4-({4-[(1H-pyrrol-l-yl)methyl]phenyl}amino)pyrrolo[1.2-6]pyridazine-6- carbonyl]azetidine-3-carbonitrile, l-{5-methyl-4-[(naphthalen-2-yl)amino]pyrrolo[l,2-&]pyridazine-6-carbonyl}azetidine-3- carbonitrile, l-{4-[(2,4-dichlorophenyl)amino]-5-methylpyrrolo[1.2-d]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo[l,2-Z>]pyridazine-6-carbonyl} azetidine-3-carbonitrile,1- {4-[(l -benzofuran-4-yl)amino]-5-methylpyrrolo[ l,2-6]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{4-[(3,4-dihydroxyphenyl)amino]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile,(3-methoxyazetidin-l-yl)(5-methyl-4-((3-methyl-2 / / -indazol-6-yl)amino)pyrrolo[l,2- &]pyridazin-6-yl)methanone,N -ethyl-7-((6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo[l,2-b]pyridazin-4- yl)oxy)-2,3-dihydro-4H-benzo[d][l,4]oxazine-4-carboxamide,7- { [6-(3-methoxyazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1.2- / ) | pvridazin-4-yl |oxy } -N- (propan-2-yl)-2,3-dihydro-4 / 7-l,4-benzoxazine-4-carboxamide,N -cyclopentyl-7-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin- 4-yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-(bicyclo[l.l.l]pentan-l-yl)-7-{[6-(3-methoxyazetidine-l-carbonyl)-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N -benzyl-7-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N -(2-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy}phenyl)- N-cyclopropylsulfuric diamide.N-[2-chloro-4-({6-[(3R)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-A | pyridazin-4-yl} oxy)phenyl]- N-methylsulfuric diamide,N -[2-chloro-4-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[1.2-b]pyridazin-4-yl}oxy)phenyl]-A"-methylsulfuric diamide,N-[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[l,2-Z)]pyridazin-4-yl}oxy)phenyl]-A"-methylsulfuric diamide,N-[2-chloro-4-({6-[(3R)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- / ) | pyndazin-4-yl} oxy)phenyl]- N-cyclopropylsulfuric diamide,N-[2-chloro-4-({6-[(3S’)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N'-cyclopropylsulfuric diamide,N-[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[l,2-&]pyridazin-4-yl}oxy)phenyl]- N-cyclopropylsulfuric diamide, (R)-3-((2-chloro-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5-methylpyrrolofl,2- i>]pyridazin-4-yl)oxy)phenyl)amino)-4-(cyclopropylamino)cyclobut-3-ene- 1,2-dione, fS^-l-(2-chloro-4-((6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4- yl)oxy)phenyl)-3-(2,2-difluorocyclopropyl)urea, (7^-l-(2-chloro-4-((6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z?]pyridazin-4- yl)oxy)phenyl)-3-(2,2-difluorocyclopropyl)urea,1 -(4-((6-hydroxy- 1 ,2,3,4-tetrahydronaphthalen-2-yl)oxy)-5-methylpyrrolo[ 1 ,2- &]pyridazine-6-carbonyl)azetidine-3-carbonitrile,l-(5-methyl-4-((2-methylbenzo[< ]thiazol-5-yl)amino)pyrrolo[l,2-i ]pyridazine-6- carbonyl)azetidine-3-carbonitrile, l-{4-[(l,3-dihydro-2-benzofuran-5-yl)amino]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile, l-{5-methyl-4-[(2-methyl-2H-indazol-6-yl)amino]pyrrolo[l,2-ft]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, ethyl (4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] amino } phenyl)acetate, l-{5-methyl-4-[(2-methyl-2H-indazol-5-yl)amino]pyrrolo[l,2- ’]pyridazine-6- carbonyl } azetidine-3-carbonitrileA-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] amino } pheny l)-2-hy droxybenzamide, l-{5-methyl-4-[(2-methyl-l,3-benzoxazol-6-yl)amino]pyrrolo[l,2-Z>]pyridazine-6- carbonyl}azetidine-3-carbonitrile. or(X)-l-(3-cyano-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2- &]pyridazin-4-yl)oxy)phenyl)-3-cyclopropylurea, or a pharmaceutically acceptable salt of any of the foregoing.References to any of Embodiments 1-14 refer to all classes.

[0023] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined therein.

[0024] In one embodiment, the present disclosure is a composition comprising an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0025] Also provided is a pharmaceutical composition comprising an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0026] Further provided is a pharmaceutical composition comprising an effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent).

[0027] In one embodiment, the present disclosure provides a method for treating cancer in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I. In a further embodiment, the cancer is associated with VEGFR upregulation.

[0028] In one embodiment, the present disclosure provides a method for inhibiting the progress of cancer in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I.

[0029] In one embodiment, the present disclosure provides a method of treating a disease or disorder in which VEGFR inhibition is beneficial, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I. In a further embodiment, the disease or disorder is a cellular proliferative disorder. In a further embodiment, the cellular proliferative disorder is cancer.

[0030] In one embodiment, the present disclosure provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula I, for treating cancer in a patient. In one embodiment, the present disclosure provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula I, for the preparation of a medicament useful for the prevention of a cell proliferative disorder.

[0031] In one embodiment, the present disclosure provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula I, for treating tumor angiogenesis and lymphangiogenesis.

[0032] The methods of the disclosure include the administration of a pharmaceutical composition comprising at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0033] "Alkyl" means branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms when noted. If no number is specified, 1-6 carbon atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups. Examples of alky l groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, buty l, sec- and tert-buty l, penty l, hexyl, octyl, nonyl, and the like. For example, the term ”C1-6alkyT‘ includes all ofCiC1.4alkyl’?defined as follows, plus the linear or branched chain alkyl groups, including all possible isomers, having 5 or 6 carbon atoms. “C1-6alkyl” means linear or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5 or 6 carbon atoms, and includes each of the alkyl groups within C1-6alkyl including each of the hexyl and pentyl isomers as well as n-, iso-, sec- and tertbutyl (butyl, i-butyl, s-butyl, t-butyl, collectively ‘'C4alkyl”; Bu = butyl), n- and i-propyl (propyl, i-propyl, collectively “Csalkyl”; Pr = propyl), ethyl (Et) and methyl (Me). Commonly used abbreviations for alkyl groups are used throughout the specification, e.g.. methyl may berepresented by conventional abbreviations including “Me7’ or CH3 or a symbol that is an extended bond as the terminal group, e.g.,, ethyl may be represented by “Et” or CH2CH3, propyl may be represented by “Pr” or CH2CH2CH3, butyl may be represented by “Bu” orCH2CH2CH2CH3, etc. For example, the structuresanhave equivalent meanings. C1-6 alkyl includes n-, iso. sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1-6 carbon atoms are intended for linear or branched alkyl groups.

[0034] “Cyclic amine’’ refers to a cy clic ring comprising one nitrogen atom.

[0035] “Alkoxy” refers to an alkyl group linked to oxygen. Examples of alkoxy groups include methoxy, ethoxy, propoxy and the like.

[0036] “Aryl” refers to a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 5-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl.

[0037] “Fused Aryl” refers to an aryl ring fused with heterocyclyl or cycloalkyl.

[0038] “Halogen” or “Halo” includes fluorine, chlorine, bromine and iodine.

[0039] “Cycloalkyl” refers to a saturated monocyclic, bicyclic or bridged carbocyclic ring, having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentanyl. The term “cycloalkyl” also includes a C3- 6cycloalkyl group fused to a benzene ring such as dihydro-indenyl, tetrahydronaphthalenyl,the like.

[0040] “Haloalkyl” refers to an alkyl group as defined within, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of haloalky l groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2CI and CCI3. The term “C1-6haloalkyl” or “haloC1-6alky Prefers to a haloalkyl group having from 1 to 6 carbons.

[0041] "Haloalkoxy,” “haloalkyl-O" and derivatives such as “halo(C1-6)alkoxy” are used interchangeably and refer to halo substituted alkyl groups linked through the oxygen atom. Haloalkoxy include mono- substituted as well as multiple halo substituted alkoxy groups. For example, trifluoromethoxy, chloromethoxy, and bromomethoxy are included as well as OCH2CF3, OCH2CHF2, OCF2CF3. and OCF2CHF2.

[0042] "Heteroaryl”, as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N, SO2, or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic. A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroary l can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring. Nonlimiting examples of heteroaryls include benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxahnyl, tetrazolyl, tetrazolopyridyl. thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroisobenzofuranyl, dihydroindolyl, dihydroquinolinyl, methylenedi oxybenzene, benzothiazolyl, benzothienyl, benzo[d] oxazolyl, quinolinyl, isoquinolinyl, oxazolyl, tetra-hydroquinoline, quinolinyl, pyrrolo[l,2-b]pyridazinyl, benzo[tZ]thiazolyl, benzo[d]isothiazolyl, pyrrolo[2,3-b]pyridinyl, dihydrobenzo[d]isothiazolyl, and benzo[c][l,2,5]thiadiazolyl. In another embodiment, heteroaryl is pyridine.

[0043] "Heterocyclyl," or "heterocyclic" refers to "Heterocyclyl" means a saturated or partly unsaturated non-aromatic monocyclic, bicyclic, spirocyclic or bridged ring or ring system having a specified number of carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O. The cycloheteroalkyl ring may be substituted on the ring carbons and / or the ring nitrogen or sulfur. Examples of cycloheteroalkyl include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, azetidinyl, piperazinyl. piperidinyl, morpholinyl. oxetanyl and tetrahydropyranyl. In one embodiment, cycloheteroalkyl is selected from: pyrrolidinyl, azetidinyl, piperazinyl, azepanyl, azocanyl, morpholinyl, thiomorpholinyl, thiomorpholine dionyl, oxazepanyl, 1,4-thiazepanyl, isoindolinyl, dihydroisoquinolinyl, tetra- hydroisoquinolinyl, octahydro-isoindolyl, azabicyclo[2.2. l]heptanyl, oxa-azabicyclo[2.2. 1] -yl, azabicyclo[3.1.1]heptanyl. azabicyclo[4.1.0]heptanyl. azabicyclo[3.2.1]octanyl, diazaspiro[3.4]octanyl, azaspiro [3.3] heptanyl, azabicyclo[2.1.1]hexanyl, hexahydrocyclopenta[c]pyrrolyl, azabicyclo[3. 1.0]hexanyl, oxa-azabicyclo[2.2. l]heptanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, oxa-azaspiro[3.4]octanyl, oxa-azaspiro[bicyclo[3.1.0]hexane-pyrrolidinyl], hexahydropyrano[3.2-c]pyridinyl. hexahydrofuro[3,2-b]pyridinyl, oxadiazaspiro[3.4]octanyl, azabicyclo[2.2. l]heptanyl, diazabicyclo[3.2.1]octanyl, oxa-azabicyclo-[3.2.1]octanyl, azabicyclo[3.2.0]heptanyl, oxa- azabicyclo[3.2.0]heptanyl, azaspiro[2.5]octanyl, azaspiro[2.6]nonanyl, azaspiro[3.5]nonanyl, oxa-azaspiro|3.5 |nonanvl. oxa-azaspiro|4.5 |decanyl. octahydro-indolyl, dihydrothieno[3,2- c]pyridinyl, dihydro-thiazolo[4,5-c]pyridinyl, dihydrooxazolo[4,5-c]pyridiyle, dihydroimidazo[l,2-a]pyrazinyl, hexahydrofuro[3,2-b]pyrrolyl, hexahydrocyclopenta[c]pyrrolyl, octahydrocyclpenta[c]pyrrolyl, dihydro-quinolinyl, dihydro-benzo[b][l,4]oxazinyl, dihydrobenzo[b][l,4]dioxinyl, dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinoxaline, dihydro- pyrrolo[2,3-b]pyridinyl, dihydrobenzo[Z?]thiophenyl, diazabicyclo[2.2. l]heptanyl, diazaspiro [3.4] octanonyl, oxaazaspiro[3.4]octanyl, and azatricyclo[4.3.1.13,8]undecanyl.

[0044] ‘‘Bicyclic heterocyclyl,” “bicyclic heterocycle” or “bicyclic heterocyclic” refers to a heterocyclic ring fused to another ring system. The fusion may be bridged or unbridged.

[0045] “Fused heteroaryl” is heteroaryl fused with an aryl or heteroaryl.

[0046] “Oxo” means an oxygen linked to an atom by a double bond. An example of an oxo group is a doubly bonded oxygen in a ketone, sulfoxide, sulfone and sulfate.

[0047] “Hydroxyalkyl” or “-hydroxy(Ci-3)alkyl” means an alkyl group having one or more hydrogen atoms replaced by hydroxyl (-OH) groups

[0048] “Cyanoalkyl” means an alkyl group having one or more hydrogen atoms replaced by cyano (-CN) groups.

[0049] “Hydroxyhaloalkyl” means an alkyl group having one or more hydrogen atoms replaced by hydroxyl (-OH) groups, and one or more hydrogen atoms replaced by a halogen.

[0050] “Hydroxycycloalkyl” means a cyclic alkyl group having one or more hydrogen atoms replaced by hydroxyl (-OH) groups.

[0051] The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0052] The term “at least one” means one or more than one. The meaning of “at least one” with reference to the number of compounds of the present disclosure is independent of the meaning with reference to the number of chemotherapeutic agents.

[0053] The term “chemotherapeutic agent” means a drug (medicament or pharmaceutically active ingredient) for treating cancer (i.e., an antineoplastic agent).

[0054] The term “effective amount” means a “therapeutically effective amount”. The term "therapeutically effective amount" means that amount of active compound or pharmaceuticalagent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0055] The term ‘‘treating cancer or “treatment of cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, and also refers to an effect that results in the inhibition of growth and / or metastasis of the cancer.

[0056] Except where noted herein, the term "carbocycle" (and variations thereof such as "carbocyclic" or "carbocyclyl") as used herein, unless otherwise indicated, refers to a C3 to Ce monocyclic ring, e.g., C3-6 monocyclic carbocycle. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. Saturated carbocyclic rings include, for example, "cycloalkyl" rings, e.g., cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings include, for example

[0057] Except where noted, the term “saturated heterocycle" refers to a stable 4- to 7- membered mono-cyclic heteroatom-containing ring system, and which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or tw o nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Representative examples include azetidine, oxetane, thietane. diazetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, oxane, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, trioxane, trithiane, azepane, oxepane, thi epane and homopiperazine. For example, a “saturated 6 membered heterocycle7’ is a stable 6- membered mono-cyclic heteroatom-containing ring system. An example of a saturated 6 membered heterocycle is piperidine. Likewise, but not limiting, a “saturated 4 membered heterocycle” is a stable 4- membered mono-cyclic heteroatom-containing ring system.

[0058] Except where noted herein, the term “unsaturated heterocycle" refers to a monocyclic unsaturated heterocycle having a specified number of ring atom members (e.g., 5 membered), including a specified number of heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms independently selected from N, O or S), e.g., 5-membered rings containing one nitrogen (pyrrole), one oxygen(furan) or one sulfur (thiophene) atom, 5-membered rings containing one nitrogen and one sulfur (thiazole) atom, 5 -membered rings containing one nitrogen and one oxygen (oxazole or isoxazole) atom, 5-membered rings containing two nitrogen (imidazole or pyrazole) atoms, fivemembered aromatic rings containing three nitrogen (triazole) atoms, five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom, five-membered aromatic rings containing two heteroatoms independently selected from oxygen, nitrogen and sulfur (e g., oxazole), Additional examples are thiophene, imidazole, isothiazole, oxadiazole, and isoxazole. For example, a “unsaturated 6 membered heterocycle'’ is a 6 membered ring containing 6 atom members including at least one heteroatom. Likewise, an “unsaturated 5 membered heterocycle” is a 5 membered ring containing 5 atom members including at least one heteroatom.

[0059] A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0060] The compounds of the present disclosure are limited to stable compounds embraced by Formula I and its embodiments. For example, certain moieties as defined in Formula I, may be unsubstituted or substituted, and the latter is intended to encompass substitution patterns (i.e., number and kind of substituents) that are chemically possible for the moiety and that result in a stable compound.

[0061] The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selected from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result. By optionally substituted, it is meant that compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional substituent(s).

[0062] The wavy line 'vvvx'usec| herein, indicates a point of attachment to the rest of the compound.

[0063] Where ring atoms are represented by variables such as “X' e.g.,the variables are defined by indicating the atom located at the variable ring position without depicting the ring bonds associated with the atom. For example, when X in the above ring is nitrogen, the definition will show “N” and will not depict the bonds associated with it, e.g., will not show “=N-“. Likewise, when X is a carbon atom that is substituted with bromide, the definition will show “C-Bf ’ and will not depict the bonds associated with it. e.g., will not show

[0064] The disclosure also includes derivatives of the compound of formula I, acting as prodrugs and solvates. Any pharmaceutically acceptable pro-drug modification of a compound of Formula I which results in conversion in vivo to a compound within the scope of the disclosure is also contemplated by the present disclosure. Prodrugs, following administration to the patient, are converted in the body by normal metabolic or chemical processes, such as through hydrolysis in the blood, to the compound of Formula I. Such prodrugs include those that demonstrate enhanced bioavailability, tissue specificity7, and / or cellular delivery, to improve drug absorption of the compound of Formula I. The effect of such prodrugs may result from modification of physicochemical properties such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine the permeation properties of the drug.

[0065] For example, esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound. Similarly, labile amides can be made. Pharmaceutically acceptable esters or amides of the compounds of the Formula I may be prepared to act as pro-drugs which can be hydrolyzed back to an acid (or - COO- depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of the disclosure. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Examples of pharmaceutically acceptable pro-drug modifications include, but are not limited to, -C1-6alkyl esters and C1-6alkyl substituted with phenyl esters.

[0066] “Celite®" (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite".

[0067] When any variable (e.g., R1etc.) occurs more than one time in any constituent or in Formulas I or other generic Formula herein, its definition on each occurrence is independent of its definition at every7other occurrence. Combinations of substituents and / or variables arepermissible only if such combinations result in stable compounds. In choosing compounds of Formula I, one of ordinary skill in the art will recognize that the various substituents, i.e., R1etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability'. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.

[0068] It should be noted that, if a discrepancy betw een the chemical name and structure exists, the structure is understood to dominate.

[0069] Compounds of structural Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereoisomeric mixtures and individual diastereoisomers. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have S configuration or R configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas provided herein, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formulas. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures w ere obtained, but this in no w ay limits the inclusion of all stereoisomers and mixtures thereof from being w ithin the scope of the present disclosure.

[0070] The compounds of this disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the present disclosure in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism, both the cis form and the trans form as well as mixtures of these forms in all ratios are included unless specified otherwise. The present disclosure is meant to comprehend all such stereo-isomeric forms of the compounds of structural Formula I.

[0071] Compounds of structural Formula I may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediatestep during the synthesis of a compound of Formula 1, or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary', with a reagent containing an asymmetric center of know n absolute configuration. Alternatively, any stereoisomer or isomers of a compound of Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. The present disclosure includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0072] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, follow ed by separation of the individual diastereoisomers bystandard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are w ell known in the art.

[0073] For compounds of Formula I described herein which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.

[0074] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.

[0075] In the compounds of structural Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. As described and claimed herein is meant to include all suitable isotopic variations of the compounds of structural Formula I and embodiments thereof are intended to be included. For example, different isotopic forms of hydrogen (H) include protium f'H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.Isotopically-ennched compounds within structural Formula 1. can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0076] It will be understood that the compounds of structural Formula I may be prepared as pharmaceutically acceptable salts or as salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations. The compounds of the present disclosure, including the compounds of the Examples, may also include all salts of the compounds of Formula I which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of phy siologically acceptable salts.[00H] The compounds of the present disclosure may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.

[0078] Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this disclosure which are generally prepared byreacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present disclosure include, but are not limited to, the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate. edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy naphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, napsylate, nitrate. N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, valerate and the like. Furthermore, where the compounds of the disclosure carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. In one embodiment,the salts of acidic compounds are as follows, the ammonium, calcium, magnesium, potassium, and sodium salts.

[0079] With basic reagents such as hydroxides, carbonates, hydrogencarbonates, alkoxides and ammonia, organic bases or alternatively basic amino acids the compounds of the formula I, form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts.

[0080] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ionexchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol. ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Also, included are the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyd sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

[0081] The preparation of pharmacologically acceptable salts from compounds of the formula I, capable of salt formation, including their stereoisomeric forms is carried out known methods, for example, by mixing a compound of Formula I with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present disclosure and salts thereof may form solvates with a solvent such as water, ethanol, or glycerol. The compounds of the present invention may form an acid addition salt and a salt with a base at the same time according to the ty pe of substituent of the side chain.

[0082] If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I by customary’ methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts.

[0083] The present disclosure includes compounds of structural Formula I, as well as salts thereof, particularly pharmaceutically acceptable salts, solvates of such compounds and solvated salt forms thereof, where such forms are possible unless specified otherwise.

[0084] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I, including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant discosure may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to EtOAc. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0085] Accordingly, the compounds within the generic structural formulas, embodiments and specific compounds described in the Examples and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise,

[0086] Further provided are medicaments containing at least one compound of the Formula I and / or of a pharmaceutically acceptable salt of the compound of the Formula I and / or an optionally stereoisomeric form of the compound of the Formulas I or a pharmaceutically acceptable salt of the stereoisomeric form of the compound of Formulas I, together with a pharmaceutically acceptable vehicle, carrier, additive and / or other active substances and auxiliaries.

[0087] The medicaments according to the present disclosure can be administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with compounds of the Formula I and other surfaces which come into contact with blood in the body is possible.

[0088] Also provided is a process for the production of a medicament, which comprises bringing at least one compound of the Formula I into a suitable administration form using a pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0089] The present disclosure also relates to processes for the preparation of the compounds of Formula I which are described in the following and by which the compounds of Formula I are obtainable.

[0090] The terms "therapeutically effective (or efficacious) amount" and similar descriptions such as "an amount efficacious for treatment" are intended to mean that amount of a pharmaceutical drug that will alleviate the symptoms of the disorder, condition or disease beingtreated (i.e., disorder, condition or disease associated with VEGFR activity) in an animal or human. The terms "prophylactically effective (or efficacious) amount" and similar descriptions such as "an amount efficacious for prevention" are intended to mean that amount of a pharmaceutical drug that will prevent or reduce the symptoms or occurrence of the disorder, condition or disease being treated (i.e., disorder, condition or disease associated with VEGFR activity) in an animal or human. The dosage regimen utilizing a compound of Formula I is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of cancer.

[0091] Disorders, conditions and diseases which can be treated or prevented by inhibiting VEGFR by using the compounds of Formulas I are, for example, cancer, and related diseases and conditions.

[0092] The compounds of Formula I and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical preparations. The term “patient” includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition. Administering of the drug to the patient includes both self-administration and administration to the patient by another person. The patient may need, or desire, treatment for an existing disease or medical condition, or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a patient "in need" of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0093] Furthermore, pharmaceutical preparations (or pharmaceutical compositions) which comprise as active component a therapeutically effective dose of at least one compound of Formula I and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0094] Thus, an aspect of this disclosure is, for example, said compound of Formula I and its pharmaceutically acceptable salts for use as a pharmaceutical, pharmaceutical preparations which comprise as active component a therapeutically effective dose of said compound and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of said compound and / or a pharmaceutically acceptable salt thereof in the therapy or prophylaxis of the above mentioned syndromes as well as their use for preparing medicaments for these purposes.

[0095] The pharmaceuticals according to the disclosure can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion. Other suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0096] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules it is possible to use, for example, lactose, starch, for example maize starch, or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example of solutions for injection, or of emulsions or syrups are, for example, water, physiologically sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of Formula I and their pharmaceutically acceptable salts and to use the resulting lyophilisates, for example, for preparing preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are. for example, copolymers of glycolic acid and lactic acid.

[0097] Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations having prolonged release of active substance, in whose preparation customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide,lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and plant oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.

[0098] Besides the active compounds and carriers, the pharmaceutical preparations can also contain customary additives, for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.

[0099] The dosage of the active compound of Formula I and / or of a pharmaceutically acceptable salt thereof to be administered depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, it depends on the nature and the severity of the disorder, condition or disease to be treated, and also on the sex, age, weight and individual responsiveness of the human or animal to be treated, on the efficacy and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to compounds of Formula I.Combination Agents

[0100] The compounds of Formula I and their pharmaceutically acceptable salts, hydrates, and solvates can be administered alone or in combination with one or more additional therapeutic agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of Formula I or a pharmaceutically acceptable salt, hydrate or ester thereof, will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is. a compound of Formula I and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of Formula I and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of Formula I can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of Formula I and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

[0101] Further contemplated is the treatment of the disease / conditions with a combination of pharmaceutically active compounds that may be administered separately, separate pharmaceutical compositions may be provided in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, parenteral; IV, transdermal and subcutaneous), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

[0102] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I. An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula I, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable additional active agent or agents, including but not limited to anti-hypertensive agents, anti-obetic, anti-inflammatory, anti-fibrotic, and anti-atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and / or anti-obesity agents may be used in any combination with the compound of Formula I in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents).

[0103] Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzy me inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat. fosinopril, imidapril. lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril). angiotensin II receptor antagonists (e.g., losartan i.e., COZAAR ®, valsartan, candesartan, olmesartan, telmesartan and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR ®); neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., urea derivatives of di- and tri-peptides, amino acids and derivatives, amino acid chains linked by non-peptidic bonds, di- and tn-peptide derivatives, peptidyl amino diols and peptidyl beta-aminoacyl aminodiol carbamates; also, and small molecule renin inhibitors including diol sulfonamides and, N-morpholino derivatives, N-heterocyclic alcohols and pyrolimidazolones; also, pepstatin derivatives and fluoro- and chloroderivatives of statone-containing peptides, enalkrein, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4- hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635), endothelin receptor antagonists. phosphodiesterase-5 inhibitors (e g., sildenafil, tadalfil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g.. hydrochlorothiazide), sympatholitics, beta- adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs (e.g., doxazosin, prazosin or alpha methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.g., hydralazine); lipid lowering agents e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEV ACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG- CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®). fluvastatin (particularly the sodium salt sold in LESCOL®), cerivastatin, and pitavastatin; a cholesterol absorption inhibitor such as ezetimibe (ZETIA®) and ezetimibe in combination with any other lipid lowering agents such as the HMG- CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms, and / or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; anti-cholesterol agents such as PCSK9 inhibitors (alirocumab, evolocumab), Nexletol™ (bempedoic acid, ACL inhibitor), and Vascepa® (Icosapent ethyl); metabolic altering agents including insulin and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g.. sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, including (i) [Lklotho / FGFRl activating monoclonal antibody (e.g., MK-3655), pan FGFR1-4 / KLB modulators, FGF19 analogue (e.g., Aldafermin) (ii) PPARy agonists, such as the glitazones (e.g., pioglitazone, AMG 131, CHS 131, MBX2044. mitoglitazone, lobeglitazone, IDR-105, rosiglitazone. and balaghtazone), and other PPAR ligands, including (1) PPARa / y dual agonists (e.g.ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARa agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate,bezafibrate), (3) selective PPARy modulators (SPPARyM’s). (e.g.. such as those disclosed in WO 02 / 060388, WO 02 / 08188, WO 2004 / 019869, WO 2004 / 020409, WO 2004 / 020408, and WO 2004 / 066963); (4) PPARy partial agonists, (5) PPAR a / 5 dual agonists (e.g., Elafibranor ); (iii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza™. Fortamet™, and GlucophageXR™; and (iv) protein tyrosine phosphatase- IB (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro and inhalable formulations of each); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide); a-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists (e.g., MK-35H, MK-0893, LY- 2409021 and KT6-971); incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide. semaglutide. albiglutide. exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-510H, including intranasal, transdermal, and once-weekly formulations thereof), bile acid sequestering agents (e.g., colestilan, colestimide. colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran), acyl CoA: cholesterol acyltransferase inhibitors, (e.g., avasimibe); antiobesity compounds; agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g., AZD6370); inhibitors of l ip-hydroxysteroid dehydrogenase type 1, (e.g., such as those disclosed in U.S. Patent No. 6.730,690, and LY-2523199); CETP inhibitors (e.g.. anacetrapib, torcetrapib. and evacetrapib); inhibitors of fructose 1,6-bisphosphatase, (e.g., such as those disclosed in U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated Protein Kinase (AMPK) activators; other agonists of the G-protein-coupled receptors: (i) GPR-109. (ii) GPR-119 (e.g.. MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., such as those disclosed in WO 2009 / 001836); neuromedin U receptor agonists (e.g., such as those disclosed in WO 2009 / 042053, including, but not limited to, neuromedin S (NMS)); SCD modulators (e.g., Aramchol); GPR-105 antagonists (e.g., such as those disclosed in WO 2009 / 000087); SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2 such as empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, BI-10H3, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-421 1); inhibitors of acyl coenzyme A carboxylase (ACC, MK-4074); inhibitors of diacylglycerolacyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid synthase; inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; IL-lb antibodies, (e.g., XOMA052 and canakinumab);, anti-fibrotic and / or anti-inflammatory agents (CCR2 / CCR5 dual receptor antagonist (e g., cenicriviroc); galectin 3 inhibitor (e.g., belapectin, GB-1107, GB-1211), siRNA against HSP 47 (e.g., BMS-986263); NSAID derived from pirfenidone (e.g., hydronidone), A3 AR agonist (e.g., namodenoson, FM101); TGFTX4 (e.g., nitazoxanide); 5-lipoxygenase inhibitor (e.g., tipelukast), Bifunctional urate inhibitor (e.g., ACQT1 127), adiponectin receptor agonist (e.g., ALY688), TNF receptor antagonist (e.g., atrosimab), Autotaxin inhibitor (e.g., BLD-0409, TJC 0265, TJC 0316), CCL24 blocking monoclonal antibody (e.g., CM101), IL-11 inhibitor (e.g., ENx 108A), LPA1 receptor antagonist (e g., EPGN 696), Dual JAK1 / 2 inhibitor (e.g.. EX 76545), GPR antagonist (e.g., GPR91 antagonist), Integrin avpi. avP3 and avP6 inhibitor (e.g., IDL 2965), NLRP3 antagonist (e.g., IFM-514), inflammasome inhibitors (e.g., JT194, JT349), Cell membrane permeability inhibitor (e.g., Larazotide), CCR5 antagonist (e.g., leronlimab), TNF inhibitor (e.g., LIVNate), integrin avP6 inhibitor (e.g., MORF beta6), NLRP inflammasome antagonists, siRNA (e g., OLX 701). dual TFGp / Hedgehog inhibitor (e.g., Oxy 200), GPR40 agonist / GPR84 antagonist (e.g., PBI-4547), neutrophil elastase inhibitor (e.g., PHP-303), integrin inhibitor (e.g., PLN-1474), TGFpi modulator (e.g.PRM-151), CCK receptor antagonist (e.g., proglumide), LOXL2 inhibitor (e.g., PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitor (e.g., cGAS / STING antagonists), kinase inhibiting RNase, membrane protein mAbs, tumor necrosis factor inhibitor, NRF2 activator (e.g., SCO 116). SSAO inhibitor (e.g., TERN 201). TRAIL2 agonist (e.g.. TLY012), IL-6 receptor antagonist (e.g., TZLS 501), AOC3 inhibitor (e.g., UD-014), SSAO / VAP-1 inhibitor, TREM2); anti-oxidant (e.g., vitamin E); anti-inflammatory agents (e.g., norfloxacin, ciprofloxacin, ceftriaxone); coagulation modifiers (e.g., anti-coagulants, anti-platelet agents, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonist (e.g., tirzepetide); dual GLP-l / GRA (e g., cotadutide, ALT-801, DD 01, G49, PB-718); dual GLP-1 (e.g., CT 868); GLP-l / GRA / GIP triple agonist (e.g., HM15211); GRP120 stimulant / inflammasome modulator / PPARy dual agonist (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonist (e.g.. Ozempic (semaglutide sc). XW 003); selective thyroid hormone receptor-P agonist (e.g., resmetirom); apoptosis modulators (JNK.-1 inhibitor (e.g., CC-90001), Peroxidase inhibitor (e.g., AZM198), ASK-1 inhibitor (e.g., CS-17919, SRT 015)); erythropoietin-stimulating agents (erythropoietin receptor agonist (e.g., cibinetide)); glucosepathway modulators (SGLT-2 inhibitor (e.g., Forxiga, Farxiga (dapagliflozin)); dual SGLT-1 / 2 inhibitor (e.g., licogliflozin), Glucose-6-P dehydrogenase inhibitor (e g., fluasterone) LAPS glucagon combo (e.g., HM14320), SGLT-1 inhibitor (e.g., SGL5213)); immune modulators (TLR4 inhibitor (e.g., GBK-233), immunomodulatory polyclonal antibody (e.g., IMM-124E), TLR4 antagonist (e.g.. JKB-122), CD3 monoclonal antibody (e.g.foralumab), TLR4 antagonist (e g., JKB 133), TLR4 inhibitor (e.g., mosedipimod), Macrophage inhibitor via CD206 targeting (e.g., MT2002), TLR2 / 4 antagonist (e.g., VB-201, VB-703), immunomodulatory7polyclonal antibody (e.g., IMM-124E)): incretin-based therapies (GLP-1 agonist (e.g., Ozempic (semaglutide sc). XW 003), GLP-l / glucagon dual receptor agonist (e.g., HM12525A), prandial insulin (e.g., ORMD 0801)); lipid modulators (AMPK Activator / Glutathione transferase (e.g., oltipraz), THR-beta agonist (e.g., resmetirom, VK2809, MGL-3745, ALG-009, ASC41, CNPT- 101101, TERN 501), IBAT inhibitor (e.g., elobixibat, CJ 14199), omega-6- fatty acid (e.g., epeleuton), FASN rnhibitor (e.g., TVB2640, FT 4101, FT 8225), ANGPTL3 inhrbrtor (e.g., vupanorsen). PNPLA3 inhibitor (e.g., AZD2693). RAS domain kinase inhibitor (e.g., BioEl 115), NTCP inhibitor (e.g., bulevirtide), P2Y13 receptor agonist (e.g., CER-209), omega-3 fatty acid, HSD17P13 inhibitor; metabolism modulators (FXR agonist (e.g., Ocaliva (obeticholic acid), IOT022). recombinant variant of FGF19 (e.g.. aldafermin), bi-specifrc FGFR1 / KLB antibody (e.g., BFKB8488A), mTOT modulator (e.g., MSDC-0602K), pegylated analog of FGF21 (e.g., pegbelfermin, BMS-986171), non-bile FXR agonist (e.g., cilofexor, EDP-305, EYP 001, tropifexor, MET409, AGN-242256, AGN-242266, EDP 297, HPG 1860, MET642, RDX023, TERN 101), ACC inhibitor (e.g., frrsocostat, PF-05221304), ketohexokinase inhibitor (e.g., PF- 06835919), AMPK activator (e.g.. PXLH0. MSTM 101, 0304), bile acid modulator (e.g., Albiero). FGF21 analog (e.g., B1089-100), MOTSc analog (e.g.. CB4211), cyclophilin inhibitor (e.g., CRV 431), FGF19 (e.g., DEL 30), mitochondrial uncoupler (e g., GEN 3026), FXR / GPCR dual agonist (e.g., INT-767), Cysteamine derivative (e.g., KB-GE-001), dual amylin and calcitonin receptor agonist (e.g., KBP-089), transient FXR agonist (e.g., M 1217), anti-beta- klotho (KLB)-FGFRlc receptor complex mAb (e.g., MK3655). GDF15 analog (e.g.. NGM395). cyclophilin inhibitor (e.g., NV556), LXR modulator (e.g., PX 329, PX 655, PX 788), LXR inverse agonist (e.g., PX016), deuterated obeticholic acid (e.g., ZG 5216)); PPAR modulators (dual PPARa / y agonist (e.g., elafibranor), PPAR pan agonist (e.g., lanifibranor), PPARa agonists (e.g., Parmodia), PPARy agonist (e.g.. CHS 131), MPC inhibitor (e.g., PXL065). PPAR 5 / y agonist (e.g.T3D 959)); RAAS mIMModulators (mineralocorticoid receptor antagonist (e.g., apararenone, eplerenone, spironolactone), angiotensin receptor blocker (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulator, CB1 receptorantagonist (e.g., CRB-4001. IM-102, nimacimab). TPH1 inhibitor (e.g., CU 02). GPR120 agonist (e.g., KBR2001), combination of cannabinoid and botanical anti-inflammatory compound (e.g., SCN 002)); PDE Modulator (PDE4 inhibitor (e.g., ART 648)); CYP2E1 inhibitor (e.g., SNP- 610); cell therapies (e.g.. HepaStem)and bromocriptine mesylate and rapid-release formulations thereof; or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including nitroprusside and diazoxide the free-acid, free-base, and pharmaceutically acceptable salt forms of the above active agents where chemically possible.

[0104] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined herein, including the pharmaceutically acceptable salts of all structural formulas, embodiments and classes defined herein. Reference to the compounds of structural Formula I includes the compounds of other generic structural Formulas, such as Formulas and embodiments that fall within the scope of Formula I.Dosages of the Compounds of Formula (I)

[0105] If the patient is responding, or is stable, after completion of the therapy cycle, the therapy cycle can be repeated according to the judgment of the skilled clinician. Upon completion of the therapy cycles, the patient can be continued on the compounds of Formula I at the same dose that was administered in the treatment protocol. This maintenance dose can be continued until the patient progresses or can no longer tolerate the dose (in which case the dose can be reduced and the patient can be continued on the reduced dose).

[0106] Those skilled in the art will recognize that the actual dosages and protocols for administration employed in the methods of the present disclosure may be varied according to the judgment of the skilled clinician. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. A determination to vary the dosages and protocols for administration may be made after the skilled clinician considers such factors as the patient’s age, condition and size, as well as the severity of the condition being treated and the response of the patient to the treatment.

[0107] The dosage regimen utilizing a compound of Formula I is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specificdaily dosage amount can simultaneously be both a therapeutically effective amount, e.g.. for treatment of an oncological condition, and a prophylactically effective amount, e.g., for prevention of an oncological condition.

[0108] While individual needs vary, determination of optimal ranges of effective amounts of the compound of Formula I is within the skill of the art. For administration to a human in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, typical dosages of the compounds of the present disclosure can be about 0.05 mg / kg / day to about 50 mg / kg / day, for example at least 0.05 mg / kg, at least 0.08 mg / kg. at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, which can be about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg), for example. For example, dosages of the compounds can be about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.05 mg / kg / day to about 10 mg / kg / day, about 0.05 mg / kg / day to about 5 mg / kg / day. about 0.05 mg / kg / day to about 3 mg / kg / day. about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / kg / day, about 0.05 mg / kg / day to about 0.1 mg / kg / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day. about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses.Pharmaceutical Compositions

[0109] The compounds of Formula I and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical compositions. The term ‘‘subject” or “patient” includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition.

[0110] Administering of the compound of Formula I to the subject includes both selfadministration and administration to the patient by another person. The subject may need, or desire, treatment for an existing disease or medical condition, or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a subject "in need" of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0111] Methods for the safe and effective administration of most of these agents are known to those skilled in the art. In addition, their administration is described in the standard literature.

[0112] If the patient is responding, or is stable, after completion of the therapy cycle, the therapy cycle can be repeated according to the judgment of the skilled clinician. Upon completion of the therapy cycles, the patient can be continued on the compounds of the disclosure at the same dose that was administered in the treatment protocol. This maintenance dose can be continued until the patient progresses or can no longer tolerate the dose (in which case the dose can be reduced and the patient can be continued on the reduced dose).

[0113] Those skilled in the art will recognize that the actual dosages and protocols for administration employed in the methods of the disclosure may be varied according to the judgment of the skilled clinician. The actual dosage employed may be varied depending upon the requirements of the patient and the severity7of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. A determination to vary the dosages and protocols for administration may be made after the skilled clinician takes into account such factors as the patient’s age, condition and size, as well as the severity of the condition being treated and the response of the patient to the treatment.

[0114] The amount and frequency of administration of the compound of formula I, and any additional agents will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the condition being treated.

[0115] The compounds of the invention are also useful in preparing a medicament that is useful in treating cancer.

[0116] The instant compounds are also useful in combination with therapeutic, chemotherapeutic and anti-cancer agents for the treatment of hepatic cellular carcinoma. Combinations of the presently disclosed compounds with therapeutic, chemotherapeutic and anticancer agents are within the scope of the disclosure. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 9thedition (May 16, 2011), Lippincott Williams & Wilkins Publishers. A person of ordinary7skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed deathligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG- CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reversetranscriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, y-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.

[0117] The chemotherapeutic agent can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent can be varied depending on the cancer being treated and the known effects of the chemotherapeutic agent on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the cancer to the administered therapeutic agents. The particular choice of chemotherapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.

[0118] The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0119] The determination of the order of administration, and the number of repetitions of administration of the chemotherapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the condition being treated and the condition of the patient.

[0120] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a chemotherapeutic agent according to the individual patient’s needs, as the treatment proceeds. All such modifications are within the scope of the present disclosure.

[0121] The agent can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the anti-cancer agent can be varied depending on the cancer being treated and the known effects of the anti-cancer agent on that disease.

[0122] The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0123] The particular choice of agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.

[0124] The determination of the order of administration, and the number of repetitions of administration of the agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the cancer being treated and the condition of the patient.

[0125] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of an anti-cancer agent according to the individual patient’s needs, as the treatment proceeds. All such modifications are within the scope of the present disclosure.

[0126] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

[0127] The compounds, compositions and methods provided herein are useful for the treatment of cancer. Cancers that may be treated by the compounds, compositions and methods disclosed herein include, but are not limited to: Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

[0128] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab and MPDL3280A. PDL- inhibitors include atezolizumab, avelumab, and durvalumab.

[0129] Further provided is a method of treating hepatic cellular carcinoma in a human patient comprising administration of a compound of Formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof and a PD-1 antagonist to the patient. The compound of Formula I and the PD-1 antagonist may be administered concurrently or sequentially.

[0130] In particular embodiments, the PD-1 antagonist is an anti-PD-1 antibody, or antigen binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-Ll antibody, or antigen binding fragment thereof. In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA™, Merck & Co., Inc., Kenilworth, NJ, USA), nivolumab (OPDIVO™. Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO™, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab (TECENTRIQ™, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI™, AstraZeneca Pharmaceuticals LP, Wilmington, DE), or avelumab (BAVENCIO™, Merck KGaA, Darmstadt, Germany).

[0131] In some embodiments, the PD-1 antagonist is pembrolizumab. In particular subembodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.

[0132] In further sub-embodiments, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every three weeks. In particular sub-embodiments, the patient is a pediatric patient.

[0133] In some embodiments, the PD-1 antagonist is nivolumab. In particular subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to the patient about every7four weeks.

[0134] In some embodiments, the PD-1 antagonist is cemiplimab. In particular embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.

[0135] In some embodiments, the PD-1 antagonist is atezolizumab. In particular subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every' three weeks.

[0136] In some embodiments, the PD-1 antagonist is durvalumab. In particular subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every' two weeks.

[0137] In some embodiments, the PD-1 antagonist is avelumab. In particular sub-embodiments, the method comprises administering 800 mg of avelumab to the patient about every' two weeks.

[0138] A compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, may also be useful for treating cancer in combination with the following therapeutic agents: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide(Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC- Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone injection®); Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP- 16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L- PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin- 50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide. VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab / I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (V el ban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®), or a pharmaceutically acceptable salt thereof.EXAMPLESMethods for Making the Compounds of Present Invention

[0139] The following examples are provided so that the invention might be more fully understood. Unless otherwise indicated, the starting materials are commercially available. They should not be construed as limiting the invention in any way.

[0140] Several methods for preparing the compounds of this invention are described in the following Schemes and Examples. Starting materials and intermediates are purchased, made from known procedures, or as otherwise illustrated. Some frequently applied routes to the compounds of Formula I are also described by the Schemes as follows. In some cases, the order of carrying out the steps of reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. For stereoisomers, enantiomer A refers to the faster / earlier eluting enantiomer and enantiomer B refers to the slower / later eluting enantiomer at the point of separation and this nomenclature is maintained through the remainder of a synthetic sequence for a given enantiomeric series regardless of the possibility that subsequent intermediates and final compounds may have the same or opposite orders of elution.

[0141] Concentration refers to the removal of the volatile components at reduced pressure (e g., by rotary evaporation) unless otherwise noted. All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI) in positive ion detection mode and m / z refers to the [ M+H | ion unless otherwise noted.

[0142] 'H NMR spectra were recorded at 400-600 MHz at ambient temperature unless otherwise noted. Purification by column chromatography on silica gel was accomplished using a flash chromatography system (e.g., ISCORor Biotage1®) and commercial pre-packed silica gel columns with elution using the stated solvent systems. Compounds described herein were synthesized as the racemates unless otherwise noted in the experimental procedures and compound tables.ABBREVIATIONS

[0143] Abbreviations used in the experimentals may include, but are not limited to, the following:GENERAL SCHEMESPreparative Examples

[0144] The compounds of the present invention can be prepared readily according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of vanants which are themselves known to those of ordinary skill in this art but are not mentioned in detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes and descriptions.General Scheme 1

[0145] One general strategy for the synthesis of compounds of type G1.5 is via the three-step procedure shown in General Scheme 1, wherein R1, R5, R6, R10, and X are as defined in Formula I. Aryl chloride Gl.l can be combined with nucleophile G1.2 in the presence of a base such as CS2CO3 or K2CO3 in solvents such as DMF by heating to 50 °C to form intermediate G1.3 In the second step, the ester intermediate G1.3 can then be treated with bases such as LiOH or NaOH in a solvent mixture such as THF:EtOH:H2O to afford hydrolyzed intermediate G1.4. Carboxylicacid intermediate G1.4 can be coupled with an appropriate amine (HNR5R6) in the presence of coupling reagents such as HATU or EDC and a base such as DIPEA in a solvent such as DMF to provide products of type G1.5. Products of type G1.5 can be purified by silica gel chromatography, preparative reversed-phase HPLC, and / or chiral SFC.General Scheme 2

[0146] One general strategy for the synthesis of compounds of type G2.3 is via the three-step procedure shown in General Scheme 2, wherein R1, R5, R6, R10, and X are as defined in Formula I. Ester intermediate G2.1 can be treated with bases such as LiOH or NaOH in a solvent mixture such as THF:EtOH:HzO to afford hydrolyzed intermediate G2.2 In the second step, carboxylic acid intermediate G2.2 can be coupled with an appropriate amine (HNR5R6) in the presence of coupling reagents such as HATU or EDC and a base such as DIPEA in a solvent such as DMF to provide intermediate G2.3. In the third and final step, aryl chloride G2.3 can be combined with nucleophile G2.4 in the presence of a base such as CS2CO3 or MTBD in solvents such as DMF by heating up to 100 °C to form products of type G2.5 Products of type G2.5 can be punfied by silica gel chromatography, preparative reversed-phase HPLC, and / or chiral SFC.General Scheme 3

[0147] One general strategy for the synthesis of compounds of type G3.3 is via the Pd- catalyzed coupling procedure shown in General Scheme 3, wherein Rl, R7, R8, RIO, and X are as defined in Formula I. Aryl chloride G3. 1 can be combined with nucleophile G3.2 in the presence of a Pd catalyst such as XantPhos Pd G3 and a base such as Cs2CO3 in solvents such as dioxane by heating to 80 °C to form products of type G3.3. Products of type G3.3 can be purified by silica gel chromatography, preparative reversed-phase HPLC, and / or chiral SFC.

[0148] One general strategy for the synthesis of compounds of type G4.3 is via the procedure shown in General Scheme 4, wherein R5, R6, RIO, and Ra are as defined in Formula I.Morpholine G4.1 can be combined with an appropriate isocyanate G4.2 in the presence of a base such as DIPEA in solvents such as THF to form products of type G4.3. Products of type G4.3 can be purified by silica gel chromatography, preparative reversed-phase HPLC, and / or chiral SFC.General Scheme 5

[0149] One general strategy for the synthesis of compounds of type G5.5 is via the three-step procedure shown in General Scheme 5, wherein R5, R6, R10, and Raare as defined in Formula I. Aniline intermediate G5.1 can be treated with an appropriate sulfamoyl chloride G5.2 and a base such as EtsN in a solvent such as THF to afford intermediate G5.3. In the second step, ester intermediate G5.3 can be treated with a base such as NaOH in a solvent mixture such as THF:EtOH:H2O to afford hydrolyzed intermediate G5.4. In the third step, intermediate G5.4 with carboxylic acid can then be combined with an appropriate amine (HNR5R6) in the presence of coupling reagents such as HATU and a base such as DIPEA in a solvent such as DMF to formproducts of type G5.5. Products of type G5.5 can be purified by silica gel chromatography, preparative reversed-phase HPLC, and / or chiral SFC.

[0150] Absolute stereochemistry of separate stereoisomers in the Examples and Intermediates was not determined unless stated otherw ise in an Example or Intermediate synthesis.SYNTHESIS OF INTERMEDIATES

[0151] Preparation of ethyl 4-chloro-5-methylpyrrolo| 1.2-6 |pyndazine-6-carboxylate (Intermediate 1-3).

[0152] Intermediate (1-3) was prepared according to synthetic route outlined in Scheme 1.Scheme 1ethyl l-amino-4-methyl-1H-pyrrole-3-carboxylate (1-1)

[0153] NaH (66.6 g, 1.66 mol) (60% dispersed in oil) was added to DMF (4.50 L) at 0 °C. To the solution, ethyl 4-methyl-1H-pyrrole-3-carboxylate (150 g, 979 mmol) was added at 0 °C. After stirring under N2 for 0.5 hours at 0 °C, (aminooxy )diphenylphosphine oxide (274 g, 1.18 mol) was added to the mixture at 0 °C. The resulting mixture was stirred at 25 °C for 0.5 hours.

[0154] The reaction mixture was quenched with NH4CI (30% aq, 40 L) and extracted with MTBE (10 L x 5). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material w as used directly in the next step without further purification. MS: 169 [M+l]+. ethyl 4-hydroxy-5-methylpyrrolo[l .2-6 |pyridazine-6-carboxylate (1-2)

[0155] Step 1 : To a solution of ethyl l-amino-4-methyl-l H -pyrrole-3-carboxylate (335 g. 1.99 mol) in THF (3.00 L) was added 5-(methoxymethylene)-2,2-dimethyl-l,3-dioxane-4, 6-dione (380 g, 1.99 mol) at 25 °C. The mixture was stirred at 25 °C for 2 hours until solid precipitates. The reaction mixture w as filtered, and the filter cake w as washed with THF (700 mL x 3). Thesolid was dried to constant weight at 45 °C to afford desired product, which was used directly in the next step without further purification.

[0156] Step 2: The reaction uses flow chemistry'. The crude product from step 1 (500 g, 1.55 mol) was charged into flow vessel 1 at 25 °C. NMP (10.0 L) was charged into flow' vessel 1 at 25 °C and was stirred for 5 minutes until the solution became clear. The backpressure regulator was adjusted to 0.5 Mpa and the flow rate of pump 1 was adjusted to 43 mL / min for solution. The oven was set at 170 °C and pump 1 was started. The reaction mixture w as collected after running for 5 minutes and was poured into sat. Na2COs (aq, 10 L). The aqueous phase was extracted with EtOAc (30 L, 10 L, 10 L). After acidifying with 2 M HC1 (aq.), aqueous phase was extracted with MTBE (5 L x 2). Combined organic layers were washed with brine (2 L), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude material was used directly in the next step without further purification. MS: 221 [M+l]+. ethyl 4-chloro-5-methylpyrrolo[ 1 ,2-61 pyridazine-6-carboxy late (1-3)

[0157] Phosphorus(V) oxychloride (1.23 L, 13.2 mol) was added to MeCN (525 mL) at 25 °C. Ethyl 4-hydroxy-5-methylpyrrolo[l,2-Z?]pyridazine-6-carboxylate (175 g, 795 mmol) and DIPEA (276 mL, 1.59 mol) were added to the mixture at 25 °C. The reaction mixture was stirred at 85 °C for 12 hours under N2. The solution was distilled in vacuum (60 °C, oil pump) and poured into water (10 L). Solid NaHCOs was added until pH 8 and the aqueous phase was extracted with EtOAc (5 L x 2). Combined organic layers were washed with brine (2 L), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Column chromatography (silica gel, EtOAc in hexanes, gradient 0 to 100%) yielded the desired product. MS: 239 [M+l]+. *HNMR (400MHz, CDCh) 6 8.18 (s, 1H), 7.85 (d, J= 4.8 Hz, 1H), 6.50 (d, J = 4.8 Hz, 1H), 4.37 (q. J= 7.2, Hz, 2H), 2.86 (s, 3 H), 1.40 (t, J = 7.2 Hz. 3 H).Preparation of intermediate 6-hydroxy-A.l-dimethyl-17f-indazole-3-carboxamide (1-4)

[0158] Intermediate 1-4 w as prepared according to synthetic route outlined in Scheme 2.Scheme 2

[0159] 6-Hydroxy-l-methyl-1H-indazole-3-carboxylic acid (0.13 g, 0.70 mmol), HATU (0.32 g, 0.84 mmol), and methanamine hydrochloride (57 mg, 0.84 mmol) were dissolved in EtOAc (7.0 mL). DIPEA (0.49 mL, 2.8 mmol) was added, and the reaction mixture was stirred at 25 °C for 18 hours. The final mixture was diluted with ethyl acetate and water. The organic layer wasseparated and washed with 1 A / HC1 (aq, 50 mL x 2) and sat. NaHCCh (aq. 50 mL x 2). The organic layer was dried (brine and MgSOi). filtered, and concentrated. Column chromatography (silica gel, EtOAc / EtOH (3 / 1) in hexanes, gradient 10 to 100%) yielded the desired product.JH NMR (500 MHz, DMSO-rfe) 5 9.86 (s, 1H), 8.17 (d, J= 4.7 Hz, 1H), 7.93 (d, J= 8.7 Hz, 1H), 6.84 (d, J= 1.7 Hz, 1H). 6.80 (dd. J= 8.7. 2.0 Hz, 1H), 3.96 (s. 3H), 2.78 (d. J= 4.7 Hz. 3H).Table 1: Using methods similar to that outlined in the synthesis of 1-4, and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediate 7 -hydroxy -A-methyl-2-naphthamide (1-8)

[0160] Intermediate 1-8 was prepared according to synthetic route outlined in Scheme 3.Scheme 3\ NH2

[0161] 7-hydroxy-2-naphthoic acid (1.00 g, 5.31 mmol) and methanamine. HC1 (718 mg, 10.6 mmol) were dissolved in DMF (15.0 mL). T3P (4.69 mL, 50% Wt, 7.97 mmol) and DIPEA (5.55 rnL, 31.9 mmol) were added, and the reaction mixture was allowed to stir at 50 °C overnight. The final mixture was diluted with ethyl acetate and washed with water (50 mL x 2) and brine (50 mL). The organic layer was dried over MgSCL, filtered, and concentrated. Column chromatography (silica gel, EtOAc in hexanes, gradient 0 to 100%) yielded the desired product. MS: 202 [M+l]+.Table 2: Using methods similar to that outlined in the synthesis of 1-8, and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediate 6-hvdroxy-A-((cA)-3-methoxycvclobutyl)-l-naphthamide (1-11)

[0162] Intermediate (1-11) was prepared according to synthetic route outlined in Scheme 4.Scheme 4

[0163] To a solution of 6-hydroxy-l -naphthoic acid (137 mg, 0.727 mmol) in DMF (5.00 mL) were added c / .s-3-methoxycyclobutanamine hydrochloride (100 mg, 0.727 mmol), DIPEA (0.635 rnL, 3.63 mmol), HOBT (98.0 mg, 0.727 mmol) and EDC (279 mg, 1.45 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water andextracted with EtOAc. The organic layer was separated and dried (brine and Na2SO4). The mixture was filtered and concentrated. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 30%) yielded the desired product. MS: 272 [M+l]+. ’H NMR (400 MHz, CD3OD) 5 8.01 (d, J= 8.8 Hz, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.16 - 7.11 (m, 2H), 4.23 - 4.14 (m, 1H), 3.79 - 3.71 (m, 1H). 3.27 (s. 3H), 2.83 - 2.76 (m, 2H), 2.04 - 1.93 (m, 2H).Table 3: Using methods similar to that outlined in the synthesis of 1-11, and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediate 7-hvdroxy-A'r.2-dimethylindolizine-3-carboxamide (1-16)

[0164] Intermediate (1-16) was prepared according to synthetic route outlined in Scheme 5.Scheme 57-methoxy-2-methylindolizine (1-13)

[0165] 4-Methoxy-2-methylpyridine (0.50 g, 4. 1 mmol) was combined with 1 -bromopropan-2- one (95% wt in MgO, 0.50 mL, 5.3 mmol). The reaction mixture was stirred at 95 °C for 2 hours. The reaction mixture was concentrated and resuspended in toluene (20 mL). 4 A molecular sieves (200 mg) were added, followed by DBU (1.3 mL, 8.9 mmol). The reaction mixture was stirred at 95 °C for 16 hours. The reaction mixture was diluted with water then extracted with EtOAc. The organic layer was separated and dried (brine and Na2SO4). The mixture was filteredand concentrated. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 5%) yielded the desired product. MS: 162 [M+l]+. methyl 7-methoxy-2-methylindolizine-3-carboxylate (1-14)

[0166] Under nitrogen. 7-methoxy-2-methylindolizine (1.0 g, 6.2 mmol) was combined with methyl chloroformate (4. 1 mL, 52.9 mmol), and the reaction mixture was cooled to 0 °C. TEA (9.00 mL, 64.6 mmol) was added dropwise to minimize gas evolution. The reaction mixture was then heated at 95 °C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with aqueous 0.5 M HO. and dried (brine and Na2SO4). The mixture was filtered then concentrated to yield the desired product, which was used without further purification. MS: 220 [M+l]+.7-methoxy-A.2-dimethylindolizine-3-carboxamide (1-15)

[0167] Methyl 7-methoxy-2-methylindolizine-3-carboxylate (400 mg, 1.8 mmol) was dissolved in THF (10.0 mL). Methylamine (3. 1 Alin THF, 3.5 mL, 10.9 mmol) was added and the reaction mixture was cooled to 0 °C. LiHMDS (1.0 in THF. 10.0 mL. 10.0 mmol) was added, and the reaction mixture was allowed to warm to 25 °C and stirred at this temperature for 16 hours. The organic layer was separated and dried (brine and Na2SO4). The mixture was filtered and concentrated to yield the desired product, which was used without further purification. MS: 219 [M+l]+.7-hvdroxy-A.2-dimethylindolizine-3-carboxamide (1-16)

[0168] 7-Methoxy-A,2-dimethylindolizine-3-carboxamide (493 mg, 2.26 mmol) was dissolved in DCM (4.00 mL) and the resulting solution was cooled to 0 °C. BBn (2.0 mL, 4.0 mmol) was added at 0 °C dropwise. The reaction mixture was allowed to warm to 25 °C and stirred for an additional 16 hours. The reaction mixture was poured over ice and diluted with water. The aqueous phase was washed with EtOAc. The aqueous phase was concentrated and purified by mass-directed reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the desired product. MS: 205 [M+l]+. 'H NMR (400 MHz, DMSO-t*) 5 = 9.04 (d. J =7.6 Hz, 1H), 7. 10 - 6.95 (m, 1H), 6.56 (d, J= 2.4 Hz, 1H), 6.33 (dd, J= 7.6, 2.4 Hz, 1H). 5.93 (s, 1H). 2.78 (s. 3H), 2.38 (s, 3H).Table 4: Using methods similar to that outlined in the synthesis of 1-16, and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediate A-(3.3-difl uorocvclobulyl )-7-hvdro\v-2-methylindolizine-3- carboxamide (1-20)

[0169] Intermediate (1-20) was prepared according to synthetic route outlined in Scheme 6.Scheme 6A-(3.3-difluorocvclobutyl)-7-methoxy-2-methylindolizine-3-carboxamide (1-19)

[0170] To a solution of methyl 7-methoxy-2-methylindolizine-3-carboxylate (420 mg, 1.92 mmol) in toluene (12.0 mL) was added 2M AlMes solution (3.35 mL, 6.70 mmol, in toluene) at 0 °C. The mixture was stirred at 0 °C for 0.5 hours and 25 °C for 0.5 hours. To this mixture was added 3,3-difluorocyclobutan-l-aminexHCl (410 mg. 3.83 mmol) under N2 atmosphere. The resulting mixture was stirred at 100 °C for 2 hours then at 80 °C for 16 hours. The mixture was cooled to 25 °C and then added to the potassium sodium tartrate (aq, 80 mL), stirred at 25 °C for 6 hours, extracted with EtOAc (30 mL x 3), washed with brine (150 mL), and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 8 to 30%) yielded the desired product. MS: 295 [M+l]+.A-(3.3-difluorocvclobut\4)-7-hvdroxy-2-methylindolizine-3-carboxamide (1-20)

[0171] A mixture of pyridine hydrochloride (1.00 g, 8.65 mmol) and A-(3,3- difluorocyclobutyl)-7-methoxy-2-methylindolizine-3-carboxamide (190 mg, 0.646 mmol) was stirred at 140 °C for 45 min. The mixture was diluted with mixed solvent (water: MeCN = 1 : 1, 10 mL), and then purified by mass-directed reverse phase MPLC (MeCN / water, gradient 0 to 35%) to afford the desired product. MS: 281 [M+l]+. 'H NMR (400 MHz, CD3OD) 8 = 8.96,8.57 (d, d, J = 7.6 Hz, 1H), 7. 14. 6.58 (d, d. J = 2.4 Hz, 1H), 7.02, 6.35 (dd, dd, J = 7.6, 2.4, Hz. 1H), 4.40 - 4.16 (m, 1H), 3.12 - 2.93 (m, 2H), 2.87 - 2.58 (m, 2H), 2.47, 2.26 (s, s, 3H).Preparation of intermediate N-(cis-3-fluorocvclobutyl)-74ivdroxy-2-methylindolizine-3- carboxamide (1-24)

[0172] Intermediate (1-24) was prepared according to synthetic route outlined in Scheme 7.Scheme 7A-(3-(benzyloxy)cvclobutyl)-7-methoxy-2-methylindolizine-3-carboxamide (1-21)

[0173] To a solution of 3-(benzyloxy)cyclobutan-l -amine hydrochloride (1.92 g, 8.98 mmol) and methyl 7-methoxy-2-methylindolizine-3-carboxylate (1.00 g. 4.56 mmol) in THF (10 mL) was added LiHMDS (30 mL, 30.0 mmol) (1 A in THF) at 0 °C. The mixture was stirred at 25 °C for 3 days. The mixture was added to the saturated NH4CI (200 mL), extracted with EtOAc (35 mL x 3), washed with brine (150 mL), and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 35 to 100%) yielded the desired product. 'H NMR (400 MHz, CDCh) 5 9.40 (d. J= 7.6 Hz. 1H), 7.40 - 7.28 (m, 5H), 6.58 (d, J = 2.4 Hz, 1H), 6.40 - 6.34 (m, 1H), 6.06 (s, 1H), 5.74 - 5.61 (m, 1H), 4.48 - 4.39 (m, 2H), 4.36 - 4.13 (m, 1H), 3.91 - 3.86 (m, 1H), 3.81 (s, 3H), 2.93 - 2.80 (m, 1H), 2.67 - 2.55 (m, 1H), 2.52 (s, 3H), 2.35 - 2.18 (m, 1H), 1.99 - 1.86 (m, 1H).A-(3-hvdroxycyclobutyl)-7-methoxy-2-methylindolizine-3-carboxamide (1-22)

[0174] To a solution of A-(3-(benzyloxy)cyclobutyl)-7-methoxy-2-methylindolizine-3- carboxamide (700 mg, 1.921 mmol) in DCM (10 mL) was added tri chloroborane (9.60 mL, 9.60 mmol) (1 M in DCM) at -65 °C under nitrogen atmosphere. After stirring at -65 °C for 6 hours, the reaction mixture was quenched by addition MeOH (10 mL) dropwise at -65 °C over 10 mins, and concentrated under reduced pressure. The mixture was purified by mass-directed reversephase MPLC (MeCN / water (0.5% TFA. gradient 15 to 70%) to afford the desired product. MS: 275 [M+l]+. '-(c7.s-3-nuorocvclobutyl )-7-methoxy-2-methylindolizine-3-carboxamide (1-23)

[0175] To a mixture of A-(3-hydroxycyclobutyl)-7-methoxy-2-methylindolizine-3-carboxamide (420 mg. 1.531 mmol) in THF (3 mL) was added 2.3.4.6.7,8,9,10-octahydropyrimido[l,2- a]azepine (0.500 mL, 3.32 mmol). To this solution was added 1,L2,2,3,3,4,4,4- nonafluorobutane-1 -sulfonyl fluoride (797 mg, 2.64 mmol) slowly at -78 °C. The resulting mixture was stirred at 25 °C for 16 hours. The mixture was diluted with water (10 mL), extracted with EtOAc (5 mL x 3). and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 38%) yielded the desired product. ’H NMR (400 MHz, CDCh) 5 9.41 (d, J= 7.6 Hz, 1H), 6.59 (d, J= 2.8 Hz, 1H), 6.38 (dd, J= 7.6, 2.8 Hz, 1H), 6.07 (s, 1H), 5.76 - 5.62 (m, 1H), 5.38 - 5.16 (m, 1H), 4.78 - 4.67 (m, 1H), 3.81 (s, 3H), 2.82 - 2.68 (m, 2H), 2.54 - 2.49 (m, 3H), 2.48 - 2.29 (m, 2H).A-(cA-3-fluorocvclobutyl)-7-hydroxy-2-methylindolizine-3-carboxamide (1-24)

[0176] A mixture of pyridine hydrochloride (1.00 g, 8.65 mmol) and A-(3-fluorocyclobutyl)-7- methoxy-2-methylindolizine-3-carboxamide (85.0 mg, 0.308 mmol) was stirred at 150 °C for 0.5 hours. The mixture w as diluted with mixed solvent (MeCN: Water = 1 : 1, 5 mL), and extracted with EtOAc (5 mL x 3). The aqueous phase was purified by mass-directed reverse phase MPLC (MeCN / water (0.5% TFA, gradient 15 to 45%) to afford the desired product. MS: 263 [M+l]+. Preparation of intermediate 6-hvdroxy-A,2-dimethylindolizine-l -carboxamide (1-29)[01H] Intermediate (1-29) was prepared according to synthetic route outlined in Scheme 8.Scheme 8methyl 6-bromo-2-methylindolizine-l -carboxylate (1-25)

[0178] A mixture of methyl 2-(5-bromopyridin-2-yl)acetate (2.00 g, 8.69 mmol), NaHCOs (2.92 g, 34.8 mmol) and 1 -chloropropan-2-one (2.08 mL, 26. 1 mmol) in butanone (45.0 mL) was stirred at 80 °C for 48 hours. The mixture was filtered and concentrated under reduced pressure.Column chromatography (silica gel. EtOAc in petroleum ether, gradient 0 to 15%) yielded the desired product. MS: 270 [M+l]+.6-bromo-2-methylindolizine-l -carboxylic acid (1-26)

[0179] A mixture of methyl 6-bromo-2-methylindolizine-l-carboxylate (100 mg, 0.373 mmol) and 2 M NaOH (aq, 0.932 mL, 1.865 mmol) in THF (1.00 mL) and MeOH (1.00 mL) was stirred at 60 °C for 16 hours. The mixture was concentrated in vacuo to remove the organic phases. The residue was adjusted to pH 5 by 1 A / HCI aq. and the mixture was lyophilized to yield the desired product, which was used without further purification. MS: 254 [M+l]+.6-bromo-A,2-dimethy lindolizine- 1 -carboxamide (1-27)

[0180] To a solution of 6-bromo-2-methylindolizine-l -carboxylic acid (1.2 g, 4.72 mmol) in DMF (20 mL) were added methanamine hydrochloride (0.957 g, 14.2 mmol), DIPEA (6.60 mL, 37.8 mmol), HOBT (2.55 g, 18.9 mmol) and EDC (3.62 g, 18.9 mmol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL). dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 100%) yielded the desired product. MS: 269 [M+l]+. A.2-dimethyl-6-(4.4.5.5-tetramethyl-1.3,2-dioxaborolan-2-yl)indolizine-l-carboxamide (1-28)

[0181] A mixture of 6-bromo-A.2-dimethylindolizine-l -carboxamide (1.00 g, 3.74 mmol), bis(pinacolato)diboron (1.43 g, 5.62 mmol), PdCh(dppf) (0.274 g, 0.374 mmol) and potassium acetate (1.10 g, 11.2 mmol) in dioxane (10 mL) was degassed and backfilled with N2 three times. The mixture was stirred at 100 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 60%) yielded the desired product. MS: 315 [M+l]+.6-hvdroxy-A.2-dimethylindolizine-l -carboxamide (1-29)

[0182] A mixture of A,2-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolizine-l- carboxamide (600 mg, 1.91 mmol) and sodium perborate tetrahydrate (1.18 g, 7.64 mmol) in THF (7.00 mL) and water (7.00 mL) was stirred at 0 °C for 2 hours. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 100%) yielded the desired product. MS: 205 [M+l]+. 'H NMR (400 MHz, CD3OD) 5 7.H (d, J = 9.6 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.10 (s, 1H), 6.70 (dd, J= 9.6, 2.0 Hz, 1H), 2.95 - 2.92 (m, 3H), 2.40 (s, 3H).Preparation of intermediate 6-hvdroxy-A-methylbenzokf]isothiazole-3-carboxamide (1-31)

[0183] Intermediate (1-31) was prepared according to synthetic route outlined in Scheme 9.Scheme 96-methoxy-A-methylbenzo[< / |isothiazole-3-carboxamide (1-30)

[0184] A mixture of DIPEA (0.301 mL, 1.721 mmol), HATU (327 mg, 0.860 mmol), methylamine hydrochloride (87 mg, 1.291 mmol) and 6-metho\ybenzo|c / |isothiazole-3- carboxylic acid (90 mg, 0.430 mmol) in DMF (2 mL) was stirred at 25 °C for 16 hours. The mixture was purified by MPLC (ICSO: 80 g Agela Silica Flash Column, Eluent of 50-78% MeCN / water gradient @ 40 mL / min) to yield the desired product. MS: 223 [M+l]+.6-hvdroxy-A- 3-carboxamide (1-31)

[0185] A solution of 6-methoxy-A-methylbenzo[< / ]isothiazole-3-carboxamide (58 mg, 0.261 mmol) in BBr? (1000 pL, 2.00 mmol) (2 M in THF) was stirred at 25 °C for 16 hours. The mixture was added to ice, lyophilized to afford the desired product, which was used directly in the next step without further purification. MS: 209 [M+l]+.Table 5: Using methods similar to that outlined in the synthesis of 1-31, and the appropriate starting materials, the following intermediate was prepared:Preparation of intermediate 4-((l-fluoro-5-(methylcarbamoyl)naphthalen-2-yl)oxy)-5- rnelhylpyrrolol 1.2- / ?|pyndazine-6-carboxylic acid (1-34),

[0186] Intermediate (1-34) was prepared according to synthetic route outlined in Scheme 10.Scheme 10ethyl 4-((l-fluoro-5-(methylcarbamoyl)naphthalen-2-yl)oxy)-5-methylpyrrolo[1.2-b1pyridazine- 6-carboxylate (1-33)

[0187] In a 30 mL vial, 5-fluoro-6-hydroxy-N-methyl-l-naphthamide (329 mg. 1.50 mmol), 1-3 (298 mg. 1.25 mmol), and cesium carbonate (489 mg. 1.50 mmol) was dissolved in DMF (12.5 mL), and the reaction mixture was stirred at 80 °C for 18 hours. The crude reaction mixture was diluted with EtOAc (50 mL) and water (50 mL). The aqueous mixture was extracted with EtOAc (50 mL x 2). The organic phases were combined, washed with 0.5 wt% LiCl (aq. 50 mL) and brine (aq, 50 mL x 3). The organic solution was then dried (Na2SO4) and concentrated. Column chromatography (silica gel, MeOH in DCM, gradient 1 to 5%) yielded the desired product. MS: 422 [M+l]+.4-((l-fluoro-5-(methylcarbamoyl)naphthalen-2-yl)oxy)-5-methylpyrrolo[1.2-&1pyridazine-6- carboxylic acid 11=341

[0188] To a stirring solution of ethyl 4-((l-fluoro-5-(methylcarbamoyl)naphthalen-2-yl)oxy)-5- methylpyrrolo[l,2-b]pyridazine-6-carboxylate (350 mg, 831 pmol) in MeOH (5.00 mL) was added 1 NaOH (aq, 4.15 mL, 4.15 mmol), and the resulting reaction mixture w as allow ed to stir at 50 °C for 18 hours. The reaction mixture was diluted with water (20 mL), and the MeOH was removed under reduced pressure. The aqueous solution was washed with EtOAc (30 mL x 2). The aqueous solution was cooled in an ice bath and acidified with 1 A / HC1 until pH of 5. The product was isolated by filtration, w ashed with cold water, air dried and further dried under high vacuum. MS: 394 [M+l]+.JH NMR (500 MHz, DMSO- e) 5 8.63 (d. J= 4.5 Hz. 1H), 8.23 - 8.15 (m, 2H), 7.84 (s, 1H). 7.80 (d, J= 5.3 Hz, 1H). 7.76 - 7.72 (m, 2H), 7.68 (t, J= 8.7 Hz. 1H), 5.57 (d, J= 5.2 Hz, 1H), 2.88 (d, J= 4.6 Hz, 3H), 2.78 (s, 3H).Table 6: Using methods similar to that outlined in the synthesis of 1-34 and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediate 4-(4-(3-cyclopropylureido)-3-methylphenoxy)-5-methylpyrrolo[ 1.2-£|pyridazine-6-carboxylic acid (I-53),

[0189] Intermediate (1-53) was prepared according to synthetic route outlined in Scheme 11.Scheme 11ethyl 4-(4-amino-3-chlorophenoxy)-5-methylpyrrolo[ 1 ,2-6 ]pyridazine-6-carboxylate (1-51)

[0190] A mixture of 1-3 (1.5 g, 6.28 mmol), 4-amino-3-chlorophenol (0.99 g, 6.91 mmol) and K2CO3 (2.61 g, 18.9 mmol) in DMF (10 mL) was stirred at 60 °C for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 30%) yielded the desired product. MS: 346 [M+l]+. ethyl 4-(3-chloro-4-(3-methylureido) phenoxy )-5 -methyl pyrrolo [1,2-6] pyridazine -6- carboxylate (1-52)

[0191] To a solution of ethyl 4-(4-amino-3-chlorophenoxy)-5-methylpynolo[ 1,2-6] pyridazine- 6-carboxylate (300 mg, 0.87 mmol) in CHCk (6 mL) was added TEA (0.36 mL, 2.60 mmol) and triphosgene (252 mg, 0.85 mmol) and stirred at 0 °C for 0.5 hours. After methanamine (1.3ml, 2.60 mmol) (2 M in THF) in CHCI3 (6 mL) was added to the mixture, the resulting reaction mixture was stirred at 25 °C for 1 hour. The mixture was quenched with sat. NaHCOs (10 mL). Water (10 mL) was added to the mixture. The mixture was extracted with DCM (10 mL x 3).The organic phase w as dried with Na2SO4, and filtered. The filtrate w as concentrated under vacuum. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 30%) yielded the desired product. MS: 403 [M+l]+.4-(3-chloro-4-(3-methylureido)phenoxy)-5-methylpyrrolo[1.2-6] pyridazine-6-carboxylic acid (I- 53)

[0192] To a solution of ethyl 4-(3-chloro-4-(3-methylureido)phenoxy)-5-methylpyrrolo[l,2- 6]pyridazine-6-carboxylate (60 mg, 0.15 mmol) and NaOH (0.15 mL, 0.3 mmol) in THF (0.4 mL), water (0.2 mL) and EtOH (0.4 mL) at 25 °C for 5 hours. The mixture was acidified withHC1 (1 M in water) to pH 5-6. then filtered and dried under high vacuum to afford the desired product. MS: 375 [M+l]+. 'H NMR (400 MHz, CD30D) 5 8.22 - 8.10 (m, 2H), 7.87 (d, J= 5.2 Hz, 1H), 7.36 (d, J= 2.8 Hz, 1H), 7.18 (dd, J= 9.2, 2.8 Hz, 1H), 5.67 (d, J= 5.6 Hz, 1H), 4.81 - 4.50 (m, 1H), 2.81 (s, 3H), 2.H (s, 3H), 1.51 - 1.15 (m. 1H).Table 7: Using methods similar to that outlined in the synthesis of 1-53, and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediates (R or .S')-4-(3-chloro-4-(3-(2.2- difluorocvclopropyl)ureido)r>henoxy)-5-methylr)yrrolo[ 1.2-61pyridazine-6-carboxylic acid I-61A1-6 IB)

[0193] Intermediate 1-61 A and I-61B was prepared according to synthetic route outlined inScheme 12.Scheme 12I-61A 1-61 B ethyl (R or 5)-4-(3-chloro-4-(3-(2.2-difluorocvclopropyl)ureido)phenoxy)-5-methylpyrrolo[1.2-Z?]pyridazine-6-carboxylate (I-60A and I-60B)

[0194] To a solution of ethyl 4-(4-amino-3-chlorophenoxy)-5-methylpyrrolo[l,2-Z?]pyridazine- 6-carboxylate (700 mg, 2.02 mmol) in CHCh (10 mb) was added TEA (0.85 mL, 6.07 mmol)and triphosgene (589 mg, 1.98 mmol). The mixture was stirred at 25 °C for 30 minutes, then 2,2- difluorocyclopropan-1 -amine hydrochloride (787 mg, 6.07 mmol) in CHCh (5 mL) was added to the mixture. The resulting reaction mixture was stirred at 25 °C for 1 hour, then quenched with sat. NaHCCb (5 mL). Water (5 mL) was added to the mixture. The mixture was extracted with CH2CI2 (10 mL x 3). The organic phase was dried with Na2SO4, filtered and the filtrate was concentrated under vacuum. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 30%) yielded the desired product.

[0195] The mixture of the two stereoisomers was purified by chiral SFC (OD column, Mobile phase A: CO2, B: 30% IPA with 0. 1% NH4OH) to afford isomer I-60A (faster eluting) and I-60B (slower eluting). Isomer I-60A: MS: 465 [M+l]+. Isomer I-60B: MS: 465 [M+l]+.(R or M-4-(3-chloro-4-(3-(2.2-difluorocyclopropyl)ureido)phenoxy)-5-methylpyrrolo[1.2- &lpyridazine-6-carboxylic acid (1-61 A)

[0196] A mixture of I-60A (180 mg, 0.39 mmol) in sulfuric acid (4.0 mL, 0.39 mmol) (70 % in water) was stirred at 80 °C for 2 hours. The mixture was filtered, and the filtrate was purified by mass-directed reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the desired product. MS: 437 [M+l]+.(S or )-4-(3-chloro-4-(3-(2.2-difluorocvclopropyl)ureido)phenoxy)-5-methylpyrrolo[ 1,2- >1pyridazine-6-carboxylic acid (1-6 IB) I-61B was prepared using methods similar to that outlined in the synthesis of 1-61A, and starting with I-61B in place of I-60A MS: 437 [M+l]+.

[0197] Preparation of intermediate 4-((l-(cyclopropylcarbamoyl)-5-fluoro-l,2,3,4- tetrahydroquinolin-6-yl)oxy)-5-methylpyrrolo[l,2-b]pyridazine-6-carboxylic acid (1-66) Intermediate 1-66 was prepared according to synthetic route outlined in Scheme 13.Scheme 13tert-butyl 6-bromo-5-fluoro-3.4-dihvdroquinoline-l(2Lf)-carboxylate (1-62)

[0198] A 40 mL vial equipped with a magnetic stir bar was charged with 6-bromo-5-fluoro-1.2.3.4-tetrahydroquinoline (1.00 g, 4.35 mmol) and di-tert-butyl dicarbonate (2.85 g, 13.0 mmol). Toluene (4.35 mL) was added, and the reaction mixture was stirred at 90 °C for 18 hours. The reaction mixture w as concentrated. Column chromatography (silica gel, EtOAc in hexanes, gradient 0 to 30%) afforded the desired product. MS: 274 [M-55]+. tert-butyl 5-fluoro-6-hvdroxy-3.4-dihvdroquinoline-l (2Z / )-carboxylate (1-63)

[0199] A 100 mL round bottom flask equipped with a magnetic stir bar was charged with tris(dibenzylideneacetone)dipalladium (137 mg, 150 pmol) and 2-(di-tert-butylphosphino)- 3,4,5,6-tetramethyl-2',4'.6'-triisopropyl-l,l'-biphenyl (216 mg, 450 pmol). The flask was evacuated and backfilled with nitrogen 3 times before 1,4-dioxane (9.00 mL) was added. In a separate 20 mL vial, 1 M KOH (aq, 9.00 mL) w as sparged with nitrogen for 15 mins before being added to the flask containing the Pd catalyst. In a separate 20 mL vial, tert-butyl 6-bromo-5- fluoro-3,4-dihydroquinoline-l(2 / 7)-carboxylate (991 mg, 3.00 mmol) was added, followed by1.4-dioxane (9.00 mL). This solution was sparged with nitrogen for 15 minutes before being added to the reaction flask containing the Pd catalyst. The reaction mixture was stirred at 100 °C for 5 hours. The crude reaction mixture was diluted with water, then acidified to pH 5 with 3 MHC1. EtOAc (50 mL) was added. The organic mixture was washed with brine and then dried (Na2SO4) and concentrated. Column chromatography (silica gel, EtOAc / EtOH (3 / 1) in hexanes, gradient 5 to 30%) afforded the desired product. MS: 212 [M-55]+. tert-butyl 6-((6-(ethoxycarbonyl)-5-methylpyrrolo[1.2- dpyridazin-4-yl)oxy)-5-fluoro-3.4- dihvdroquinoline- 1 -carboxylate (1-64)

[0200] To tert-butyl 5-fluoro-6-hydroxy-3,4-dihydroquinoline-l(2H)-carboxylate (348 mg, 1.30 mmol), ethyl 4-chloro-5-methylpyrrolo[l,2-Z>]pyridazine-6-carboxylate (311 mg, 1.30 mmol), and CS2CO3 (636 mg, 1.95 mmol), DMF (5.00 mL) was added, and the mixture was allowed to stir at 80 °C for 16 hours. The crude reaction mixture was diluted with EtOAc and water. The aqueous mixture was extracted with EtOAc. The organic phases were combined, washed with brine, dried (MgSO4) and concentrated. Column chromatography (silica gel, EtOAc / EtOH(3 / l) in hexanes, gradient 0 to 30%) yielded the desired product. MS: 492 [M+23]+. ethyl 4-((l-(cvclopropylcarbamoyl)-5-fluoro-1.2.3.4-tetrahvdroquinolin-6-yl)oxy)-5- methylpyrrolol L2-6]pyridazine-6-carboxylate (1-65)

[0201] Step 1 : To a solution of tert-butyl 6-((6-(ethoxycarbonyl)-5-methylpyrrolo[l,2- Z’]pyridazin-4-yl)oxy)-5-fluoro-3,4-dihydroquinoline-l(2EZ)-carboxylate (800 mg, 1.70 mmol) in DCM (10 mL). TFA (1 mL, 1.70 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The crude reaction mixture was diluted with DCM and was washed with NaHCO? (sat. aq). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude material was used directly in the next step without further purification. MS: 370 [M+l]+.

[0202] Step 2: A mixture of ethyl 4-((5-fluoro-l,2,3,4-tetrahydroquinolin-6-yl)oxy)-5- methylpyrrolo[1.2-d]pyridazine-6-carboxylate (300 mg. 0.81 mmol) and isocyanatocyclopropane (0. 17 mL, 2.44 mmol) in DMF (3.0 mL) was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 50%) yielded the desired product. MS: 453 [M+l]+.4-((l-(cyclopropylcarbamoyl)-5-fluoro-1.2.3.4-tetrahvdroquinolin-6-yl)oxy)-5- rnethylpyrrolol 1.2- / >|pyndaziiie-6-carboxylic acid (1-66)

[0203] A mixture of ethyl 4-((l-(cyclopropylcarbamoyl)-5-fluoro-l,2,3,4-tetrahydroquinolin-6- yl)oxy)-5-methylpyrrolo[l,2-i>] pyridazine-6-carboxylate (180 mg, 0.40 mmol) and 2 M NaOH (aq, 0.6 mL, 1.19 mmol) in THF (2 mL) and ethanol (2.0 mL) was stirred at 50 °C for 4 hours.The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired product. MS: 425 [M+l]+.Table 8: Using methods similar to that outlined in the synthesis of 1-66, and the appropriate starting materials, the following intermediates were prepared:

[0204] Preparation of intermediate 4-(4-(3-cyclopropylureido)-3-(difluoromethyl)phenoxy)-5- methylpyrrolo [ 1.2-bp ]yridazine-6-carboxylic acid (1-78)Intermediate (1-78) was prepared according to synthetic route outlined in Scheme 14.Scheme 14

[0205] A mixture of 1-3 (500 mg, 2. 1 mmol), 4-bromo-3-(difluoromethyl)phenol (514 mg, 2.3 mmol) and Cs2CO3 (1.4 g, 4.2 mmol) in DMF (20 mL) was stirred at 80 °C for 3 hours. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with LiCl (0.5 wt% aq, 50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOH / EtOAc (1 / 3) in hexanes, gradient 5 to 60%) yielded the desired product. MS: 425 [M+l]+, 427 [M+3]+. ethyl 4-(3-(difluoromethyl)-4-((diphenylmethylene)amino)phenoxy)-5-methylpyrrolo[ 1 ,2- 6|pyridazine-6-carbo.xylate (1-75)

[0206] A mixture of ethyl 4-(4-bromo-3-(difluoromethyl)phenoxy)-5-methylpyrrolo[l,2- Z>]pyridazine-6-carboxylate (210 mg, 0.5 mmol), benzophenone imine (180 mg, 1.0 mmol), XantPhos Pd G3 (95 mg, 0.1 mmol), and CS2CO3 (650 mg, 2.0 mmol) were suspended in dioxane (10 mL) under nitrogen. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was diluted with EtOAc (50 mL). The organic mixture was washed with NaHCOs (sataq. 50 mL), brine (50 mL), dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOH / EtOAc (1 / 3) in hexanes, gradient 5 to 40%) yielded the desired product. MS: 526 [M+l]+. ethyl 4-(4-amino-3-(difluoromethyl)phenoxy)-5-methylpyrrolori.2-d]pyridazine-6-carboxylate 0=761

[0207] Ethyl 4-(3-(difluoromethyl)-4-((diphenylmethylene)amino)phenoxy)-5- methylpyrrolo[l,2-Z?]pyridazine-6-carboxylate (250 mg, 0.48 mmol) was dissolved in MeOH (5.0 mL). HC1 (4 Alin dioxane, 0.24 mL. 0.95 mmol) was added. Then the reaction mixture was stirred at 25 °C for 1 hour, then was concentrated under reduced pressure. Column chromatography (silica gel, MeOH in DCM, gradient 0 to 3%) yielded the desired product. MS: 362 [M+l]+. ethyl 4-(4-(3-cvclopropylureido)-3-(difluoromethyl)phenoxy)-5-methylpyrrolo[1.2-6]pyridazine- 6-carboxylate (1-H)

[0208] To a solution of Ethyl 4-(4-amino-3-(difluoromethyl)phenoxy)-5-methylpyrrolo[l,2- Zi]pyridazine-6-carboxylate (160 mg, 0.44 mmol) in THF (4.4 mL), cyclopropyl isocyanate (0.2 mL, 2.7 mmol) and DIPEA (0.8 mL, 4.4 mmol) were added. The reaction mixture was stirred at 50 °C for 18 hours. The mixture was diluted with DCM (200 mL). The organic mixture was washed with NH4CI (sat aq, 50 mL). brine (50 mL). dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. Column chromatography (silica gel, MeOH in DCM, gradient 0 to 5%) yielded the desired product. MS: 409 [M+l]+.4-(4-(3-cyclopropylureido)-3-(difluoromethyl)phenoxy)-5-methylpyrrolo[1.2- / >]pyridazine-6- carboxylic acid (1-78)

[0209] A solution of ethyl 4-(4-(3-cyclopropylureido)-3-(difluoromethyl)phenoxy)-5- methylpyrrolo[l,2- / i]pyridazine-6-carboxylate (250 mg, 0.56 mmol) and NaOH (1 M, 2.8 mL, 2.8 mmol) in THF (2.8 mL) and EtOH (2.8 mL) was stirred at 50 °C for 1 hour. THF and EtOH were removed under reduced pressure. The remaining aqueous solution was acidified with HC1 (1 M in water) to pH 5-6, then filtered and dried under high vacuum to afford the desired product. MS: 417 [M+l]+.

[0210] Preparation of intermediate 4-(3-cyclopropyl-4-(3-cyclopropylureido)phenoxy)-5- methylpyrrolof l .2- / >|pyndazine-6-carboxylic acid (1-82)Intermediate 1-82 was prepared according to synthetic route outlined in Scheme 15.Scheme 151-81 I-82 ethyl 4-(4-amino-3-bromophenoxy)-5-methylpyrrolo[ 1.2- / ? | pyndazine-6-carboxylate (1-79)

[0211] A mixture of 4-amino-3 -bromophenol (1 g, 5.32 mmol), ethyl 4-chloro-5- methylpyrrolo[L2-6]pyridazine-6-carboxylate (1.269 g, 5.32 mmol) and CS2CO3 (3.47 g, 10.64 mmol) in DMF (25 mL) was stirred at 80 °C for 3 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 20%) yielded the desired product. MS: 392 [M+3]+. ethyl 4-(4-amino-3-cyclopropylphenoxy)-5-methylpyrrolo[ 1 ,2-61pyridazine-6-carboxylate (1-80)

[0212] A mixture of ethyl 4-(4-amino-3-bromophenoxy)-5-methylpyrrolo[l,2-Z?]pyridazine-6- carboxylate (1.75 g, 4.48 mmol), cyclopropylboronic acid (1.156 g. 13.45 mmol), potassium phosphate tribasic (3.81 g, 17.94 mmol) and Pd(dppf)Ch (0.328 g, 0.448 mmol) in 1,4-dioxane (17 mL) was stirred at 100 °C for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 20%) yielded the desired product. MS: 352 [M+l]+. ethyl 4-(3-cyclopropyl-4-(3-cvclopropylureido)phenoxy)-5-methylpyrrolo[L2-d1pyridazine-6- carboxylate 11=811

[0213] To a solution of ethyl 4-(4-amino-3-cyclopropylphenoxy)-5-methylpyrrolo[l,2- d]pyridazine-6-carboxylate (400 mg, 1.138 mmol) and TEA (0.476 mL, 3.41 mmol) in DCM (10 mL) was added bis(trichloromethyl) carbonate (280 mg, 0.944 mmol) at 0 °C over 1 min. After stirring for 0.2 hours at 25 °C, cyclopropanamine (0.237 mL, 3.41 mmol) was added to themixture at 0 °C, and the resulting mixture was stirred for another 1 hour at 25 °C. The solvent was removed under reduced pressure and the residue was dissolved in water (40 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous was re-extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 80%) yielded the desired product. MS: 435 [M+l]+. 4-(3-cyclopropyl-4-(3-cvclopropylureido)phenoxy)-5-methylpyrrolo[1.2-61pyridazine-6- carboxylic acid (1-82)

[0214] To a solution of ethyl 4-(3-cyclopropyl-4-(3-cyclopropylureido)phenoxy)-5- methylpyrrolo| 1.2-6 |pyndazine-6-carboxylate (75 mg, 0.173 mmol) in THF (0.5 mL) and EtOH (0.5 mL) was added NaOH (0.259 mL, 0.518 mmol) in water (0.1 mL) at 25 °C and the reaction mixture was allowed to stir for 2 hours at 60 °C. The solvent was removed under reduced pressure, and the residue was dissolved in water (5 mL) to give a mixture, which was adjusted pH to 6.5 ~ 7 by using 1 ALHC1 and then lyophilized to give the desired product, which was used in the next step directly without further purification. MS: 407 [M+l]+.Preparation of intermediate 4-(4-(3-cyclopropylureido)-2-fluoro-3-methylphenoxy)-5- methylpyrrolol 1.2-6 |pyndazine-6-carboxylic acid (1-88)

[0215] Intermediate 1-88 was prepared according to synthetic route outlined in Scheme 16.Scheme 161-87 1-88te / 7-butyl (4-bromo-3-fluoro-2-methylphenyl)carbamate (1-83)

[0216] To a solution of 4-bromo-3-fluoro-2 -methylaniline (2.00 g, 9.80 mmol) in THF (40 rnL) was added BOC2O (2.48 mL, 10.8 mmol) and the resulting mixture was stirred at 70 °C under N2 protection for 12 hours. The reaction mixture was concentrated. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 30%) afforded the desired product. MS: 248 [M- 55]+. tert-butyl (3-fluoro-4-hvdroxy-2-methylphenyl)carbamate (1-84)

[0217] To a solution of tert-butyl (4-bromo-3-fluoro-2-methylphenyl)carbamate (500 mg, 1.64 mmol) in 1,4-dioxane (5 mL) were added 2-di-tert-butylphosphino-3.4.5.6-tetramethyl-2',4',6'- triisopropyl-l,l'-biphenyl (119 mg, 0.247 mmol) and Pd2(dba)? (75 mg, 0.082 mmol) and 1.6 M KOH (aq, 461 mg, 8.22 mmol). The resulting mixture was stirred at 110 °C under N2 for 2 hours. The reaction mixture was adjusted pH to 4 by using 2MHC1, extracted with EtOAc (10 mLx3). The organic layer was washed with brine (10 mL), dried over Na2SOr and filtered. The filtrate was concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 50%) afforded the desired product. MS: 186 [M-55]+. ethyl 4-(4-( butoxycarbonyl)amino)-2-fluoro-3-methylphenoxy)-5-methylpyrrolo| 1.2- / ?|pyndazine-6-carboxylate (1-85)

[0218] To a solution of tert-butyl (3-fluoro-4-hydroxy-2-methylphenyl)carbamate (180 mg, 0.746 mmol) in DMF (6 mL) were added ethyl 4-chloro-5-methylpyrrolo[l,2-Z?]pyridazine-6- carboxylate (196 mg, 0.821 mmol) and CS2CO3 (729 mg, 2.238 mmol), and the resulting mixture was stirred at 50 °C under N2 for 2 hours. The reaction mixture was poured into water (10 mL and extracted with EtOAc (10 mLx3). The organic layer was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 60%) yielded the desired product. MS: 444 [M+l]+. ethyl 4-(4-amino-2-fluoro-3-methylphenoxy)-5-methylpyrrolo[1.2-61pyridazine-6-carboxylate (I- 86)

[0219] To a solution of ethyl 4-(4-((tertebutoxycarbonyl)amino)-2-fluoro-3-methylphenoxy)-5- methylpyrrolo [ 1.2-bp ]yridazine-6-carboxylate (150 mg, 0.338 mmol) in DCM (1.5 mL) was added TFA (0.5 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into aq. NaHCOs (5 mL) and extracted with DCM (5 mLx3). The organic layer was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the crude material was used directly in the next step without further purification. MS: 344 [M+l]+.ethyl 4-(4-(3-cyclopropylureido)-2-fluoro-3-methylphenoxy)-5-methylpyrrolo[L2-d1pyridazine- 6-carboxylate d-87)

[0220] To a solution of ethyl 4-(4-amino-2-fluoro-3-methylphenoxy)-5-methylpyrrolo[l,2- d]pyridazine-6-carboxylate (110 mg, 0.320 mmol) in DCM (1.5 mL) were added TEA (0.134 mL, 0.961 mmol) and triphosgene (57.0 mg, 0. 192 mmol) at 0 °C. The resulting mixture was stirred at 0 °C under N2 for 0.5 hours. Then, to the mixture was added cyclopropanamine (36.6 mg, 0.641 mmol, in 0.5 mL DCM). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 50 to 100%) yielded the desired product. MS: 427 [M+l]+.4-(4-(3-cvclopropylureido)-2-fluoro-3-methylphenoxy)-5-methylpyrrolo[1.2-i lpyridazine-6- carboxylic acid (1-88)

[0221] To ethyl 4-(4-(3-cyclopropylureido)-2-fluoro-3-methylphenoxy)-5-methylpyrrolo[l,2- 6]pyridazine-6-carboxylate (120 mg, 0.281 mmol) in THF (1 mL) and EtOH (1 mL). 2 A NaOH (aq, 0.211 mL. 0.422 mmol) was added. The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated and adjusted pH to 4 by using 2 A / HC1 (0.5 mL). The aqueous phase was lyophilized, and the crude material was used directly in the next step without further purification. MS: 399 [M+l]+. ’H NMR (400 MHz, CD3OD) 5 8. 13 (s, 1H), 7.86 (d, J = 5.6 Hz. 1H), 7.51 (d. J= 8.8 Hz. 1H), 7.17 (t, J= 8.4 Hz, 1H), 5.65 (d, J= 5.6 Hz, 1H), 2.79 (s, 3H), 2.68 - 2.57 (m, 1H), 2.22 (d, J= 2.0 Hz, 3H), 0.80 - 0.74 (m, 2H), 0.60 - 0.51 (m, 2H). Preparation of intermediate 4-((l-(ethylcarbamoyl)-l / 7-indazol-5-yl)oxy)-5-methylpyrrolo[1.2- &]pyridazine-6-carboxylic acid (1-91),

[0222] Intermediate (1-91) was prepared according to synthetic route outlined in Scheme 17.Scheme 171-90 1-91ethyl 4-(( 1H-indazol-5-yl)oxy)-5-methylpyrrolo[l,2-&]pyridazine-6-carboxylate (1-89)

[0223] A mixture of ethyl 4-chloro-5-methylpyrrolo[l,2-Z?]pyridazine-6-carboxylate (300 mg, 1.26 mmol) and 1H-indazol-5-ol (169 mg, 1.26 mmol), CS2CO3 (819 mg, 2.51 mmol) in DMF (4 mL) was stirred at 100 °C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 50%) yielded the desired product. MS: 337 [M+l]+. ethyl 4-((l-(ethylcarbamoyl)- indazol-5-yl)oxy)-5-methylpyrrolo[ 1.2-61pyridazine-6-carboxylate d-90)

[0224] A mixture of ethyl 4-((1H-indazol-5-yl)oxy)-5-methylpyrrolo[l,2-Z?]pyridazine-6- carboxylate (120 mg, 0.357 mmol) and isocyanatoethane (0.034 mL, 0.428 mmol) in THF (2.00 mL) was stirred at 70 °C for 16 hours. The mixture was concentrated under reduced pressure to afford the desired product, which was used directly in the next step without further purification. MS: 408 [M+l]+.4-((l-(ethylcarbamoyl)- indazol-5-yl)oxy)-5-methylpyrrolo[1.2-Zdpyridazine-6-carboxylicacid (1-91)

[0225] To a solution of ethyl 4-((l-(ethylcarbamoyl)-lH-indazol-5-yl)oxy)-5- methylpyrrolo[l,2-b]pyridazine-6-carboxylate (130 mg, 0.319 mmol) in DCM (2.00 mL) was added BBr3 (0.600 mL, 6.35 mmol) at 0 °C, and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with H2O (2.00 mL) at 0 °C and lyophilized to afford the desired product, which was used directly in the next step without further purification. MS: 380 [M+l]+.Preparation of intermediate 4-((l-(ethylcarbamoyl)-4-fluoro- indazol-5-yl)oxy)-5-methylpyrrolol 1.2-A>|pyndazme-6-carboxylic acid (1-97),

[0226] Intermediate 1-97 was prepared according to synthetic route outlined in Scheme 18.Scheme 185-bromo-4-fluoro-l-(tetrahvdro-2H-pyran-2-yl)-l H-indazole (1-92)

[0227] A mixture of 5-bromo-4-fluoro-l / / -indazole (500 mg, 2.325 mmol) and p- toluenesulfonic acid (80 mg, 0.465 mmol), 3,4-dihydro-2H-pyran (0.318 mL, 3.49 mmol) in DCM (8.00 mL) was stirred at 35 °C for 16 hours. The mixture was concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 20%) yielded the desired product. MS: 301 [M+l-84]+.4-fluoro-l-(tetrahvdro-2H-pyran-2-yl)-l / / -indazol-5-ol (1-93)

[0228] A mixture of 5-bromo-4-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (580 mg, 1.94 mmol), 2-di-fert-butylphosphino-3.4.5.6-tetramethyl-2',4'.6'-triisopropyl-l,r-biphenyl (140 mg, 0.291 mmol), Pd2(dba)s (89 mg, 0.097 mmol) and KOH (326 mg, 5.82 mmol) in dioxane (4.00 mL) and water (4.00 mL) was degassed and backfdled with N2 three times. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was adjusted pH to 3-4 with 6 A / HC1 (aq), quenched with H2O (4.00 mL). and extracted with EtOAc (4.00 mL x 3). The combined organic phases were washed with brine (2.00 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 35%) yielded the desired product. MS: 237 [M+l]+. ethyl4-((4-fluoro-l-(tetrahvdro-2H-pyran-2-yl)-lH-indazol-5-yl)oxy)-5-methylpyrrolo[1.2- / >1pyridazine-6-carboxylate (1-94)

[0229] A mixture of 4-fluoro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-ol (400 mg, 1.69 mmol) and ethyl 4-chloro-5-methylpyrrolo[l,2-(>]pyridazine-6-carboxylate (404 mg, 1.69 mmol), CS2CO3 (1.10 g, 3.39 mmol) in DMF (4.00 mL) was stirred at 100 °C for 2 hours. The reaction mixture was quenched with H2O (40 mL) and extracted with EtOAc (40 mL x 3). The combinedorganic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 30%) yielded the desired product. MS: 439 [M+l]+. ethyl 4-((4-fluoro- indazol-5-yl)oxy)-5-methylpyrrolo[l .2-6] pyridazine-6-carboxylate (1-95)

[0230] A mixture of ethyl 4-((4-fluoro-l-(tetrahydro-2H-pyran-2-yl)-l / f-indazol-5-yl)oxy)-5- methylpyrrolo [ 1.2-bp ]yridazine-6-carboxylate (340 mg, 0.H5 mmol) and 2 MHCl (28.3 mg, 0.H5 mmol, in dioxane) in dioxane (2.00 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 60%) yielded the desired product. MS: 355 [M+l]+. ethyl 4-((l-(ethylcarbamoyl)-4-fluoro-l / f-indazol-5-yl)oxy)-5-methylpyrrolo[1.2-6]pyridazine-6- carboxylate (1-96)

[0231] A mixture of ethyl 4-((4-fluoro-lE7-indazol-5-yl)oxy)-5-methylpyrrolo[l,2- 6]pyridazine-6-carboxylate (100 mg, 0.282 mmol) and isocyanatoethane (0.027 mL, 0.339 mmol) in THF (2.00 mL) was stirred at 70 °C for 16 hours. The mixture was concentrated under reduced pressure to yield the desired product, which was used in the next step directly without further purification. MS: 426 [M+l]+.4-((l-(ethylcarbamoyl)-4-fluoro-l / f-indazol-5-yl)oxy)-5-methylpyrrolo[1.2-b]pyridazine-6- carboxylic acid (1-97)

[0232] To a solution of ethyl 4-((l-(ethylcarbamoyl)-4-fluoro-l / 7-indazol-5-yl)oxy)-5- methylpyrrolo [ 1.2-bp ]yridazine-6-carboxylate (100 mg, 0.235 mmol) in DCM (2.00 mL) was added BBn (0.600 mL, 6.35 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with H2O (2.00 mL) at 0 °C, concentrated under reduced pressure and lyophilized to yield the desired product, which was used in the next step directly without further purification. MS: 398 [M+l]+.Preparation of intermediate I -(4-chloro-5-methylpyrrolo| 1 .2-6 |pyridazine-6-carbonyl jazetidine- 3-carbonitrile (1-99)

[0233] Intermediate 1-99 was prepared according to synthetic route outlined in Scheme 19.Scheme 194-chloro-5-methylpyrrolo[L2-d1pyridazine-6-carboxylic acid (1-98)

[0234] To a stirring solution of 1-3 (2.0 g, 8.38 mmol) in THF (50.0 mL) and ethanol (50.0 mL) was added 2 M NaOH (aq, 12.6 mL, 25.1 mmol), and the resulting reaction mixture was allowed to stir at 50 °C for 16 hours. The reaction mixture was quenched with 1 M HC1 (aq, 20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic fractions were dried (MgSCL). and fdtered. The solvent was evaporated under reduced pressure to afford the desired product, which was used in the next step without further purification. MS: 211 [M+l]+. l-(4-chloro-5-methylpyrrolo[1.2-d1pyridazine-6-carbonyl)azetidine-3-carbonitrile (1-99)

[0235] A 100 mL round bottom flask was charged with 4-chloro-5-methylpyrrolo[l,2- £>]pyridazine-6-carboxylic acid (1. 14 g, 5.41 mmol), azetidine-3-carbonitrile HC1 (H0 mg, 6.49 mmol), HATU (2.47 g, 6.49 mmol) and DMF (18.0 mL). DIPEA (2.83 mL,16.2 mmol) was added, and the resulting reaction mixture was stirred at 25 °C for 16 hours. The mixture was concentrated, diluted with EtOAc (20 mL), washed with aqueous lithium chloride (1 M. 20 mL x 2), dried (MgSO4). and filtered. The solvent was evaporated under reduced pressure. Column chromatography (silica gel, EtOAc in hexanes, gradient 0 to 50%) yielded the desired product. MS: 275 [M+l]+. *H NMR (600 MHz, DMSO-i / e) 3 8.25 (s, 1H), 8.12 (d, J= 4.9 Hz, 1H), 6.85 (d, J= 4.9 Hz, 1H), 4.55 (d, J= 39.2 Hz, 2H), 4.34 (s. 1H), 4.17 (s, 1H), 3.87 - 3.76 (m, 1H), 2.67 (s, 3H).Table 9: Using methods similar to that outlined in the synthesis of 1-99 and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediate (A)-(4-chloro-5-methylpyrrolo[ 1.2-6|pyridazin-6-yl)(3-hvdroxy-3- methylpyrrolidin- 1 -vDmethanone (1-104)

[0236] Intermediate 1-104 was prepared according to synthetic route outlined in Scheme 20.Scheme 20

[0237] 4 -Chloro-5-methylpyrrolo[l ,2- / ’]pyridazine-6-carboxylic acid (527 mg, 2.50 mmol) and (R)-3-methylpyrrolidin-3-ol HC1 (460 mg, 3.34 mmol) were dissolved in DMF (20.0 mL). T3P (2.21 mL, 3.75 mmol) and DIPEA (0.87 mL, 5.0 mmol) were added, and the resulting reaction mixture was stirred at 50 °C for 16 hours. The mixture was concentrated, diluted with EtOAc (20 mL), washed with water and brine (20 mL x 2). The organic layer was dried (MgSO i). filtered and the solvent was evaporated under reduced pressure. Column chromatography (silica gel, EtOAc / EtOH (3 / 1) in hexanes, gradient 0 to 100%) yielded the desired product. MS: 294 [M+l]+. 'H NMR (600 MHz, CDCls) 5 7.87 - 7.78 (m, 2H), 6.53 (d. J = 4.8 Hz. 1H), 3.95 - 3.38 (m. 4H), 2.67 (s, 3H), 2.09 - 1.92 (m, 2H), 1.56 - 1.40 (m, 3H). Table 10: Using methods similar to that outlined in the synthesis ofl-102, and the appropriate starting materials, the following intermediates were prepared:Preparation of intermediate (4-((3.4-dihvdro-2 / 7-benz.o|6 || 1.4|oxaz.in-7-yl )oxy)-5- melhylpyrrolol l .2-6|pyndazin-6-yl )(3-methoxyazetidin- l -yl jmethanone (1-107)

[0238] Intermediate 1-107 was prepared according to synthetic route outlined in Scheme 21.Scheme 21tert-butyl 7-((6-(3-methoxyazetidine- l -carbonyl )-5-methylpyrrolo| 1 ,2-6|pyridazin-4-yl )oxy)-2.3- dihvdro-4 / 7-benzo|A>|| 1 .4|oxazine-4-carboxylate (1-106)

[0239] A 30 mb vial equipped with a magnetic stir bar was charged with 4-((4-(tert- butoxycarbonyl)-3,4-dihydro-2 / 7-benzo[6][1.4]oxazin-7-yl)oxy)-5-methylpyrrolo[1.2- Z’lpyndazine-6-carboxylic acid (170 mg, 400 pmol), 3-methoxyazetidine hydrochloride (148 mg, 1.20 mmol), and HATU (456 mg, 1.20 mmol). DMF (7.99 mb) and DIPEA (487 pL, 2.80 mmol) were added, and the reaction mixture was stirred at 25 °C for 18 hours. The crude reaction mixture was diluted with EtOAc (50 mL) and water (50 mL). The aqueous mixture was extracted with EtOAc (50 mL x 2). The organic phases were combined, washed with 0.5 wt% LiCl (aq, 50 mL) and brine (aq, 50 mL x 3). The organic solution was then dried (Na2SO4) and concentrated. Column chromatography (silica gel, MeOH in DCM, gradient 1 to 10%) yielded the desired product. MS: 495 [M+l]+.(4-((3.4-dihydro-2 / f-benzo|£ || L4|oxazin-7-yl)oxy)-5-methylpyrrolo| 1.2- / ?|pyridazin-6-yl)(3- methoxyazetidin-l-yl)methanone (1-107)

[0240] To a solution of tert-buty l 7-((6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo[l,2- d]pyridazin-4-yl)oxy)-2,3-dihydro-427-benzo[6][l,4]oxazine-4-carboxylate (130 mg, 263 pmol) in DCM (2.63 mL), TFA (405 pL. 5.26 mmol) was added and the reaction mixture was stirred at 25 °C for 18 hours. The crude reaction mixture was diluted with DCM and was washed with NaHCOs (sat. aq). The organic layer was then washed with brine, dried (NazSO-i) and concentrated to afford the desired product. MS: 395 [M+l]+.Preparation of intermediate 2.3-dimethylazetidin-3-ol. hydrochloride (1-109)

[0241] Intermediate 1-109 was prepared according to synthetic route outlined in Scheme 22.Scheme 22tert-butyl 3-hydroxy-2.3-dimethylazetidine-l-carboxylate (1-108)

[0242] To an ice-cooled solution of tert-butyl 2-methyl-3-oxoazetidine-l -carboxylate (250 mg, 1.4 mmol) in THF (10.0 mL) was added dropwise a solution of magnesium methylbromide (483 mg, 1.2 mL, 3.4 AL, 4.1 mmol) in 2-MeTHF. The resulting reaction mixture was stirred at 0 °C for 3 hours and then warmed to ambient temperature for 16 hours. The reaction mixture was quenched with saturated NH4CI (aq) (10 mL), and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic fractions were dried (MgSCh). and fdtered. The solvent was evaporated under reduced pressure to afford the desired product, which was used in the next step directly without further purification.JH NMR (600 MHz, CDCh) 5 4.04 (q, J = 6.5 Hz, 1H), 3.82 (d, 7= 9.3 Hz, 1H), 3.76 (d, 7= 9.3 Hz, 1H), 1.47 (s, 3H), 1.47 (s, 10H), 1.34 (d, 7= 6.5 Hz, 3H). 2.3-dimethylazetidin-3-ol, hydrochloride (1-109)

[0243] To a stirring solution of tert-butyl 3-hydroxy-2,3-dimethylazetidine-l-carboxylate (244 mg, 1.2 mmol) in 1,4-dioxane (4.0 mL) and water (1.0 mL) was added hydrochloric acid (619 mg, 4.2 mL, 4.0 AL, 17.0 mmol), and the resulting reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated and lyophilized overnight to afford the desired product. 'H NMR (600 MHz, CD?OD) 5 4.30 (q, 7= 6.9 Hz, 1H), 3.93 (d, 7= 10.9 Hz, 1H). 3.H - 3.73 (m, 1H), 1 .48 (s, 3H), 1 .45 (d, J= 6.9 Hz, 3H).EXAMPLESPreparation of Example 1.1; 7-({6-[(3S)-3-hvdroxy-3-methylpyrrolidine-l-carbonyl]-5- iiiethylpyrrolol 1.2-b|pyridazin-4-yl!oxy)-\.2-diiiielhylindolizine-3-carboxaniide1*41 Example 1.1

[0244] A 250 mL RBF equipped with a magnetic stirrer was charged with 5-methyl-4-((2- methyl-3-(methylcarbamoyl)indolizin-7-yl)oxy)pyrrolo [ 1.2-bp ]yridazine-6-carboxylic acid (4.50 g, 11.9 mmol), HATU (6.78 g, 17.8 mmol), and (S)-3-methylpyrrolidin-3-ol, hydrochloride (2.05 g, 14.9 mmol). The flask was sealed with a rubber septum and its contents were placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles. Then, under a positive flow of nitrogen, anhydrous acetonitrile (59.5 mL) was added through the rubber septum. Finally, DIPEA (7.25 mL, 41.6 mmol) was added, and the reaction was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure, which was then purified by column chromatography (amino-functionalized silica geL EtOAc / EtOH(3 / l) in hexanes, gradient 10 to 60%) to afford the product. 50.0 mg of the product was dissolved in IP Ac (4.00 mL) and sonicated (Solution A). The rest of the product was dissolved in 600 mL of IP Ac, which was then concentrated under reduced pressure to a total volume of 400 mL. To this mixture, Solution A was added. The mixture was then slowly concentrated under reduced pressure to a total volume of -150 mL. The slurry was stirred at 40 °C for 3 days and the solids were collected by vacuum filtration after the mixture was cooled down. The collected solid was further dried in the vacuum oven (50 °C, 25 inHg) overnight to afford the desired product. MS: 462 [M+l]+. *HNMR (400 MHz, CD3OD) 5 9.17 (d, J= 7.6 Hz, 1H), 7.94 - 7.84 (m, 2H), 7.22 (d, J= 2.4 Hz, 1H), 6.61 (dd, J= 7.6, 2.4 Hz, 1H), 6.35 (s, 1H), 5.86 (d, J= 5.4 Hz, 1H), 3.87 - 3.H (m, 1H). 3.76 - 3.64 (m. 1H), 3.62 - 3.40 (m, 2H), 2.98 (s, 3H), 2.58 (s, 3H), 2.51 (s, 3H), 2.05 - 1.91 (m, 2H), 1.45, 1.36 (s, s, 3H).Preparation of Example 2.1; 7-(f6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[l,2-b]pyridazin-4-ylloxy)-N,2-dimethylindolizine-3-carboxamidei- 1 Example 2.1

[0245] A mixture of 5-methyl-4-((2-methyl-3-(methylcarbamoyl)indolizin-7- yl)oxy)pyrrolo [ 1.2-bp ]yridazine-6-carboxylic acid (100 mg, 0.132 mmol), (S)-3- methylpyrrolidin-3-ol, hydrochloride (20 mg, 0.145 mmol), and EDC (140 mg. 0.730 mmol) in pyridine (0.5 mL) was stirred at 25 °C for 1 hour. The mixture was filtered, and the filtrate waspurified by mass-directed reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the desired product. MS: 462 [M+l]+. 'H NMR (400 MHz, CD3OD) 5 9.17 (d, J= 7.6 Hz, 1H), 7.94 . 7.84 (m, 2H), 7.22 (d, J= 2.4 Hz, 1H), 6.61 (dd, J= 7.6, 2.4 Hz, 1H), 6.35 (s, 1H), 5.86 (d, J= 5.4 Hz, 1H), 3.87 - 3.H (m, 1H), 3.76 - 3.64 (m, 1H), 3.62 - 3.40 (m, 2H), 2.98 (s, 3H), 2.58(s, 3H), 2.51 (s, 3H). 2.05 - 1.91 (m. 2H), 1.45, 1.36 (s, s, 3H).Table 11: Utilizing a method similar to that described for the preparation of Example 2.1 and the appropriate starting materials, the following examples were prepared:NNPreparation of Example 3.1; l A.5-diinetliyl-4-((2-inetliyl-3-(inethylcarbainoyl)iiidolizin-7- yl )oxy )-.¥-( l-methylazetidin-3-yl)pyrrolo [ 1.2-Z>1 pyridazine-6-carboxamidei-41 Example 3.1

[0246] To a mixture of 5-methyl-4-((2-methyl-3-(methylcarbamoyl)indolizin-7- yl)oxy)pyrrolo [ 1.2-bp ]yridazine-6-carboxylic acid (20.0 mg, 52.9 pmol). N-methyl- 1 - methylazetidin-3-amine (10.6 mg, 106 pmol) and HATU (40.2 mg, 106 pmol) in DMF (1.00 mL), DIPEA (46.0 pL, 264 pmol) was added. The reaction mixture was stirred at 25 °C for 18 hours. The mixture was fdtered, and the filtrate was purified by mass-directed reverse phase HPLC (MeCN / water with 0.1% NH-iOH modifier) to afford the desired product. MS: 461 [M+l]+. 'H NMR (500 MHz, DMSO-uY) 5 9.18 (d, J= 7.7 Hz, 1H), 7.98 (d, J= 5.4 Hz, 1H), 7.92 (s, 1H), 7.44 (d, J= 4.6 Hz, 1H), 7.39 (d, J= 2.5 Hz, 1H), 6.74 (dd, J= 7.8, 2.6 Hz, 1H), 6.34 (s, 1H), 5.91 (d, J = 5.4 Hz, 1H), 4.57 (s, 1H), 3.40 (s, 2H), 3.20 - 3.02 (m, 5H), 2.84 (d, J = 4.6 Hz. 3H), 2.47 (s, 3H), 2.42 (s, 3H), 2.23 (s, 3H).Table 12: Utilizing a method similar to that described for the preparation of Example 3.1 and the appropriate starting materials, the following examples were prepared:Preparation of Example 4.1: l-(3-((6-(3-cvanoazetidine-l-carbonyl)-5-methylpyrroloH.2- / >|pyridaziii-4-yl)oxy)pheiiyl)-3-(4-fluorophenyl)urea1-99 Example 4.1 N

[0247] A 2 mL vial was charged with l-(4-chloro-5-methylpyrrolo[l,2-d]pyridazine-6- carbonyl)azetidine-3-carbonitrile (15.0 mg, 54.6 pmol), l-(4-fluorophenyl)-3-(3- hydroxyphenyl)urea (24.9 mg, 101 pmol), l-methyl-2,3,4,6,7,8-hexahydro-lH-pyrimido[l,2- « | pyrimidine (23.5 pL, 164 pmol) and DMF (1.50 mL). The vial was capped, and the reaction mixture heated to 80 °C for 16 hours. The reaction mixture was treated with Biotage® MP- Carbonate resin (16 eq, 200 mg) for 2 hours at room temperature. The reaction mixture was filtered and purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient) to afford the desired product. MS: 485 [M+l]+.JH NMR (600 MHz, DMSO-O 5 8.96 (s. 1H), 8.81 (s, 1H), 8.15 (s, 1H), 8.00 (d, J= 5.4 Hz, 1H), 7.58 (t, J = 2.2 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.42 (t, J= 8.2 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.16 - 7.09 (m, 2H), 6.93 - 6.89 (m, 1H), 5.74 (d, J= 5.4 Hz, 1H), 4.58 (bs, 2H), 4.35 (bs, 1H), 4.17 (bs, 1H), 3.86 (ddd, J = 15.3, 8.9, 6.4 Hz, 1H), 2.64 (s, 3H).Table 13: Utilizing a method similar to that described for the preparation of Example 4.1 and the appropriate starting materials, the following examples were prepared:Preparation of Example 5.1: l-(5-methyl-4-((2-methyl- 5-yl)oxy)pyrrolo [1,2-b] pyridazine-6-carbonyl)azetidine-3-carbonitrile 2, 2, 2- trifluoroacetate

[0248] A 5 mL vial was charged with l-(4-chloro-5-methylpyrrolo[1.2-d]pyridazine-6- carbonyl)azetidine-3-carbonitrile (25.0 mg, 91.0 pmol), 2-methyl-l / 7-pyrrolo[2,3- / >]pyridin-5-ol (14.8 mg, 100 pmol), CS2CO3 (32.6 mg, 100 pmol) and DMF (2.00 mL). The vial was capped,and the reaction mixture heated to 80 °C for 16 hours. The reaction mixture was concentrated. diluted with EtOAc (10 mL) and washed with aqueous 0.5 wt% LiCl (10 mL x 2) and water (10 mL). The organic fractions were dried (MgSCti). and filtered, and the solvent was evaporated under reduced pressure. The reaction mixture was filtered and purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient) to afford the desired product. MS: 387 [M+l]+. ‘H NMR (600 MHz, DMSO- e) 8 11.73 (s, 1H), 8.14 (s, 1H), 8.09 (d, J= 2.6 Hz, 1H), 7.93 (d, J= 5.4 Hz, 1H), 7.80 (d, J= 2.5 Hz, 1H), 6.21 (s, 1H), 5.57 (d, J= 5.4 Hz, 1H), 4.58 (bs, 2H), 4.36 (bs, 1H), 4.12 (bs, 1H), 3.91 - 3.81 (m, 1H), 2.69 (s. 3H), 2.43 (s, 3H).Table 14: Utilizing a method similar to that described for the preparation of Example 5.1 and the appropriate starting materials, the following examples were prepared:Preparation of Example 6.1: l-(4-((6-methoxy-l,2,3,4-tetrahydronaphthalen-2-yl)oxy)-5- methylpyrrolo [1,2-Z>] pyridazine-6-carbonyl)azetidine-3-carbonitrile

[0249] To a solution of l-(4-chloro-5-methylpyrrolo[l,2-Z>]pyridazine-6-carbonyl)azetidine-3- carbonitrile (200 mg, 0.73 mmol) in DMF (3 mL) was added NaH (60% in oil) (58.3 mg, 1.46 mmol) at 0 °C. After stirring for 0.5 hours at 0 °C, 6-methoxy-l,2,3,4-tetrahydronaphthalen-2-ol (130 mg, 0.73 mmol) was added to the mixture at 25 °C. The resulting mixture was stirred for an additional 1 hour at 25 °C. The mixture was cooled, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (10 mL x 3), dried (Na2SO4), and filtered. The solvent was evaporated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 10%) yielded the racemic product.

[0250] The mixture of the two stereoisomers was purified by chiral SFC (AD-3 column, Mobile phase A: CO2, B: 40% EtOH with 0.05% DEA) to afford isomer Example 6.1 (faster eluting). MS: 417 [M+l]+.XH NMR (400 MHz, CDCk) 5 7.86 (d, J= 5.6 Hz, 1H), 7.66 - 7.63 (m, 1H), 7.01 (d, J - 8.4 Hz. 1H), 6.74 (dd, J= 8.4, 2.4 Hz, 1H), 6.68 (d, J= 2.8 Hz, 1H), 5.89 (d, J= 5.6 Hz. 1H), 4.98 - 4.88 (m, 1H), 4.53 - 4.44 (m, 4H), 3.80 (s, 3H), 3.57 - 3.49 (m, 1H). 3.25 - 3.18 (m. 1H), 3. 10 - 3.02 (m. 2H), 2.94 - 2.86 (m, 1H), 2.54 (s, 3H), 2.26 - 2. 18 (m, 2H).Preparation of Example 7.1; 7-((6-((2A,3A)-3-hvdroxy-2,3-dimethylazetidine-1-carbonyl)-5- methylpyrrolo[l,2-Z>]pyridazin-4-yl)oxy)- 2-dimethylindolizine-3-carboxamide and 7-((6- ((2R,3R)-3-hvdroxy-2.3-dimethylazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4- yl)oxy)-A.2-dimethylindolizine-3-carboxamide1-102 Example 7.1 A & B

[0251] A vial was charged with (4-chloro-5-methylpyrrolo[L2-b]pyridazin-6-yl)(3-hydroxy- 2,3-dimethylazetidin-l-yl)methanone (50.0 mg, 170 pmol), 7-hydroxy-A,2-dimethylindolizine-3- carboxamide (52.1 mg, 255 pmol), cesium carbonate (83.2 mg, 255 pmol) and DMF (3.4 mL). The resulting reaction mixture was heated to 80 °C for 16 hours. The reaction mixture was concentrated, diluted with EtOAc (10 mL) and washed with aqueous lithium chloride (5%. 2 x 10 mL) and water (10 mL). The organic fractions were dried (MgSCL). and fdtered. The solvent was evaporated under reduced pressure. The resulting crude mixture was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient) to afford the desired product.

[0252] The mixture of the two stereoisomers was purified by chiral SFC (IZ, 21x250 mm, 5 pm column, Mobile phase A: CO2, B: 80% MeOH with 0.1% NH4OH) to afford isomer Example 7.1A (faster eluting) and Example 7.1B (slower eluting). Isomer 7.1A: MS: 462 [M+l]+. Isomer 7.1B: MS: 462 [M+l]+.Preparation of Example 8.1: l-(5-methyl-4-((2-methyl-lH-pyrrolo[2,3-6]pyridin-5- yl)amino)pyrroloH,2-Z>]pyridazine-6-carbonyl)azetidine-3-carbonitrile 2,2,2- trifluoroacetate

[0253] A vial was charged with l-(4-chloro-5-methylpyrrolo[l,2-b]pyridazine-6- carbonyl)azetidine-3-carbonitrile (25.0 mg, 91.0 pmol), 6-methyl-7F7-pyrrolo[2,3-b]pyridin-3- amine (14.7 mg, 100 pmol), cesium fluoride (41.5 mg, 273 pmol) and DMSO (1.50 mL). The reaction mixture was heated to 100 °C for 16 hours. The reaction mixture was filtered and purified by mass triggered reverse phase HPLC (MeCN / water with 0. 1% TFA modifier, linear gradient) to afford the desired product. MS: 386 [M+l]+. 'H NMR (600 MHz, DMSO-t / e) 5 8.41 (d, .7= 4.7 Hz, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.88 - 7.81 (m, 1H), 6.85 (d, J= 4.7 Hz, 1H), 6.65 - 6.60 (m, 1H), 4.60 (d, J= 23.0 Hz, 3H), 4.29 (s, 2H), 4.13 (s, 2H), 3.83 (ddd. J= 15.4, 9.0, 6.4 Hz. 2H), 2.28 (s, 3H), 1.39 (s, 3H)Table 15: Utilizing a method similar to that described for the preparation of Example 8.1 and the appropriate starting materials, the following examples were prepared:Preparation of Example 9.1: (3-methoxyazetidin-l-yl)(5-methyl-4-((3-methyl-2Jf-indazol-6- yl)amino)pyrrololl.2-Z>l pyridazin-6-yl)methanone1-100 Example 9.1

[0254] To a solution of 3-methyl-2 / / -indazol-6-amine (25.0 mg, 0. 170 mmol) in THF (3.00 rnL) was added NaHMDS (0.425 mL, 0.425 mmol) (1 Min THF) at 0 °C. After stirring for 0.5 hours at 25 °C, (4-chloro-5-methylpyrrolo [ 1.2-bp ]yridazin-6-yl)(3-methoxyazetidin-l- yl)methanone (47.5 mg, 0.170 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred for another 2 hours. The reaction mixture was quenched with H2O (1 mL) and extracted with EtOAc (2 mL x 3). The combined organic phases were washed with brine (1 rnL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC (Column Boston Prime C18 150 * 30 mm * 5 pm Condition Water (0.05% NH3H2O+IO mM NH4HCO?)-ACN Begin B 2 End B 32 Gradient Time(min) 10 100% B Hold Time 2 Flow Rate(mL / min) 25 Injections 1) to yield the desired product. MS: 391 [M+l]+. 'H NMR (400 MHz, DMSO-A) 8 12.51 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.79 (d, J= 5.6 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.33 (d, J= 1.2 Hz, 1H), 7.07 (dd, J= 8.8, 1.6 Hz, 1H), 5.98 (d, J= 5.6 Hz. 1H), 4.52 - 4.36 (m, 1H), 4.28 - 4.18 (m, 2H). 4.17 - 4.08 (m, 1H), 3.86 - 3.76 (m, 1H), 3.23 (s, 3H), 2.70 (s, 3H). 2.47 (s. 3H).Preparation of Example 10.1: N-ethyl-7-((6-(3-methoxyazetidine-l-carbonyl)-5- methylpyrrolo[l,2-b]pyridazin-4-yl)oxy)-2,3-dihydro-41f-benzo [l,4]oxazine-4-carboxamide

[0255] To a solution of (4-((3.4-dihydro-2H-benzo|51 [l,4]oxazin-7-yl)oxy)-5- methylpyrrolo[1.2-6]pyridazin-6-yl)(3-methoxyazetidin-l-yl)methanone (19.7 mg. 0.05 mmol) in THF (0.50 mL) was added ethyl isocyanate (17.8 mg, 0.25 mmol) and DIPEA (44 pL, 0.25 mmol). The reaction mixture was stirred at 25 °C for 36 hours. The reaction mixture was concentrated, taken up in DMSO (1.5 mL), filtered and purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient) to afford the desired product. MS: 466 [M+l]+.XH NMR (500 MHz, DMSO-ds) 5 8.07 (s, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 6.98 (t, J= 5.4 Hz, 1H), 6.83 (d, J= 2.7 Hz, 1H), 6.79 (dd, J= 8.9, 2.8 Hz, 1H),5.70 (d, J = 5.4 Hz, 1H). 4.54 - 4.38 (m. 1H). 4.28 - 4. 11 (m. 5H), 3.85 - 3.H (m. 1H), 3.76 -3.70 (m, 2H), 3.23 (s, 3H), 3.14 (p, J= 1A Hz, 2H), 2.61 (s, 3H), 1.08 (t, J= 7.1 Hz, 3H).Table 16: Utilizing a method similar to that described for the preparation of Example 10.1 and the appropriate starting materials, the following examples were prepared:Preparation of Example 11.1:JV-(2-chloro-4-il6-(3-cvanoazetidine- l-carbonyl)-5- methylpyrrolo[l,2-Z>]pyridazin-4-yl]oxy}phenyl)- N’-cvclopropylsulfuric diamideEthyl 4-(3-chloro-4-((A-cyclopropylsulfamoyl)amino)phenoxy)-5-methylpyrrolo[1.2- 61pyridazine-6-carboxylate (1-108)

[0256] A 20 mL scintillation vial was charged with ethyl 4-(4-amino-3-chlorophenoxy)-5- methylpyrrolo[l,2-A]pyridazine-6-carboxylate (145.0 mg, 419.3 pmol), cyclopropylsulfamoyl chloride (71.8 mg, 461 pmol) and THF (10 mL). TEA (64.3 pL, 461 pmol) was added, and the resulting reaction mixture was heated to 80 °C for 2 hours. The reaction mixture was quenched with hydrochloric acid (1 N, 10 mL) and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic fractions were dried (MgSO i). and filtered. The solvent was evaporated under reduced pressure and the reaction mixture w as used directly in the next step without further purification. MS: 465 [M+l]+.Ethyl 4-(3-chloro-4-((A-cvclopropylsulfamoyl)amino)phenoxy)-5-methylpyrrolo[ 1,2- Alpyridazine-6-carboxylate (1-109 )

[0257] 2 A NaOH (aq, 629 pL, 1.26 mmol) w as added to a stirring solution of ethyl 4-(3- chloro-4-((A-cyclopropylsulfamoyl)amino)phenoxy)-5-methylpyrrolo[ 1.2-h|pyridazine-6- carboxylate (195 mg, 419 pmol) in THF (2.5 mL) and ethanol (2.5 mL). The resulting reaction mixture was heated to 50 °C and stirred for 16 hours. The reaction mixture was quenched with hydrochloric acid (1 AC 10 mL), and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic fractions were dried (MgSCL), and filtered. The solvent was evaporated under reduced pressure to afford the desired product. MS: 437 [M+l]+.A-(2-chloro-4-([6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[L2-d]pyridazin-4- yl loxy jphenyl )-A’-cvclopropylsulfuric diamide (Example 11.1)

[0258] Azetidine-3-carbonitrile hydrochloride (8. 14 mg, 68.7 pmol) and DIPEA (22.2 mg. 29.9 pL, 172 pmol) was added to a stirring solution of 4-(3-chloro-4-((A- cyclopropylsulfamoyl)amino)phenoxy)-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carboxylic acid (25 mg, 57.2 pmol) and HATU (26. 1 mg, 68.7 pmol) in DMF (1.5 mL). The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, dissolved in DMSO (1.5 mL), filtered and purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% NH4OH modifier, linear gradient) to afford the desired product. MS: 501 [M+l]+. 'l l NMR (600 MHz, DMSO-rfe) 5 9.24 (s, 1H), 8.15 (s, 1H). 8.01 (d, J= 5.4 Hz, 1H), 7.81 (s, 1H), 7.63 (d, J= 8.9 Hz, 1H), 7.56 (d, J= 2.7 Hz, 1H), 7.32 (dd, J= 8.9, 2.7 Hz, 1H), 5.72 (d, .7= 5.4 Hz, 1H), 4.59 (d, J = 25.8 Hz, 2H), 4.35 (s, 1H), 4.17 (s, 1H), 3.85 (ddd, J = 15.3, 8.9, 6.4 Hz, 1H), 2.62 (s, 3H), 2.42 (tt, J= 6.9, 3.5 Hz, 1H), 1.03 (d, J= 6.6 Hz, 1H), 0.58(td, J= 7.0, 4.8 Hz, 2H), 0.53 - 0.43 (m, 2H).Table 17: Using methods similar to that outlined in the synthesis of Example 11.1, and the appropriate starting materials, the following Examples were prepared:Preparation of Example 12.1: (R)-3-((2-chloro-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5- methylpyrrolo[l,2-Z>]pyridazin-4-yl)oxy)phenyl)amino)-4-(cvclopropylamino)cvclobiit-3- ene-1, 2-dione4-(4-amino-3-chlorophenoxy)-5-methylpyrrolo[ L2-d1pyridazine-6-carboxylic acid (1-110)

[0259] In a ventilated balance enclosure, a 30 mL scintillation vial equipped with a magnetic stir bar was charged with ethyl 4-(4-amino-3-chlorophenoxy)-5-methylpyrrolo[l,2-&]pyridazine- 6-carboxylate (204 mg, 591 nmol) and LiOH (142 mg, 5.91 mmol). The vial was sealed with a rubber septum. Then, under a positive flow of nitrogen. THF (4.43 mL) and ethanol (1.48 mL) were added through the rubber septum. Finally, water (1.06 mL, 59.1 mmol) was added, and the reaction was heated to 65 °C with stirring. After 5 hours, the reaction was removed from the heat and allowed to cool to room temperature. The reaction was quenched by addition of a 4 M dioxane solution of HC1 (1.48 mL. 5.91 mmol). After 15 mins of stirring at room temperature,the stir bar was removed, and the volatiles were removed under reduced pressure. The resultant material was re-suspended in toluene (10 mL), and the mixture was again evaporated to dryness under reduced pressure. The crude material was used in the next step without further purification. MS: 318 [M+l]+. -(4-(4-amino-3-chloroDhenoxy)-5-methylDyrrolo| 1.2-^|pyridazin-6-yl)(3-hvdroxyDyrrolidin- 1 -vDmethanone (I- 111)

[0260] In a ventilated balance enclosure, a 30 mL scintillation vial equipped with a magnetic stirbar was charged with 4-(4-armno-3-chlorophenoxy)-5-meth lpyrrolo| 1 ,2- / > |pyndazine-6- carboxylic acid (188 mg, 591 pmol). The vial was sealed with a rubber septum and its contents were placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles. Then, under a positive flow of nitrogen, anhydrous DMF (2.96 mL) was added through the rubber septum. To the stirring mixture at room temperature were added in sequence (R)-3 -hydroxy pyrrolidine (257 mg, 2.96 mmol), DIPEA (1.0 mL, 5.91 mmol), and T3P (1.04 mL, 50% Wt, 1.H mmol). The resultant mixture was stirred overnight at room temperature. The reaction was diluted with DMSO (14 mL), and the mixture was warmed to 65 °C with stirring. This mixture was then filtered through a coarse frit while still hot. The filtrate was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient). The obtained TFA salt of the product was diluted with DCM and transferred to a separatory funnel containing sat. aq. NaHCCL The aqueous phase was extracted twice using 3: 1 CHCh / IPA. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and the collected filtrate was concentrated to dryness on the rotovap to afford the free-based product. MS: 387 [M+l]+.CR)-3-((2-chloro-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5-methylpyrrolo[1.2-Z>]pyridazin-4- yl)oxy)phenyl)amino)-4-methoxycyclobut-3-ene-L2-dione (1-112 1-112)

[0261] In a ventilated balance enclosure, a 30 mL scintillation vial equipped with a magnetic stir bar was charged with (R)-(4-(4-amino-3-chlorophenoxy)-5-methylpyrrolo| 1 ,2- / > |pyridazm-6- yl)(3-hydroxypyrrolidin-l-yl)methanone (152 mg, 393 pmol) and l,2-dimethoxy-3,4- dioxocyclobut-l-ene (128 mg. 904 pmol). The vial was sealed with a rubber septum. Then under a positive flow of nitrogen, anhydrous methanol (3.9 mL) and DIPEA (0.14 mL, 786 pmol) were added through the rubber septum. Finally, zinc trifluoromethanesulfonate (200 mg, 550 pmol) was added, and the reaction was allowed to stir overnight at 50 °C. To the mixture was added DMSO (3.5 mL), and the mixture was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient). The obtained fractions were diluted with DCM and transferred to a separatory funnel containing sat. aq. NaHCOs. The aqueous phase was extracted twice using 3: 1 CHCh / IPA. The combined organic layers were dried overanhydrous Na2SO4, filtered, and the collected filtrate was concentrated to dryness to afford the desired product. MS: 497 [M+l]+.(R)-3-((2-chloro-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5-methylpyrrolo[1.2-A|pyridazin-4- yl)oxy)phenyl)amino)-4-(cvclopropylamino)cvclobut-3-ene-l,2-dione (Example 12.1)

[0262] In a ventilated balance enclosure, a 5 mL microwave vial equipped with a magnetic stirrer was charged with (R)-3-((2-chloro-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5- methylpyrrolo[l,2-Z>]pyridazin-4-yl)oxy)phenyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione (53 mg, 107 pmol), and zinc trifluoromethanesulfonate (54.3 mg, 149 pmol). The vial was sealed with a rubber septum. Then under a positive flow of nitrogen, anhydrous methanol (2. 13 mL) was added through the rubber septum. DIPEA (55.7 pL, 320 pmol) was then added, followed by cyclopropyl amine (22.2 pL, 320 pmol). The reaction was heated to 40 °C with stirring. After 1 hour, DMSO (1.0 mL) was added to the mixture, which was then filtered through a syringe filter into a 5 mL high recovery vial. The sample was purified by mass triggered reverse phase HPLC (MeCN / water with 0. 1% TFA modifier, linear gradient). The obtained fractions were diluted with DCM and transferred to a separatory funnel containing sat. aq. NaHCOs. The aqueous phase was extracted twice using 3: 1 CHCh / IPA. The combined organic layers were dried over anhydrous Na2SC>4, filtered, and the collected filtrate was concentrated to dryness to afford the desired product. MS: 522 [M+l]+. ' H NMR (500 MHz, DMSO-tL) 5: 9. 19 (s, 1H). 8.43 (s. 1H), 8.05 (d, J= 18.1 Hz, 1H), 7.97 (d, J= 5.4 Hz, 1H), 7.71 (s, 1H), 7.60 (d, J= 8.7 Hz, 1H), 7.04 (dd, J= 8.6, 2.3 Hz, 1H), 5.87 (d, J= 5.4 Hz, 1H), 4.96 (d, J= 30.5 Hz, 1H), 4.29 (d, J= 312 Hz, 1H), 3.70 - 3.47 (m, 3H), 3.39 (d, J= 13.0 Hz, 1H), 3.12 (dt, J= 6.9, 3.4 Hz, 1H), 2.02 - 1.87 (m, 1H), 1.82 (s, 1H). 0.87 - 0.73 (m, 2H), 0.67 (s. 2H).Preparation of Example 13.1A & 13.1B: (S or R)-l-(2-chloro-4-((6-(3-cyanoazetidine-l- carbonyl)-5-methylpyrrolo [ 1,2-b] py ridazin-4-yl)oxy)phenyl)-3-(2,2- difluorocvclopropyDurea and (R or S)-l-(2-chloro-4-((6-(3-cvanoazetidine-l-carbonyl)-5- methylpyrrolo[l.,2-blpyridazin-4-yl)oxy)phenyl)-3-(2,2-difluorocvclopropyl)ureaExample 13.1A and 13.1B ethyl 4-(4-amino-3-chlorophenoxy)-5-methylpyrrolo[ 1 .2- / i|pyridazine-6-carboxylate (1-113)

[0263] A mixture of l-(4-chloro-5-methylpyrrolo[l,2-Z)]pyridazine-6-carbonyl)azetidine-3- carbonitrile (300 mg, 1.09 mmol) and 4-amino-3 -chlorophenol (172 mg, 1.20 mmol), K2CO3 (453 mg, 3.28 mmol) in DMF (4.00 mL) was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (35 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 50%) yielded the desired product. MS: 382 [M+l]+.(R or )-l-(2-chloro-4-((6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[L2-61pyridazin-4- yl)oxy)phenyl)-3-(2.2-difluorocvclopropyl)urea (Example 13.1A and 13.1B)

[0264] To a solution of l-(4-(4-amino-3-chlorophenoxy)-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl)azetidine-3-carbonitrile (250 mg, 0.66 mmol) in CHCk (4.00 mL) was added TEA (0.27 mL, 1.96 mmol) and triphosgene (190 mg, 0.64 mmol) and stirred at 25 °C for 30 minutes. After 2,2-difluorocyclopropan-l -amine hydrochloride (254 mg. 1.96 mmol) was added to the mixture, the resulting mixture was stirred at 25 °C for 1 hour. The mixture was quenched with sat. NaHCOs (5 mL). Water (5 mL) was added to the mixture. The mixture was extracted with CH2CI2 (10 mL x 3). The organic phase was dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum. Column chromatography (silica gel, EtOAc in petroleum ether, gradient 0 to 60%) yielded the desired product.

[0265] The mixture of the two stereoisomers was purified by chiral SFC (OD column, Mobile phase A: CO2, B: 55% EtOH with 0.1% NH4OH) to afford Example 13.1A (faster eluting enantiomer) and Example 13. IB (slower eluting enantiomer).

[0266] Example 13.1A: MS: 501 [M+l]+. ’H NMR (400MHZ, CDsOD) 6 8.18 (d, 9.2 Hz,1H), 7.95 (s, 1H), 7.86 (d, J = 5.2 Hz, 1H), 7.37 (d, J = 2.8 Hz, 1H), 7. 19 (dd, J= 9.2, 2.8 Hz, 1H), 5.69 (d, J= 5.2 Hz, 1H), 4.69 - 4.25 (m, 4H), 3.84 - 3.74 (m, 1H), 3.30 - 3.25 (m, 1H), 2.68 (s, 3H), 1.92 - 1.H (m, 1H), 1.49 - 1.35 (m, 1H).

[0267] Example 13.1B: MS: 501 [M+l]+.JH NMR (400MHz, CD3OD) 6 8.18 (d, J= 9.2 Hz, 1H), 7.96 (s, 1H), 7.87 (d, J= 5.2 Hz, 1H), 7.37 (d, J= 2.8 Hz, 1H), 7. 19 (dd, J= 9.2, 2.8 Hz, 1H), 5.70 (d, J= 5.6 Hz, 1H), 4.61 - 4.22 (m, 4H), 3.86 - 3.70 (m, 1H), 3.30 - 3.25 (m, 1H), 2.68 (s, 3H), 1.92 - 1.76 (m, 1H), 1.50 - 1.36 (m, 1H).Preparation of Example 14.1; (R or >y)-l-(4-((6-hvdroxy-1.2,3.,4-tetrahvdronaphthalen-2- yl)oxy)-5-methylpyrroloH,2-6]pyridazine-6-carbonyl)azetidine-3-carbonitrileethyl 4-((6-methoxy- 1 ■2.3.4-tetrahvdronaphthalen-2-yl)oxy)-5-methylpyrrolo[ 1 ,2-Zilpyridazine- 6-carboxylate (1-114)

[0268] To a solution of ethyl 4-chloro-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carboxylate (335 mg, 1.40 mmol) and 6-methoxy-1.2.3.4-tetrahydronaphthalen-2-ol (250 mg, 1.40 mmol) in DMF (3.00 ml) was added NaH (60% in oil) (112 mg. 2.81 mmol) at 0 °C. The resulting mixture was stirred for 1 hour at 25 °C. The mixture was diluted with water (2 mL), extracted with EtOAc (2 mL x 3). The combined organic fractions were washed with brine (3 mL x 2), dried (Na2SC>4), filtered and the solvent w as evaporated under reduced pressure. The mixture was purified by prep-TLC (petroleum ether: EtOAc = 3: 1) to afford the desired product. MS: 381 [M+l]1.ethyl 4-((6-hvdroxy- 1.2.3.4-tetrahvdronaphthalen-2-yl)oxy)-5-methylpyrrolo| L2- / 4pyridazine-6- carboxylate (1-115)

[0269] To a solution of ethyl 4-((6-methoxy-l,2,3,4-tetrahydronaphthalen-2-yl)oxy)-5- methylpyrrolo[l,2-A]pyridazine-6-carboxylate (110 mg. 0.29 mmol) in DCM (3.00 ml) was added BBrs (0.060 ml. 0.58 mmol) at 0 °C. The resulting mixture was stirred for 0.5 hour at 0 °C. The mixture was added to ice water at 0 °C and the mixture was extracted with EtOAc (3 mL x 2). The combined organic fractions were washed with brine (3 mL x 2), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The mixture was purified by prep-TLC (DCM:MeOH = 20: 1) to give the desired product. MS: 367 [M+l]+.4-((6-hvdroxy-L2.3.4-tetrahvdronaphthalen-2-yl)oxy)-5-methylpyrrolo[1.2-A]pyridazine-6- carboxylic acid (1-116)

[0270] A mixture of ethyl 4-((6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)oxy)-5- methylpyrrolo[1.2-A]pyridazine-6-carboxylate (100 mg. 0.273 mmol), Lithium hydroxide monohydrate (11.5 mg, 0.27 mmol) in EtOH (5 ml), THF (5 ml) and water (0.25 ml) was stirred at 40 °C for 2 hours. The mixture was acidified with 1 M HC1 (aq) to pEI 3~4 and lyophillized to give the desired product. MS: 339 [M+l]+.1 -(4-((64ivdroxy- 1.2.3.4-tetrahvdronaphthal en-2-yl )oxy )-5-methylpyrrolo| 1.2- / i |pyndazine-6- carbonyl)azetidine-3-carbonitrile (Example 14.1)

[0271] To a solution of 4-((6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)oxy)-5- methylpyrrolo[l,2-A]pyridazine-6-carboxylic acid (85 mg, 0.25 mmol) ,1H- benzo[< ][l,2,3]triazol-l-ol (71.3 mg, 0.53 mmol), EDC (57.8 mg, 0.30 mmol), DIPEA (0.09 ml, 0.50 mmol) in DMF (1 ml) was added azetidine-3-carbonitrile hydrochloride (32.8 mg, 0.28 mmol). The mixture was stirred at 25 °C for 2 hours. Water (5 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (5 mL x 3). The combined organic fraction was washed with brine (5 mL x 3). dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The mixture was purified by prep-TLC (petroleum ether:EtOAC = 1: 1).

[0272] The mixture of the two stereoisomers was purified by chiral SFC (AD-3 column, Mobile phase A: CO2, B: 40% EtOH with 0.05% DEA) to afford Example 14.1 (slower eluting). MS: 403 [M+l]+.1H NMR (400 MHz, CD3C1) 5 7.88 (d, J = 7.6 Hz, 1H), 7.68 (br d, J= 2.4 Hz, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.69 - 6.63 (m, 2H), 5.89 (d, J= 5.6 Hz, 1H), 4.98 - 4.92 (m, 1H), 4.62 - 4.39 (m, 4H), 3.62 - 3.49 (m, 1H), 3.24 - 3.17 (m, 1H), 3.10 - 2.99 (m, 2H), 2.93 - 2.83 (m, 1H), 2.55 - 2.49 (m, 3H), 2.25 - 2. 17 (m, 2H).Preparation of Example 15.1: l-(5-methyl-4-((2- 5-yl )ami noipyrrolo [ 1 ,2- pyridazine-6-carbonyl)azetidine-3-carbonitrile

[0273] A vial was charged with l-(4-chloro-5-methylpyrrolo[1.2-6]pyridazine-6- carbonyl)azetidine-3-carbonitrile (55.0 mg, 200 pmol), 5-amino-2-methylbenzothiazole (41 mg, 250 pmol), XantPhos Pd G3 (19 mg, 2 pmol), cesium carbonate (19.5 mg, 600 pmol) and dioxane (2.0 mL). The reaction mixture was heated to 80 °C for 16 hours. The reaction mixture was cooled to room temperature and MP-TMT (150 mg, 0.66 mmol / g loading, 100 pmol) was added. The reaction mixture was stirred for an additional 3 hours at room temperature. The reaction was filtered and purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient) to afford the desired product. MS: 404 [M+l]+.rH NMR (600 MHz, DMSO-O 5 8.24 (s, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.81 (d, J= 5.4 Hz. 1H), 7.41 (d. J= 8.4 Hz. 1H), 5.98 (d. J= 5.4 Hz. 1H), 4.55 (bs, 2H). 4.34 (bs, 1H), 4.16 (bs, 1H), 3.88 (q, J = 7.5 Hz, 1H), 2.84 (s, 3H), 3.09 (s, 3H).Table 18: Using methods similar to that outlined in the synthesis of Example 15.1, and the appropriate starting materials, the following Examples were prepared:NPreparation of Example 16.1; (R)-l-(3-cyano-4-((6-(3-livdroxypyrrolidine-l-carbonyl)-5- methylpyrrolo [1,2-Z>] pyridazin-4-yl)oxy)phenyl)-3-cvclopropylurea-(3-((terLbutyldimethylsilyl)oxy)pyrrolidin-l-yl)(4-chloro-5-methylpyrrolo[1.2- >1pyridazin- 6-yl)methanone (1-117)

[0274] terf-Butyldimethylchlorosilane (349 mg. 2.3 mmol) was added dropwise to a stirring solution of (R)-(4-chloro-5-methylpyrrolo[l ,2- / ?]pyridazin-6-yl)(3-hydroxypyrrolidin-l - yl)methanone (540 mg, 1.9 mmol) and imidazole (263 mg, 3.9 mmol) in DMF (9.7 mL). The resulting solution was stirred at room temperature for 16 hours. The mixture was concentrated, diluted with ethyl acetate (20 mL), washed with hydrochloric acid (1 N, 20 mL), dried (MgSO-i). and filtered. The solvent was evaporated under reduced pressure to afford the product, which was used directly in the next step without further purification. MS: 394 [M+l]+.(R)-5-amino-2-((6-(3-((to7-butyldimethylsilyl)oxy)pyrrolidine-l-carbonyl)-5-methylpyrrolo[1.2- b]pyridazin-4-yl)oxy)benzonitrile (1-118)

[0275] A vial was charged with (A)-(3-((terCbutyldimethylsilyl)oxy)pyrrolidin-l-yl)(4-chloro- 5-methylpyrrolo[l,2-b]pyridazin-6-yl)methanone (40.0 mg, 102 pmol), 5-amino-2-hydroxy benzonitrile (20.4 mg, 152 pmol), cesium carbonate (49.6 mg, 152 pmol) and DMF (2.0 mL). The resulting reaction mixture was heated to 80 °C for 16 hours. The reaction mixture was concentrated, diluted with ethyl acetate (10 mL) and washed with aqueous lithium chloride (5%. 2 x 10 mL) and brine (10 mL). The organic fractions were dried (MgSCL), and filtered. The solvent was evaporated under reduced pressure to afford the product, which was used directly in the next step without further purification. MS: 492 [M+l]+. fR)-l-(3-cvano-4-((6-(3-hvdroxypyrrolidine-l-carbonyl)-5-methylpyrrolori.2-b1pyridazin-4- yl)oxy)phenyl)-3-cyclopropylurea (Example 16.1)

[0276] Cyclopropyl isocyanate (29.6 mg, 24.9 pL, 356 pmol) was added to a stirring solution of (R)-5-amino-2-((6-(3-((tert-buty'ldimethylsilyl)oxy)pyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2- 6]pyridazin-4-yl)oxy)benzonitrile (35.0 mg, 71.2 pmol) and DIPEA (92.0 mg, 124 pL, 712 pmol)in THF (1.4 mL). The resulting solution was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated, and the resulting crude was taken up in TFA (2.0 mL) and stirred at 25 °C for 2 hours. The reaction mixture was concentrated, diluted with DCM (5 mL) and washed with aqueous NaHCCh (sat., 10 mL). The organic layer was collected using a phase separator column (25 mL). concentrated, taken up in DMSO (1.5 mL), filtered and purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier, linear gradient) to afford the desired product. MS: 461 [M+l]+. 'HNMR (600 MHz, DMSO) 5 8.81 (s, 1H), 8.13 - 8.06 (m, 1H), 8.09 (d, J = 2.7 Hz, 1H), 7.99 (d, J= 5.4 Hz, 1H), 7.H (dd, J= 9.0, 2.5 Hz, 1H). 7.49 (d, J= 9.1 Hz, 1H), 6.68 (s. 1H), 5.74 (d. J= 5.3 Hz. 1H), 4.31 (d. J = 42.8 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.62 - 3.50 (m, 2H), 3.38 (dd, J= 40.2, 11.9 Hz, 1H), 2.57 (dq, J= 7.0, 3.2 Hz, 1H), 2.54 (s, 3H), 2.01 - 1.90 (m, 1H), 1.87 - 1.78 (m, 1H), 0.69 - 0.64 (m, 2H), 0.47 - 0.42 (m, 2H).ASSAY[02H] The enzymatic activity of hVEGFR2 was measured using the TR-FRET based Ulight assay (Revvity) which measures phosphorylation of a fluorescently tagged peptide substrate with the Europium labeled PT66 Antibody that specifically recognizes phosphorylated tyrosine residues. The assay is performed in a buffered solution (50 mM HEPES pH 7.5, 10 mM MgCh, 1 mM EGTA, 0.01% Tween-20. 0.5 mM TCEP) with an ATP concentration of the measured Km of the VEGFR2 (150 pM ATP). Enzyme concentrations of 50 pM VEGFR2 and Ulight peptide concentration of 50 nM Ulight-JAKl were used. Reactions w ent 1 hour before being quenched with a quenching solution (buffered solution above with 20 mM EDTA and 0.5 nM Europium- anti-phosphotyrosine (PT66) Ab). The assay was further incubated for 30 minutes to allow for complete binding of the antibody and then read on a Envision plate reader to measure TR-FRET signal.

[0278] DMSO solutions of potential TKI compounds w ere dispensed using an ECHO 655 to dispense into White Proxi-plus 384-well plates with a total DMSO volume of 50 nl. Each compound was assessed at 10 concentrations in 3-fold serial dilutions starting at a high concentration of 2.5 pM and with a low concentration of 124 pM. After compound dispensing, 2.5 pl of a 4x concentration of ATP w as added to each plate well. Then 2.5 pl if a 4x concentration of the tyrosine kinase was added to each well and allow ed to incubate at RT for 30 minutes. After the incubation, the kinase reaction was started with the addition of 5 pl of a 2x concentration of one of the Ulight peptides and incubated at RT for 30 or 60 minutes as indicated above. The reaction was then quenched with the addition of 5 pl of the quenching solution. Doseresponse curves were generated by plotting percent inhibition (Y-axis) vs. LoglO compoundconcentrations (X-axis). ECso values were calculated using a non-linear regression, four- parameters sigmoidal dose-response model.POTENCY TABLE

Claims

1. WHAT IS CLAIMED IS:

1. A compound of formula I:or a pharmaceutically acceptable salt thereof whereinX is selected from -O-, -NH-, -N-C1-6alkyl-, and -S-; ring A is selected from:(1) aryl,(2) cycloalkyl.(3) heteroaryl, and(4) heterocyclyl; n is 0, 1 , 2, or 3;R1is independently selected from:(1) -C1-6alkyl,(2) halo,(3) -C0-6alkyl-C(0)NHRa,(4) -NHC(O)NHRa,(5) -NHC(O)Ra,(6) -C0-6alkyl-ORa,(7) -C0-6alkyl-C(0)ORa,(8) -C0-6alkyl-C(0)Ra,(9) -C0-6alkyl-cyano,(10) -C0-6alkyl-NHRa,(11) -C0-6alkyl-aryl, wherein the ary l is unsubstituted or substituted with 1-3 substituents independently selected from Ra,(12) -C0-6alkyl-(5-6 membered heteroaryl) wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1 -3 substituents independently selected from Ra,(13) -C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents selected from Ra,(14) -C0-6alkyl-C(0)NR3R4.(15) -C0-6alkyl-NHS(0)2NHRa.(16) -C0-6alkyl-S(0)2NHRa,(17) C2-6alkynyl,(18) =0, and(19) hydrogen;When present, Rais selected from:(1) hydrogen;(2) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, -NR3R4, cyano, -C1-6alkyl, -O-Co-ealkyl, and -C1-6haloalkyl;(3) -C0-6alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo; -OH; =0; -NH-Cs-ecycloalkyl; -C0-6alkyl-NR3R4; -Co- ealkyl-cyano; -C1-6alkyl; -O-Co-ealkyl; -C(O)-C1-6alkyl; -C(O)NH-C5-6aryl, wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from -Ci- ealkyl, -OH, and halo; and -C1-6haloalkyl;(4) -C0-6alkyl-aryl, unsubstituted or substituted with 1-3 substituents independently selected from halo, =0, and -NH-cyclopropyl, -OH, -C0-6alkyl-NR3R4, -C0-6alkyl-cyano, - C1-6alkyl, -O-Co-ealkyl, and -C1-6haloalkyl;(5) -O-C1-6alkyl;(6) -C0-6alkyl-(5-6 membered monocyclic heteroaryl), wherein the hcteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with 1-3 substituents independently selected from halo, =0, -NH-cyclopropyl, -OH, - Co- ealkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl, -O-Co-ealkyl, -C(O)OC1-6alkyl, -C1-6alkyl-Cs- ecycloalkyl, and -C1-6haloalkyl;(7) -C1-6alkyl-S-C1-6alkyl;(8) -C3-6 monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, and unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, - C0-6alkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl, -OCo-ealkyl, -C1-6haloalkyl, and =0;(9) 5-10 membered spiro bicyclic or tricyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, -C0-6alkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl, -OCo-ealkyl, -C1-6haloalkyl. and =0;(10) 5-10 membered spiro bicyclic or tricyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S unsubstituted or substituted with 1-3 substituents independently selected from halo. -OH, -C0-6alkyl-NR?R4, -C0-6alkyl-cyano, -Ci- ealkyl, -OCo-ealkyl, -C1-6haloalkyl, and =0;(11) 5-6 membered bridged bicyclic cycloalkyd, unsubstituted or substituted with one substituent selected from -OH, halo and haloalkyl;(12) halo;(13) -C(O)O-C1-6alkyl;(14) -NH2; and(15) -C=C; when present, each of R3and R4is independently selected from:(1) hydrogen,(2) -C0-6alkyl- 3-6 membered heterocyclyl having 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rb,(4) -C1-6 alkyl-O-C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rb,(5) -C0-6alkyl- C3-6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb, and(6) 5-10 membered bicyclic or tricyclic cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb; when present, Rbis selected from:(1) -C1-6alkyl,(2) halo,(3) -NH2,(4) =0, and(5) -OH; or alternatively, R3and R4together with the nitrogen to which they are attached form 3-10 membered heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S, in addition to the nitrogen to which R3and R4are attached, wherein the heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from Rc; when present, Rcis selected from(1) -C0-6alkyl-OH,(2) -C1-6alkyl, unsubstituted or substituted with 1-3 -OH substituents.(3) -C0-6alkyl-cyano,(4) -C0-6alkyl-O-Ci-3alkyl,(5) -C0-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected fromN, O, and S, and is unsubstituted or substituted with 1-3 C1-6alkyl substituents,(6) halo,(7) -C 1-6thaloalkyl.(8) C0-6alkyl-aryl, wherein the aryl is unsubstituted or substituted with 1 -3 substituents independently selected from C1-6haloalkyl and halo,(9) -C3-6cycloalkyl,(10) -C0-6alkyl-N(Rg)2, wherein each Rgis independently selected from hydrogen and C1-6alkyl,(11) -NH-C(O)C1-6alkyL(12) -Co-3alkyl-(3-6 membered monocyclic heterocyclyl). wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one =0 substituent,(13) -O-C1-6haloalkyl,(14) =0,(15) hydrogen, and(16) -C(O)OC1-6alkyl; sXR5hKR2isr6, each of R5and R6is independently selected from:(1) hydrogen,(2) -C0-6alkyl-(3-6 membered heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S. and is unsubstituted or substituted with 1-3 substituents independently selected from Rd,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently- selected from Rd,(4) -C1-6 alkyl-O-C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rd,(5) -C0-6alkyl- Cs-6 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1 -3 substituents independently selected from Rd, and(6) 5-10 membered bicyclic or tricyclic cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently7selected from Rd: when present, Rdis selected from:(1) -C1-6alkyL(2) halo,(3) -NH2.(4) =0. and(5) -OH; or alternatively, R5and R6together with the nitrogen to which they are attached form 4-10 membered heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S, in addition to the nitrogen to which R5and R6are attached, wherein the heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from Re, when present, Reis selected from(1) -C0-6alkyl-OH,(2) -C1-6alkyl, unsubstituted or substituted with 1-3 -OH substituents,(3) -C0-6alkyl-cyano,(4) -C0-6alkyl-O-C i salkyl,(5) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1-3 -C1-6alkyl substituents,(6) halo,(7) -C1-6haloalkyl,(8) -C0-6alkyl-aryl, wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl, and halo,(9) -C3-6cycloalkyl,(10) -C0-6alkyl-N(Rf)2. wherein each Rfis independently selected from hydrogen and C1-6alkyl. or two Rftogether form =OC1-6alkyl,(11) -NHC(O)C1-6alkyl,(12) -Co-3alkyl-(3-6 membered monocyclic heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1 -3 =0 substituents.(13) -O-C1-6haloalkyl,(14) =0,(15) hydrogen,(16) -C(O)OC1-6alkyl,(17) -N(CH3)-C3-6Cycloalkyl, wherein the cycloalkyl is substituted with 1 -OH substituent,(18) -N(CHs)-(3-7 membered monocyclic heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one -Ci-3alkyl substituent,(19) -C(O)C1-6alkyl, and(20) 5-8 membered bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with 1-3 substituents independently selected from -Ci-3alkyl, -Ci-3alkyl-0H, and hydrogen.R10is selected from:(1) hydrogen,(2) -C1-6alkyl,(3) -C3-6cycloalkyl,(4) -C i-ehaloalkyl,(5) -C1-6alkyl-O-C1-6alkyl, and(6) -C1-6alkyl-OH;2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is(1) -Ce-ioaryl,(2) -Ce-iocycloalkyl,(3) 5-10 membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, or(4) 5-10 membered heterocyclyl having one to 2 ring heteroatoms independently selected from N, O, and S.

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein ring A is(1) pheny l or naphthyl,(2) tetrahydronaphthalenyl,(3) indazolyl. indolizinyl, quinolinyl, isoquinolinyl, pyrrolo[l,2-b]pyridazinyl, benzo[rf]thiazolyl, benzo[d]isothiazolyl, dihydrobenzo[d]isothiazolyl, benzofuranyl, pyrrolo[2,3-b]pyridinyl, dihydroisobenzofuranyl, benzo[c][ 1,2,5 ]thiadiazolyl, isoxazolyl, benzo[d]oxazolyl, or oxadiazolyl, or(4) dihydro-quinolinyl. dihydrobenzo[b][l,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, dihydrobenzo[b][ 1,4] dioxinyl, dihydro-pyrrolo[2,3-6]pyridinyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is(1) C1-6alkyl.(2) halo,(3) -Ci-3alkyl-(0)NH-(Co-3alkylcyclobutanyl), wherein the cyclobutanyl is unsubstituted or substituted with 1-3 fluoro substituents; -Ci-3alkyl-(0)NH-(Co-3alkyl- bicyclof l.

1. l]pentanyl); -Ci-3alkyl-(0)NH-(Co-3alkyl-cyclopropanyl); -Ci-3alkyl-(O)NH- (Co-3alkyl-phenyl), wherein the phenyl is unsubstituted or substituted with 1-3 substituents independently selected from methyl or -F; -Ci-3alkyl-(0)NH-(Co-3alkyl- thiazolyl), wherein the thiazolyl is unsubstituted or substituted with one methyl substituent; -Ci-3alkyl-(O)NH-Ci-3alkyl; or -Ci-3alkyl-(0)NH-(Co-3alkyl-cyclopentanyl),(4) -NHC(O)NH(C3-6cycloalkyl), wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from -OCH3 and halo; - NHC(O)NH(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ringheteroatoms independently selected from N. O, and S. and is unsubstituted or substituted with 1 -C1-6alkyl substituent; -NHC(O)NH(-Ci-3alkyl); or -NHC(0)NH(-Co-3alkyl-aryl), wherein the aryl is unsubstituted or substituted with 1 -3 halo substituents,(5) -NHC(O)-aryl, wherein the aryl is substituted with one -OH substituent; - NHC(O)-heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1-3 -Ci- ealkyl substituents; -NHC(O)C1-6alkyl, wherein the alkyl is unsubstituted or substituted with 1 cycloalkyl substituent; -NHC(O)O-C1-6alkyl; -NHC(O)-C1-6alkyl; or - NHC(O)CH2S-C1-6alkyl,(6) -C0-6alkyl-OH, -C0-6alkyl-O-C1-6alkyl, or -C0-6alkyl-O-aryl-O-C1-6alkyl,(7) -Co-3alkyl-C(0)0-Ci-3alkyl, wherein the -Co-3alkyl is unsubstituted or substituted with one -NH2substituent,(8) -Co-3alkyl-cyano,(9) -Co-3alkyl-NH2; or -C0-6alkyl-NH-phenyl,(10) -C0-6alkyl-phenyl, wherein the phenyl is unsubstituted or substituted with 1-3 halo substituents,(11) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S,(12) -NH-C3-6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1- 3 substituents independently selected from =0 and -NH-cyclopropyl,(13) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1-3 substituents independently selected from -C(0)0C1-6alkyl. -C1-6alkyl, -NH2, and -C1-6alkyl-Cs-ecycloalkyl.(14) -C3-6Cycloalkyl, unsubstituted or substituted with one -C(0)0C1-6alkyl substituent,(15) =0,(16) hydrogen,(17) -C1-6haloalkyl,(18) -C=C,(19) -NHC(O)-C3-6Cycloalkyl, unsubstituted or substituted with -C(O)NH-C5-6aryl, wherein the ar l is unsubstituted or substituted with 1-3 substituents independently selected from -C1-6alkyl, -OH, and halo, or(20) -NHS(=0)2NH -Ci-3alkyl, or -NHS(=O)2NH-C3-6cycloalkyl.

5. The compound of any one of claims 1-4. or a pharmaceutically acceptable salt thereof, wherein R1is(1) -C1-6alkyl,(2) -F or -Cl,(3) -C(0)NH-(Co-ialkyl-cyclobutanyl), unsubstituted or substituted with 1-2 substituents independently selected from -OCH3 and -F; -C(O)NH- bicyclo[l. l.l]pentanyl; -C(0)NH-(Co-ialkyl-cyclopropanyl); -C(0)NH-(Co-ialkyl- phenyl), wherein the phenyl is unsubstituted or substituted with one substituent selected from methyl or -F; -C(O)NH-thiazolyl, wherein they thiazolyl is substituted with one methyl substituent; -C(O)NH-Ci-3alkyl; -CH2C(O)NHCH3; or -C(0)NH-(Co-ialkyl- cyclopentanyl),(4) -NHC(O)NH-cyclopropanyl, wherein the cyclopropanyl is unsubstituted or substituted with 1-2 -F substituents; -NHC(O)NH-isoxazolyl, wherein the isoxazolyl is substituted with one methyl substituent; -N(CH3)(O)NH-cyclopropyl; or -NHC(O)NH- phenyl, w herein the phenyl is unsubstituted or substituted with one -F substituent,(5) -NHC(O)-phenyl, wherein the phenyl is substituted with one -OH substituent; - NHC(O)-thiophenyl, wherein the thiophenyl is unsubstituted or substituted with one methyl substituent; -NHC(O)OCH(CH3)2; -NHC(O)CH2CH2CH3; -NHC(O)CH3; - NHC(O)CH2SCH3, -NHC(O)OCH3, -NHC(O)CH2-cycloproanyl; or -NHC(O)OCH2CH3,(6) -CH2CH2OH, -OCHs, or -O-phenyl-OCHs,(7) -CH2CH2C(O)OCH2CH3, -CH2CH(NH2)C(O)OCH3, -C(O)OCH3. or CH2CH2C(O)OCH3,(8) cyano or -CH2-cyano,(9) -NH2 or -CH2NH-phenyl,(10) -Co-ialkyl-phenyl, substituted with 1-2 substituents independently selected from - Cl and -F; or -CH(CH3)-phenyl,(11) -CH2-pyrrolyl,(12) -NH-cyclobutenyl, wherein the cyclobutenyl is substituted with 3 substituents independently selected from =0 and -NH-cyclopropyl,(13) dihydrooxazolyl, substituted with one -C(O)OCH2CH3 substituent; oxadiazole substituted with one substituent selected from methyl or -CH2CH2-cyclopentyl; oxazole; isoxazolyl substituted with -C(O)OCH3; thiazolyl substituted with methyl; triazolyl substituted with -NH2; or -CH2-pyrrolyl,(14) cyclobutanyl substituted with one -C(O)OCH3 substituent; or cyclopropanyl,(15) =0.(16) hydrogen,(17) -CF3, or -CHF2,(18) C=C,(19) -NHC(O)-cyclopropyl, substituted with -C(O)NH-phenyl. wherein the phenyl is substituted with -F, or(20) -NHS(=O)2NH-CH3, or -NHS(=O)2NH-cyclopropyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2is(1) 3-7 membered monocyclic heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S, in addition to the nitrogen to which R3and R4are attached, wherein the monocyclic heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from:(a) -C0-6alkyl-OH,(b) -Co-6alkyl,(c) -C0-6alkyl-cyano,(d) -C0-6alkyl-0-Ci-3alkyl,(e) -NHC(O)C1-6alkyl,(f) 3-7 membered monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with one =0 substituent,(g) -Ci shaloalkyl, and(h) halo;(2) -N(CH3)-C3-6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one -OH or -Ci-3alkyl substituent;(3) -N(CH3)-(3-7 membered monocyclic heterocyclyl), wherein the heterocyclyl has one nitrogen and 0-3 additional ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one -Ci-3alkyl substituent;(4) 5-8 membered bridged bicyclic heterocyclyl having one nitrogen atom and 0-3 additional ring heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from -C(O)CH3, -Ci-3alkyl, and -C1-6alkyl-OH,(5) 7-10 membered fused bicyclic heterocyclyl having one nitrogen ring atom and 0-3 additional ring heteroatoms independently selected from N, O, and S, or(6) 7-10 membered spiro bicyclic heterocyclyl having one nitrogen ring atom and 0-3 additional ring heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from -H, =0, -Ci-3alkyl, and -OH.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2is(1) pyrrolidinyl, substituted with 1-2 substituents independently selected from: -OH; - CH2OCH3; -C1-6alkyl-OH; -Cwalkyl; or -NHC(O)CH3;(2) azetidinyl, substituted with 1-2 substituents independently selected from: methyl; cyano; -OCHs; -Co-ialkyl-OH; -NHC(O)CHs; cyclopropyl; -CF3; -CHF2; -F; piperidinyl, substituted with -CH2CH3; and pyrrolidinyl, substituted with one =0 substituent;(3) -N(CH3)-cyclobutanyl substituted with one -OH substituent;(4) -N(CH3)-azetidinyl, substituted with one methyl substituent; or -N(CH3)- pyrrolidinyl, substituted with 1 methyl substituent;(5) azabicyclo[2.1.1]hexanyl, unsubstituted or substituted with one substituent selected from methyl, -OH, -CH2OH and hydrogen; and diazabicyclo[2.

2. l]heptanyl, substituted with 1 -C(O)CH3 substituent,(6) oxa-azabicyclo[3.2.0]heptanyl, or(7) diazaspiro[3.4]octanonyl, substituted withl-2 substituents independently selected from =0, methyl and -H; oxaazaspiro[3.4]octanyl, unsubstituted or substituted with -OH.

9. The compound of any one of claims 1-8. or a pharmaceutically acceptable salt thereof, wherein R2is -OCH3, -OCH2CH3,10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X is -O-, -NH-, or -N-C1-6alkyl-.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R10is methyl.

12. A compound or pharmaceutically acceptable salt thereof selected from:

13. A compound or pharmaceutically acceptable salt thereof selected from: 7-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl}oxy)-A.2-dimethylindolizine-3-carboxamide,7-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyridazin-4-yl}oxy)-A,2-dimethylindolizine-3-carboxamide,7-({6-[(2R,3^)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2- 6]pyridazin-4-yl}oxy)-A,2-dimethylindolizine-3-carboxamide,7-({6-[(2R,45)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyridazin-4-yl}oxy)-A,2-dimethylindolizine-3-carboxamide,7-({6-[(2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyridazin-4-yl}oxy)-A,2-dimethylindolizine-3-carboxamide,7-({6-[(2 .3R)-3-methoxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyridazin-4-yl}oxy)-A,2-dimethylindolizine-3-carboxamide,A-(c / .s-3-fluorocyclobutyl)-7-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| 1.2- / > |pyndazin-4-yl} oxy )-2-rnethylindolizine-3-carbo.\amide.A-(3,3-difluorocyclobutyl)-7-({6-[(2A,3^)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| 1.2-6 |pyndazin-4-ylJ o.xy)-2-methylindolizine-3-carboxamide.8-fluoro-7-({6-[(2R,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2-Z>]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-3-carboxamide,8-fluoro-7-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- d]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-3-carboxamide,6-( { 6- [ (2R.3R)-3-hydroxy-2-methylazetidine- l-carbonyl]-5-methylpyrrolo[ 1.2- b\ py ridazin-4-y 1 } oxy )-M2-dimethy 1 indol izine- 1 -carboxamide,6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl } oxy )- / V.2-dimethylindolizine- 1 -carboxamide.6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- / )|pyndazin-4-yl }oxy)-M2-dimethylindolizine- 1 -carboxamide.6-[(6-{(3<S)-3-[acetyl(methyl)amino]pyrroli dine-1 -carbonyl} -5-methylpyrrolo[l, 2- b ] py ridazin-4-y l)oxy] -H.2-di methy lindolizine- 1 -carboxamide,6-[(6-{(3R)-3-[acetyl(methyl)amino]pyrrolidine-l-carbonyl}-5-methylpyrrolo[l,2- / ) | py n dazm-4-y I )oxy | - N.2-dimethy lindolizine- 1 -carboxamide,6-({6-[(2R,45)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-&]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-l-carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- / )|pyndazin-4-yl }oxy)- / V.2-dimethylindolizine- 1 -carboxamide.6-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-l-carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)-N-methyl-2 / 7-indazole-3-carboxamide,6-({6-[(36’)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-ib]pyridazin-4-yl} oxy )-;V-methyl- 1 ,2-benzothiazole-3-carboxamide,6-( {6-[(3R)-3-hy droxy-3-methylpyrrolidine- 1 -carbonyl]-5-methylpyrrolo[ 1 ,2- b\ pyridazin-4-yl} oxy )- N-methyl-l,2-benzothiazole-3 -carboxamide.N-cyclobutyl-6-({6-[(2A.4S’)-4-hydroxy-2-methylpyrrolidine-l-carbonyll-5- methylpyrrolo| l.2-6|pyndazin-4-yl}oxy)naphthalene-l -carboxamide,N-cyclobutyl-6-({6-[(2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b ] py ri dazin-4-y 1 } oxy)naphthalene- 1 -carboxamide,N-cyclopropyl-7-({6-[(2R,3S)-3-fluoro-2-rnethylazetidine-l-carbonyl]-5- methylpyrrolo| l.2- / )|pyridazin-4-yl}oxy)-2.3-dihydro-4H-l .4-benzoxazine-4-carboxamide.N-[2-chloro-4-({6-[(3S)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-&]pyridazin-4-yl}oxy)phenyl]- N-cyclopropylurea,N-[2-chloro-4-({6-[(3R)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[1.2- 6|pyridazin-4-yl}oxy)phenyl l-M-cyclopropylurea.(R)-Af-[2-chloro-4-({6-[3-(2-hydroxypropan-2-yl)pyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-b p ]y ri dazi n-4-y I } oxy)pheny 1] - N-cy clopropylurea,(<S’)- N-[2-chloro-4-({6-[3-(2-hydroxypropan-2-yl)pyrrolidine-l-carbonyl]-5- methylpyrrolo[ 1 ,2-6]pyridazin-4-yl] oxy )phenyl|-.V-cyclopropyl urea.N-(2-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } phenyl )-A'r'-cyclopropy I urea.N-[2-chloro-4-({6-[(3S)-3-methoxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- 6|pyndazin-4-yl}oxy)phenyl|- N'-cyclopropylurea.N-[2-chloro-4-({6-[(3R)-3-methoxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyridazin-4-yl}oxy)phenyl]- N-cyclopropylurea,N -(2-chloro-4-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl] oxy } pheny l)- N-methy lurea,N -[2-chloro-4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy)phenyl]- N-methylurea,N -[4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-61 py ndazin-4-yl } oxy)-2-methylpheny 1] - / V-melhy lurea,N-cyclopropyl- N-[4-({6-[(2JR,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b ] py ri dazin-4-y 1 } oxy )-2-(trifluoromethy l)phenyl] urea,N-cyclopropyl- N-[3-fluoro-4-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2 -b] pyridazin-4-yl } oxy )pheny 1] urea.N-cyclopropyl- N-[3-fluoro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1,2-6] pyridazin-4-yl } oxy )phenyl] urea,N-cyclopropyl- N-[3-fluoro-4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6] pyridazin-4-yl } oxy)pheny 1] urea,N-cyclopropyl- N-[2-fluoro-4-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1,2-6] pyridazin-4-y 1 } oxy )phenyl] urea,N-cyclopropyl- N-[2-fluoro-4-({6-[(3i?)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [1,2-6] pyridazin-4-yl } oxy)phenyl] urea,N-cyclopropyl- N'-[2-fluoro-4-({6-[(2.R,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1, 2-6] pyridazin-4-yl} oxy )phenyl] urea,N-cyclopropyl-An-[2-cyclopropyl-4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l- carbonyl] -5-methy Ipyrrolo [ 1 ,2-6]py ridazin-4-yl } oxy )phenyl] urea,N-cyclopropyl- N-[3-fluoro-4-({6-[(2R, S')-4-hydroxy-2-methylpyrrolidine-l-carbonyl]- 5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-2-methylphenyl]urea,N-cyclopropyl- N-[3-fluoro-4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-b p ]y ri dazi n-4-y I } oxy )-2-methylpheny l]urea.N-[2-fluoro-4-({6-[(2A,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[ 1.2-6 |pyndazin-4-yl} oxy)phenyl]- N-(5-methyl- 1 ,2-oxazol-3-yl)urea,A-ethy l-5-( {6-| (2R.3R)-3-hydroxy-2-methyl a / etidine- 1 -carbonyl]-5-methylpyrrolo[ 1 ,2-6|pyridazin-4-yl}oxy)-lH-indazole-l -carboxamide,N-ethyl-4-fluoro-5-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-1H-indazole-l-carboxamide,2-[4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- 6]pyridazin-4-yl}oxy)phenyl |-H-mcthyl acetamide.2- [4-( {6-[(2R,3A)-3-hydroxy-2-methylazetidine-l -carbonyl]-5-methylpyrrolo[ 1 ,2- 61 pyridazm-4-yl} oxy )phenyl |- / V-(4-methyl- 1.3-thiazol-2-yl)acetamide.2-[4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy)pheny 1] -H-(5-methy I - 1 ,2-oxazol-3 -y l)acetamide,(S’)- N-ethyl-7-((6-(3-hydroxy-3-methylpyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2-6]pyridazin-4-yl)oxy)-2-methylindolizine-3-carboxamide,7-((6-(3-hydroxy-2,2-dimethylazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl)oxy)- N,2-dimethylindolizine-3-carboxamide,7-((6-((2R,3R)-3 -hy droxy-2-methylazetidine- 1 -carbony l)-5 -methylpy rrolo [ 1 ,2-6|pyndazin-4-yl)oxy)-,'V.2.8-trimethylindolizine-3-carboxarmde.(R)- N-ethyl-2-methyl-7-((5-methyl-6-(3-( N-methylacetamido)pyrrolidine-l- carbonyl)pyrrolo [ 1.2-bp ]yridazin-4-yl)oxy)indolizine-3-carboxamide,N,5-dimethyl-4-((2-methyl-3-(methylcarbamoyl)indolizin-7-yl)oxy)- N-(l-methylazetidin-3-yl)pyrrolo[ 1 ,2-6]pyridazine-6-carboxamide.N-(ira«.,-3-hydroxycyclobutyl)- N,5-dimethyl-4-{[2-methyl-3-(methylcarbamoyl)indolizin-7-yl]oxy}pyrrolo [ 1.2-bp ]yridazine-6-carboxamide,N-(c / .s-3-hydroxycyclobutjl)- N,5-dimethyl-4-{[2-methyl-3-(methylcarbamoyl)indolizin-7-yl]oxy}pyrrolo [ 1.2-bp ]yridazine-6-carboxamide, ,5-dimethyl-4- {[2-methyl-3-(methylcarbamoyl)indolizin-7-yl]oxy } -N-[(3 )- 1 - methylpyrrolidin-3-yl]pyrrolo [ 1.2-bp ]yridazine-6-carboxamide,N,5-dimethyl-4- { [2-methyl-3-(methylcarbamoyl)indolizin-7 -yl]oxy } -N-[(3S - 1 - methylpyrrolidin-3-yl]pyrrolo [ 1.2-bp ]yridazine-6-carboxamide,7-({6-[3-(acetylamino)azetidine-l-carbonyl]-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-N,2-dimethylindolizine-3-carboxamide,7-{[6-(3-hydroxyazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}- N,2- dimethylindolizine-3-carboxamide,7-{[6-(3-hydroxy-3-methylazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy}- N,2-dimethylindolizine-3-carboxamide,7-({6-[3-hydroxy-3-(hydroxymethyl)azetidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-3-carboxamide, , 2-dimethyl-7-({5-methyl-6-[3-(2-oxopyrrolidin-l-yl)azeti dine- l-carbonyl]pyrrolo[ 1.2- 6]pyridazin-4-yl}oxy)indolizine-3-carboxamide,7-({6-[(2R,3S)-3-hydroxy-2-(trifluoromethyl)azetidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N,2-dimethylindolizine-3-carboxamide,7-[(6-{(3R)-3-[acetyl(methyl)amino]pyrrolidine-l-carbonyl}-5-methylpyrrolo[l,2-6]pyridazin-4-yl)oxy]- N.2-dimethylindolizine-3-carboxamide,7- { [6-(4-hydroxy-2-azabicyclo[2.

1. l]hexane-2-carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin-4-yl]oxy}- N,2-dimethylindolizine-3-carboxamide,N ,2-dimethyl-7-{[5-methyl-6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl)pyrrolo[l,2-6] pyridazin-4-yl] oxy }indolizine-3 -carboxamide,N,2-dimethyl-7-({5-methyl-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carbonyl]pyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)indolizine-3-carboxamide,N,2-dimethyl-7-({5-methyl-6-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5- carbonyl]pyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)indolizine-3-carboxamide,6-({6-[(2A.3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2-6]pyridazin-4-yl}oxy)- N,l-dimethyl-1H-indazole-3-carboxamide,6-({6-[(2R,3iS)-3-hydroxy-2-methylazetidine- 1 -carbonyl] -5-methylpy rrolo[l ,2- d]pyridazin-4-yl}oxy)- N,l-dimethyl-1H-indazole-3-carboxamide,6-( { 6- [ (2R.4S’)-4-hydroxy-2-methylpyrrolidine- 1 -carbonyl]-5-methylpyrrolo[ 1.2- £>]pyridazin-4-yl}oxy)- N,2-dimethyl-2H-indazole-3-carboxamide,6-({6-[(35)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl }oxy)- / V.2-dimethyl-2H-indazole-3-carboxamide.6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2-6]pyridazin-4-yl}oxy)- N,2-dimethyl-2H-indazole-3-carboxamide,6- { [6-(3 -methoxy azeti dine- 1 -carbony l)-5 -methylpyrrolo [ 1 ,2-6] py ridazin-4-y 1] oxy } -N- methylnaphthalene- 1 -carboxamide,6- { [6-(3-cyanoazetidine- l-carbonyl)-5-methylpyrrolo[l .2-A | pyndazin-4-yl |oxy } -N- methylnaphthalene-1 -carboxamide,6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-( {6-[ (2S,3S)-3-hydroxy -2 -methylazetidine- 1 -carbonyl] -5-methylpy rrol o| 1 ,2- b\ py ridazin-4-y 1 } oxy )-H-methy Inaphthalene- 1 -carboxamide,6-({6-[(2S',3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(2R,35)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- / )|pyndazin-4-yl}oxy)-H-methylnaphthalene- l -carboxamide.6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo [ 1.2-bp ]yridazin- 4-y 1 } oxy )- / V-methy Inaphthalene- 1 -carboxamide,6-({6-[(2R,45)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- A'-methy Inaphthalene- 1 -carboxamide,6-( {6-[(2R,41?)-4-hy droxy-2-methylpy rrolidine- 1 -carbonyl]-5-methylpyrrolo[ 1 ,2- b ] py ridazin-4-y 1 } oxy )- / V-methy Inaphthalene- 1 -carboxamide,6-({6-[(2S',4R)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )- A'-methy Inaphthalene- 1 -carboxamide,6-( {6-[(2S,45)-4-hydroxy-2-methylpyrrolidine- 1 -carbonyl] -5-methylpyrrolo[ 1 ,2- b ] py ridazin-4-y 1 } oxy )-A-methy Inaphthalene- 1 -carboxamide,6-({6-[(2A.3S)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[1.2- b ] py ridazin-4-y 1 } oxy )- A-methy Inaphthalene- 1 -carboxamide,6-( |6-| (2R.3R)-3-hy droxy-2-methy I py rrolidine- 1 -carbonyl]-5-methylpyrrolo[ 1 ,2- h\ py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-( { 6- [ (2S,3S)-3-hydroxy-2-methyl pyrrolidine- 1 -carbonyl]-5-methylpyrrolo[ 1.2- b\ py ridazin-4-y 1 } oxy )-H-methy Inaphthalene- 1 -carboxamide,6-( {6-| (2S.3R)-3-hydroxy-2-methyl pyrrol idine- 1 -carbonyl]-5-methylpyrrolo[ 1 ,2- b ] py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,6-({6-[(2S)-2-(methoxymethyl)pyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-d]pyridazin-4-yl} oxy )-yV-methy Inaphthalene- 1 -carboxamide,Ncyclobutyl-6-( {6-|C2R.3R)-3-hydroxy-2-melhylazetidine- 1 -carbonyl |-5- methylpyrrolo [ 1 , 2-b ] py ri dazin-4-y 1 } oxy)naphthalene- 1 -carboxamide,N-cyclobutyl-6-({6-[(25.3 / S’)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-b p ]y n dazm-4-y I } oxy )naphthalene- 1 -carboxamide,N -cyclobutyl-6-({6-[(2S,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-b p ]y ri dazi n-4-y I } oxy)naphthalene- 1 -carboxamide,N-cyclobutyl-6-({6-[(2A.3S’)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| l.2-6|pyndazin-4-yl}oxy)naphthalene-l -carboxamide,5-fluoro-6-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } -H-methy I naphthalene- 1 -carboxamide,6-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}-5- fluoro- N-methy Inaphthalene- 1 -carboxamide,5-fluoro-6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )-N\-mcthy Inaphthalene- 1 -carboxamide,5-fluoro-6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- b\ py ridazin-4-y 1 } oxy )- N-methy Inaphthalene- 1 -carboxamide,7-({6-[(2S',35)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] py ridazin-4-y 1 } oxy )-N-methy Inaphthal ene-2-carboxami de.7-( {6-[(2R,31?)-3 -hydroxy -2-methy lazeti dine- 1 -carbonyl] -5-methylpyrrolo [ 1.2- b ] py ridazin-4-y 1 } oxy )- / V-methy Inaphthal ene-2-carboxamide.7-({6-[(2R,35)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- 6] py ridazin-4-y 1 } oxy )- N-methy lnaphthalene-2-carboxamide,7 - { [6-(3 -hydroxy azetidine- 1 -carbonyl)-5-methy Ipyrrolo [ 1.2-6 | py ridazin-4-yl] oxy } -N- methylnaphthalene-2-carboxamide,7-{[6-(3-hydroxy-3-methylazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl] oxy } - A'-melhy I naphthal ene-2-carbox ami de.6-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}- N- cyclopropyl-5-fluoro-3,4-dihydroquinoline-l(2H)-carboxamide,N-cyclopropyl-5-fluoro-6-({6-f(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[ 1.2-6 |pyridazin-4-yl| oxy)-3,4-dihydroquinoline-l (2H)-carboxamide,N-cyclopropyl-5-fluoro-6-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-cyclopropyl-5-fluoro-6-({6-[(2R,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-cyclopropyl-5-fluoro-6-({6-[(2S',3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-cyclopropyl-5-fluoro-6-({6-[(2^,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N -cyclopropyl-5-fluoro-6-({6-[(2S,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| 1.2-A |pyridazin-4-yl} oxy)-3.4-dihy droquinoline- 1 (2H)-carboxarnide.N-ethyl-5-fluoro-6-({6-[(2R.3R)-3-hydroxy-2-methylazetidine-l-carbonyll-5- methylpyrrolo[ 1.2-6 |pyridazin-4-yl| oxy)-3,4-dihydroquinoline-l (2H)-carboxamide, / V-ethyl-5-fluoro-6-({6-[(2S,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N-ethyl-5-fluoro-6-({6-[(2R,3S )-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide, / V-ethyl-5-fluoro-6-({6-[(2S,3i?)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N -cyclopropyl-6-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[1.2-6]pyridazin-4-yl}oxy)-3.4-dihydroquinoline-l(2H)-carboxamide.N -cyclopropyl-6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-3,4-dihydroquinoline-l(2H)-carboxamide,N -cy clopropyl-7 - { [6-(3-methoxy azetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin- 4-y 1] oxy } -2,3 -dihydro-417- 1 ,4-benzoxazine-4-carboxamide,7- { [6-(3-cyanoazetidine- l-carbonyl)-5-methylpyrrolo[l ,2-6]pyridazin-4-yl]oxy } -N- cyclopropyl-2.3-dihydro-46 / -l .4-benzoxa / ine-4-carboxamide.N-cyclopropyl-7-({6-[(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| l.2-6|pyndazin-4-yl}oxy)-2.3-dihydro-47 / - l.4-benzoxazine-4-carboxamide.N-cyclopropyl-7-(' |6-|(2R.3R)-3-hydroxy-2-methylazetidine-l-carbonyl|-5- melhyl pyrrolo| 1.2-61 pyridazin-4-yl}oxy)-2.3-dihydro-4H- 1 .4-benzoxazine-4-carboxamide.N -cyclopropyl-7-({5-methyl-6-[2-(propan-2-yl)azetidine-l-carbonyl]pyrrolo[l,2- 6]pyridazin-4-yl}oxy)-2.3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-cy clopropyl-7 - { [ 6-(2-cy clopropylazetidine- 1 -carbony l)-5-methy Ipy rrolof 1,2- 6]pyridazin-4-yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,A-cyclopropyl-7-( {5-methyl-6-| (2S)-2-(tri fl iioromethyl)azeti dine- 1 -carbonyl | pyrrolo| 1.2- 6]pyridazin-4-yl}oxy)-2,3-dihydro-4 / 7-l,4-benzoxazine-4-carboxamide,N-cy clopropyl-7 -( { 6- 1 (2S)-2-(di fl uoromethy I )azeti dine- 1 -carbony l]-5-methy Ipy rrolo[ 1 ,2- 6]pyridazin-4-yl}oxy)-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-cy clopropyl-7 -( { 6-[(3R)-3-hy droxy-3-methylpyrrolidine- 1 -carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-cyclopropyl-7-( {6-|(3X)-3-hydroxy-3-methylpyrrolidine-l-carbonyl |-5- methylpyrrolo[l,2-Z)]pyridazin-4-yl}oxy)-2,3-dihydro-47Z-l,4-benzoxazine-4-carboxamide, 7-{[6-(2-azabicyclo[2.1.1]hexane-2-carbonyl)-5-methylpyrrolo[l,2- / )]pyridazin-4- y 1] oxy } - N-cy clopropy 1-2.3-dihy dro-4H- 1 ,4-benzoxazine-4-carboxamide, / V-cyclopropyl-7-{[6-(4-hydroxy-2-azabicyclo[2.

1. l]hexane-2-carbonyl)-5- methylpyrrolo[ 1 ,2- / )]pyridazin-4-yl]oxy } -2, 3 -dihydro-4H-1 ,4-benzoxazine-4-carboxamide,N-cyclopropyl-7-{[5-methyl-6-(l-methyl-2-azabicyclo[2.1.1]hexane-2- carbonyl)pyrrolo[l,2- / )]pyridazin-4-yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-cyclopropyl-7-({6-[l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carbonyl]-5- methylpyrrolo| 1.2- / ) |pyndazin-4-yl} oxy )-2.3-dihy dro-4H- 1.4-benzoxazine-4-carboxamide.N-cyclobutyl-7-{[6-(3-methoxyazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide, 7-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z)]pyridazin-4-yl]oxy}- N- cy clobutyl-2.3-dihy dro-4 / 7- 1 ,4-benzoxazine-4-carboxamide,N-cyclobutyl-7-({6-[(37,)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo| 1.2- / ) |pyndazin-4-yl]oxy)-2.3-dihy dro-4H- 1 .4-benzoxazine-4-carboxamide.N-cyclobutyl-7-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo| 1.2- / ) | pyndazin-4-yl} oxy )-2.3-dihy dro-47 / - 1.4-benzoxazine-4-carboxamide.N -cyclobutyl-7-({6-[(2S,3y)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methyl pyrrolo| 1.2- / ) | pyndazin-4-yl}oxy)-2.3-dihy dro-4H- 1 .4-benzoxazine-4-carboxamide. / V-cyclobutyl-7-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| 1.2- / ) |pyndazin-4-yl} oxy)-2.3-dihy dro-47 / - 1.4-benzoxazine-4-carboxamide. / V-ethyl-7-({6-[(2A,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- / )]pyridazin-4-yl}oxy)-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-ethyl-7-( {6-| (2.S'.3S)-3-hy droxy-2-methylazetidine- 1 -carbonyl] -5-methylpyrrolo[l,2- / ) | py ndazin-4-yl } oxy )-2.3-dihy dro-47 / - 1.4-benzoxazine-4-carboxamide.(4-{[3-(2?6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolofl,2- / )]pyridazin-6- yl)(3-hydroxy-3-methylazetidin-l-yl)methanone,(4-{[3-(2,6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo[l,2- / >]pyridazin-6- y 1)(3 -methoxy azeti din- 1 -y l)methanone, l-(4-{[3-(2,6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo[l,2- / )]pyridazine- 6-carbonyl)azetidine-3-carbonitrile,(4-{[3-(2.6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo[l,2- / )]pyridazin-6- yl)|(3R)-3-hydroxy-3-mcthylpyrrolidin-l -yl|mcthanonc.(4-{[3-(2.6-difluorophenyl)-l,2-oxazol-5-yl]amino}-5-methylpyrrolo[l,2-i>]pyridazin-6- yl)[(3S)-3-hydroxy-3-methylpyrrohdin-l-yl]methanone,N -[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-((R or S)-2,2-difluorocyclopropyl)urea,N-[2-chloro-4-({6-f(3.R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N’-((S or R)-2,2-difluorocyclopropyl)urea,N-cyclopropyl- N-[4-({6-[(2R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b ] py ri dazin-4-y 1 } oxy)phenyl] -Mmethy 1 urea.N-cyclopropyl- N-[4-({6-[(2R,3S)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-methylurea,N-cyclopropyl- N-[4-({6-[(2R,4R)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 , 2-b ] py ri dazin-4-y 1 } oxy)phenyl] - N-methy lurea,N -cyclopropyl- N-[4-({6-[(2R,45)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[1.2-d]pyridazin-4-yl}oxy)phenyl]- N-methylurea,.V-cyclopropyl-Az-[4-({6-[(2i?,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpy rrolo [ 1 ,2-b\ pyridazin-4-yl } oxy)phenyl] -V-methy 1 urea.N -cy clopropy 1- N- [4-( { 6- [(2R,3R)-3 -hy droxy-2-methy lazetidine- 1 -carbonyl] -5 - methylpy rrolo [ 1.2-b] pyridazin-4-yl } oxy )phenyl] -'V-methy lurea,N-cyclopropyl- N-[4-({6-[(2.R,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-h\ pyridazin-4-yl } oxy )-2-methylphenyl]urea,N-cyclopropyl- N-[4-({6-[(2R,3S)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo| l.2- / )|pyndazin-4-yl]oxy)-2-methylphenyl |urea.N -cyclopropyl- N-[4-({6-[(2.K.4R)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b} pyridazin-4-yl } oxy )-2 -methylphenyl] urea,N-cyclopropyl- N-[4-({6-[(2R,4<S)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b] pyridazin-4-yl } oxy )-2-methylpheny l]urea.N-cyclopropyl-A"-[4-({6-f(2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo| l.2-6|pyndazin-4-yl}oxy)-2-methylphenyl |urea.N-cyclopropyl- N-[4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-b] pyridazin-4-yl } oxy )-2-methylpheny l]urea.N-|2-chloro-4-(]6-|(2R.3R)-3-hydroxy-2-methy]pyrrolidine-l-carbonyl|-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-cyclopropylurea,N-[2-chloro-4-({6-[(2R,3S)-3-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methy Ipy rrolo [ l,2-6]pyridazin-4-yl]oxy)phenyl]- N-cyclopropylurea,N-[2-chloro-4-({6-[(2R,4A)-4-hydroxy-2-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]-A"-cyclopropylurea, |2-chloro-4-( {6-|(2RAV)-4-hydroxy-2-rnethylpyrrolidine- 1 -carbonyl |-5- methylpyrrolo [ 1.2-7> | py ri dazi n-4-y I } oxy)pheny 1] - N-cy clopropylurea,N-(2-chloro-4- { [ 6-(3-methoxy azetidine- 1 -carbonyl)-5-methylpyrrolof 1 ,2- )]pyridazin-4- yl] oxy } pheny l)- N-cy clopropylurea,N-[2-chloro-4-({6-[(2i?,3 )-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo[l,2-&]pyridazin-4-yl}oxy)phenyl]-jV-cyclopropylurea,N-[2-chloro-4-({6-[(2R,3A)-3-hydroxy-2-methylazetidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-cyclopropylurea,N-(2-chloro-4-{[6-(4-hydroxy-2-azabicyclo[2.1.1]hexane-2-carbonyl)-5- methylpyrrolo [ 1 , 2-b ] py ri dazi n-4-y 1 ] oxy } phenyl)- N-cy clopropylurea,N -cyclopropyl- N-(2-cyclopropyl-4-{[6-(4-hydroxy-2-azabicyclo[2.1.1]hexane-2- carbonyl)-5-methylpyrrolo[l,2- ?]pyndazin-4-yl]oxy}phenyl)urea,N-cyclopropyl-An-[2-cyclopropyl-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l- carbonyl] -5-methylpyrrolo [ 1 ,2-b ] pyri dazi n-4-y 1 } oxy )phenyl] urea,N -cyclopropyl- N-[4-{[6-(4-hydroxy-2-azabicyclo[2.1.1]hexane-2-carbonyl)-5- methylpy rrolo [ 1.2-b] pyridazin-4-yl] oxy } -2-(trifluoromethy l)pheny 1] urea,N-cyclopropyl- N-[4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2- / ) | py n dazin-4-y I } oxy)-2-(trifluoromethy l)phenyl] urea,N-cyclopropyl- N-[2-(difluoromethyl)-4-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l- carbonyl]-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]urea,N-(4-fluorophenyl)- N-(4-((6-((27^.3R)-3-hydroxy-2-methylazetidine-l-carbonyl)-5- methylpyrrolo[ 1 ,2-6]pyridazin-4-yl)oxy)phenyl)cy clopropane- 1 , 1 -di carboxamide, 7-((6-((1R,4R)-5-acetyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-5-methylpyrrolo[l,2- 6]pyridazin-4-yl)oxy)- N.2-dirnethylindolizine-3-carboxamide,(R)-7-((6-(3-acetamidopyrrolidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl)oxy)- N,2-dimethylindolizine-3-carboxamide,7-((6-(3 -hydroxy -3-(hy droxy methy l)py rrolidine- 1 -carbonyl)-5 -methylpyrrolo [ 1 ,2- Z>]pyridazin-4-yl)oxy)- N.2-dimethylindolizine-3-carboxamide,7-((6-(2-oxa-6-azabicyclo[3.2.0]heptane-6-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl)oxy)- N,2-dimethylindolizine-3-carboxamide,7-((6-((2S,3R)-3-hydroxy-2-methylpyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2- &]pyridazin-4-yl)oxy)- N,2-dimethylindolizine-3-carboxamide,N,2-dimethyl-7-((5-methyl-6-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)pyrrolo[l,2- Z>]pyridazin-4-yl)oxy)indolizine-3-carboxamide,(R)-N-(l-acetylpyrrolidin-3-yl)- / V,5-dimethyl-4-((2-rnethyl-3-(methy lcarbamoyl)indolizin-7 -y l)oxy)pyrrolo[ 1 ,2-d ] py ridazine-6-carboxamide, / V-(l-ethylpiperidin-4-yl)- / V,5-dirnethyl-4-((2-methyl-3-(rnethylcarbamoyl)indolizin-7- yl)oxy)pyrrolo[l,2- / ?]pyridazine-6-carboxamide, / V,2-dimethyl-7-((5-methyl-6-(6-oxa-l-azaspiro[3.4]octane-l-carbonyl)pyrrolo[l,2- Z>]pyridazin-4-yl)oxy)indolizine-3-carboxamide,7-((6-(7-hydroxy-2-oxa-5-azaspiro[3.4]octane-5-carbonyl)-5-methylpyrrolo[l,2- / )|pyndazin-4-yl)oxy)- / V.2-dimethylindohzine-3-carboxamide. l-(3-((6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl)oxy)phenyl)-3-(4-fluorophenyl)urea, ethyl 2-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4- yl] oxy } phenyl)- 1 ,3-oxazole-4-carboxy late,1 - {4-[(3-fluoroquinolin-6-yl)oxy]-5-methylpyrrolo[ 1 ,2-d]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[(l-benzofuran-7-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carbonyl}azetidine-3- carbonitrile, / V-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2- / >]pyridazin-4- y 1] oxy } pheny l)benzamide,I- 14-|( I -chloronaphthal en-2-yl)oxy|-5-rnethylpyrrolo| 1.2- / ? |pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{5-methyl-4-[(quinohn-3-yl)oxy]pyrrolo[l,2-ft]pyridazine-6-carbonyl}azetidine-3- carbonitrile, l-[4-(3-chloro-2-fluorophenoxy)-5-methylpyrrolo[l,2-Z>]pyridazine-6-carbonyl]azetidine- 3-carbonitrile, l-{5-methyl-4-[(2-methyl-1.3-benzothiazol-5-yl)oxy]pyrrolo[1.2- / >]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{5-methyl-4-[(2-methylquinolin-6-yl)oxy]pyrrolo[l,2-Z>]pyridazine-6- carbony 1 } azetidine-3-carbonitrile,N-(4- { [6-(3-cy anoazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2- / >]pyridazin-4- yl] oxy } pheny l)butanamide, l-{4-[(8-aminonaphthalen-2-yl)oxy]-5-methylpyrrolo[l,2-Z>]pyridazine-6- carbony 1 } azetidine-3-carbonitrile,l-{4-[(1H-indazol-5-yl)oxy]-5-methylpyrrolo[1.2-h]pyridazine-6-carbonyl} azetidine-3- carbonitrile,1 - {4- [( 1 -fluoronaphthal en-2-yl)oxy] -5-methy lpyrrolo[ 1 ,2-&]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-[4-(3-chloro-4-methylphenoxy)-5-methylpyrrolo[ l,2-h]pyridazine-6- carbonyl]azetidine-3-carbonitrile, l-{5-methyl-4-[(naphthalen-2-yl)oxy]pyrrolo [ 1.2-bp ]yridazine-6-carbonyl}azetidine-3- carbonitrile, ethyl 3-(2-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-h]pyridazin- 4-yl] oxy } phenyl)propanoate,N-(3-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-b]pyridazin-4- y 1] oxy } pheny l)acetamide, l-[4-(4-ethylphenoxy)-5-methylpyrrolo[l,2-Z>]pyridazine-6-carbonyl]azetidine-3- carbonitrile, l-{4-[3-fluoro-4-(2-hydroxyethyl)phenoxy]-5-methylpyrrolo[l,2-h]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[(2,3-dihydro-l,4-benzodioxin-6-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile, methyl 3-(4- { [6-(3-cyanoazetidine-l -carbonyl)-5-methylpyrrolo[l ,2-h]pyridazin-4- y 1] oxy } pheny l)propanoate, l-{4-[(3-chloroisoquinolin-7-yl)oxy]-5-methylpyrrolo[l,2-b]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{5-methyl-4-[4-(5-methyl-1.2.4-oxadiazol-3-yl)phenoxy]pyrrolo[1.2-b]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-[4-(4-benzylphenoxy)-5-methylpyrrolo[l,2-h]pyridazine-6-carbonyl]azetidine-3- carbonitrile, l-{5-methyl-4-[4-(1.3-oxazol-4-yl)phenoxy pyrrolo [ 1.2-bp ]yridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{5-methyl-4-[(quinolin-6-yl)oxy]pyrrolo[l,2-b]pyridazine-6-carbonyl] azetidine-3- carbonitrile, l-{4-[(l,2-benzothiazol-5-yl)oxy]-5-methylpyrrolo[1.2-6]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{4-[(5-cyanonaphthalen-2-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile,l-{5-methyl-4-[(3-methylquinolin-6-yl)oxy]pyrrolo[l,2-i>]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, methyl 3-(4- { [6-(3-cyanoazetidine-l -carbonyl)-5-methylpyrrolo[l ,2-b]pyridazin-4- y 1] oxy } pheny l)cy clobutane- 1 -carboxylate, methyl 5-(3- { f6-(3-cyanoazetidine-l -carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin-4- yl]oxy}phenyl)-l,2-oxazole-3-carboxylate, l-{5-methyl-4-[(8-methylquinolin-4-yl)oxy]pyrrolo[l,2-Z>]pyridazine-6- carbony 1 } azetidine-3-carbonitrile, l-{4-[2-fluoro-4-(2-methyl-l,3-thiazol-4-yl)phenoxy]-5-methylpyrrolo[l,2-Z)]pyridazine- 6-carbonyl} azetidine-3 -carbonitrile,3-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy}- N-(4- methylphenyl)benzamide, propan-2 -yl (3-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2- b\ py ridazin-4-yl] oxy } phenyl)carbamate, l-[5-methyl-4-(4-propylphenoxy)pyrrolo [ 1.2-bp ]yridazine-6-carbonyl]azetidine-3- carbonitrile,N -(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } pheny l)acetami de, l-{4-[(isoquinolin-3-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6-carbonyl}azetidine-3- carbonitrile, l-{5-methyl-4-[(l-oxo-l,2-dihydroisoquinolin-7-yl)oxy]pyrrolo[l,2-b]pyridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[4-(5-amino-lH-l,2,4-triazol-3-yl)phenoxy]-5-methylpyrrolo[1.2-d]pyridazine-6- carbonyl } azetidine-3 -carbonitrile,1 - {4-[(4-fluoronaphthalen-2-yl)oxy] -5-methylpyrrolo[ 1 ,2-&]pyridazine-6- carbony 1 } azetidine-3-carbonitrile,3- { [6-(3-cyanoazetidine- l-carbonyl)-5-methylpyrrolo[l,2-i>]pyridazin-4-yl]oxy } -N- phenylbenzamide, l-{4-[(8-fluoroquinolin-3-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile, methyl <9-[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[1.2-6]pyridazin-4-yl]-Z-tyrosinate. l-{5-methyl-4-[(3-methylnaphthalen-2-yl)oxy]pyrrolo[l,2-ft]pyridazine-6- carbonyl } azetidine-3 -carbonitrile,l-{4-[(8-methoxyquinolin-3-yl)oxy]-5-methylpyrrolo[l,2-i ]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-[4-(2-fluoro-3-methylphenoxy)-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl]azetidine-3-carbonitrile, ethyl (4-{f6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-ft]pyridazin-4- yl] oxy } pheny l)carbamate,N-(4-{[6-(3-cy anoazetidine- 1 -carbonyl)-5-methy lpyrrolo[l, 2-6]pyridazin-4- yl] oxy } pheny l)thiophene-3-carboxami de,N-(4- { [6-(3-cy anoazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin-4- yl] oxy} pheny l)-3-methylthiophene-2-carboxamide, l-{4-[4-(cyanomethyl)-2-methylphenoxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile,N-(4- { [6-(3-cy anoazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-Z>]pyridazin-4- yl] oxy } pheny l)- N-phenylurea,N-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy}phenyl)-2-(methylsulfanyl)acetamide, l-(4-{4-[5-(2-cyclopentylethyl)-l,2,4-oxadiazol-3-yl]phenoxy}-5-methylpyrrolo[l,2-6]pyridazine-6-carbonyl)azetidine-3-carbonitrile, l-{5-methyl-4-[(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]pyrrolo [ 1.2-bp ]yridazine-6-carbonyl} azetidine-3 -carbonitrile, l-{5-methyl-4-[(5-methylnaphthalen-l-yl)oxy]pyrrolo[l,2-Z?]pyridazine-6- carbonyl}azetidine-3-carbonitrile,3- { [6-(3-cy anoazetidine- 1 -carbonyl)-5-methylpyrrolo[l .2-61 pyndazin-4-yl |oxy } - N-(4- fluorophenyl)benzamide, l-[4-(2,3-difluoro-4-methylphenoxy)-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl]azetidine-3-carbonitrile, l-(5-methyl-4-{4-[(phenylamino)methyl}phenoxy}pyrrolo[ l,2-&]pyridazine-6- carbonyl)azetidine-3-carbonitrile, l-{5-methyl-4-[(6-methylnaphthalen-2-yl)oxy]pyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile, methyl 7 - { [6-(3-cy anoazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1 ,2-6]pyridazin-4-yl] oxy } -1 -benzofuran-4-carboxylate, l-{5-methyl-4-[4-(l-phenylethyl)phenoxy]pyrrolo[l,2-Z?]pyridazine-6- carbony 1 } azetidine-3-carbonitrile,l-{4-[(2,3-dihydro-l / 7-pyrrolo[2,3-b]pyndin-5-yl)oxy]-5-methylpyrrolo[1.2-&]pyridazine-6-carbonyl}azetidine-3-carbonitrile, methyl (4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- y 1] oxy } pheny l)carbamate, l-{4-[4-(5-amino-4H-l,2,4-triazol-3-yl)-2-chlorophenoxy]-5-methylpyrrolo[l,2- i>]pyridazine-6-carbonyl}azetidine-3-carbonitrile, l-{4-[(2-amino-l,3-benzothiazol-5-yl)oxy]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile, l-{4-[(8-chloroquinolin-4-yl)oxy]-5-methylpyrrolo[1.2-6]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-(5-methyl-4-((2-methyl-17f-pyrrolo[2,3-6]pyridin-5-yl)oxy)pyrrolo [ 1.2-bp ]yridazine-6- carbonyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate,1-{5-methyl-4-[(3-methyl-1H-indazol-6-yl)oxy]pyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile.6- { [6-(3 -cyanoazetidine- l-carbonyl)-5-methylpyrrolo[l ,2-Z?]pyridazin-4-yl]oxy } -N- methyl-2H-indazole-3-carboxamide,7 - { [6-(3 -methoxy azetidine- 1 -carbony l)-5 -methylpy rrolo [ 1.2-b\ py ridazin-4-y 1] oxy } - N,2- dimethylindolizine-3-carboxamide,6- { [6-(3 -methoxy azeti dine- 1 -carbony l)-5-methy Ipyrrolofl ,2-b\ pyridazin-4-yl] oxy } -N- methyl-2£7-indazole-3-carboxamide, methyl 5-({ 6- 1 ( 3R)-3-hy droxy-3-methy Ipy rrolidine- 1 -carbonyl] -5-methy Ipy rrolo[ 1 ,2-6] pyridazin-4-yl } oxy )naphthalene- 1 -carboxylate,2-cyclopropyl- N-[3-fluoro-4-({6-[(3A)-3-hydroxy-3-methylpyrrohdine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl]oxy)phenyl]acetamide,N -cyclobutyl-6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1 ,2-6] pyridazin-4-yl } oxy)naphthalene- 1 -carboxamide,N-(bicyclo[l.l. l]pentan-l-yl)-6-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo| l.2-6|pyndazin-4-yl}oxy)naphthalene-l -carboxamide,7-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2-Z>]pyridazin-4-yl}oxy)- N-methylnaphthalene-2-carboxamide,N -[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo| l.2- / )|pyrida / in-4-yl}o.\y)phenyl|- / V-cyclopropylurea.6-({6-[(2R,3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[l,2- b ] pyridazin-4-yl}oxy)- N-(cz\s-3-methoxycyclobutjd)naphthal ene- 1 -carboxamide,6-({6-[(2A.3R)-3-hydroxy-2-methylazetidine-l-carbonyl]-5-methylpyrrolo[1.2-?]pyridazin-4-yl}oxy)- N-(fraw5'-3-methoxycyclobutyl)naphthalene-l-carboxamide,1 -(4-((6-methoxy- 1 ,2,3 ,4-tetrahy dronaphthalen-2-y l)oxy)-5 -methylpyrrolo [ 1,2- d]pyridazine-6-carbonyl)azetidine-3-carbonitrile,7-((6-((2R,3S)-3-hydroxy-2,3-dimethylazeti dine- l-carbonyl)-5-methylpyrrolo[ 1,2- £]pyridazin-4-yl)oxy)- N,2-dimethylindolizine-3-carboxamide,7-((6-((2R,3R)-3-hydroxy-2,3-dimethylazetidine-l-carbonyl)-5-methylpyrrolo[l,2- &]pyridazin-4-yl)oxy)-lV.2-dimethylindolizine-3-carboxamide, l-(5-methyl-4-((2-methyl-l / f-pyrrolo[2,3-6]pyridin-5-yl)amino)pyrrolo[l,2-ft]pyridazine- 6-carbonyl)azetidine-3-carbonitrile 2,2,2-trifluoroacetate,1 -(4- { [3-fluoro-4-(3-methoxyphenoxy)phenyl] amino} -5 -methylpyrrolo} 1 ,2-Z?]pyridazine- 6-carbonyl)azetidine-3-carbonitrile, l-{4-[(2,3-dimethyl-2 / 7-indazol-6-yl)amino]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile. lV-[3-({[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z?]pyridazin-4- yl] amino } methy l)pheny 1] -IV-cy clopropylurea,1 - {4- [( 1 ,2-benzothiazol-5 -yl)amino]-5-methy Ipy rrolo} 1 ,2-b] py ridazine-6- carbonyl}azetidine-3-carbonitrile,1-(4-{[3-(2-chlorophenyl)-l,2,4-oxadiazol-5-yl]amino}-5-methylpyrrolo[l,2-6]pyridazine-6-carbonyl)azetidine-3-carbonitrile,2-(4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]amino}phenyl)- N-(4-methyl-l,3-thiazol-2-yl)acetamide, l-{4-[(5-hydroxynaphthalen-2-yl)amino]-5-methylpyrrolo[l,2-ft]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{4-[(2,l,3-benzothiadiazol-5-yl)amino]-5-methylpyrrolo[l,2-h]pyridazine-6- carbonyl } azetidine-3-carbonitrile, l-(4-{[5-(4-fluorophenyl)-l,2-oxazol-3-yllamino}-5-methylpyrrolo}l,2-6}pyridazine-6- carbonyl)azetidine-3-carbonitrile, l-[5-methyl-4-({4-[(1H-pyrrol-l-yl)methyl]phenyl}amino)pyrrolo[l,2-h]pyridazine-6- carbonyl]azetidine-3-carbonitrile, l-{5-methyl-4-[(naphthalen-2-yl)amino]pyrrolo[l,2-Z)]pyridazine-6-carbonyl} azetidine-3- carbonitrile, l-{4-[(2,4-dichlorophenyl)amino]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbony 1 } azetidine-3-carbonitrile,l-{4-[(3-ethynylphenyl)amino]-5-methylpyrrolo [ 1.2-bp ]yndazine-6-carbonyl} azeti dine-3-carbonitrile, l-{4-[(l-benzofuran-4-yl)amino]-5-methylpyrrolo [ 1.2-bp ]yridazine-6- carbonyl}azetidine-3-carbonitrile, l-{4-[(3,4-dihydroxyphenyl)amino]-5-methylpyrrolo[ 1.2-6]pyridazine-6- carbonyl } azeti dine-3 -carbonitrile,(3 -methoxy azeti din- 1 -y 1)(5 -methy l-4-((3 -methy I -2H-i ndazol -6- l)amino)pyrrolo [ 1 ,2- b ] py ridazin-6-y l)methanone.N-ethyl-7-((6-(3-methoxy azeti dine- l-carbonyl)-5-methylpyrrolo[l,2-b]pyridazin-4- yl)oxy)-2,3-dihydro-4H-benzo[6][l,4]oxazine-4-carboxamide,7- { [6-(3 -methoxy azetidine- 1 -carbony l)-5 -methylpyrrolo [ 1 ,2-6] py ridazin-4-y 1] oxy } -N- (propan-2-yl)-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-cy clopentyl-7-{[6-(3-methoxy azeti dine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4-y 1] oxy } -2,3 -dihy dro-4H- 1 ,4-benzoxazine-4-carboxamide,N-(bicy clo[l. l. l]pentan-l -yl)-7-{[6-(3-methoxy azeti dine-1 -carbonyl)-5- methylpy rrolo [ 1 ,2-b ] py ri dazi n-4-y 1 ] oxy } -2,3 -dihydro-4H- 1 ,4-benzoxazine-4-carboxamide,N-benzyl-7-{[6-(3-methoxy azeti dine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy}-2,3-dihydro-4H-l,4-benzoxazine-4-carboxamide,N-(2-chloro-4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl]oxy)phenyl)- N-cyclopropylsulfuric diamide,N-[2-chloro-4-({6-[(3R)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[l,2- 1 pyndazin-4-yl} oxy)phenyl]- N-methylsulfuric diamide,N -[2-chloro-4-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo[l,2-b]pyridazin-4-yl]oxy)phenyl]- "-methylsulfuric diamide,N-[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-methylsulfuric diamide,N -[2-chloro-4-({6-[(3R)-3-hydroxypyrrolidine-l-carbonyl]-5-methylpyrrolo[ 1,2- 6]pyridazin-4-yl}oxy)phenyl]- N-cyclopropylsulfuric diamide,N-[2-chloro-4-({6-[(3S)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-cyclopropylsulfuric diamide,N -[2-chloro-4-({6-[(3R)-3-hydroxy-3-methylpyrrolidine-l-carbonyl]-5- methylpyrrolo [ 1.2-bp ]yridazin-4-yl}oxy)phenyl]- N-cyclopropylsulfuric diamide, (R)-3-((2-chloro-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2- 6]pyridazin-4-yl)oxy)phenyl)amino)-4-(cyclopropylamino)cyclobut-3-ene-l, 2-dione,fS^-l-(2-chloro-4-((6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z?]pyridazin-4- yl)oxy)phenyl)-3-(2,2-difluorocyclopropyl)urea,(7^-l-(2-chloro-4-((6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo [ 1.2-bp ]yridazin-4- yl)oxy)phenyl)-3-(2,2-difluorocyclopropyl)urea, l-(4-((6-hydroxy-l,2,3,4-tetrahydronaphthalen-2-yl)oxy)-5-methylpyrrolo[ 1.2- A|pyridazme-6-carbonyl)azetidine-3-carbonitnle. l-(5-methyl-4-((2-methylbenzo[< / |thiazol-5-yl)amino)pyrrolo [ 1.2-bp ]yridazine-6- carbonyl)azetidine-3-carbonitrile, l-{4-[(l,3-dihydro-2-benzofuran-5-yl)amino]-5-methylpyrrolo[1.2-6]pyridazine-6- carbonyl } azetidine-3 -carbonitrile, l-{5-methyl-4-[(2-methyl-27f-indazol-6-yl)amino]pyrrolo[l,2-A]pyridazine-6- carbony 1 } azetidine-3-carbonitrile, ethyl (4-{[6-(3-cyanoazetidine-l-carbonyl)-5-methylpyrrolo[l,2-Z>]pyridazin-4- yl]amino}phenyl)acetate, l-{5-methyl-4-[(2-methyl-27f-indazol-5-yl)amino]pyrrolo[l,2- / )]pyridazine-6- carbonyl}azetidine-3-carbonitrile,N-(4- { [6-(3-cy anoazetidine- 1 -carbonyl)-5-methylpyrrolo[ 1.2- / ? | py n da / in-4- yl] amino }phenyl)-2 -hydroxybenzamide, l-{5-methyl-4-[(2-methyl-l,3-benzoxazol-6-yl)amino]pyrrolo[l,2-Z?]pyridazine-6- carbonyl}azetidine-3-carbonitrile, and(R)-l-(3-cyano-4-((6-(3-hydroxypyrrolidine-l-carbonyl)-5-methylpyrrolo[l,2- 6]pyridazin-4-yl)oxy)phenyl)-3-cyclopropylurea.

14. A composition for treating a cancer in a patient comprising a compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.

15. A composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

16. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

17. Use of a compound of any of claims 1 to 13. or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition selected from cancer.

18. A compound of formula I:I or a pharmaceutically acceptable salt thereof whereinX is selected from -O-, -NH-, -N-C1-6alkyl-, and -S-; ring A is selected from:(1) aryl,(2) cycloalkyl,(3) heteroaryl, and(4) heterocyclyl; n is 0, 1, 2, or 3;R1is independently selected from:(1) -C1-6alkyl,(2) halo,(3) -C0-6alkyl-C(0)NHRa,(4) -NHC(O)NHRa,(5) -NHC(O)Ra,(6) -C0-6alkyl-ORa,(7) -C0-6alkyl-C(0)ORa,(8) -C0-6alkyl-C(0)Ra,(9) -C0-6alkyl-cyano,(10) -C0-6alkyl-NHRa,(11) -C0-6alkyl-aryl, wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from Ra,(12) -C0-6alkyl-(5-6 membered heteroaryl) wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N. O, and S. and is unsubstituted or substituted with 1 -3 substituents independently selected from Ra,(13) -C3-6cycloalkyl. unsubstituted or substituted with 1-3 substituents selected fromRa,(14) -C0-6alkyl-C(0)NR3R4,(15) -C0-6alkyl-NHS(0)2NHRa,(16) -C0-6alkyl-S(0)2NHRa,(17) C2-6alkynyl,(18) =0, and(19) hydrogen;When present, Rais selected from:(1) hydrogen,(2) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, -NR3R4, cyano, -C1-6alkyl, -O-Co-ealkyl, and -C1-6haloalkyl,(3) -C0-6alkyl-C3-6cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, -C0-6alkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl. - O-Co-ealkyl, -C(0)-C1-6alkyl, and -C1-6haloalkyl,(4) -C0-6alkyl-aryl, unsubstituted or substituted with 1-3 substituents independently selected from halo, =0, and -NH-cyclopropyl, -OH, -C0-6alkyl-NR3R4, -C0-6alkyl-cyano, - C1-6alkyl. -O-Co-ealkyl. and -C1-6haloalkyl.(5) -O-C1-6alkyl,(6) -C0-6alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with 1-3 substituents independently selected from halo, =0. -NH-cyclopropyl, -OH, - Co- ealkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl, -O-Co-ealkyl, -C(O)OC1-6alkyl, -C1-6alkyl-Cs- ecycloalkyl, and -C1-6haloalkyl,(7) -C1-6alkyl-S-C1-6alkyl,(8) -C3-6 monocyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, and unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, - C0-6alkyl-NR3R4, -C0-6alkyl-cyano, -C1-6alkyl, -OCo-ealkyl, -Ci- ehaloalkyl, and =0,(9) 5-10 membered spiro bicyclic or tricyclic cycloalkyl, unsubstituted or substituted with 1-3 substituents independently selected from halo, -OH, - C0-6alkyl-NR3R4, -Co- ealkyl-cyano, -C1-6alkyl, -OCo-ealkyl, -C1-6haloalkyl, and =0,(10) 5-10 membered spiro bicyclic or tricyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S unsubstituted or substituted with 1-3 substituents independently selected from halo. -OH. - C0-6alkyl-NR3R4. -C0-6alkyl- cyano, -C1-6alkyl, -OCo-ealkyl, -C1-6haloalkyl, and =0,(11) 5-6 membered bridged bicyclic cycloalkyd, unsubstituted or substituted with one substituent selected from -OH, halo and haloalkyl,(12) halo,(13) -C(O)O-C1-6alkyl,(14) -NH2, and(15) -C =C: when present, each of R3and R4is independently selected from:(1) hydrogen,(2) -Co ealkyl- 3-6 membered heterocyclyl having 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rb,(4) -C1-6 alkyl -O-C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rb,(5) -C0-6alkyl- Cs-ecycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb, and(6) 5-10 membered bicyclic or tricyclic cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from Rb; when present, Rbis selected from:(1) -C1-6alkyl,(2) halo,(3) -NH2,(4) =0, and(5) -OH; or alternatively, R3and R4together with the nitrogen to which they are attached form 3-10 membered heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S, in addition to the nitrogen to which R3and R4are attached, wherein the heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from Rc; when present, Rcis selected from(1) -Co ealkyl-OH,(2) -C1-6alkyl, unsubstituted or substituted with 1-3 -OH substituents,(3) -C0-6alkyl-cyano.(4) -C0-6alkyl-0-Ci-3alkyl,(5) -Co-3alkyl-(5-6 membered monocyclic heteroaryl), wherein the heteroaryl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1-3 C1-6alkyl substituents.(6) halo,(7) -C i-ehaloalkyl,(8) C0-6alkyl-aryl, wherein the aryl is unsubstituted or substituted with 1 -3 substituents independently selected from C1-6haloalkyl and halo,(9) -C3-6cycloalkyl,(10) -C0-6alkyl-N(Rg)2, wherein each Rgis independently selected from hydrogen and C1-6alkyl,(11) -NH-C(O)C1-6alkyl,(12) -Co-3alkyl-(3-6 membered monocyclic heterocyclyl). wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one =0 substituent,(13) -O-C1-6haloalkyl,(14) =0.(15) hydrogen, and(16) -C(O)OC1-6alkyl;each of R5and R6is independently selected from:(1) hydrogen,(2) -C0-6alkyl-(3-6 membered heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N. O, and S. and is unsubstituted or substituted with 1 -3 substituents independently selected from Rd,(3) -C1-6alkyl, unsubstituted or substituted with 1-3 substituents independently selected from Rd,(4) -C1-6 alkyl-O-C1-6alkyl. unsubstituted or substituted with 1-3 substituents independently selected from Rd,(5) -Co-r, alkyl- Cs-6 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1 -3 substituents independently selected from Rd, and(6) 5-10 membered bicyclic or tricyclic cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from Rd; when present, Rdis selected from:(1) -C1-6alkyl,(2) halo,(3) -NH2,(4) =0, and(5) -OH; or alternatively, R5and R6together with the nitrogen to which they are attached form 4-10 membered heterocyclyl having 0-3 ring heteroatoms independently selected from N, O, and S, in addition to the nitrogen to which R5and R6are attached, wherein the heterocyclyl is unsubstituted or substituted with 1-4 substituents independently selected from Re, when present, Reis selected from(1) -C0-6alkyl-OH,(2) -C1-6alkyL unsubstituted or substituted with 1-3 -OH substituents,(3) -C0-6alkyl-cyano,(4) -Co-ealky l-O-C1-6alkyl,(5) -C0-6alkyl- 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, and S, unsubstituted or substituted with 1-3 -C1-6alkyl substituents,(6) halo,(7) -C1-6haloalkyl,(8) -Co-ealky 1-ary 1. wherein the aryl is unsubstituted or substituted with 1-3 substituents independently selected from -C1-6haloalkyl. and halo.(9) -C3-6Cycloalkyl,(10) -Ci)-r>alkyl-N(Rf)2. wherein each Rfis independently selected from hydrogen and C1-6alkyl, or two Rftogether form =OC1-6alkyl,(11) -NHC(O)C1-6alkyl.(12) -Co-3alkyl-(3-6 membered monocyclic heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with 1 -3 =0 substituents,(13) -O-C1-6haloalkyl,(14) =0,(15) hydrogen,(16) -C(O)OC1-6alkyl,(17) -N(CH3)-C3-6cycloalkyl, wherein the cycloalkyl is substituted with 1 -OH substituent,(18) -N(CHs)-(3-7 membered monocyclic heterocyclyl), wherein the heterocyclyl has 1-3 ring heteroatoms independently selected from N, O, and S, and is unsubstituted or substituted with one -C1-6alkyl substituent, and(19) 5-8 membered bridged bicyclic heterocyclyl having 1-3 ring heteroatoms independently selected from N, O, and S, unsubstituted or substituted with 1-3 substituents independently selected from -Ci-3alkyl, -Ci-3alkyl-OH, and hydrogen.R10is selected from:(1) hydrogen,(2) -Ci ealkyl,(3) -C3-6Cycloalkyl,(4) -C1-6haloalkyl,(5) -C1-6alkyl-O-C1-6alkyl, and(6) -C1-6alkyl-OH;

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