Tyrosine kinase inhibitors

Abstract

Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein R1, R2, R3, R4, Y3, Y2, Y1, Y, Z, U, X1, and X2 are defined herein, and methods of making such compounds. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

Description

ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014TYROSINE KINASE INHIBITORSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 761,385, filed on February 21, 2025, U. S. Provisional Application No. 63 / 853,889, filed on July 30, 2025, and U. S. Provisional Application No. 63 / 902,281, filed on October 20, 2025, the disclosures of each of which are incorporated by reference herein in its entirety.BACKGROUND

[0002] Janus kinase (JAK) is a family of non¬ receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The JAK-STAT signaling pathway is critical in immune regulation and is involved in various allergic reactions, autoimmune diseases, inflammation responses, and cancers. The mammalian JAK family consists of four members, JAK1, JAK2, JAK3, and Tyrosine kinase 2 (TYK2). TYK2 has been shown to be critical in regulating the signal transduction cascade downstream of receptors for IL- 12, IL-23 and type I interferons. TYK2 mediates the receptor-induced phosphorylation of members of the S TAT family of transcription factors, an essential signal that leads to the dimerization of S TAT proteins and the transcription of STAT- dependent pro-inflammatory genes.

[0003] There remains a need for inhibitors of TYK2, including TYK2 selective inhibitors as well as compositions comprising same.SUMMARY

[0004] The present disclosure relates to compounds and methods of making such compounds useful for inhibition (e.g., allosteric inhibition) of non-receptor tyrosine-protem kinase 2, also known as Tyrosine kinase 2 (TYK2), as well as pharmaceutical compositions comprising such compounds.

[0005] In embodiments, compounds of the present disclosure are selective for TYK2 over other J AKs, for example selective for TYK2 over JAK1. In embodiments, the compounds of the present disclosure selectively inhibit the function of cytokines such as IFNa e.g., by acting on TYK2 toATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014mediate signal transduction. In embodiments, the compounds of the present disclosure penetrate the blood brain barrier. In embodiments, compounds of the present disclosure are effective in treating TYK2 mediated diseases or disorders. For example, in embodiments, compounds of the present disclosure are effective in treating inflammatory and autoimmune diseases, neurode enerative and neuroinflammatory diseases, or cancer (e.g., lung cancer, breast cancer, liver cancer, hematological malignancy such as leukemia, or sarcoma).

[0006] The present disclosure also provides processes and intermediates for making the compounds of the present invention.

[0007] In embodiments, the present disclosure provides a compound of Formula (I):■3* Y2s. SY1x2C(R4)3a‘N(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-e alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, - H(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), - N(CI-6 alkyl)?., -NH(C3-6 cycloalkyl), or -N(Ci-s alkyl)(C’3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-s alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or Rland R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are eachATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014independently optionally substituted with 1 or more halo, -OCi-e alkyl, -Ci-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -C1-6 alkyl, -O-C1-6 alkyl,, -OH, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(Ci-e alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ct-e alkyl)(C3-6 cycloalkyl), or -CN; wherein the -Cue alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2, NH, or C(R8)2NH;each R8is independently H, halo, -C1-6 alkyl, -Ci-s haloalkyl, -O-Ci-e alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;R1A, R'13, RYC, and RYDare each independently -H, -CN, -halo, -NRARB, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl, wherein the, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl are each optionally substituted with -halo, -Ci-e alkyl, -C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or - CN;RAand RBare each independently -H, -C1-C6 alkyl, cycloalkyl, or heterocyclyl;U is H;Z is -ORZ-Ci-galkyl, -(CH2)o-3-(C3-6 cycloalkyl), or -(CH2.)o-3-(C3-C4 heterocyclyl),, and wherein the -Ci -ealkyl, -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, - C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014and provided the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; or6-(cyclopropanecarboxamido)-4-((2-( 1 -hydroxy ethyl)-3 -( 1 -methyl- 1 H- 1,2,4-triazol-3 -yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0008] In embodiments, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Ci-e alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), - N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-6 alkyl, -OC1-6 alkyl, -Cue alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -Cue alkyl, -OCi-s alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -Cs-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014R3is -H, -halo, -Ci-e alkyl, -O-Ci-6 alkyl, or -CN; wherein the -Ci-6 alkyl or -OCi-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OCi-6 alkyl, -OCi-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -Cue alkyl, -Ci -6 haloalkyl, -O-Ci-e alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;YA, RYB, RiC, and R1Dare each independently -H, -CN, -halo, -NRARB, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl, wherein the, -C1-6 alkyl, -OCi-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl are each optionally substituted with -halo, -C1-6 alkyl, -C1-6 haloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -CN;RAand RBare each independently -H, -C1-C6 alkyl, cycloalkyl, or heterocyclyl;U is H;Z is -ORZ-Ci-salkyl, -(CH2)o-3-(Cs-6 cycloalkyl), or -(CH2)o-3-(C3-C! heterocyclyl),, and wherein the -Ci-ealkyl, -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -C1-6 haloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; orATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20146-(cyclopropanecarboxamido)-4-((2-( 1 -hydroxy ethyl)-3 -(1 -methyl- 1 H- 1,2,4-triazol-3 - yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0009] In embodiments the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Civ alkyl, -Civ alkenyl, -Civ alkynyl, -Csv cycloalkyl, -OH, -OCi-6 alkyl, -OCsv cycloalkyl, -Oheterocyclyl, -NH?_, -NH(Civ alkyl), -N(Civ alkyl)?., -NH(C3-6 cycloalkyl), or -N(Civ alkyl)( Csv cycloalkyl); wherein the -Cue alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OCiv alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(Civ alkyl), -N(Civ alkyl)?, -NH(C3v cycloalkyl), or -N(Civ alkyl)(C3v cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OCiv alkyl, -OCiv haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Civ alkyl, -OCiv alkyl, -Civ alkenyl, -Civ alkynyl, -Csv cycloalkyl, or heterocyclyl; wherein the -Civ alkyl, -OCiv alkyl, -Civ alkenyl, -Civ alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OCiv alkyl, -OCiv haloalkyl, or -CO?alkyl;or Rland R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently optionally substituted with 1 or more halo, -OCiv alkyl, -Civ alkyl, -Csv cycloalkyl, or -CN; wherein the -Civ alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OCiv alkyl, -OCiv haloalkyl, or -CO?alkyl;R3is -H, -halo, -Civ alkyl, -O-Civ alkyl, or -CN; wherein the -Civ alkyl or -OCiv alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OCiv alkyl, -OCiv haloalkyl, or -CO?alkyl;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014each R4is independently -H or -D;X1is CH or N;X2is C(R8)2 or NH;each Rsis independently H, halo, -Ci-e alkyl, -Ci-ehaloalkyl, -O-Ci-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl; or U and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRzis -C1-6 alkyl, or -C3-6 cycloalkyland provided the compound is not:3-pyridinecarboxamide, 6-[(cy clopropylcarbonyl)amino]-4-[[2-(l -hydroxy- 1 - methylethyl)phenyljamino]-N-methyl-; or6-( cyclopropanecarboxamido)-4-((2-( 1 -hydroxy ethyl)-3 -(1 -methyl- 1 H- 1,2,4-triazol-3 -yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0010] In embodiments the present disclosure provides a compound of Formula (I):U(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH?_, -NH(CI-6 alkyl), -N(CI-6 alkyl)?., -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)( C3-6 cycloalkyl); wherein the -Cue alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), -N(CI-6 alkyl)?, -NH(C3-6 cycloalkyl), or -N(Ci-s alkyl)(C’3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-s alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or Rland R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -Ci-e alkyl, -O-Ci-e alkyl, or -CN; wherein the -C1-6 alkyl or -OCi-e alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OCi-e haloalkyl, or -CO?alkyl;each R4is independently -H or -D;X1is CH or N;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014X2is C(R8)2or NH;each R8is independently H, halo, -Ci-6 alkyl, -Ci-ehaloalkyl, -O-Ci-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -Ci-6 alkyl, -OCi-6 alkyl, - Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZor ~(CH2)O-3-(C3-6 cycloalkyl), or -(CH2)o-3-(C3-4 heterocyclyl), wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -Ci-s alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRzis -Ci-s alkyl, or -C3-6 cycloalkyland provided the compound is not:3 -pyri dinecarboxaini de, 6- [(cy cl opropy 1 carbony l)amino] -4- [ [2-( 1 -hydroxy- 1 - m ethyl ethy 1 )pheny 1] amino] -N -methy 1-; or6-(cyclopropanecarboxainido)-4-((2-(l -hydroxy ethyl)-3-(l -methyl- 1H- 1,2, 4-triazol-3-yl)phenyl)aniino)-N-(methyl-d3)pyridazine-3 -carboxamide.

[0011] In embodiments the present disclosure provides a compound of Formula (I):UATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Ci-e alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC... cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-e alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(Cs-6 cycloalkyl); wherein the -C1-6 alkyl, -Cue alkenyl, -Cue alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), - N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-e alkyl, -OC1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OCi-s alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -Cs-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R is -H, -halo, -Ci-e alkyl, -O-C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OCi-s alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -Ci -6 haloalkyl, -O-C1-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -Ci-e alkyl, -OC1-6 alkyl, - C1-6 alkenyl, -Cue alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014U is H;Z is -ORZ, -NR9R!0, or -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -Ci -6 alkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl;R9and R10are each independently -H or -Cue alkyl; orU and one of R9or R10are taken together to form a 5-7 membered heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3-pyndinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; or6-(cyclopropanecarboxamido)-4-((2-(l -hydroxy ethyI)-3 -( 1 -methyl- 1 H- 1,2,4-triazol-3 -yl)phenyl)amino)-N-(methyl-d3)pyndazine-3-carboxamide.

[0012] In embodiments, the present disclosure provides a compound having a structure of Formula (IA):R2R3R1O HN^Y"Yor a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein R!, R2, R3, R4, Y3, Y2, Y1, Y, Rz, X\ and X2are defined herein.

[0013] In embodiments, the present disclosure provides a compound having a structure of Formula (IB):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(IB)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein R1, R2, R3, R4, R3, R6, R7, Y3, Y2, Y1, Y, X1, and X2are defined herein.

[0014] In embodiments, the present disclosure provides a compound having a structure of Formula (HA):H (IIA)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein R1, R2, R3, R4, RYD, RYC, RYB, Y, Rz, X1, and X2are defined herein.

[0015] In embodiments, the present disclosure provides a compound having a structure of Formula (IIB):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014R2R3 RYDV X pYCR’T SO HN N RYBX2' l<|| H R6I. y1» 11 / C(R4)3A'NZSN / 7T^R7HR5 V(IIB)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein R1, R2, R3, R4, R5, R6, R7, RYD, RYC, RYB, X1, and X2are defined herein.

[0016] In embodiments provided herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and a pharmaceutically acceptable carrier.BRIEF DESCRIPTION OF THE FIGURES

[0017] FIG. 1A shows inhibition of IFNa-stimulated ISG production in the blood by brain¬ penetrant Compound 12 compared to peripherally restricted inhibitor deucravacitinib.

[0018] FIG. IB shows inhibition of IFNa-stimulated ISG production in the brain by brainpenetrant Compound 12 compared to peripherally restricted inhibitor deucravacitinib.

[0019] FIG. 2A shows inhibition of IFNa-stimulated ISG production in the blood by brainpenetrant Compound 20.

[0020] FIG. 2B shows inhibition of IFN -stimulated ISG production in the brain by brainpenetrant Compound 20.DETAILED DESCRIPTION

[0021] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Definitions

[0022] Listed below are definitions of various terms used in the specification and claims to describe the present disclosure.

[0023] Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0024] The term “about” when immediately preceding a numerical value means a range encompassing said numerical value plus or minus an acceptable amount of variation in the art (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55,...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50,5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range,

[0025] As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moietyATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014by conventional chemical methods. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pa. (1990), the disclosure of which is hereby incorporated by reference.

[0026] Compounds described herein may also comprise one or more isotopic substitutions. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include2H and3H. Isotopes of carbon includenC,!3C andl4C. Isotopically enriched compounds of the disclosure can be prepared, for example, by conventional techniques 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.

[0027] All stereoisomers of the compounds of the present disclosure are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). Compounds of the present disclosure and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the all tautomeric forms, insofar as they may exist, are included within the present disclosure.

[0028] In embodiments, the compounds of the present disclosure are provided as a mixture of diastereomers. In embodiments, a diastereomer of a compound of the present disclosure is provided substantially free of other possible diastereomer(s). Additionally, compounds of the present disclosure may have trans- and cis-isomers.

[0029] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, C2, C3, Ci. C5, Ce, Ci-6, Ci -5, C. CI -3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and CM alkyl.

[0030] “Halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

[0031] “Cyano” refers to the -CN radical.

[0032] “Hydroxy” or “hydroxyl” refers to the -OH radical,

[0033] “Oxo” refers to the =0 substituent.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0034] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a G-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes Cs alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and G-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically 111 the specification, an alkyl group can be optionally substituted.

[0035] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0036] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a Cc-Ce alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes Cs alkenyls, C4 alkenyls, Cs alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and -Ce, alkenyls, but also includes C7, Cs, and Go alkenyls.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes Gi and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -pentenyl, 2- pentenyl, 3 -pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3 -hexenyl, 4-hexenyl, 5 -hexenyl, 1- heptenyl, 2-heptenyl, 3 -heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1 -octenyl, 2-octenyl, 3- octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1 -decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5- decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2-undecenyl, 3-undecenyl, 4- undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11 -dodecenyl. Unless stated otherwise specifically in the specification, an alkenyl group can be optionally substituted.

[0037] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethenylene, propenylene, butenylene, and the like. The alkenylene chain is attached to the rest of the mol ecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenyl ene chain can be optionally substituted.

[0038] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes Cs alkynyls, C4 alkynyls, G alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes G alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes G, Cs, and Go alkynyls. Similarly, a G-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014limiting examples of C2-C12 alkenyl include etliynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group can be optionally substituted.

[0039] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted,

[0040] “Aryl” refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, and which is atached to the rest of the mol ecule by a single bond. For purposes of this disclosure, the aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems (when fused with a saturated or partially unsaturated ring, the aryl is bonded through an aromatic ring atom). In embodiments, the aryl is a 6-10 membered aryl. Examples of aryl groups include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, a -indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the “aryl” can be optionally substituted.

[0041] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ring structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0042] “Cycloalkyl” refers to a stable non-aroinatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged or spirocyclic ring systems, having from three to twenty carbon atoms (e.g., C3-C12, C3-(AO, C3-C8, or C3-C6), and which is attached to the rest of the molecule by a single bond.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyi, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, spirocyclic cycloalkyl such as spiro[2.2]pentanyl, spiro[2.3]hexyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0043] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0044] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0045] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more (e.g., 1, 2, 3, 4, 5, or 6) halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0046] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable saturated, unsaturated, or aromatic 3- to 20-membered ring which consists of two to nineteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond. Heterocyclyl or heterocyclic rings include heteroaryls, partially unsaturated heterocyclyls and fully unsaturated heterocyclyls.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Unless stated otherwise specifically in the specification, the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, niorpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidmyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwi e specifically in the specification, a heterocyclyl group can be optionally substituted,

[0047] “Heteroaryl” refers to a 5- to 20-membered aromatic ring system comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which is attached to the rest of the molecule by a single bond. For purposes of this disclosure, the heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Heteroaryl groups can also be fused or bridged with carbocyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system, wherein the heteroaryl is attached to the rest of the molecule by a single bond to an aromatic atom. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl. Examples include, but are not limited to, azepmyl, acridinyl, benzimidazolyl, benzothiazolyl, benzmdolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxmyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, mdazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1 -oxidopyridinyl, 1 -oxidopyrimidinyl, 1 -oxidopyrazinyl, 1 -oxidopyridazinyl, 1 -phenyl- 1 / f-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phtlialazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pynmidinyl, pyndazinyl, quinazolinyl, quinoxalinyl,ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0048] “The term “substituted” used herein means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, aryl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) wherein at least one hydrogen atom is replaced by a bond to a non¬ hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylaryl amines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyl diary Isilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triplebond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(===O)Rh, -NRgC(::::O)NRgRh, -NRgC(==O)ORh, -NRgSO2Rh, -0C(O)NRgRh, - ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, -NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an ammo, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In embodiments, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with halo, nitro, -CN, -Ci-C6alkyl, -NRARB, Ci-Cs-haloalkyl, -Ci-C6-alkyl-NRARB, -Ci-Ce-alkyl-OH, -C(=O)RD, -ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014C(=O)N(RE)RF, -C(=O)-ORD, -N(RG)C(=O)RD, -N(RG)C(=O)N(RE)RF, -N(RG)C(=O)ORD, -N(RG)S(=O)RD, -N(RG)S(=0)2RD, -N=S(=O)(RE)RF, -0RD, -O(C=O)RD, -O(C=O)N(RE)RF, -O(C=O)ORU, -C2-C6 alkenyl, or -C2-C6 alkynyl; wherein RAand RBare each independently -H, - Ci-Ce alkyl, cycloalkyl, aryl, heteroaryl, -C(O)Rc, -C(O)ORc, -S(O)RC, or -S(O)2RG; Rcis H, - Ci-Ce alkyl, aryl, cycloalkyl, or heterocyciyl; and RD, RE, RF, RG, are each independently selected from -H, Ci-Ce-alkyl-, Ci-Ce-haloalkyl-, -Ci-Ce-alkyl-OH, cycloalkyl, C2-Ce-alkenyl-, heterocyciyl, aryl, or heteroaryl. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0049] The present disclosure relates to compounds and methods of making such compounds useful for inhibiting non-receptor tyrosine-protein kinase 2, also known as Tyrosine kinase 2 (TYK2), as well as pharmaceutical compositions comprising such compounds.

[0050] In embodiments, compounds of the present disclosure are selective for TYK2 over other JAKs, for example selective for TYK2 over JAK1. In embodiments, the compounds of the present disclosure selectively inhibit the function of cytokines such as IFNa eg., by acting on TYK2 to mediate signal transduction. In embodiments, the compounds of the present disclosure penetrate the blood brain barrier. In embodiments, compounds of the present disclosure are effective in treating TYK2 mediated diseases or disorders. For example, in embodiments, compounds of the present disclosure are effective in treating inflammatory and autoimmune diseases, neurodegenerative and neuroinflammatory diseases, or cancer (e.g., lung cancer, breast cancer, liver cancer, hematological malignancy such as leukemia, or sarcoma).

[0051] The present disclosure also provides processes and intermediates for making the compounds of the present invention.Compounds

[0052] In embodiments, the present disclosure provides a compound of Formula (I):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Ci-e alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NH(C3-6cycloalkyl), or -N(C1-6alkyl)(C3-6cycloalkyl); wherein the -C1-6alkyl, -C1-6alkenyl, -C1-6alkynyl, -C3-6cycloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, -Oheterocyclyl, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NH(C3-6cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-e alkyl, -OC1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-s alkyl, -Cue alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -Cue alkyl, -O-C1-6 alkyl, -OH, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, - NH(Ci-6 alkyl), -N(Ci-e alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl), or -CN; wherein the -Cue alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OCi-e alkyl, -OCne haloalkyl, or -CO2alkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2, NH, or C(R8)2NH;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014each R8is independently H, halo, -Ci-6 alkyl, -Ci-6haloalkyl, -O-Cne alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -NRARB, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl, wherein the, -Ci-e alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl are each optionally substituted with -halo, -Ci-e alkyl, -C1-6haloalkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, or -CN;RAand RBare each independently -H, -C1-C6 alkyl, cycloalkyl, or heterocyclyl;U is H;Z is -ORZ-Ci-ealkyl, -(CH2)o-3-(C3-6 cycloalkyl), or -(CH2)o-3-(C 3-C 4 heterocyclyl),, and wherein the -Ci-ealkyl, -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -Cnehaloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -Ch-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; or6-(cyclopropanecarboxamido)-4-((2-( 1 -hydroxy ethyl)-3 -(1 -methyl- 1 H- 1,2,4-triazol-3 - yl)phenyl)aniino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0053] In embodiments, the present disclosure provides a compound of Formula (I):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Ci-e alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NH(C3-6cycloalkyl), or -N(C1-6alkyl)(C3-6cycloalkyl); wherein the -C1-6alkyl, -C1-6alkenyl, -C1-6alkynyl, -C3-6cycloalkyl, -OC1-6alkyl, -OC3-6cycloalkyl, -Oheterocyclyl, -NH(C1-6alkyl), -N(C1-6alkyl)2, -NH(C3-6cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-e alkyl, -OC1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-s alkyl, -Cue alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -Cue alkyl, -O-C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OCne haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2 or NH;each R8is independently H, halo, -Ci-e alkyl, -Ci-e haloalkyl, -O-C1-6 alkyl, or -CN;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -NRARB, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyi, -C3-6 cycloalkyl, heterocyclyl, or aryl, wherein the, -C1-6 alkyl, -OC1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyi, -C3-6 cycloalkyl, heterocyclyl, or aryl are each optionally substituted with -halo, -C1-6 alkyl, -C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN;RAand RBare each independently -H, -C1-C6 alkyl, cycloalkyl, or heterocyclyl;U is H;Z is -ORZ-Ci-ealkyl, -(CH2)o-3-(C3-6 cycloalkyl), or -(CH2)o-3-(C3-C4 heterocyclyl),, and wherein the -Ci-ealkyl, -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -C1-6 haloalkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OCi-e alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; or6-( cyclopropanecarboxamido)-4-((2-( 1 -hydroxy ethyl)-3 -(1 -methyl- 1 H- 1,2,4-triazol-3 -yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0054] In embodiments the present disclosure provides a compound of Formula (I):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014u(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(C1-6 alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-s alkyl)(C’3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-e alkyl, -OC1-6 alkyl, -Ci-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-e alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OCi-s alkyl, -OCi-s haloalkyl, or -CChalkyl;R3is -H, -halo, -C1-6 alkyl, -O-C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6alkyl, -C1-6haloalkyl, -O-C1-6alkyl, or -CN;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -Ci-6 alkyl, -OCi-6 alkyl, - Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl; or U and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OCi-e alkyl; andRzis -C1-6 alkyl, or -C3-6 cycloalkyl.

[0055] In embodiments the present disclosure provides a compound of Formula (I):2 R3U(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Cue alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-e alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), -N(Ci-e alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-s alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OCi-e alkyl, -OC1-6 haloalkyl, or -CO2alkyl;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014R2is -H, -halo, -CN, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OCi-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3- 6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OCi-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OCi-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -C1-6alkyl, -O-C1-6alkyl, or -CN; wherein the -C1-6alkyl or -OC1-6alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OCi-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -Ci-e haloalkyl, -O-C1-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -Ci-s alkyl, -OCi-6 alkyl, - C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZor -(CH2)0-3-(C3-6cycloalkyl), or -(CH2)0-3-(C3-4heterocyclyl), and wherein the -C’3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRzis -Ci-e alkyl, or -C3-6 cycloalkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0056] In embodiments the present disclosure provides a compound of Formula (I):(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Ci-e alkyl, -Cue alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(Ci-s alkyl)2, -NH(Cs-6 cycloalkyl), or -N(Ci-s alkyl)(C3-e cycloalkyl);R2is -H, -halo, -Ci-e alkyl, -C1-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; orR1and R2are taken together to form a carbocyclyl or a saturated heterocyclyl;RJis -H, -halo, -C1-6 alkyl, -O-C1-6 alkyl, or -CN;each R4is independently -H or -D;X1is CH or N;X2is CH2or NH;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -C1-6 alkyl, -OC1-6 alkyl, - C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014alkyl, -OCi-6 alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6alkyl, or -C3-6cycloalkyl.

[0057] In embodiments the present disclosure provides a compound of Formula (I):(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-e alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), - N(CI-6 alky 1)2, -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OCi-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-s alkyl, -OCi-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OCi-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OCi-6 alkyl, -OCi-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Ci-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -Ci-e alkyl, -O-C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -Ci-e haloalkyl, -O-C1-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -C1-6alkyl, -OC1-6alkyl, -C1-6alkenyl, -C1-6alkynyl, -C3-6cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZ, -NRyRi0, or -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl;R9and R10are each independently -H or -C1-6alkyl; orU and one of R9or R10are taken together to form a 5-7 membered heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; or6-(cyclopropanecarboxamido)-4-((2-( 1 -hydroxy ethyl)-3 -( 1 -methyl- 1 H- 1,2,4-triazol-3 -yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0058] In embodiments, the compound (e.g., of Formula (1) or (IB)) is not:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof. In embodiments, the compound of Formula (I) or (IB) is not Compound A, Compound B or a pharmaceutically acceptable salt or deuterated form thereof. In embodiments, the compound of Formula (I) or (IB) is not Compound A, Compound B, or a pharmaceutically acceptable salt thereof. In embodiments, the compound of Formula (I) or (IB) is not Compound A or Compound B.

[0059] In embodiments of the compounds of Formula (I), Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.

[0060] In embodiments of the compounds of Formula (I), Z is -ORZ, -C3-6 cycloalkyl, or -C3-C4 heterocyclyl, wherein the -C3-6 cycloalkylor heterocyclyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, - OC1-6 alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.

[0061] In embodiments of the compounds of Formula (I), Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.

[0062] In embodiments of the compounds of Formula (I ), Z is -ORZor cyclopropyl, wherein the cyclopropyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OCi-s alkyl, -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0063] In embodiments of the compounds of Formula (I), Z is -OR7or cyclopropyl, cyclobutyl, bicyclopentyl, or spirohexyl, or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclopentyl, or spirohexyl, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-6 alkyl, -OCi -6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl.

[0064] In embodiments of the compounds of Formula (I), the bicyclyopentyl is bicyclo[l.l.l]pentane. embodiments of the compounds of Formula (I), the spirohexyl is spiro[2.3]hexyl.

[0065] In embodiments of the compounds of Formula (I), Z is -OR7, -NR9R10, or -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -Cue alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.

[0066] In embodiments of the compounds of Formula (I), Z is -OR7or -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or two substituents on the same atom are taken together to form a C3-6 cycloalkyl.

[0067] In embodiments of the compounds of Formula (I), Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or two substituents on the same atom are taken together to form a -C3-6 cycloalkyl.

[0068] In embodiments of the compounds of Formula (I), Z is -OR7or cyclopropyl, wherein the cyclopropyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or two substituents on the same atom are taken together to form a -C3-6 cycloalkyl.

[0069] In embodiments of the compounds of Formula (I), Z is -ORZ, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentane, spiro[2.3]hexane, or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentane, or spiro[2.3]hexane, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OCi-eATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents on the same atom are taken together to form a -C3-6 cycloalkyl.

[0070] In embodiments of the compounds of Formula (I), Z is -OR7or cyclopropyl, wherein the cyclopropyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl.

[0071] In embodiments of the compounds of Formula (I), Z is -OR7

[0072] In embodiments of the compounds of Formula (1), Z is -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -Cue alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.

[0073] In embodiments of the compounds of Formula (I), Z is -C3-6 cycloalkyl, wherein the - C3-6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Cue alkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.

[0074] In embodiments of the compounds of Formula (I), Z is -C3-6 cycloalkyl, wherein the - C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -Cue alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl, or two substituents on the same atom are taken together to form a -C3-6 cycloalkyl.

[0075] In embodiments of the compounds of Formula (I), Z is -C3-6 cycloalkyl, wherein the - C3-6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or two substituents on the same atom are taken together to form a -C3-6 cycloalkyl.

[0076] In embodiments of the compounds of Formula (I), Z is cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentane, or spiro[2.3]hexane, or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclo[l.l,l]pentane, or spiro[2.3]hexane, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl,

[0077] In embodiments of the compounds of Formula (I), Z is cyclopropyl, cyclobutyl, bicyclo[l.l,l]pentane, or spiro[2.3]hexane, or oxetanyl, wherein the cyclopropyl, cyclobutyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014bicyclofl. l.l]pentane, or spiro[2.3]hexane, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OCi-6 alkyl, or -OC3-6 cycloalkyl.

[0078] In embodiments of the compounds of Formula (I), Z is unsubstituted cyclopropyl. 10079] In embodiments of the compounds of Formula (I ), U is H; or U and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl.

[0080] In embodiments of the compounds of Formula (I), U is H.

[0081] In embodiments of the compounds of Formula (I), U and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl.

[0082] In embodiments of the compounds of Formula (I), U and Z are taken together to form a 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or - OC1-6 alkyl.

[0083] In embodiments of the compounds of Formula (I), U and Z are taken together to form a 5-membered saturated heterocyclyl, wherein the 5-membered saturated heterocyclyl is optionally substituted with -C1-6 alkyl.

[0084] In embodiments of the compounds of Formula (I), U and Z are taken together to form a 5-membered saturated heterocyclyl, wherein the 5-membered saturated heterocyclyl is optionally substituted with -C1-3 alkyl.

[0085] In embodiments of the compounds of Formula (I), the 5 -membered saturated heterocyclyl is optionally substituted with CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2.

[0086] In embodiments of the compounds of Formula (I), Z is -NR9Ri0.

[0087] In embodiments of the compounds of Formula (I), Z is -NR9R10, wherein one of R9and R'° is -H or -C1-6 alkyl; and the other R9or R10is taken together with U to form a 5-7 membered heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -Ci-e alkyl, and -OC1-6 alkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0088] In embodiments of the compounds of Formula (I), R9and R10are each independently - H or -Ci-6 alkyl or one of R9and R10is -H or -Cue alkyl, and the other of R9or R10is taken together with U to form a 5-7 membered heterocyclyl optionally substituted with -Cue alkyl.

[0089] In embodiments of the compounds of Formula (I), R9is -H or -Ci-e alkyl; and R'° and U are taken together to form a 5-7 membered heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -Ci-e alkyl, or -OCi-6 alkyl.

[0090] In embodiments of the compounds of Formula (I), R9is -H or -Cue alkyl; and R10and U are taken together to form a 5 membered heterocyclyl.

[0091] In embodiments, the compounds of Formula (I) is a compound having a structure of Formula (IA):(IA)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein:R1is -H, -halo, -CN, -Cue alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(Ci-e alkyl)2, -NHfCs-e cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OCne alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(Cne alkyl), - N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-6 alkyl, -Ci-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -Ci-6 alkyl, -O-Cne alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OCne haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -C1-6 haloalkyl, -O-Ci-e alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -C1-6alkyl, -OC1-6alkyl, -C1-6alkenyl, -C1-6alkynyl, -C3-6cycloalkyl, heterocyclyl, or aryl; andRzis -C1-6 alkyl, or -C3-6 cycloalkyl.

[0092] In embodiments, the compound of Formula (I) is a compound having a structure of Formula (IB):2 R3y2I%y1X2X1* ILC(R4)3‘N NH(IB)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014R1is -H, -halo, -CN, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-6 alkyl), -N(Ci-e alkyl)2, -NHfCs-e cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), - N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -C1-6alkyl, -O-C1-6alkyl, or -CN; wherein the -C1-6alkyl or -OC1-6alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6alkyl, -OC1-6haloalkyl, or -CO2alkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -Ci -6 haloalkyl, -O-C1-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -C1-6alkyl, -OC1-6alkyl, -C1-6alkenyl, -C1-6alkynyl, -C3-6cycloalkyl, heterocyclyl, or aryl; andR5, R6and R7are each independently selected from the group consisting of -H, -CN, - halo, -C1-6 alkyl, -C1-6 haloalkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or R6and R7are taken together to form a carbocyclyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0093] In embodiments of the compounds of Formula (IB), the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl- (shown below), or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, NH; or6-(cyclopropanecarboxamido)-4-((2-(l -hydroxy ethyl)-3-(l -methyl- 1H- 1,2, 4-triazol-3-yl)phenyl)ammo)-N-(methyl-d3)pyridazine-3-carboxamide (shown below), or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof

[0094] In embodiments of the compounds of Formula (I), (IA), or (IB):Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD

[0095] In embodiments of the compounds of Formula (I), (IA), or (IB):Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Y3is CRYD

[0096] In embodiments of the compounds of Formula (I), (IA), or (IB), Y, Y1, and Y2are not all CH.

[0097] In embodiments of the compounds of Formula (1), (IA), or (IB), at least one of Y, Y1, Y2, and Y3is N.

[0098] In embodiments of the compounds of Formula (1), (IA), or (IB), one or two of Y1, Y2, and YJis N.

[0099] In embodiments of the compounds of Formula (I), (IA), or (IB):Y is N;Y1is CRYB;Y2is CRYC; andY3is CRYD.

[0100] In embodiments of the compounds of Formula (I), (IA), or (IB), Y is N. In embodiments of the compounds of Formula (I), (IA), or (IB), Y is CRYA

[0101] In embodiments of the compounds of Formula (I), (IA), or (IB), Y1is N. In embodiments of the compounds of Formula (I), (IA), or (IB), Y1is CRYB.

[0102] In embodiments of the compounds of Formula (I), (IA), or (IB), Y2is N. In embodiments of the compounds of Formula (I), (IA), or (IB), Y2is CRY C.

[0103] In embodiments of the compounds of Formula (I), (IA), or (IB), YJis N. In embodiments of the compounds of Formula (I), (IA), or (IB), Y3is CRYD.

[0104] In embodiments of the compounds of Formula (I), (IA), or (IB), Y is N and Y2is N.

[0105] In embodiments of the compounds of Formula (I), (IA), or (IB), Y is N and Y3is N,

[0106] In embodiments of the compounds of Formula (I), (IA), or (IB), Y is N and Y2is CRYCwherein RYcis CHs, -CN, F, or Cl; or wherein Y is N and Y3is CRYDwherein RYDis CH.-, -CN, F, or Cl

[0107] In embodiments of the compounds of Formula (I) or (IA), the compound is of Formula (IIA):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014H (HA),or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-e alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), - N(CI-6 alky 1)2, -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OCi-e alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with I or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Cue alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -Ci-s alkyl, -O-C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -Ci -6 haloalkyl, -O-C1-6 alkyl, or -CN;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Y is N or CRYA;RYA, RYB, RYC, and RYUare each independently -H, -CN, -halo, -Ci-e alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;Rzis -C1-6 alkyl, or -C3-6 cycloalkyl.

[0108] In embodiments of the compounds of Formula (IIA), Y is N.

[0109] In embodiments of the compounds of Formula (I) or (IB), the compound is of Formula (IIB):R2 R3RYDV 1 pYCR1]|o HN^N^RYBC(R4)3Xk*N*l^XN' i / VVr*6R7HR5(IIB),or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-e alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), - N(Ci-e alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-s alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OCi-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-s alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OCi-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OCi-6 alkyl, -OCi-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-6 alkyl, -C1-6 alkyl, -C3-6ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014cycloalkyl, or -CN; wherein the -Cue alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -Ci-e alkyl, -O-C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -Ci-e haloalkyl, -O-C1-6 alkyl, or -CN;YB, RYC, and RYDare each independently -H, -CN, -halo, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl; andR5, R6and R7are each independently selected from the group consisting of -H, -CN, -halo, -C1-6 alkyl, -C1-6 haloalkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or R6and R7are taken together to form a carbocyclyl.

[0110] In embodiments of the compounds of Formula (I), (TA), or (IB), the compound is of Formula (II ) or (IIB):or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

[0111] In embodiments of the compounds of Formula (I), (IA), or (IIA), Rzis -Ci-6 alkyl, or - C’3-6 cycloalkyl.

[0112] In embodiments of the compounds of Formula (I), (IA), or (IIA), Rzis -Ci-s alkyl.

[0113] In embodiments of the compounds of Formula (I), (IA), or (IIA), Rzis -CH3.

[0114] In embodiments of the compounds of Formula (I), (IA), or (IIA), Rzis -C3-6 cycloalkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0115] In embodiments of the compounds of Formula (IB) or (IIB), R3, R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl, or R6and R7are taken together to form a carbocyclyl.

[0116] In embodiments of the compounds of Formula (IB) or (IIB), R5, R6and R7are each independently selected from the group consisting of -H, -halo, -C1-6 alkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or R6and R7are taken together to form a C3-6cycloalkyl.

[0117] In embodiments of the compounds of Formula (IB) or (IIB), R3, R6and R7are each independently selected from the group consisting of -H, -halo, -CN, -C1-6 alkyl, -C1-6 haloalkyl, - OC1-6 alkyl, or -OC3-6 cycloalkyl, or R6and R7are taken together to form a carbocyclyl.

[0118] In embodiments of the compounds of Formula (IB) or (IIB), R6and R7are each independently selected from the group consisting of -H, -halo, -CN, -Ci-e alkyl, or -C1-6 haloalkyl, or R6and R' are taken together to form a Cs-ecycloalkyl.

[0119] In embodiments of the compounds of Formula (IB) or (IIB), R5is -H, -Cue alkyl, -CN, or halo.

[0120] In embodiments of the compounds of Formula (IB) or (IIB), R3is -H or halo.

[0121] In embodiments of the compounds of Formula (IB) or (IIB), R6and R7are each independently selected from the group consisting of -H, -halo, -C1-6 alkyl, or -OCi-s alkyl, or R6and R7are taken together to form a Cs-scarbocyclyl.

[0122] In embodiments of the compounds of Formula (IB) or (IIB), R° and R7are each independently selected from the group consisting of -H, -halo, -Cue alkyl, or -OCi-e alkyl, or R6and R7are taken together to form a Cs-ecycloalkyl.

[0123] In embodiments of the compounds of Formula (IB) or (IIB), R6and R7are each independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl, or R6and R' are taken together to form a Cs-ecarbocyclyl.

[0124] In embodiments of the compounds of Formula (IB) or (IIB), R° and R7are each independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl, or R6and R7are taken together to form a Cs-ecycloalkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0125] In embodiments of the compounds of Formula (IB) or (IIB), R° and R7are each independently selected from the group consisting of -H, -halo, -Ci-e alkyl, or -OCi-e alkyl, or R6and R7are taken together to form a cyclopropyl or cyclobutyl.

[0126] In embodiments of the compounds of Formula (IB) or (IIB), R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-6 alkyl.

[0127] In embodiments of the compounds of Formula (IB) or (IIB), R5, R6and R ' are H.

[0128] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), RYA, RB, and RYCare each independently -H, -CN, -halo, -N(CI-6 alkyl)(saturated heterocyclyl), -Cue alkyl, -Cn 6 alkenyl, -Ci-6 alkynyl, -OCi-6 alkyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl, wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -OCi-6 alkyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl are optionally substituted with -F, -C1-6 alkyl, or -OCi-e alkyl and RYDis -H, -CN, -halo, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, a saturated heterocyclyl, or aryl.

[0129] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), RYB, RYC, and Rware each independently -H, -N(Ci-e alkyl)(saturated heterocyclyl), -C1-6 alkyl, -OCi-6 alkyl, - CN, halo, saturated heterocyclyl, or heteroaryl, wherein the -Ci-e alkyl, -OCi-e alkyl, saturated heterocyclyl, or heteroaryl are optionally substituted with -F, -C1-6 alkyl, or -OCi-6 alkyl.

[0130] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), RYBand RYDare-H, -F -CN, or -CHs and RYCis -H, -CN, -F, -OCHF2, -OCF3, -OCH3, -CH3, -Cl;

[0131] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), RYBand RYDare -H, -F -CN, or -CH. and RYCis -H, -CN, -F, -OCHF2, -OCF3, -OCH3, -CH3, or -Cl.

[0132] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -C1-6 alkyl, -OCi-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0133] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), R'A, RB, R'C, and RYDare each independently -H, -CN, -halo, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl.

[0134] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, saturated heterocyclyl, or aryl.

[0135] In embodiments of the compounds of Formula (I), (IA), (IB), or (IIA), R'A, RB, and RYCare each independently -H, -CN, -halo, -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl and RYDis -H, -CN, -halo, -C1-6 alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, a saturated heterocyclyl, or aryl.

[0136] In embodiments of the compounds of Formula (IIB), RYB, Rc, and RYDare each independently -H, -CN, -halo, -Ci-e alkyl, -OC1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl.

[0137] In embodiments of the compounds of Formula (IIB), RYB, RYC, and Rware each independently -H, -CN, -halo, -Ci-e alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl.

[0138] In embodiments of the compounds of Formula (IIB), RYB, and RCare each independently -H, -CN, -halo, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl and RYDis -H, -CN, -halo, -C1-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, a saturated heterocyclyl, or aryl.

[0139] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), RYB, RYc, and RYDare each independently -H, -Ci-e alkyl, -OC1-6 alkyl, -CN, or halo,

[0140] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), RYBand RYDare -H and RYCis -H, -Ci-e alkyl, -OC1-6 alkyl, -CN, or -F

[0141] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), RYB, RYc, and RYDare -H

[0142] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), two or three of RYB, RYC, and RYDare -HATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0143] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R' is -H, - halo, -CN, -Ci-6 alkyl, -Ci-e alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Cne alkyl), -N(Ci-e alkyl)2, -NH(Cs-6 cycloalkyl), or -N(Ci- 6 alkyl) (C3 -6 cycloalkyl); orR1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl.

[0144] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R' is -H, - halo, -CN, -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(Cne alkyl)2, -NH(Cs-6 cycloalkyl), or -N(Ci- 6 alkyl) (Cs -6 cycloalkyl); orR1and R2are taken together to form a C3-6 cycloalkyl or saturated or partially unsaturated heterocyclyl,

[0145] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), at least one of R1, R2, and RJis not -H. In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), at least one of RbR2, and R3is -halo, -Ci-e alkyl, -O-Cne alkyl, or -CN,

[0146] In embodiments of the compounds of Formula (I), (I A), (IB), (IIA), or (IIB), R1. R2, and R3is not -OH. In embodiments of the compounds of Formula (I), (IA), (IB), (II A), or (IIB), when two of R1. R2, and R3are -C1-6 alkyl, the other is not -OH.

[0147] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), when R1and R2are taken together to form a cyclopropyl, R3is not H.

[0148] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-e cycloalkyl), or -N(Ci- 6 alkyl)(Cs-6 cycloalkyl); wherein the -Ci-e alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, -NH(Cb-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -(X alkyl; orR1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014wherein the -Ci-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl.

[0149] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R' is -H, - halo, -CN, -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Cne alkyl), -N(Cne alkyl)2, -NH(Cs-6 cycloalkyl), or -N(Ci- 6 alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, - OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(Ci-e alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-e cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl; orR1and R2are taken together to form a C3-6 cycloalkyl or saturated or partially unsaturated heterocyclyl, wherein the C3-6 cycloalkyl or saturated or partially unsaturated heterocyclyl are optionally substituted with 1 or more halo, -OCi-s alkyl, -Ci-e alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl.

[0150] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-s alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -NH(C3-e cycloalkyl), or -N(Ci- 6 alkyl)(Cs-6 cycloalkyl); wherein the -C1-6 alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OCi-s alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(Ci-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more -halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CX alkyl.

[0151] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more -halo, -OC1-6 alkyl, -Ci-e alkyl, -C3-6 cycloalkyl, or -CN; wherein the - C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, - OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl.

[0152] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a Ca-ecycloalkyl or saturated or partially unsaturated heterocyclyl, wherein the C3 -6 cycloalkyl or saturated or partially unsaturated heterocyclyl are eachATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014independently optionally substituted with 1 or more -halo, -OCi-e alkyl, -Ci-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OCi-e alkyl, -OCi-e haloalkyl, or -CChalkyl.

[0153] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -C1-6 alkyl or -C3-6 cycloalkyl optionally substituted with 1 or more halo;R2is -H, -C1-6 alkyl, or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are optionally substituted with 1 or more halo.

[0154] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB ),R1is -C1-6 alkyl or -C3-6 cycloalkyl optionally substituted with 1 or more halo;R2is -C1-6 alkyl or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are optionally substituted with 1 or more halo.

[0155] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB):R1is -H, -halo, -CN, -C1-6 alkyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl;R2is -H, -halo, -Ci -6 alkyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0156] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB ):R1is -H, -halo, -CN, -Ci-s alkyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl;R2is -H, -halo, -C1-6 alkyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; orR1and R2are taken together to form a -C3-6 cycloalkyl or saturated heterocyclyl.

[0157] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is -H, -halo, -CN, -C1-6 alkyl, -Ci-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC’3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CJ-6 alkyl), -N(CI-6 alkyl)?., -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3- 6 cycloalkyl); wherein the -Ci-s alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014OC3-6 cycloalkyl, -O heterocyclyl, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, -NH(Cs-6 cycloalkyl), or -N(Ci- 6 alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more -halo, -CN, -OCi-6 alkyl, -OCi-6 haloalkyl, or -CChalkyl;R2is -H, -halo, -Cue alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OCi-e alkyl, -OCi-6 haloalkyl, or -CChalkyl; orR1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are optionally substituted with 1 or more -halo, -OCi-s alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OCi-6 alkyl, -OCi-e haloalkyl, or -CChalkyl.

[0158] In embodiments of the compounds of Formula (I), (TA), (IB), (IIA), or (IIB), R1is -H, -halo, -CN, -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH2, -NH(CI-6 alkyl), -N(Ci-s alkyl)2, -NH(Cs-6 cycloalkyl), or -N(Ci- 6 alkyl)(Cs-6 cycloalkyl); wherein the -Ci-e alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH(CI-6 alkyl), -N(Ci-e alkyl)2, -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OCi-6 alkyl, -OCi-s haloalkyl, or -CO2alkyl;R² is -H, -halo, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO₂alkyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are optionally substituted with 1 or more halo, -OCi-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OCi-s alkyl, -OCi-6 haloalkyl, or - CChalkyl.

[0159] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is -H, -halo, -CN, -Ci-e alkyl, -C3-6 cycloalkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl; wherein the -C1-6 alkyl, -C3-6 cycloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -O-ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014saturated heterocyclyl, are each independently optionally substituted with 1 or more halo, -CN, - OCi-6 alkyl, -OCi-e haloalkyl, or -CChalkyl;R2is -H, -halo, -Ci-e alkyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -C1-6 alkyl, -C3-6 cycloalkyl, or a saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OCi-e alkyl, -OCi-e haloalkyl, or -CChalkyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are optionally substituted with 1 or more halo, -OCi-6 alkyl, -Ci-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OCi-6 haloalkyl, or -CO2alkyl.

[0160] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -H, -halo, -OH, -CN, -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl;R2is -H, -halo, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0161] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -H, -halo, -OH, -CN, -C1-6 alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OCi-e alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl;R2is -H, -halo, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl; orR1and R2are taken together to form a -C3-6 cycloalkyl or saturated heterocyclyl.

[0162] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -Ci-e alkyl;R2is -H or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0163] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -Ci-e alkyl;R2is -H or -halo; orATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014R1and R2are taken together to form a -C3-6 cycloalkyl or saturated heterocyclyl.

[0164] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -C1-6 alkyl;R2is -H, -Ci -6 alkyl, or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0165] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -C1-6 alkyl;R2is -H, -Ci -6 alkyl, or -halo; orR1and R2are taken together to form a -C3-6 cycloalkyl or saturated heterocyclyl.

[0166] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -C1-6 alkyl;R2is -H, -CH₃, -F; orR1and R2are taken together to form a cyclopropyl, spiropentyl, or oxetanyl.

[0167] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB),R1is -C1-6 alkyl;R2is -H or -F; orR1and R2are taken together to form a cyclopropyl, spiropentyl, or oxetanyl.

[0168] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OH, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci- 6 alkyl)(C3-6 cycloalkyl).

[0169] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is -H, - halo, -CN, -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH₂, -NH(C1-6 alkyl), -N(C1-6 alkyl)₂, -NH(C3-6 cycloalkyl), or -N(C1-6 alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, - OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH(CI-6 alkyl), -N(Ci-s alkyl)2, - NH(C -6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0170] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is Ci-6 alkyl.

[0171] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1is -CH3.

[0172] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R' and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl.

[0173] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R' and R2are taken together to form a -C3-6 cycloalkyl or saturated or partially unsaturated heterocyclyl.

[0174] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R' and R2are taken together to form a -C3-6 cycloalkyl or saturated 4-7 membered saturated heterocyclyl.

[0175] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R' and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3- 6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OCi-e haloalkyl, or -CChalkyl.

[0176] In embodiments of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a Ce-s bicyclic cycloalkyl.

[0177] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a -C3-6 cycloalkyl or saturated heterocyclyl, wherein the -C3-6 cycloalkyl or saturated heterocyclyl are optionally substituted with 1 or more halo, -OC1-6 alkyl, -Ci-e alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OCi-e alkyl, -OC1-6 haloalkyl, or -CChalkyl.

[0178] In embodiments of the compounds of Formula (I), (I A), (IB), (IIA), or (IIB), R1and R2are taken together to form a carbocyclyl.

[0179] In embodiments of the compounds of Formula (I), (I A), (IB), (IIA), or (IIB), R1and R2are taken together to form a saturated heterocyclyl,

[0180] In embodiments of the compounds of Formula (I), (I A), (IB), (IIA), or (IIB), R1and R2are taken together to form a -C3-6 cycloalkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0181] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a cyclopropyl optionally substituted with 1 or 2 -F, oxetanyl, cyclobutyl,

[0182] In embodiments of the compounds of Formula (I), (I A), (IB), (IIA), or (IIB), R1and R2are taken together to form a cyclopropyl or

[0183] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a cyclopropyl or oxetanyl.

[0184] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a cyclopropyl.

[0185] In embodiments, the carbocycle or heterocycle formed by R1and R2is substituted with -C1-6 alkyl-OCi-6 alkyl. In embodiments, the carbocycle or heterocycle formed by R1and R2is substituted with -C1-3 alkyl-OCi-3 alkyl. In embodiments, the carbocycle or heterocycle formed by R1and R2is substituted with -CH2OCH3.

[0186] In embodiments, R1and R2are taken together to form a cyclopropyl, wherein the carbocycle is substituted by two substituents which come together to form a cyclopropyl or cyclobutyl ring.

[0187] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB):R1is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; orR1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl.

[0188] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H, - halo, -CN, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or heterocyclylATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014are each independently optionally substituted with 1 or more halo, -CN, -OCi-e alkyl, -OC1-6 haloalkyl, or -CO₂alkyl; orR1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -Ci-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl.

[0189] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H, - halo, -Cue alkyl, -C1-6 alkenyl, -Cue alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl.

[0190] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl.

[0191] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OCi-e alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OCi-e alkyl, -OC1-6 haloalkyl, or -CChalkyl.

[0192] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H, -halo, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO₂alkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0193] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H, - Ci-6 alkyl or -halo.

[0194] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -Ci- 6 alkyl or -halo.

[0195] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H, -CH₃, or -halo.

[0196] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is -H or -halo.

[0197] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB ), R2is -H.

[0198] In embodiments of the compounds of Formula (I), (IA), (IB), (HA), or (IIB), R2is -C1-6 alkyl.

[0199] In embodiments of the compounds of Formula (I), (IA), (IB), (HA), or (IIB), R2is -CH₃.

[0200] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is halo.

[0201] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R2is F.

[0202] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H, - halo, -Ci -6 alkyl, or -CN; wherein the -Ci-6 alkyl is independently optionally substituted with 1 or more halo.

[0203] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -halo, -Ci-6 alkyl, or -CN; wherein the -Ci-6 alkyl is independently optionally substituted with 1 or more halo.

[0204] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R5is -halo or -Ci-6 alkyl; wherein the -Ci-6 alkyl is independently optionally substituted with 1 or more halo.

[0205] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H, -halo, -C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OCi-6 alkyl, -OCi-6 haloalkyl, or -CChalkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0206] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H, - halo, -Ci-6 alkyl, -Cue haloalkyl, -O-Ci-e alkyl, or CN, wherein the -Ci-6 alkyl is optionally substituted with 1 or more OCi-6 alkyl.

[0207] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H, - halo, -Ci-6 alkyl, -Ci -6 haloalkyl, -O-Ci-e alkyl, or CN.

[0208] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H, - halo, -Ci-6 haloalkyl, -O-Ci-6 alkyl, or CN.

[0209] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -halo, -Ci -6 haloalkyl, -O-Ci-6 alkyl, or CN.

[0210] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is Ci-6 haloalkyl, -OCi-6 alkyl, or CN.

[0211] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is C1-3 haloalkyl, -OC1-3 alkyl, or CN.

[0212] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is halo, -C1-6 alkyl, -Ci -6 haloalkyl or CN.

[0213] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H, -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -OCH3, -OCH2CH3, -CH2CH3, -CH2OCH3 or CN.

[0214] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H, -F, -CHs, -CF3, -OCH3, -OCH2CH3, or CN.

[0215] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -F, -CHs, -CFs, -OCHs, -OCH2CH3, or CN.

[0216] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), -CHs, -CF3, -OCH 3, -OCH2CH3, or CN.

[0217] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R3is -H or halo.

[0218] In embodiments, R3is F or Cl. In embodiments, R3is F.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0219] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a carbocyclyl, and R3is -halo, -Ci-6 alkyl, -Ci-6 haloalkyl, -O-Ci-6 alkyl, or CN. In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), Rland R2are taken together to form a carbocyclyl, and R3is -halo or -O-Ci-6 alkyl.

[0220] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), R1and R2are taken together to form a cyclopropyl, and R3is -Cue alkyl, -Ci-6 haloalkyl, -O-Ci-6 alkyl, or CN. In embodiments, R3is -C1-3 alkyl, -C1-3 haloalkyl, -O-C1-3 alkyl, or CN. In embodiments, R3is -CH3 -CF3, -O-CH3, or CN.

[0221] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), X2is C(R8)2, NH, or C(R8)2NH.

[0222] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), X2is C(R8)2or NH.

[0223] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), each R8is independently H, halo, -Ci-e alkyl, -Cue haloalkyl, -O-Ci-6 alkyl, or -CN.

[0224] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), X2is C(R8)2.

[0225] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), X2is C(R8)2NH.

[0226] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), X2is CHR8.

[0227] In embodiments of the compounds of Formula (I), (I A), (IB), (IIA), or (IIB), X2is CH2.

[0228] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), X2is NH.

[0229] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), each R4is independently -H or -D.

[0230] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), two R4are H and one R4is D.

[0231] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), two R4are D and one R4is H.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0232] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), each R4is -H.

[0233] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), each R4is -D.

[0234] In embodiments of the compounds of Formula (1), (IA), (IB), (HA), or (IIB), X1is CH or N.

[0235] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB ), X1is CH.

[0236] In embodiments of the compounds of Formula (I), (IA), (IB), (IIA), or (IIB), X1is N.

[0237] In embodiments of Formula (I), (IA), (IB), (IIA), or (IIB): R1and R2are taken together to form a carbocyclyl; and R5is halo, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH₂, -NH(C1-6 alkyl), -N(C1-6 alkyl)₂, -NH(C3-6 cycloalkyl), or -N(C1-6 alkyl)(C3-6 cycloalkyl). In embodiments, the carbocyclyl is cyclopropyl, spiropentyl, or oxetanyl. In embodiments, each R4is D. In embodiments, X1is N. In embodiments, X2is NH. In embodiments, Y is N. In embodiments, Y' is CH. In embodiments, In embodiments, Y2is CH. In embodiments, Y3is CH. In embodiments, Y1, Y2, Y3are each CH. In embodiments, U is H. In embodiments, Z is cyclopropyl.

[0238] In embodiments of Formula (I), (IA), (IB), (IIA), or (IIB):R1and R2are independently -C1-3 alkyl or fluoro, or R1and R2are taken together to form a cyclopropyl;R3is -C1-3 alkyl or fluoro, wherein the -C1-3 alkyl is optionally substituted with 1 or more fluoro;R4is D;X1is N;X2is NH;Y is N;Y1, Y2, and Y3are each CH;U is H; andATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Z is cyclopropyl.

[0239] In embodiments of Formula (I), (IA), (IB), (IIA), or (IIB):R1and R2are independently -CH3 or fluoro, or R1and R2are taken together to form a cyclopropyl;R3is -CH3, -CF3, or fluoro;R4is D;X’ is N;X2is NH;Y is N;Y1, Y2, and Y3are each CH;U is H; andZ is cyclopropyl.

[0240] In some embodiments, provided herein is one or more compounds selected from Table 1, or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof. wherein:

[0241] In some embodiments, provided herein is one or more compounds selected from Table 1, or a pharmaceutically acceptable salt or deuterated form thereof.

[0242] In some embodiments, provided herein is one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, provided herein is one or more compounds selected from Table 1.Table 1. CompoundsATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014\o=J TS,.Xx■z" x z..7T"'"2E 3E SZF ||z Z ZZ0 V fy / t0 / \4 i °">0H \ / F j'*' |1A 0 HN''' JMo'^S>NX*^-- FH \ / F J'’ yo HN^^T'“N oH I aJk.H yyATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0244] In embodiments, compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof modulate TYK2. In embodiments, the modulating is binding TYK2. In embodiments, the modulating is binding to the pseudokinase domain (JH2) of TYK2. In embodiments, the modulating is inhibiting TYK2. In embodiments, TYK2 is selectively inhibited e.g., over other JAK family members, such as JAK1. In embodiments, compounds of the present disclosure exhibit at least about a 2-fold selectivity for inhibiting TYK2 over JAK1 in an assay described herein e.g., in Example 19. In embodiments, compounds of the present disclosure exhibit at least about a 5-fold selectivity for inhibiting TYK2 over JAK1 in an assay described herein e.g., in Example 19. In embodiments, compounds of the present disclosure exhibit at least about a 10- fold selectivity for inhibiting TYK2 over JAK1 in an assay described herein e.g., in Example 19. In embodiments, compounds of the present disclosure exhibit at least about a 20-fold selectivityATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014for inhibiting TYK2 over JAK1 in an assay described herein e.g., in Example 19. In embodiments, compounds of the present disclosure exhibit at least about a 50-fold selectivity for inhibiting TYK2 over JAK1 in an assay described herein e.g., in Example 19. In embodiments, compounds of the present disclosure exhibit at least about a 100-fold selectivity for inhibiting TYK2 over JAK1 in an assay described herein e.g., in Example 19.

[0245] In another embodiment, compounds of the present disclosure have an ICso<lOOO nM in at least one of the assays described below. In another embodiment, compounds of the present disclosure have an IC5o<5OO nM in at least one of the assays described below. In another embodiment, compounds of the present disclosure have an ICso<25O nM in at least one of the assays described below. In another embodiment, compounds of the present disclosure have an IC50<100 nM in at least one of the assays described below. In another embodiment, compounds of the present discl osure have an ICso<5O nM in at least one of the assays described below. In another embodiment, compounds of the present disclosure have an ICso<25 nM in at least one of the assays described below. In another embodiment, compounds of the present disclosure have an ICso<lO nM in at least one of the assays described below.Compositions

[0246] The present disclosure provides pharmaceutical compositions for modulating Tyrosine kinase 2 (TYK2) in a subject. In embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof. In embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (TIB), or Table 1) or a pharmaceutically acceptable salt, or deuterated form thereof. In embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1)

[0247] In embodiments of the present disclosure, a pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present disclosure (e.g., aATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof. In embodiments of the present disclosure, a pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt or deuterated form thereof In embodiments of the present disclosure, a pharmaceutical composition comprises a therapeutically effective amounts of one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt thereof. In embodiments of the present disclosure, a pharmaceutical composition comprises a therapeutically effective amounts of one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1).

[0248] In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof. In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt, or deuterated form thereof. In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof. In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1.

[0249] In embodiments of the present disclosure, a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and a pharmaceutically acceptable excipient or adjuvant is provided. In embodiments of the present disclosure, a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt or deuterated form thereof, and a pharmaceutically acceptable excipient or adjuvant is provided. In embodiments of the present disclosure, a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula (I), (I A), (IB), (IIA), (IIB), or Table 1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or adjuvant is provided. In embodiments of the presentATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014disclosure, a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula (I), (IA), (IB), (IIA), (IIB), or Table 1), and a pharmaceutically acceptable excipient or adjuvant is provided.

[0250] The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.

[0251] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.

[0252] Generally, the compounds of the present disclosure are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.EMBODIMENTSEmbodiments A

[0253] Embodiment 1A. A compound of Formula (I):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20146 (i)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-6 alkyl), -N(C1-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(C1-6 alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(C1-6 alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R3is -H, -halo, -C1-6 alkyl, -O-C1-6 alkyl, or -CN; wherein the -Ci-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -Ci-6 alkyl, -Ci-6haloalkyl, -O-Ci-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RY A, RYB, RYC, and RYDare each independently -H, -CN, -halo, -Ci-6 alkyl, -OCi-6 alkyl, - Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, - OC1-6 alkyl, or -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl; or U and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3-pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l -hydroxy- 1 - methy lethy l)pheny 1] amino] - N -methyl-; or6-(cyclopropanecarboxamido)-4-((2-(l -hydroxyethyl)-3-(l -methyl- 1H-1, 2, 4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0254] Embodiment 2A. The compound of embodiment 1, wherein Z is -ORZor -C3-6 cycloalkyl, wherein the -C3-6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0255] Embodiment 3 A. The compound of embodiment 1 or 2, wherein Z is -ORZor cyclopropyl, wherein the cyclopropyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Cue alkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or two substituents are taken together to form a carbocyclyl.

[0256] Embodiment 4A. The compound of embodiment 3, wherein Z is -ORZor cyclopropyl, wherein the cyclopropyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OCi-6 alkyl, or -OC3-6 cycloalkyl.

[0257] Embodiment 5 A. The compound of any one of embodiments 1-4, wherein U is H.

[0258] Embodiment 6A. The compound of embodiment 1, wherein U and Z are taken together to form a 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OCi-6 alkyl.

[0259] Embodiment 7A. The compound of embodiment 6, wherein U and Z are taken together to form a 5-membered saturated heterocyclyl, wherein the 5-membered saturated heterocyclyl is optionally substituted with -C1-6 alkyl.

[0260] Embodiment 8 A. The compound of embodiment 1, having a structure of Formula (IA):H (IA)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof,

[0261] Embodiment 9A. The compound of any one of embodiments 1-3, having a structure of Formula (IB):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein R5, R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, -OCi-e alkyl, or -OCs-s cycloalkyl, or R6and R' are taken together to form a carbocyclyl.

[0262] Embodiment 10A. The compound of any one of embodiments 1-9, wherein Y, Y1, Y, and Y3are not all CH.

[0263] Embodiment 11 A. The compound of any one of embodiments 1-10, wherein at least one of Y, Y1, Y2, and Y3is N.

[0264] Embodiment 12A. The compound of any one of embodiments 1 -11, wherein Y is N.

[0265] Embodiment 13A, The compound of any one of embodiments 1-12, wherein one or two ofY1, Y2, and Y3isN.

[0266] Embodiment 14A, The compound of any one of embodiments 1-5 or 8-12, having a structure of Formula (II A) or (IIB):or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0267] Embodiment 15 A. The compound of any one of embodiments 9-14, wherein R5is -H or halo.

[0268] Embodiment 16A. The compound of any one of embodiments 9-15, wherein R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-6 alkyl, or R6and R7are taken together to form a Cs-ecycloalkyl.

[0269] Embodiment 17A. The compound of embodiment 16, wherein R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-e alkyl, or R6and R7are taken together to form a cyclopropyl or cyclobutyl.

[0270] Embodiment 18A. The compound of embodiment 17, wherein R6and R' are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-e alkyl.

[0271] Embodiment 19A. The compound of any one of embodiments 9-18, whereinR3, R6and R7are H.

[0272] Embodiment 20A. The compound of any one of embodiments 1-19, wherein RYA, RYB, and RYCare each independently -H, -CN, -halo, -Ci-6 alkyl, -Ci-e alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl and RYDis -H, -CN, -halo, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, a saturated heterocyclyl, or aryl.

[0273] Embodiment 21A. The compound of any one of embodiments 1-20, wherein RYB, R'c, and RYUare each independently -H, -C1-6 alkyl, -CN, or halo.

[0274] Embodiment 22A. The compound of embodiment 21, wherein RBand RYDare -H and RYCIS -H, -C1-6 alkyl, -CN, or -F

[0275] Embodiment 23 A. The compound of embodiment 21, wherein two or three of RYB, RYC, and RYDare -H.

[0276] Embodiment 24A. The compound of any one of embodiments 1-23, wherein:R1is -H, -halo, -CN, -Ci-e alkyl, -Cue alkenyl, -Cue alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH2, -NH(CI-6 alkyl), -N(Cne alky 1)2, -NH(C3-e cycloalkyl), or -N(Cne alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH(CI-6 alkyl), -ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014N(Ci-e alkyl)2, -NH(Cs-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OCi-6 alkyl, -OCi-6 haloalkyl, or -CChalkyl;R2is -H, -halo, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -Cue alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OCi-6 alkyl, -OCi-6 haloalkyl, or -CChalkyl;or R1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-6 alkyl, -Ci-e alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OCi- 6 haloalkyl, or -CChalkyl.

[0277] Embodiment 25A. The compound of any one of embodiments 1-23, wherein:R1is -H, -halo, -OH, -CN, -Cue alkyl, -Ci-e alkenyl, -Cue alkynyl, -C3-6 cycloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl:R2is -H, -halo, -Ci-e alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0278] Embodiment 26A. The compound of any one of embodiments 1-25, wherein:R1is -C1-6 alkyl;R2is -H, -C1-6 alkyl, or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0279] Embodiment 27A. The compound of any one of embodiments 1-26, wherein R1is C1-6 alkyl.

[0280] Embodiment 28 A. The compound of embodiment 27, wherein R1is -CH3.

[0281] Embodiment 29A. The compound of any one of embodiments 1-26, wherein R1and R2are taken together to form a carbocyclyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0282] Embodiment 30A. The compound of any one of embodiments 1-26, wherein R1and R2are taken together to form a -C3-6 cycloalkyl or saturated heterocyclyl.

[0283] Embodiment 31 A. The compound of embodiment 29 or 30, wherein R1and R2are taken together to form a -C3-6 cycloalkyl.

[0284] Embodiment 32 A. The compound of embodiment 25 or 26, wherein R1and R2are taken together to form a cyclopropyl or oxetanyl.

[0285] Embodiment 33A. The compound of any one of embodiments 29-32, wherein R1and R2are taken together to form a cyclopropyl.

[0286] Embodiment 34A. The compound of any one of embodiments 1-28, wherein R2is -H or -halo.

[0287] Embodiment 35A. The compound of embodiment 34, wherein R2is -H.

[0288] Embodiment 36A. The compound of embodiment 34, wherein R2is halo.

[0289] Embodiment 37A. The compound of embodiment 36, wherein R2is F.

[0290] Embodiment 38 A. The compound of any one of embodiments 1-37, wherein R3is -H, -halo, -C1-6 alkyl, -Ci -6 haloalkyl, -O-C1-6 alkyl, or CN.

[0291] Embodiment 39A. The compound of any one of embodiments 1-38, wherein R3is -halo, -C1-6 haloalkyl, -O-C1-6 alkyl, or CN.

[0292] Embodiment 40A. The compound of any one of embodiments 1-39, wherein R3is C1-6 haloalkyl, -OC1-6 alkyl, or CN.

[0293] Embodiment 41 A. The compound of any one of embodiments 1-40, wherein R3is C1-3 haloalkyl, -OC1-3 alkyl, or CN.

[0294] Embodiment 42A. The compound of embodiment 38, wherein R3is -H, -F, -CH3, -CFs, -OCHs, -OCH2CH3, or CN.

[0295] Embodiment 43 A. The compound of embodiment 38, wherein R3is -F, -CHs, -CF3, -OCHs, -OCH2CH3, or CN.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0296] Embodiment 44A. The compound of embodiment 43, wherein R3is -CHs, -CFs, - OCH3, -OCH2CH3, or CN.

[0297] Embodiment 45 A. The compound of embodiment 38, wherein R3is H or halo.

[0298] Embodiment 46A. The compound of any one of embodiments 1-45, wherein X2is CHR8.

[0299] Embodiment 47A. The compound of any one of embodiments 1-46, wherein X2is CHz.

[0300] Embodiment 48 A. The compound of any one of embodiments 1-45, wherein X2is NH.

[0301] Embodiment 49A. The compound of any one of embodiments 1 -48, wherein each R4is -H.

[0302] Embodiment 50A. The compound of any one of embodiments 1-48, wherein each R4is

[0303] Embodiment 51 A. The compound of any one of embodiments 1-50, wherein X1is CH.

[0304] Embodiment 52A. The compound of any one of embodiments 1-50, wherein X]is N.

[0305] Embodiment 53 A. The compound of embodiment 1, wherein the compound is selected from the group consisting of:ATTORNEY DOCKET No.: TTTI-OO3 / O3WG 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

[0306] Embodiment 54A, A pharmaceutical composition comprising a compound of any one of embodiments 1-53, or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and a pharmaceutically acceptable carrier.Embodiments B

[0307] Embodiment IB. A compound of Formula (I):(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein:ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010R' is -H, -halo, -CN, -Ci-e alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, - OC1-6 alkyl, -OC... cycloalkyl, -Oheterocyclyl, -NHz, -NH(CI-6 alkyl), -N(CJ-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(Cs-6 cycloalkyl); wherein the -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, - H(CJ-6 alkyl), -N(Ci-e alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -Ci-e alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -Cs- 6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -Ci-e alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;R3is -H, -halo, -C1-6 alkyl, -O-C1-6 alkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -CN; wherein the -Ci-e alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;X’ is CH or N;X2is C(R8)2 or NH;each R8is independently H, halo, -C1-6 alkyl, -Ci-s haloalkyl, -O-C1-6 alkyl, or -CN; Y is N or CRYA;Y’ is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;R^A, RB, RYC, andRYDare each independently -H, -CN, -halo, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZ-(CH2)O-3-(C3-6 cycloalkyl), or -(CH2)o-3-(C3-C4 heterocyclyl), and wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independentlyATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010selected from the group consisting of -halo, -Ci-6 alkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; and RZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)ammo]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; or6-(cyclopropanecarboxamido)-4-((2-(l -hy droxyethyl)-3-(l -methyl- 1H-1, 2, 4-tnazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0308] Embodiment 2B. The compound of embodiment 1, wherein Z is -ORZor -C3-6 cycloalkyl, or -C3-C4 heterocyclyl wherein the -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN or two substituents are taken together to form a carbocyclyl.

[0309] Embodiment 3B. The compound of embodiment 1 or 2, wherein Z is -ORZ, cyclopropyl, cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-s alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl.

[0310] Embodiment 4B. The compound of embodiment 3, wherein Z is -ORZ, cyclopropyl, cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN.

[0311] Embodiment 5B. The compound of any of embodiments 1-4, wherein Z is -(CH2)o-3-(C3-C6 cycloalkyl).ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010

[0312] Embodiment 6B. The compound of any of embodiments 1-4, wherein Z is -(CH2)-(C3-C6 cycloalkyl).

[0313] Embodiment 7B. The compound of any one of embodiments 1-4, wherein U is H.

[0314] Embodiment 8B. The compound of embodiment 1, wherein U and Z are taken together to form a 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -halo, -Ci -6 alkyl, or -OC1-6 alkyl.

[0315] Embodiment 9B. The compound of embodiment 8, wherein U and Z are taken together to form a 5-membered saturated heterocyclyl, wherein the 5-membered saturated heterocyclyl is optionally substituted with -C1-6 alkyl.

[0316] Embodiment 10B. The compound of embodiment 9, wherein the 5-membered saturated heterocyclyl is substituted with CH3, CH2CH3, CH2CH2CH3, or CH(CH3)?„

[0317] Embodiment I IB. The compound of embodiment 1, having a structure of Formula (IA):R2 R3. Y\2Iy-Y1(IA)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

[0318] Embodiment 12B. The compound of any one of embodiments 1-3, having a structure of Formula (IB):ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010(IB)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein R5, R6and R7are each independently selected from the group consisting of -H, -halo, -Ci -6 alkyl, -OCi-e alkyl, or -OC3-6 cycloalkyl, or R6and R7are taken together to form a carbocyclyl.

[0319] Embodiment 13B. The compound of any one of embodiments 1-12, wherein Y, Y1, Y2, and Y3are not all CH.

[0320] Embodiment 14B. The compound of any one of embodiments 1-13, wherein at least one of Y, Y1, Y2, and YJis N.

[0321] Embodiment 15B. The compound of any one of embodiments 1-14, wherein Y is N.

[0322] Embodiment 16B. The compound of any one of embodiments 1-15, wherein one or two of Y!, Y2, and Y3is N.

[0323] Embodiment 17B. The compound of any one of embodiments 1-13, wherein Y is N and Y is N.

[0324] Embodiment 18B. The compound of any one of embodiments 1-13, wherein Y is N and Y3is N.

[0325] Embodiment 19B. The compound of any one of embodiments 1-12, wherein:Y is N and Y is CR1' wherein R'cis CHs, -CN, F, or Cl; or whereinY is N and Y3is CRYDwherein RYDis CH3, -CN, F, or Cl.ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010

[0326] Embodiment 20B. The compound of any one of embodiments 1-7 or 12-15, having a structure of Formula (II A) or (IIB):Hor a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

[0327] Embodiment 21B. The compound of any one of embodiments 13-20, wherein R3is -H or halo.

[0328] Embodiment 22B. The compound of any one of embodiments 13-20, wherein R6and R7are each independently selected from the group consisting of -II, -halo, -Ci-6 alkyl, or -OCi-6 alkyl, or R6and R7are taken together to form a Cb-ecycloalkyl.

[0329] Embodiment 23B. The compound of embodiment 22, wherein R6and R' are each independently selected from the group consisting of -II, -halo, -C1-6 alkyl, or -OC1-6 alkyl, or R° and R7are taken together to form a cyclopropyl or cyclobutyl.

[0330] Embodiment 24B. The compound of embodiment 23, wherein R6and R7are each independently selected from the group consisting of -El, -halo, -C1-6 alkyl, or -OC1-6 alkyl.

[0331] Embodiment 25B. The compound of any one of embodiments 13-21, wherein R5, R° and R7are II.

[0332] Embodiment 26B. The compound of any one of embodiments 1 -25, wherein R'A, RYB, and RYCare each independently -H, -CN, -halo, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl and RYDis -H, -CN, -halo, -Ci-e alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, a saturated heterocyclyl, or aryl.ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010

[0333] Embodiment 27B. The compound of any one of embodiments 1-26, wherein RYB, R'c, and RYUare each independently -H, -Ci-6 alkyl, -CN, or halo.

[0334] Embodiment 28B. The compound of embodiment 27, wherein RYBand RYDare -H and RYCIS -H, -CI-6 alkyl, -CN, or -F.

[0335] Embodiment 29B. The compound of embodiment 27, wherein two or three of RYB, RY C, and RY Dare -H.

[0336] Embodiment 30B. The compound of any one of embodiments 1-29, wherein:R1is -H, -halo, -CN, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH?., -NH(Ci-e alkyl), -N(CI-6 alkyl)?., - NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C'3-6 cycloalkyl); wherein the -C1-6 alkyl, -C1-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH(C -6 alkyl), -N(Ci-6 alkyl)?., -NH(C'3-6 cycloalkyl), or -N(Ci-6 alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -C1-6 alkyl, -Ci-e alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -Cue alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OCne alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -Ci-e alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-s alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OCi- 6 haloalkyl, or -CO?alkyl.

[0337] Embodiment 3 IB. The compound of any one of embodiments 1-29, wherein:R1is -H, -halo, -OH, -CN, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl;R2is -H, -halo, -Ci-s alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010

[0338] Embodiment 32B. The compound of any one of embodiments 1-31, wherein:R1is -Ci-6 alkyl;R2is -H, -Ci -6 alkyl, or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0339] Embodiment 33B. The compound of any one of embodiments 1-32, wherein R1is Ci-e alkyl.

[0340] Embodiment 34B. The compound of embodiment 33, wherein R1is -CHs.

[0341] Embodiment 35B. The compound of any one of embodiments 1-34, wherein R1and R2are taken together to form a carbocyclyl.

[0342] Embodiment 36B. The compound of any one of embodiments 1-32, wherein R1and R2are taken together to form a -Cs-6 cycloalky 1 or saturated heterocyclyl.

[0343] Embodiment 37B. The compound of embodiment 32 or 33, wherein R1and R2are taken together to form a -C -6 cycloalkyl.

[0344] Embodiment 38B. The compound of embodiment 28 or 29, wherein R1and R2are taken together to form a cyclopropyl or oxetanyl.

[0345] Embodiment 39B, The compound of any one of embodiments 32-35, wherein R1and R are taken together to form a cyclopropyl.

[0346] Embodiment 40B, The compound of any of embodiments 35-39, wherein the carbocycle or heterocycle is substituted with -CH2OCH3.

[0347] Embodiment 41B, The compound of any of embodiments 35-40, wherein R1and R2are taken together to form a cyclopropyl, wherein the carbocycle is substituted by two substituents which come together to form a cyclopropyl or cyclobutyl ring,

[0348] Embodiment 42B. The compound of any one of embodiments 1-41, wherein R2is -H or -halo.

[0349] Embodiment 43B. The compound of embodiment 42, wherein R2is -H.ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010

[0350] Embodiment 44B. The compound of embodiment 42, wherein R2is halo.

[0351] Embodiment 45B. The compound of embodiment 42, wherein R2is E

[0352] Embodiment 46B. The compound of any one of embodiments 1-45, wherein R5is -H, -halo, -Ci-6 alkyl, -Ci-e haloalkyl, -O-Ci-6 alkyl, or CN.

[0353] Embodiment 47B. The compound of any one of embodiments 1-46, wherein R3is - halo, -Ci-6 haloalkyl, -O-Ci-6 alkyl, or CN.

[0354] Embodiment 48B. The compound of any one of embodiments 1-47, wherein R3is Ci-6 haloalkyl, -OCi-6 alkyl, or CN.

[0355] Embodiment 49B. The compound of any one of embodiments 1-48, wherein R3is C1-3 haloalkyl, -OC1-3 alkyl, or CN.

[0356] Embodiment SOB. The compound of embodiment 46, wherein R3is -H, -F, -CHs, -CHE CHF2, -CF3, -OCH3, -OCH2CH3, or CN

[0357] Embodiment SIB. The compound of embodiment 46, wherein R3is -F, -CHs, -CF3, -OCH3, -OCH2CH3, or CN.

[0358] Embodiment 52B. The compound of embodiment 51, wherein R3is -CH3, -CF3, - OCH3, -OCH2CH3, or CN.

[0359] Embodiment 53B. The compound of embodiment 46, wherein R3is H, F, or Cl.

[0360] Embodiment 54B. The compound of embodiment 53, w’herein R3is F.

[0361] Embodiment 55B. The compound of any one of embodiments 1-54, wherein X2is CHRS.

[0362] Embodiment 56B. The compound of any one of embodiments 1-55, wherein X2is CH2.

[0363] Embodiment 57B. The compound of any one of embodiments 1-54, wherein X2is NH.ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010

[0364] Embodiment 58B. The compound of any one of embodiments 1-57, wherein each R4is -H.

[0365] Embodiment 59B. The compound of any one of embodiments 1-57, wherein each R4is -D.

[0366] Embodiment 60B. The compound of any one of embodiments 1-59, wherein X1is CH.

[0367] Embodiment 61B. The compound of any one of embodiments 1 -59, wherein X1is N.

[0368] Embodiment 62B. The compound of embodiment 1, wherein the compound is selected from the group consisting of:ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010ATTORNEY DOCKET NO.: TTTI-003 / 01US 354643-2010or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

[0369] 63. The compound of embodiment 1, wherein the compound is selected from the group consisting of:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014I l lATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0370] Embodiment 64B. A pharmaceutical composition comprising a compound of any one of embodiments 1-62, or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and a pharmaceutically acceptable earner.I lATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Embodiments C

[0371] Embodiment 1C. A compound of Formula (I):R2 R3v3R1if ' Y2J I O HN^Y^YC(R4)3X‘N^N^Zu(I)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(Ci-e alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl); wherein the -Ci-s alkyl, -Ci-e alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(Ci-6 alkyl), -N(Ci-e alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-s alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -Ci-e alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OCi-e haloalkyl, or -CO2alkyl;R3is -H, -halo, -C1-6alkyl, -O-C1-6 alkyl, -C1-6 alkylene-O-Ci-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CChalkyl;each R4is independently -H or -D;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -Ci-6 alkyl, -Ci-6haloalkyl, -O-Cne alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -Ci-6 alkyl, -OCi-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl;U is H;Z is -ORZ-(CH2)o-3-(C3-6 cycloalkyl), or -(CH2)o-3-(C3-C4 heterocyclyl), and wherein the -C3-6 cycloalkyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OCi-e alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3-pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l -hydroxy- 1-methylethyl)phenyl]amino]-N-methyl-; or6-(cyclopropanecarboxamido)-4-((2-(l-hydroxyethyl)-3-(l -methyl- 1H-1, 2, 4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0372] Embodiment 2C. The compound of embodiment 1, wherein Z is -ORZor -C3-6 cycloalkyl, or -C3-C4 heterocyclyl wherein the -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of - halo, -Ci -6 alkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -CN or two substituents are taken together to form a carbocyclyl.

[0373] Embodiment 3 C. The compound of embodiment 1 or 2, wherein Z is -ORZ, cyclopropyl, cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl, wherein the cyclopropyl,ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl.

[0374] Embodiment 4C. The compound of embodiment 3, wherein Z is -ORZ, cyclopropyl, cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclopentyl, spirohexyl, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Cue alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN.

[0375] Embodiment 5C. The compound of any of embodiments 1-4, wherein Z is -(CH2)o-3- (C3-C6 cycloalkyl).

[0376] Embodiment 6C. The compound of any of embodiments 1-4, wherein Z is -(CH2)-(C3-C6 cycloalkyl).

[0377] Embodiment 7C. The compound of any one of embodiments 1-4, wherein U is H.

[0378] Embodiment 8C. The compound of embodiment 1, wherein U and Z are taken together to form a 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -halo, -Ci -6 alkyl, or -OC1-6 alkyl.

[0379] Embodiment 9C. The compound of embodiment 8, wherein U and Z are taken together to form a 5-membered saturated heterocyclyl, wherein the 5-membered saturated heterocyclyl is optionally substituted with -Ci-e alkyl.

[0380] Embodiment 10C. The compound of embodiment 9, wherein the 5-membered saturated heterocyclyl is substituted with CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2.

[0381] Embodiment 11C. The compound of embodiment 1, having a structure of Formula (IA):ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Hor a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

[0382] Embodiment 12C. The compound of any one of embodiments 1-3, having a structure of Formula (IB):(IB)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein R5, R6and R7are each independently selected from the group consisting of -H, -halo, -C1-6alkyl, -OC1-6alkyl, or -OC3-6cycloalkyl, or R6and R7are taken together to form a carbocyclyl.

[0383] Embodiment 13C. The compound of any one of embodiments 1-12, wherein Y, Y1, Y2, and Y3are not all CH.

[0384] Embodiment 14C. The compound of any one of embodiments 1-13, wherein at least one of Y, Yl, Y2, and Y3is N.

[0385] Embodiment 15C. The compound of any one of embodiments 1-14, wherein Y is N.

[0386] Embodiment 16C. The compound of any one of embodiments 1-15, wherein one or two of Y1, Y2, and Y3is N.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0387] Embodiment 17C. The compound of any one of embodiments 1-13, wherein Y is N and Y2is N.

[0388] Embodiment 18C. The compound of any one of embodiments 1-13, wherein Y is N and Y3is N.

[0389] Embodiment 19C. The compound of any one of embodiments 1-12, wherein:Y is N and Y2is CRYCwherein RYCis CFE, -CN, F, or Cl; or whereinY is N and Y3is CRYDwherein RYDis CEE, -CN, F, or Cl.

[0390] Embodiment 20C. The compound of any one of embodiments 1-7 or 12-15, having a structure of Formula (II A) or (II B):or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

[0391] Embodiment 21 C, The compound of any one of embodiments 13-20, wherein R5is -H or halo,

[0392] Embodiment 22C, The compound of any one of embodiments 13-20, wherein R6and R' are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-e alkyl, or R6and R7are taken together to form a C3-6cycloalkyl.

[0393] Embodiment 23C. The compound of embodiment 22, wherein R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-e alkyl, or R6and R7are taken together to form a cyclopropyl or cyclobutyl.

[0394] Embodiment 24C, The compound of embodiment 23, wherein R6and R7are each independently selected from the group consisting of -H, -halo, -C1-6alkyl, or -OC1-6alkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0395] Embodiment 25C. The compound of any one of embodiments 13-21, wherein R3, R6and R7are H.

[0396] Embodiment 26C. The compound of any one of embodiments 1 -25, wherein RYA, RYB, and RYCare each independently -H, -CN, -halo, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-6 alkynyl, -OCi-6 alkyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl and RYDis -H, -CN, -halo, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, a saturated heterocyclyl, or aryl.

[0397] Embodiment 27C. The compound of any one of embodiments 1-26, wherein RYB, RYC, and RYDare each independently -H, -C1-6 alkyl, -OC1-6 alkyl, -CN, or halo.

[0398] Embodiment 28C. The compound of embodiment 27, wherein RYBand RYDare -H and RYCis -H, -C1-6 alkyl, -CN, or -F

[0399] Embodiment 29C. The compound of embodiment 27, wherein two or three of RYB, RYC, and RYDare -H.

[0400] Embodiment 30C. The compound of any one of embodiments 1-29, wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NEE, -NH(CI-6 alkyl), -N(CI-6 alkylh, - NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3-6 cycloalkyl); wherein the -Ci-e alkyl, -C1-6 alkenyl, - C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, - NH(CJ-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -Ci-e alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -Ci-e alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, - OC1-6 haloalkyl, or -CC alkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Embodiment 31C. The compound of any one of embodiments 1-29, wherein:R1is -H, -halo, -OH, -CN, -Ci-6 alkyl, -Ci-6 alkenyl, -Ci-e alkynyl, -C3-6 cycloalkyl, -OCi-6 alkyl, -OC3-6cycloalkyl, or -O-saturated heterocyclyl;R2is -H, -halo, -Ct-e alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.Embodiment 32C. The compound of any one of embodiments 1-31, wherein:R1is -C1-6 alkyl;R2is -H, -Ci-6 alkyl, or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl.

[0401] Embodiment 33C. The compound of any one of embodiments 1-32, wherein R1is C1-6 alkyl.

[0402] Embodiment 34C. The compound of embodiment 33, wherein R1is -CH3.

[0403] Embodiment 35C. The compound of any one of embodiments 1-34, wherein R1and R2are taken together to form a carbocyclyl.

[0404] Embodiment 36C. The compound of any one of embodiments 1-32, wherein R1and R2are taken together to form a -C3-6 cycloalkyl or saturated heterocyclyl.

[0405] Embodiment 37C. The compound of embodiment 32 or 33, wherein Rland R2are taken together to form a -C3-6 cycloalkyl.

[0406] Embodiment 38C. The compound of embodiment 37, wherein R1and R2are taken together to form a cyclopropyl, spiropentyl, or oxetanyl.

[0407] Embodiment 39C. The compound of any one of embodiments 32-35, wherein R1and R2are taken together to form a cyclopropyl or spiropentyl.

[0408] Embodiment 40C. The compound of any of embodiments 35-39, wherein the carbocycle or heterocycle is substituted with -CH2OCH3.

[0409] Embodiment 41 C. The compound of embodiment 35, wherein R1and R2are taken together to form a Ce-s bicyclic cycloalkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0410] Embodiment 42C. The compound of any one of embodiments 1-36, wherein R2is -H or -halo.

[0411] Embodiment 43C. The compound of embodiment 42, w’herein R2is -H.

[0412] Embodiment 44C. The compound of embodiment 42, wherein R2is halo.

[0413] Embodiment 45C. The compound of embodiment 42, wherein R2is F.

[0414] Embodiment 46C. The compound of any one of embodiments 1-45, wherein R3is -H, -halo, -Ci-6 alkyl, -Ci -6 haloalkyl, -O-Ci-e alkyl, or CN.

[0415] Embodiment 47C. The compound of any one of embodiments 1-46, wherein R3is -halo, -C1-6 haloalkyl, -O-C1-6 alkyl, or CN.

[0416] Embodiment 48C. The compound of any one of embodiments 1-47, wherein R3is C1-6 haloalkyl, -OC1-6 alkyl, or CN.

[0417] Embodiment 49C. The compound of any one of embodiments 1-48, wherein R3is C1-3 haloalkyl, -OC1-3 alkyl, or CN.

[0418] Embodiment 50C. The compound of embodiment 46, wherein R3is -H, -F, -CH3, -CH2F, CHF2, -CF3, -OCH3, -OCH2CH3, or CN.

[0419] Embodiment 51C. The compound of embodiment 46, wherein R3is -F, -CH3, -CF3, -OCH3, -OCH2CH3, or CN.

[0420] Embodiment 52C. The compound of embodiment 51, wherein R3is -CH3, -CF3, - OCH3, -OCH2CH3, or CN.

[0421] Embodiment 53C. The compound of embodiment 46, wherein R3is H, F, or Cl.

[0422] Embodiment 54C. The compound of embodiment 53, wherein R3is F.

[0423] Embodiment 55C. The compound of any one of embodiments 1-54, wherein X2is CHR8.

[0424] Embodiment 56C. The compound of any one of embodiments 1-55, wherein X2is CH2.

[0425] Embodiment 57C. The compound of any one of embodiments 1-54, wherein X2is NH.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0426] Embodiment 58C. The compound of any one of embodiments 1-57, wherein each R4is -H.

[0427] Embodiment 59C. The compound of any one of embodiments 1-57, wherein each R4is -D.

[0428] Embodiment 60C. The compound of any one of embodiments 1-59, wherein X1is CH.

[0429] Embodiment 61 C. The compound of any one of embodiments 1-59, wherein X1is N.

[0430] Embodiment 62C. The compound of embodiment 1, wherein the compound is selected from the group consisting of:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014acceptable salt, deuterated form, or stereoisomer thereof.

[0431] Embodiment 63C. A pharmaceutical composition comprising a compound of any one of embodiments 1-62, or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and a pharmaceutically acceptable carrier.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014EXAMPLES

[0432] The disclosure now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.LC-MS Method A:|0433] Instrumentation

[0434] LC: Waters Acquity UPLC

[0435] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0436] MS Detection: Waters Acquity QDa, ESI (ES+ / ES-, 120-1200 amu)

[0437] Mobile Phase

[0438] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0439] Eluent B1: ACN

[0440] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0441] Gradient: 5% to 100% B in 2,0 minutes; hold 100% B for 0.7 minute

[0442] Flow: 0.9 mL / min

[0443] Run Time: 2,7 minutesLC-MS Method AA:

[0444] Instrumentation

[0445] LC: Waters Acquity UPLC

[0446] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0447] MS Detection: Waters Acquity QDa, ESI (ES+ / ES-, 120-1200 amu)

[0448] Mobile Phase

[0449] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0450] Eluent B1: ACN

[0451] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0452] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0453] Flow: 1.1 mL / min

[0454] Run Time: 1.9 minutesLC-MS Method B:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0455] Instrumentation

[0456] LC: Waters Acquity UPLC

[0457] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0458] MS Detection: Waters Acquity QDa ESI (ES+ / ES-, 120-1200 amu)

[0459] Mobile Phase

[0460] Eluent A1: Milli-Q H2O + 10 mM AmB pH: 10.0

[0461] Eluent B1: ACN

[0462] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0463] Gradient: 5% to 100% B in 2,0 minutes; hold 100% B for 0.7 minute

[0464] Flow: 0.9 mL / min

[0465] Run Time: 2.7 minutes

[0466] LC-MS Method BB:

[0467] Instrumentation

[0468] LC: Waters Acquity UPLC

[0469] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0470] MS Detection: Waters Acquity QDa ESI (ES+ / ES-, 120-1200 amu)

[0471] Mobile Phase

[0472] Eluent A1: Milli-Q H2O + 10 mM AmB pH: 10.0

[0473] Eluent B1: ACN

[0474] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0475] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0476] Flow: 1.1 mL / min

[0477] Run Time: 1.9 minutesLC-MS Method C:

[0478] Instrumentation

[0479] LC: Waters Acquity UPLC

[0480] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0481] MS Detection: Waters Acquity QDa, ESI (ES+ / ES-, 120-1200 amu)

[0482] Mobile Phase

[0483] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0484] Eluent Bl: ACN

[0485] Column: Waters Acquity UPLC CSH Cl 8, 1.7 m, 2.1 x 30 mm at 40°C

[0486] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minute

[0487] Flow: 0.9 mL / min

[0488] Run Time: 7 minutesLC-MS Method D:

[0489] Instrumentation

[0490] EC: Waters Acquity UPLC

[0491] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0492] MS Detection: Waters Acquity QDa, ESI (ES+ / ES-, 120-1200 amu)

[0493] Mobile Phase

[0494] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10.0

[0495] Eluent Bl: ACN

[0496] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0497] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1,8 minute

[0498] Flow: 0.9 mL / min

[0499] Run Time: 7 minutesLC-MS Method E:

[0500] Instrumentation

[0501] LC: Waters Acquity UPLC

[0502] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0503] MS Detection: Waters 3100 MS, ESI (ES+ / ES-, 120- 1900 amu)

[0504] Mobile Phase

[0505] Eluent Al: Milli-Q H2O + 10 mM AmF pH: 3.8

[0506] Eluent BI: ACN

[0507] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0508] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0509] Flow: 0.9 niL / min

[0510] Run Time: 2.7 minutesLC-MS Method EE:

[0511] InstrumentationATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0512] LC: Waters Acquity UPLC

[0513] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0514] MS Detection: Waters 3100 MS, ESI (ES+ / ES-, 120-1900 amu)

[0515] Mobile Phase

[0516] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0517] Eluent Bl: ACN

[0518] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0519] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0520] Flow: 1.1 mL / min

[0521] Run Time: 1.9 minutesLC-MS Method F:

[0522] Instrumentation

[0523] LC: Waters Acquity UPLC

[0524] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0525] MS Detection: Waters 3100 MS, ESI (ES+ / ES-, 120-1900 amu)

[0526] Mobile Phase

[0527] Eluent A1: Milli-Q H2O + 10 mM AmB pH: 10.0

[0528] Eluent Bl: ACN

[0529] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0530] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0531] Flow: 0.9 mL / min

[0532] Run Time: 2.7 minutesLC-MS Method FF:

[0533] Instrumentation

[0534] LC: Waters Acquity UPLC

[0535] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0536] MS Detection: Waters 3100 MS, ESI (ES+ / ES-, 120- 1900 amu)

[0537] Mobile Phase

[0538] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10.0

[0539] Eluent Bl: ACN13ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0540] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0541] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0542] Flow: 1.1 mL / min

[0543] Run Time: 1.9 minutesLC-MS Method G:

[0544] Instrumentation

[0545] LC: Waters Acquity UPLC

[0546] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0547] MS Detection: Waters 3100 MS, ESI (ES+ / ES-, 120-1900 amu)

[0548] Mobile Phase

[0549] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0550] Eluent Bl: ACN

[0551] Column: Waters Acquity UPLC CSH Cl 8, 1,7 pm, 2.1 x 30 mm at 40°C

[0552] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1,8 minute

[0553] Flow: 0.9 mL / min

[0554] Run Time: 7 minutesLC-MS Method H:

[0555] Instrumentation

[0556] EC: Waters Acquity UPLC

[0557] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0558] MS Detection: Waters 3100 MS, ESI (ES+ / ES-, 120-1900 amu)

[0559] Mobile Phase

[0560] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10.0

[0561] Eluent Bl: ACN

[0562] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0563] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minute

[0564] Flow: 0.9 mL / min

[0565] Run Time: 7 minutesLC-MS Method I:

[0566] Instrumentation

[0567] LC: Waters Acquity UPLCATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0568] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0569] MS Detection: Waters SQD, ESI (ES+ / ES-, 120-1900amu)

[0570] Mobile Phase

[0571] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0572] Eluent Bl: ACN

[0573] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0574] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0575] Flow: 0.9 mL / min

[0576] Run Time: 2.7 minutesLC-MS Method II:

[0577] Instrumentation

[0578] LC: Waters Acquity UPLC

[0579] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0580] MS Detection: Waters SQD, ESI (ES+ / ES-, 120-1200 amu)

[0581] Mobile Phase

[0582] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0583] Eluent Bl: ACN

[0584] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0585] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0586] Flow: 1.1 mL / min

[0587] Run Time: 1.9 minutesLC-MS Method J:

[0588] Instrumentation

[0589] LC: Waters Acquity UPLC

[0590] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0591] MS Detection: Waters SQD, ESI (ES+ / ES-, 120-1200 amu)

[0592] Mobile Phase

[0593] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10.0

[0594] Eluent Bl: ACN

[0595] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°CATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0596] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0597] Flow: 0.9 mL / min

[0598] Run Time: 2.7 minutesLC-MS Method JJ:

[0599] Instrumentation

[0600] LC: Waters Acquity UPLC

[0601] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0602] MS Detection: Waters SQD, ESI (ES+ / ES-, 120-1200 amu)

[0603] Mobile Phase

[0604] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10.0

[0605] Eluent Bl: ACN

[0606] Column: Waters Acquity UPLC CSH C18, 1.7 pm, 2.1 x 30 mm at 40°C

[0607] Gradient: 5% to 100% B in 2,0 minutes; hold 100% B for 0.7 minute

[0608] Flow: 1.1 mL / min

[0609] Run Time: 1.9 minutesLC-MS Method K:

[0610] Instrumentation

[0611] LC: Waters Acquity UPLC

[0612] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0613] MS Detection: Waters SQD, ESI (ES+ / ES-, 120-1200 amu)

[0614] Mobile Phase

[0615] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0616] Eluent B I: ACN

[0617] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0618] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minute

[0619] Flow: 0.9 mL / min

[0620] Run Time: 7 minutesLC-MS Method L:

[0621] Instrumentation

[0622] LC: Waters Acquity UPLC

[0623] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / secATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0624] MS Detection: Waters SQD, ESI (ES+ / ES-, 120-1200 amu)

[0625] Mobile Phase

[0626] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10

[0627] Eluent Bl: ACN

[0628] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0629] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minute

[0630] Flow: 0.9 mL / min

[0631] Run Time: 7 minutesLC-MS Method M:

[0632] Instrumentation

[0633] EC: Waters Acquity H-Class

[0634] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0635] MS Detection: Waters ZQ 2000, ESI (ES+, 120-1900 amu)

[0636] Mobile Phase

[0637] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0638] Eluent Bl: ACN

[0639] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0640] Gradient: 5% to 100% B in 1.4 minutes; hold 100% B for 0.4 minute

[0641] Flow: 1.1 mL / min

[0642] Run Time: 1.8 minutesLC-MS Method N:

[0643] Instrumentation

[0644] EC: Waters Acquity H-Class

[0645] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0646] MS Detection: Waters ZQ 2000, ESI (ES+, 120-1900 amu)

[0647] Mobile Phase

[0648] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10

[0649] Eluent Bl: ACN

[0650] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0651] Gradient: 5% to 100% B in 1.4 minutes; hold 100% B for 0.5 minuteATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0652] Flow: 1.1 mL / min

[0653] Run Time: 1.9 minutesLC-MS Method O:

[0654] Instrumentation

[0655] LC: Waters Acquity H-Class

[0656] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0657] MS Detection: Waters ZQ 2000, ESI (ES+, 120-1900 amu)

[0658] Mobile Phase

[0659] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0660] Eluent Bl: ACN

[0661] Column: Waters Acquity UPLC CSH Cl 8, 1,7 pm, 2.1 x 30 mm at 40°C

[0662] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1,8 minute

[0663] Flow: 0.9 mL / min

[0664] Run Time: 7 minutesLC-MS Method P:

[0665] Instrumentation

[0666] EC: Waters Acquity H-Class

[0667] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0668] MS Detection: Waters ZQ 2000, ESI ( ES+, 120-1900 amu)

[0669] Mobile Phase

[0670] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10

[0671] Eluent Bl: ACN

[0672] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0673] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minute

[0674] Flow: 0.9 mL / min

[0675] Run Time: 7 minutesLC-MS Method Q:

[0676] Instrumentation

[0677] LC: Waters Acquity UPLC

[0678] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / secATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0679] MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu)

[0680] Mobile Phase

[0681] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0682] Eluent Bl: ACN

[0683] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0684] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0685] Flow: 1.1 mL / min

[0686] Run Time: 1.9 minutesLC-MS Method R:

[0687] Instrumentation

[0688] LC: Waters Acquity UPLC

[0689] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0690] MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu)

[0691] Mobile Phase

[0692] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10.0

[0693] Eluent Bl: ACN

[0694] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0695] Gradient: 5% to 100% B in 2.0 minutes; hold 100% B for 0.7 minute

[0696] Flow: 1.1 mL / min

[0697] Run Time: 1.9 minutesLC-MS Method S:

[0698] Instrumentation

[0699] EC: Waters Acquity UPLC

[0700] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0701] MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu)

[0702] Mobile Phase

[0703] Eluent A1: Milli-Q H2O + 10 mM AmF pH: 3.8

[0704] Eluent Bl: ACN

[0705] Column: Waters Acquity UPLC CSH Cl 8, 1.7 pm, 2.1 x 30 mm at 40°C

[0706] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1.8 minuteATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0707] Flow: 0.9 mL / min

[0708] Run Time: 7 minutesLC-MS Method T:

[0709] Instrumentation

[0710] LC: Waters Acquity UPLC

[0711] UV Detection: Waters Acquity PDA (198-360nm), 20 pts / sec

[0712] MS Detection: Waters Acquity QDa Performance, ESI (ES+ / ES-, 120-1200 amu)

[0713] Mobile Phase

[0714] Eluent Al: Milli-Q H2O + 10 mM AmB pH: 10.0

[0715] Eluent Bl: ACN

[0716] Column: Waters Acquity UPLC CSH Cl 8, 1,7 pm, 2.1 x 30 mm at 40°C

[0717] Gradient: 5% to 100% B in 5.2 minutes; hold 100% B for 1,8 minute

[0718] Flow: 0.9 mL / min

[0719] Run Time: 7 minutes

[0720] Abbreviations:AmB ammonium bicarbonateAmF ammonium formateanh. anhydrousaq. aqueousbpy bipyridinedba di benzy li deneacetoneDCM dichloromethanedppf 1, 1 '-bis(dicyclohexy lphosphino)ferroceneDIPEA A^V-diisopropylethylamineDMA A / A-dimethylacetamideDMAP 4- (d imethy lamino)pyridineDMB 2, 4-dimethoxy benzylDMF A^V-dimethylformamideDMSO dimethyl sulfoxidedppf 1, 1 '-bis(diphenylphosphino)ferroceneATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014EDC A-(3-dimethylaminopropyl)-7V'-ethylcarbodiimideequiv. equivalent(s)EtOAc ethyl acetateg gram(s)h hour(s)HFIP 1,1, 1,3,3,3 -hexafluoroisopropanolIPA isopropyl alcohol (2-propanol)K3PO4 potassium phosphate tribasicEC liquid chromatographyLiHMDS lithium bis(trimethylsilyl)amideMeCN acetonitrileMeOH methanolmg milligram(s)min minute(s)mL milliliter(s)mmol millimolesMsCl methanesulfonyl chlorideNaH sodium hydrideNaHMDS sodium bis(trimethylsilyl)amideNaOtBu sodium te / 7-butoxideNAU 1 -methylimidazolePcb(dba)3 tris(dibenzylideneacetone)dipal!adium(0)satd. or sat. saturatedT3P Propylphosphonic anhydridetBuDavePhos 2-di-tert-butylphosphino-2'-(AjV-dimetliylamino)biphenylTCFII A, A, A', A"-tetramethylchloroformamidimum hexafluorophosphate TMSC1 trimethylsilyl chlorideuL microliter(s)umol micromolesXantPhos 4, 5 -bi s(diphenylphosphino)-9,9-dimethylxantheneATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014XPhos (2-dicyclohexylphosphino-2’,4',6'-tri isopropylbiphenyl)Synthetic procedures

[0721] The compounds of the present disclosure can be prepared m a variety of ways known to one skilled in the art of organic synthesis. The compounds of the present disclosure can be synthesized using the methods as hereinafter described below, together with synthetic methods known m the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.

[0722] Additionally, preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as in Jerry March, Advanced Organic Chemistry, 4thedition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.

[0723] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol, isopropyl alcohol, acetonitrile combinations thereof and the like, reverse phase flash chromatography using various solvents such as acetonitrile, AmB buffer, preparative high pressure liquid chromatography, preparative reverse phase high pressure liquid chromatography.

[0724] The following schemes are presented with details as to the preparation of representative compounds that have been listed herein.

[0725] Synthesis of Intermediates

[0726] The following known intermediates were made according to reported procedures in WO2023027948A1, WO2024257023 Al, WO2022241174A1, US20130225552, WO2023227946, W02020086616, and WO2018071794 which are each incorporated by reference herein.Name Structure referenceATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20140 Ci4, 6-dichl oro-N-(methyl- WO2023027948A1 tTOpyridazine- 3 -carboxamid e H IJK.N Clo NH24-amino-6- (cyclopropanecarboxamido)- N oH 1 II II WO2023027948A1 N-(methy l-i / 3)pyi’idazine-3 - carboxamide H0 Br4-bromo-6- D, C^ JL(cyclopropanecarboxam ido)- N OH 1 || WO2023027948 Al N-(methyl-J3)pyridazine-3- AL JLcarboxamide H0 C!4-chloro-6- D, C. JJL JX.N o(cyclopropanecarboxamido)- H 1 1] |j WO2024257023 Al N -(methy l-t / 3)nicotinamideH O CiN-(4-chloro-5- propionylpyridin-2- WO2022241174A1 yljcyclopropanecarboxamideH \ / O^GH1 -(2-chloro-5-fluoropyridin- 3 -yl)cyclopropane- 1 - US20130225552A1 carboxylic acid2-chloro-5-fluoro-JV- 0methoxy-JV- N || WO2023227946 Al m ethy 1 ni coti naini de0 ClA'-(4- chi or o- 5 - ( propanoy 1- 3,3,3-c / 3)pyridm-2- W02020086616A1 yl)cy cl opropanecarboxamide H yQS,2S)'-2- 0fluorocyclopropane- 1 - WO2018071794 AlcarboxamideATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Synthesis of 4-amino-6-(cyclopropanecarboxamido)-7V-(methyI-< / 3)nicotinamide:

[0727] Step 1: Synthesis of 6~(cyclopropanecarboxamido)-4-((2,4-dimethoxybenzyl)amino)-N- (methyl-ds nicotinamide

[0728] 4-chloro-6-(cyclopropanecarboxaniido)-JV-(methyl-t / 3)nicotinamide (1.20 g, 4.67 mmol), potassium fluoride (815 mg, 14.0 mmol), 2,4-dimethoxybenzylamine (3.58 mL, 23.4 mmol) and DMSO (24.0 mL) were stirred at 120 °C overnight (18 h). The reaction was cooled to ambient temperature and ca. 30 mL of water was added. The resulting precipitate was filtered and suction-dried affording the title compound (2.05 g, 113 %) as a pale brown solid. LCMS method B (m / z): [M+H]+= 388.3, retention time = 1.01 min. Note: product contaminated with starting material 2,4-dimethoxybenzylamine resulting m higher than 100% yield. Carried forward without purification

[0729] Step 2: Synthesis of 4-amino-6-(cyclopropanecarboxamido)-N-(melhyl-d inicotinanhde

[0730] 6-(cyclopropanecarboxamido)-4-((2,4-dimethoxybenzyl)ammo)- / V-(methyl-t / 3)nicotinamide (2.00 g, 5.16 mmol) and TFA (18.0 mL, 235 mmol) were stirred at ambient temperature for 30 mins. The TFA was removed under a stream of compressed air leaving a thick pink suspension which was made basic with 20% NFLOH resulting in a yellow heterogenous mixture. 10% MeOH in DCM was added and the mixture stirred at room temperature for 15 min. The mixture was filtered and the precipitate was washed with water and suction-dried. The organic portion of the filtrate was separated and extracted with water. The combined aqueous portions were concentrated under a stream of compressed air. The residue was taken up in DMSO andATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014purified by reverse phase flash chromatography (Cl 8 silica with water / ACN: 5% - 50%), the fractions containing product were combined and concentrated under vacuum. The resulting white solid was combined with the precipitate and triturated in DCM, filtered and air dried affording the title compound (1.06 g, 87 %) as a white solid. LCMS method B (m / z): [M+H = 238.3, retention time = 0.47 min.Synthesis of (lA,2A)- / V-(4-amino-5-propionyIpyridin-2-yI)-2-fliiorocycIopropane-l- carboxamide:

[0731] Step 1: Synthesis of 4, 6-dichloro-A-methoxy-A-methylnicotinamide

[0732] To a solution of 4, 6-di chloronicotinic acid (3.38 g, 17.6 mmol) in DCM (40.0 mL) was added oxalyl chloride (4.00 mL, 46.3 mmol) followed by 2 drops of dimethylformamide (20.0 uL, 255 umol). The reaction was stirred at room temperature for 4 h. The reaction was concentrated and then redissolved in DCM (40.0 mL) to be added dropwise to a mixture of N, O- dimethylhydroxylamine hydrochloride (4.00 g, 40.1 mmol), THF (40.0 mL) and saturated aqueous NaHCOs (150 mL, 171 mmol). The mixture was stirred at room temperature for 60 min. The mixture was extracted with DCM (3x 100 mL). The combined organic was washed with sat. NaHCOs, sat. NH4Q, H2O and brine, dried over Na2SO4, filtered, concentrated under reduced pressure and to provide the title compound (3.85 g, 93 %) as an amber oil which was used without further purification. LCMS Method Q (m / z): [M+H]+= 234.9, retention time = 0.81 min.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0733] Step 2: Synthesis of 6-chloro-4-((2,4-dimethoxybenzyl)amino)-2V-metlioxy-AT-methylnicotinamide

[0734] 4,6-dichloro-A’-niethoxy-2V-methylnicotinaniide (4.93 g, 21.0 mmol), potassium fluoride (1.64 g, 27.9 mmol), 2,4-dimethoxybenzylamine (5.00 mb, 32.9 mmol) and DMSO (75.0 mL) were stirred at room temperature for 24 h. More 2,4-dimethoxybenzylamine (5.00 mL, 32.9 mmol) was added and the mixture was heated to 40 °C and stirred for 3.5 h and then at 60 °C for 6 h and back at 30 °C overnight (18 h). The mixture was diluted with water and extracted with DCM (3x 100 mL). The combined organic was washed with NH4CI sat. (3x 100 mL), half brine (lx 100 mL) and brine (100 mL). The organic was dried over Na2SO4, filtered, concentrated under reduced pressure and dried under high vacuum to provide the title compound (9.06 g, 100 %) as a viscous yellow oil which was used without purification. LCMS Method Q (m / z): [M+H]+= 366.2, retention time = 1.1 min,

[0735] Step 3: Synthesis of l-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3-yl)propan-1 -one

[0736] A stirring solution of 6-chloro-4-((2,4-dimethoxybenzyl)amino)-Ar-methoxy-Ar-methylnicotinamide (7.67 g, 21.0 mmol) in DCM (200 mL) was cooled at -78 °C in a dry ice / acetone bath for 30 min under nitrogen, A solution of 3M ethylmagnesium bromide (27.0 mL, 80,9 mmol) in Et O was added dropwise and the mixture was stirred at -78 °C for 2,5 h. More ethylmagnesium bromide, 3 M in ether (2,00 mL, 6.00 mmol) was added and the mixture was stirred at -78 °C for 2.5 h. The mixture was stored in the freezer (-20 °C) 18 h. The mixture was then cooled back at -78 °C, quenched with 50 mL sat. NH4CI added dropwise and then allowed to warm to room temperature. Water and DCM were added. The organic phase was separated, washed with NHiCl half sat. (3x), water, NaHCOs sat. and brine, dried over Na2S(>4, filtered and concentrated under reduced pressure and dried under high vacuum to provide the title compound (7.56 g, 108 %) as a yellow solid which was used without further purification. LCMS Method Q (m / z): [M+H]+:=== 335.0, retention time::::1.28 min.

[0737] Step 4: Synthesis of (lA,25)-A6(4-((2,4-dimethoxybenzyl)amino)-5-propionylpyridm- 2-yl)-2-fl uorocy cl opr opane- 1 -carboxamide

[0738] The title compound was prepared according to General Procedure FATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0739] To a degassed mixture of l-(6-chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3- yl)propan-l-one (5.85 g, 17.5 mmol), (1 S', 25)-2-fluorocy cl opropane-1 -carboxamide (1.80 g, 17.5 mmol) and K3PO4 (10.3 g, 47.5 mmol) in dioxane (200 mb) was added Pd2(dba)3 (803 mg, 859 umol) and dppf (1.07 g, 1.76 mmol). Nitrogen was immediately bubbled in the mixture for 25 min and the mixture was heated at 100 °C for 10 h. The mixture was cooled, diluted with EtOAc and filtered on Celite®. The Celite® cake was rinsed with 10% MeOH in EtOAc and the combined organic was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% MeOHDCM) to provide the title compound (5.44 g, 76 %) as a yellow solid. LCMS Method Q (m / z): [M+H]' = 402.2, retention time = 1.13 min,

[0740] Step 5: Synthesis of (l ',2S -7-(4-amino-5-propionylpyridin-2-yl)-2- fluorocyclopropane- 1 -carboxamide

[0741] To a stirring solution of (lS',2S')-JV-(4-((2,4-dimethoxybenzyl)amino)-5- propionylpyridin-2-yl)-2-fluorocyclopropane-l -carboxamide (5.44 g, 13.6 mmol) in DCM (100 mL) was added trifluoroacetic acid (5.00 mL, 65,3 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. More trifluoroacetic acid (5.00 mL, 65,3 mmol) was added and the mixture was stirred at room temperature for 4.5 h. The mixture was added to stirring ice / water (300 mL) and was stirred for 2 h. The pH was adjusted to 12 with NaOH (5N and IN). The mixture was filtered and the solid washed with water and DCM, The solid was dried under high vacuum for 2 days to provide the title compound (5.18 g, 152 %) as a off-white solid which was used without further purification. LCMS Method Q (m / z): [M+H]+:::252.0, retention time:::0.68 min.

[0742] The following compound was prepared in a similar manner using the corresponding 4,6- dichloropyridazine-3-carboxylic acidName Structure MW (g / mol) (m / z) [M+H]1(method) N-(5-amino-6-propionylpyridazin-3- O NH2234.3 235.0 y l)cy clopropanecarboxam ide (Q)ON> JxN N JL \H V>ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014General Procedure AX = Cl, Br

[0743] A mixture of an appropriately substituted heteroaryl aniline (1.1 equiv), 2-halo-heteroarene (1.0 equiv.), Pd2(dba)3, dppf or XantPhos (0.2 - 0.4 equiv.), K3PO4 or Cs2CO3 or K2CO3 (2.5-4.0 equiv.), and dioxane (0.1 - 0.2 M) in a pressure vessel was degassed with nitrogen gas for 5 mins. The vessel was sealed and placed on a heating block at 80 -125 °C for 1 - 24 h. The reaction was cooled to ambient temperature and filtered through ca. 10 g of silica gel topped with Celite® using EtOAc as eluent. The filtrate was adsorbed onto silica gel and purified over normal phase flash chromatography to afford the final product. Oftentimes the final compound required another purification by reverse phase flash chromatography on Cl 8 column to provide the product with acceptable purity..General Procedure B

[0744] A mixture of an appropriately substituted heteroaryl chloride (1.1 equiv.), 2- aminoheteroarene or pyrazine (1.0 equiv.), Pd2(dba)3 (0.1 - 0.2 equiv.), dppf or XantPhos (0.2 -0.4 equiv.), K3PO4 or Cs2CO3 (2.5-4, 0 equiv.), and dioxane (0.1 - 0,2 M) in a pressure vessel was degassed with nitrogen gas for 5 mins. The vessel was sealed and placed on a heating block at 80 - 125 °C for 1 - 24 h. The reaction was cooled to ambient temperature and filtered through ca. 10ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014g of silica gel topped with Celite® using EtOAc as eluent. The filtrate was adsorbed onto silica gel and purified over normal phase flash chromatography to afford the final product. Oftentimes the final compound required another purification by reverse phase flash chromatography on Cl 8 column to provide the product with acceptable purity.General Procedure C|0745] A mixture of an appropriately substituted 2-aminopyridine (1.0 equiv.), 4,6-dichloro-N-(methyl-d3)pyndazme-3-carboxamide (1.0 equiv.), and THE (0.1 - 0.3 M) were added to a flask and cooled in an ice bath. The vessel was purged with nitrogen and then 1 M LiHMDS solution in THF (2 - 4 equiv.) was added dropwise. The reaction was allowed to warm to ambient temperature and stirring continued for 1 - 24 h. The mixture was acidified to pH - 3, and the resulting precipitate was collected by suction filtration, washed with water, and dried under vacuum affording the product with adequate purity.General Procedure D

[0746] EDC (1.10 equiv.) was added to a stirring solution of carboxylic acid (1.00 equiv.), N-hydroxyphthalimide (1.05 equiv.), and DMAP (0.2 equiv.) in DCM at room temperature. Stirring continued overnight, diluted with DCM, and was washed with 1 MHC1 (xl), brine (xl), dried over anh. magnesium sulfate, filtered, and concentrated under reduced pressure to afford the desired product in adequate purity. In some cases, the product required further purification by reverse phase flash chromatography on Cl 8 column using a gradient of ACN in 10 mM AmF buffer.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0747] The following activated esters were synthesized in this fashion from their corresponding commercially available carboxylic acids:Name Structure III NMRl,3-dioxoisoindolin-2-yl 1-;H NMR (500 MHz, DMSO-tfc) 88.01 methoxy cyclopropane- 1 - - 7.94 (m, 4H), 3.45 (s, 3H), 1.55 - carboxylate: o 1.51 (m, 2H), 1.47 - 1.41 (m, 2H).5H NMR (400 MHz, CDCh) 57.90 - l,3-dioxoisoindolin-2-yl 1- < A° 1 7.85 (m, 2H), 7.80 - 7.75 (m, 2H), 1.59 methylcy clopropane- 1 - ^ 00- 1.55 (m, 2H), 1.48 (s, 3H), 0.99 - carboxyate: o0.95 (m, 2H).’H NMR (500 MHz, DMSO-de) 88.05 l,3-dioxoisoindolin-2-yl 1- o - 7.92 (m, 4H), 3.72 (q, J = 7.0 Hz, ethoxy cyclopropane- 1 - 2H), 1.57 - 1.50 (m, 2H), 1.48 - 1.41 carboxylate (m, 2H), 1.16 ( t, J --- 7.0 Hz, 3H). (m,2H).1H NMR (500 MHz, CDCh) 87.92 - l,3-dioxoisoindolin-2-yl 1- 7.84 (m, 2H), 7.81 - 7.73 (m, 2H), 3.69 (methoxymethyl)cyclopropan(s, 2H), 3.40 (s, 3H), 1.62 (q, J= 4.4 e-1 -carboxylateHz, 2H), 1.22 (q,.7= 4.5 Hz, 2H).!H NMR (500 MHz, CDCh) 87.93 - 7.87 (m, 2H), 7.83 - 7.77 (m, 2H), 6.52 l,3-dioxoisoindolin-2-yl 1- (t, J= 56.8 Hz, 1H), 1.72 - 1.67 (m, (difluoromethyl)cy clopropane'-c °vO 2H), 1.55 (dd, J= 8.1, 4.8 Hz, 2H). -1 -carboxylate F Z?0r H NMR (500 MHz, CDCh) 87.92 - l,3-dioxoisoindolin-2-yl 2,2- Vxi0° 7.89 (m, 1H), 7.82 - 7.79 (m, 1H), 2.42 difluoro-1- (ddd, J= 12.1, 8.1, 6.8 Hz, 1H), 1.67- methylcy clopropane- 1 - 1.65 (m, 2H), 1.60 (ddd, J= 10.7, 8.2, carboxylate o5.9 Hz, 1H).!H NMR (400 MHz, DMSO-sfc) 88.05 l,3-dioxoisoindolin-2-yl 1- / \<d O o- 7.93 (m, 4H), 2.48 - 2.40 (m, 1H), fluorospiro[2.3]hexane-l - 2.38 -2.23 (m, 2H), 2.18 - 2.03 (m, carboxylateO 3H), 1.90 - 1.72 (m, 2H).JH NMR (500 MHz, CDCh) 87.94 - l,3-dioxoisoindolin-2-yl 1- 7.88 (m, 2H), 7.85 - 7.78 (m, 2H), 1.70 fluorocyclopropane- 1 - - 1.64 (m, 4H).!9F NMR (471 MHz, carboxylateCDCh) 8 -200.33.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014General Procedure ER2R3 NiCI2(bpy), TMS-CI Zinc dust DMA, 0.2 M I 0 °C R 1 -18 h

[0748] A reaction vessel containing 6-chloro-4-((3-iodopyridin-2-yl)amino)-N-(methyl-d3)pyndazine-3-carboxamide or the corresponding 2-amino pyridazine (1 equiv.), N-hydroxyphthalimide ester (1.2 - 2 equiv.), NiC12(bpy) (15 mol%), and zinc dust (8 equiv.) was evacuated and backfilled with nitrogen gas (x3) before DMA (0.2 M) was added, followed by TMS-G (3 equiv.). The reaction vessel was quickly placed in an ice bath (0 °C) and stirred vigorously for 0.1 - 4 h. The reaction mixture was diluted with EtOAc and passed over a plug of silica gel or Celite® (eluting with EtOAc). The volatiles were removed under reduced pressure, and the crude material was purified by flash chromatography to afford the desired product.General Procedure FPd2(dba)3, ligand, base dioxane, 110 - 125 °C, 4 - 24 hR2R3R = Cl, Nalkyl,|

[0749] Chloropyridazine or chloropyridine (1.0 equiv.), an appropriate carboxamide (2 equiv.), Pd2(dba)3 (0.15 equiv,), -XantPhos or dppf (0,3 equiv,), Cs2CO3 or K3PO4 (2.5 equiv,), and dioxane (0.05 - 0.1 M) were added to a pressure vial. Nitrogen gas was bubbled through the mixture for 5 mins, the vial sealed and heated to 110 — 125 °C for 4 - 18 h with stirring on a heating block. The reaction was cooled to room temperature and fi ltered through ca, 10g of silica gel topped withATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Celite® using EtOAc or DCM as eluent. The filtrate was adsorbed onto silica gel and purified by flash chromatography to afford the final product. Oftentimes the final compound required another purification by reverse phase flash chromatography on Cl 8 column to provide the product with acceptable purity.

[0750] The following intermediates were prepared according to general procedure F from commercially available starting materials:.(m / z) MWName Structure [M+IIf (g / mol)(method) 4-chloro-6-(l- o Cl235.0 fluorocy clopropane- 1 - hr 7) °H 1 |l II F 234.3carboxami do)-Ar-(m ethy 1 - (Q) <73)ni cotinamide H v(15,25>.¥-(4-chloro-5- O Cl271.2 propionylpyridm-2-yl)-2- o270.7fluorocy clopropane- 1 - L, JI JL. F(H) carboxamide HGeneral Procedure GOR2MgBr DCM, -78 °C, 1 - 18 h X = Cl, Br X = Cl, Br R1= e.g., OAlk, Me R1- e.g., MeR2= e.g., Me, Et

[0751] A mixture of an appropriately substituted heteroaryl ketone or ester (1.0 equiv.) in DCM (0.1 - 0.2 M) was cooled at -78 °C in a dry ice / acetone bath for 30 min under nitrogen, A solution of alkyl (Me or Et) magnesium bromide in Et20 (1.2 - 3 equiv.) was added dropwise and the mixture was stirred at -78 °C for 1 - 6 h. A saturated solution of NH₄Cl was added and the mixture was allowed to warm to room temperature. Water and DCM were added. The organic phase was separated, washed with brine, dried over anh. Na2SO4, filtered and concentrated under reducedATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014pressure. Oftentimes the product required a purification by reverse or normal phase flash chromatography. (SiCh, 0 - 50 % EtOAc in Heptanes).General Procedure HDAST DCM, rt - 45 °C, 1 - 48 hX = Cl, BrR1, R2= e.g., Me, Et, -CH2OCH2-, -(CH2)n-

[0752] To a solution of an appropriately substituted heteroaryl ketone or carbinol (1.0 equiv.) in DCM or DCE (0.1 - 0.5 M) was added (diethylamino)sulfur trifluoride (1.5 - 10 equiv.). The solution was stirred at a temperature ranging from room temperature to 60 °C for 1 - 48 h. The mixture was added to a stirred solution of NaHCOs sat. at room temperature and stirred for 1 h. The mixture was extracted with DCM (2x). The combined organic was washed with aq. NaHCOs sat., brine, dried over anh. Na2SO4, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica gel and purified over normal phase flash chromatography to afford the final product.General Procedure ItBuLi Hept, Tol, -78 °C, 1 - 4 h Y= CH2. O

[0753] A dried vessel was charged with 2-chloro-3 -iodoheteroarene (1.0 equiv.) in a 1:1 mixture of dry heptane and toluene (0.1 - 0.2 M) and was cooled at -78 °C in a dry ice / acetone bath for 30 min under nitrogen. A solution of 1.7 M rert-butyllithium in pentane (2.5 equiv.) was added dropwise and the mixture was stirred at -78CC for 5 - 15 min. Cyclobutanone (or Oxetane-3-one)ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(3 - 5 equiv.) was added and the mixture was stirred at -78 °C for 1 - 4 h. NH4CI sat. was added dropwise at -78 °C and the mixture was allowed to warm to room temperature. The mixture was partitioned between EtOAc, water and brine. The aqueous phase was extracted with EtOAc (3x). The combined organic was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was used as-is in the next step.General Procedure J

[0754] Aminopyridazine or aminopyridine (1.0 equiv.), and a corresponding carboxylic acid (2 - 5 equiv.), were dissolved in DMF or MeCN (0.05 - 0.2 M). 1 -Methylimidazole (10 - 40 equiv.) and TCFH (5 - 20 equiv. ) were added and the reactions were allowed to stir at 23 - 50 °C for 2 - 24 h. The cooled solutions were diluted with EtOAc, and washed with saturated ammonium chloride and brine, dried over anh. Na₂SO₄ and filtered. The filtrate was adsorbed onto silica gel and purified by flash chromatography to afford the final product. Oftentimes the final compound required another purification by reverse phase flash chromatography on Cl 8 column to provide the product with acceptable purity.General Procedure K

[0755] Aminopyridazine or aminopyridine ( (1.0 equiv.),), and a corresponding carboxylic acid (2 - 5 equiv.), were dissolved in DMF (0.05 - 0.2M). DI PEA (5 - 10 equiv.) and 50 % T3P solution in DMF (5 - 10 equiv.) were added and the reactions were allowed to stir at 23 - 50 °C for 2 - 24 h. The cooled solutions were diluted with EtOAc, washed with saturate ammonium chloride and brine, dried over anh. Na2SO4 and filtered. The filtrate was adsorbed onto silica gel and purifiedATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014by flash chromatography to afford the final product. Oftentimes the final compound required another purification by reverse phase flash chromatography on Cl 8 column to provide the product with acceptable purity.Example 1A: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(l- (trifliioromethyl)cyclopropyI)pyridin-2-yl)amino)pyridazine-3-carboxamide (Compounddioxane, water, 90 °C, 24 hStep 1 Step 2Pd2(dba)3dppf, K3PO4dioxane, 125 °C, 24 hStep 3

[0756] Step 1: Synthesis of 2-chloro-3-(3, 3, 3-trifluoroprop-l-en-2-yl)pyridine

[0757] 2 -chloro-3 -iodopyridine (1.50 g, 6.26 mmol), 1 -(trifluoromethyl)vinylboronic acid hexylene glycol ester (1.71 mL, 8,14 mmol), Pd(dppf)C12 (327 mg, 439 umol), K2CO3 (2.60 g, 18.8 mmol), dioxane (16.0 mL), and water (4.00 mL) were stirred in a sealed tube at 75 °C for 24 h. The reaction was cooled to ambient temperature and filtered through a plug of ca. 10 g silica gel topped with Celite® using DCM as eluent. The filtrate was adsorbed onto silica gel and purified by normal phase flash chromatography using DCM m hexanes (40% - 100%) as eluent.Fractions containing product were combined and the solvent removed under reduced pressure, affording the title compound (1.05 g, 81%) as a pale brown oil. LCMS Method B (m / z): no ionization, retention time:::1.14 mm.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0758] Step 2: Synthesis of 2-chloro-3-(l-(trifluoromethyl)cyclopropyl)pyridine

[0759] 2-Chloro-3 -(3, 3,3 -trifluoroprop- 1 -en-2-yl)pyridine (1.05 g, 5.06 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (3.00 g, 10.1 m mol) were suspended in dry THF (12.0 mL) and the flask was purged with nitrogen gas under so nication for 2 mins. The mixture was cooled in an ice bath with stirring under nitrogen atmosphe re, and NaHMDS (10.1 mL, 10.1 mmol) 1 M m THF was added dropwise. The reaction was allo wed to warm to ambient temperature, stirring continued for another hour, and then quenched wit h sat. aq. NH4CI. The mixture was extracted with EtOAc, the combined organics were washed w ith brine, dried over anh. Na2SO4 filtered and adsorbed onto silica gel. Purified over normal phas e flash chromatography using DCM in heptanes (5% - 100%) as eluent. The fractions containing product were combined and the solvent removed under reduced pressure affording the title comp ound (550 mg, 49%) as a pale brown oil. LCMS Method B (m / z): no ionization, retention time = 1.17 min.

[0760] Step 3: Synthesis of 6-(cyclopropanecarboxaniido)-N-(niethyl-c / 3)-4-((3-(l- (trifluoroniethyI)cyclopropyI)pyridm-2-yl)ammo)pyridazine-3-carboxamide:

[0761] The title compound was prepared according to General Procedure A using 4-amino-6-(cyclopropanecarboxamido)-N-(methyl-r / 3)pyridazine-3-carboxamide (461 mg, 1.94 mmol) and 2-chloro-3-(l -(trifluoromethyl)cyclopropyl)pyridine (390 mg, 1.76 mmol). The product was purified by normal phase flash chromatography (dry load) using IPA in DCM (0.1% - 10%) as eluent. Fractions containing product were combined and the solvent removed under reduced pressure. The reside was further purified by reverse phase flash chromatography on Cl 8 column using MeCN in 10 mM AmB buffer (5% - 30%) as eluent. Concentration of the pure fractions afforded the title compound (180 mg, 31%). LCMS Method G (m / z): [M+H]+-:::424.3, retention time:::2.44 min.1H NMR (400 MHz, DMSO-ds) 5 12.10 (s, 1 FI), 11.29 (s, 1H), 9.74 (s, 1H), 9.18 (s, III), 8.35 (dd, === 4.8, 1.8 Hz, 1H), 7.87 (dd, • / 7.6, 1.8 Hz, 1H), 7.10 (dd,. / 7.5, 4.9 Hz, 1H), 2.14 - 2.07 (m, 1H), 1.70 -• 1.51 (m, 2H), 1.31 -- 1.17 (m, 2H), 0.92 - 0.79 (m, 4H).Examples 1B-1C:

[0762] The following compounds were prepared m a similar manner to Compound 1 described in Example 1 A.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Table 2:(m / z)Ex. Compd MWStructure [M+H]+H 1 NMRNo. No. (g / mol)(method)FsCZ<Nf,^S'NrH NMR (500 MHz, DMSO-t / s)8 12.59 (s, 1H), 11.47 (s, 1H), 425.22 O HN JU6 N 9.94 (s, 1H), 9.32 (s, 1H), 8.86 IB 424.4D3C(s, 1H), 8.65 (s, 1H), 2.20 -2.08 I^SAI ° (G)(m, 1H), 1.62 (s, 2H), 1.34 (s, 2H), 0.96- 0.81 (m, 4H). H X / ’ H NMR (500 MHz, DMSO-Js) 8 12.42 (s, 1H), 11.40 (s, 1H), 9.72 (s, 1H), 9.26 (s, 1H), 8.42 425.222 O H& T N (d, J= 2.5 Hz, 1H), 8.30 (d, J = 1C 424.4DSC2.5 Hz, 1H), 2.19-2.08 (m, " H^VS ° (G)1H), 1.68 - 1.59 (m, 2H), 1.42 - 1.33 (m, 2H), 0.94- 0.80 (m, H Y4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 2: 6-(cyclopropanecarboxamido)-N-(methyI-d3)-4-((3-(l-(trifluoromethyl)cyclopropyI)pyridin-2-yl)amino)nicotinamide (Compound 2):NHMDS, THF, 0 °C, 10 min Step 2B2(OH)4, 4,4'-bipyrldine DMF, RT, 20 min Step 3

[0763] Step 1: Synthesis of 2-nitro-3-(3, 3, 3 -trifluoroprop- l-en-2-yl)pyri dine:

[0764] 3 -Bromo-2-nitropyridine (350 mg, 1.72 mmol), l-(trifluoroniethyl)vinylboronic acid hexylene glycol ester (470 uL, 2.24 mmol), Pd(dppf)C12 (90.1 mg, 121 umol), K2. CO3 (715 mg, 5.17 mmol), dioxane (4.40 mL), water (1.10 mL) were stirred in a sealed tube at 90 °C for 24 h. The reaction was cooled to ambient temperature and filtered through a plug of ca. 10 g silica gel topped with Celite® using EtOAc as eluent. The filtrate was adsorbed onto silica gel and purified over normal phase flash chromatography using DCM in hexanes (40% - 100%) as eluent. Fractions containing product were combined and the solvent removed under reduced pressure affording the title compound (295 mg, 78%) as a pale brown oil. LCMS Method F (m / z): no ionization, retention time = 1.06 min.

[0765] Step 2: Synthesis of 2-nitro-3-(l-(trifluoromethyl)cyclopropyl)pyridme:

[0766] 2 -Nitro-3-(3,3,3-trifluoroprop-l-en-2-yl)pyridine (290 mg, 1.33 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (790 mg, 2.66 mmol) were suspended in dry’ THF (3.15 mb) and flask was purged with nitrogen gas under sonication for 2 mins. The mixture was cooled in an ice bath with stirring under nitrogen atmosphere, NaHMDS (2.66 niL, 2.66 mmol) 1 M in THF was added dropwise, stirring continued for 10 mm, and then was quenched with satd.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014aq. NH4C1. The mixture was extracted with EtOAc, the combined organics were washed with brine, dried over anh. Na2SO4, filtered and concentrated under reduced pressure affording the title compound (305 mg, 99%) as an orange oil which was used as is in the next step. Assumed quantitative yield. LCMS Method F (m / z): no ionization, retention time = 1.12 min.

[0767] Step 3: Synthesis of 3-(l-(trifhioromethyl)cyclopropyl)pyridin-2-amine:

[0768] 2-Nitro-3-(l-(trifluoromethyl)cyclopropyl)pyridine (300 mg, 1.29 mmol) was stirred in DMF (5.95 niL) and tetrahy dr oxy diboron (466 mg, 5.17 mmol) was added at room temperature. The mixture was cooled in an ice bath and 4,4'-dipyridyl (204 uL, 258 umol) was added (exotherm, color changed to deep purple, and then back to light brown). The reaction was stirred at room temperature for 4 h, then volatiles were removed under reduced pressure. The residue was taken up in EtOAc and the product was extracted into 2 M HC1 (aq.). The organic layer was discarded, and the aqueous layer pH was adjusted to -~12 by adding KOH pellets under stirring. The product was extracted into EtOAc and the aqueous layer was discarded. The organic portion was washed with brine, dried over anh, Na2SO4, filtered, and concentrated under reduced pressure affording the title compound (205 mg, 78%) as a brown wax which was used in the next step without further purification. LCMS Method E (m / z): [M+H]+ = 203.2, retention time = 0.54 min.

[0769] Step 4: Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(l- (trifluorom ethyl )cyclopropyl)pyri din-2-yl)am ino)n icotinamide:

[0770] The title compound was prepared according to General Procedure B using 4-chloro-6-(cyclopropanecarboxamido)-N-(methyl-d3)nicotinamide (120 mg, 467 umol) and 3-(l-(trifluoromethyl)cyclopropyI)pyridm-2-amme (85,9 mg, 425 umol). The product was purified by normal phase flash chromatography (dry load) using IPA in DCM (0.1% - 10%) as an eluent. Fractions containing product were combined and the solvent removed under reduced pressure. The residue was further purified over reverse phase flash chromatography on Cl 8 column, using MeCN in 10 mM AmB buffer (5% - 30%). Concentration of the pure fractions afforded the title compound (19.5 mg, 9.9% yield). LCMS Method G (m / z): [M+H]+:::423.3, retention time::::2.11 min. IH NMR (400 MHz, acetone-d6) S 11.68 (s, HI), 9.68 (d, J === 3.6 Hz, IH), 9.52 (s, IH), 8.51 (s, IH), 8.35 (dd, J === 4.8, 1.9 Hz, III), 7.85 (d, J ===:1.8 Hz, HI), 7.83 (d, J === 1.8 Hz, IH), 7.02 (dd, J== 7.5, 4.8 Hz, IH), 2.77 (s, 3H), 2,03 - 1.99 (m, IH), 1.73 - 1.66 (m, 2H), 1.26 - 1.22 (m, 2H),ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20140.95 - 0.91 (m, 2H), 0.85 - 0.80 (m, 2H). Note: Cyclopropyl amide peak is obscured by solvent signal. Peak @,2.77 ppm is the result of deuterium - proton exchange on the methyl amide.Example 3: N-(5-propionyl-4-((3-(l-(trifhioromethyl)cycIopropyl)pyridin-2-yl)amino)pyridin-2-yI)cyclopropanecarboxamide (Compound 3):Pd2(dba)3dppf, K3PO4dioxane, 120 °C, 18 h

[0771] The title compound was prepared according to General Procedure B using N-(4-chloro-5-propionylpyridin-2-yl)cyclopropanecarboxannde (45 mg, 178 umol) and 3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-amine (39.6 mg, 196 umol). The product was purified by normal phase flash chromatography (dry load) using IPA in DCM (0.1% - 10%) as an eluent. Fractions containing product were combined and the solvent removed under reduced pressure. The reside was further purified by reverse phase flash chromatography on Cl 8 column, using MeCN in 10 mM AmB buffer (5% - 30%) as eluent. Concentration of the pure fractions afforded the title compound (5.0 mg, 6.7%). LCMS Method C (m / z): [M+H]+ = 419.3, retention time = 2.81 mm.!H NMR (500 MHz, DMSO-d6) 5 11.90 (s, 1H), 10.80 (s, 1H), 9.41 (s, 1H), 8.86 (s, 1H), 8.31 (dd, J = 4.8, 1.8 Hz, 1H), 7.82 (dd, = 7.5, 1.8 Hz, 1H), 7.06 (dd, J = 7.5, 4.8 Hz, 1H), 3.07 (q,,7= 7.2 Hz, 2H), 2.04 - 1.93 (m, 1H), 1.62 - 1.49 (m, 2H), 1.23 - 1.13 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H), 0.83 - 0.69 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 4: 4-((5-cyano-3-(l-(trifluoromethyl)cycIopropyl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 4):NIS, DMF CuCN, pyridine, 40 °C, 2 h 120 °C, 18 h Step 1 Step 2Pd2(dba)3dppf, K3PO4dioxane, 125 °C, 24 hStep 3

[0772] Step 1: Synthesis of 5-iodo-3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-amine:

[0773] 3 -(1 -(trifluor omethyl)cy cl opr opyl)pyridin-2-amine (500 mg, 2.47 mmol) and DMF (8.00 mL) were stirred at room temperature and N-iodosuccinimide (869 mg, 3.71 mmol) was added. The reaction was heated to 40 °C for 2 h. The reaction was concentrated to near dryness under reduced pressure and the residue was taken up in EtOAc The organic portion was washed with satd. aq. NaHCO3 and brine, the organic portion was dried over anh. Na2SO4, filtered and adsorbed onto silica gel. Purified by normal phase flash chromatography using IPA in DCM (0% - 10%) as an eluent. Fractions containing product were combined and the solvent removed under reduced pressure affording the title compound (485 mg, 60%) as a brown solid. LCMS Method B (m / z): [M+H]+ = 329.1, retention time = 1.21 min.

[0774] Step 2: Synthesis of 6-amino-5-(l-(trifluoromethyl)cyclopropyl)nicotinonitrile:

[0775] 5-iodo-3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-amine (100 mg, 305 umol), copper(I) cyanide (41.4 mg, 457 umol), and pyridine (1.84 mL) were stirred in a sealed tube at 120 °C for 18 h on a heating block. The solvent was removed under reduced pressure and the residue was taken up in EtOAc, adsorbed onto silica gel, and purified over normal phase flash chromatography using IPA in DCM (0% - 10%). Fractions containing product were combined and the solvent removed under reduced pressure affording the title compound (40 mg, 58%) as a pale brown solid.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014LCMS Method B (m / z): [M-H]- = 226.1, retention time = 0.93 min. Step 3: Synthesis of 4-((5-cyano-3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl- 3)pyridazine-3-carboxamide:

[0776] The title compound was prepared according to General Procedure B using 4-bromo-6-(cyclopropanecarboxamido)-N-(methyl- 3)pyridazine-3-carboxamide (53.2 mg, 176 umol) and 6-amino-5-(l-(trifluoroniethyl)cyclopropyl)nicotinonitrile (40.0 mg, 176 umol). The product was purified by reverse phase flash chromatography on Cl 8 column using ACN in 10 mM AmB buffer (20% - 60%). Concentration of the pure fractions afforded the title compound (19.5 mg, 9.9%). LCMS Method G (m / z): [M+H]+ = 449.3, retention time = 2.51 min.1HNMR(500MHz, DMSO-<7* ) 5 12.17 (s, 1H), 11.00 (s, 1H), 9.37 (s, 1H), 8.85 (s, 1H), 8.35 (d, J= 1.7 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.18 (br s, 2H), 0.96 - 0.85 (m, 2H), 0.48 - 0.36 (m, 4H). Example 5: 6-(cyclopropanecarboxamido)-N-(methyI-d3)-4-((5-methyI-3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 5):TrimethylboroxineK2CO3, Pd(dppf)CI2dioxane, water90 °C, 24 hStep 1General Procedure BStep 2

[0777] Step 1: Synthesis of 5-methyl-3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-amine:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0778] 5-iodo-3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-amine (85.0 mg, 259 umol), trimethylboroxine (724 uL, 2.59 mmol), K2CO3 (107 mg, 777 umol), Pd(dppf)Ch (19.3 mg, 25.9 umol), dioxane (1.31 mb) and water (261 uL) were added to a vial fitted with a stir bar. The vial was sealed and heated to 90 °C for 24 h with stirring. The mixture was filtered through a plug of ca. 5 g silica gel with EtOAc as eluent, filtrate was adsorbed onto silica gel and purified over normal phase flash chromatography using IPA in DCM (0% - 10%) as a mobile phase.. Concentration of the pure fractions afforded the title compound (35.0 mg, 62%). LCMS Method A (m / z): [M+H]+ = 217.3, retention time = 0.67 min.

[0779] Step 2: Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl- 3)-4-((5-methyl-3-(l-(trifluoromethyl)cyclopropyl)pyridin-2-yl)amino)pyridazine-3-carboxamide:

[0780] The title compound was prepared according to General Procedure B using 4-bromo-6-(cyclopropanecarboxaniido)-N-(methyl-<73)pyridazine-3-carboxamide (48.9 mg, 162 umol) and 5-methyl-3-(l -(trifluoromethyl)cyclopropyl)pyridin-2-amine (35,0 mg, 162 umol). The product was purified by reverse phase flash chromatography on C 18 column using ACN in 10 mM AmB buffer (20% - 60%) as an eluent. Concentration of the pure fractions afforded the title compound (4,5 mg, 6,4%). LCMS Method G (m / z): [M+H]+ = 438.3, retention time = 2.11 mm.NMR (500 MHz, DMSO-t / .s) 8 11.98 (s, 1H), 11.27 (s, 1H), 9.65 (s, 1H), 9.16 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.73 (d, J= 1.9 Hz, 1H), 2.28 (s, 3H), 2.17 - 2.05 (m, 1H), 1.66 - 1.51 (m, 2H), 1.27 - 1.18 (m, 2H), 0.91 - 0.79 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 6: 4-((3-(1-cyanocyclopropyl)pyridin-2-yI)amino)-6-(cyclopropanecarboxamido)- N-(methyl-d3)pyridazine-3-carboxamide (Compound 6):

[0781] Step 1: Synthesis of l-(2-chlor opyridin-3-yl)cy cl opropane-1 -carbonitrile:

[0782] (2-Chloropyridin-3-yl)acetonitrile (1.00 g, 6.36 mmol) and DMF (15.0 mL) were cooled in an ice bath and 60% NaH in mineral oil (1.27 g, 31.8 mmol) was added with stirring. The reaction was stirred at room temperature for 15 mins then 1,2-dibromoethane (603 uL, 6.99 mmol) was added dropwise. The reaction was heated to 40 °C on a heating block for 18 h, then cooled to room temperature. The excess NaH was quenched with slow addition of MeOH until gas evolution ceased, then the mixture was concentrated to near-dryness under reduced pressure. The residue was taken up in EtOAc and washed with brine. The organic portion was dried over anh. Na₂SO₄, filtered and concentrated under vacuum. The residue was taken up in DMSO and p urified by reverse phase flash chromatography on Cl 8 column using ACN in 10 mM AmB buffe r (5% - 30%) as an eluent. Fractions containing product were combined, extracted with EtOAc, organics were washed with water and brine, dried over anh. Na2SO4 and vacuum filtered. The filtrate was concentrated under reduced pressure affording the title compound (810 mg, 71%) as a yellow solid.. LCMS Method B (m / z): no ionization, retention time:::0.76 mm.

[0783] Step 2: 4-((3-( 1 -cyanocyclopropyl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014The title compound was prepared according to General Procedure A 4-amino-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (88.0 mg, 370 umol) and 1-(2-chloropyndin-3-yl)cyclopropane-l-carbonitrile (60 mg, 336 umol). The product was purified over reverse phase flash chromatography on Cl 8 column using MeCN in 10 rnM AmB buffer (25% - 60%) as an eluent. Concentration of the pure fractions afforded the title compound (22.4 mg, 22%). LCMS Method G (m / z): [M+H]+ = 381.2, retention time = 1.84 min. 1H NMR (500 MHz, DMSO-d6) 5 12.36 (s, 1H), 11.36 (s, 1H), 9.77 (s, 1H), 9.28 (s, 1H), 8.35 (dd, J = 4.9, 1.7 Hz, 1H), 7.86 (dd, J = 7.6, 1.8 Hz, 1H), 7.09 (dd, J = 7.6, 4.9 Hz, 1H), 2.17 - 2.09 (m, 1H), 1.92 -1.84 (m, 2H), 1.56 - 1.49 (m, 2H), 0.92 - 0.82 (m, 4H).Example 7: 6-(cyclopropanecarboxamido)-4-((3-(l-methoxycyclopropyI)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 7):

[0784] Step 1: Synthesis of 6-chloro-4-((3-iodopyridin-2-yl)amino)-N-(methyl-d3)pyridazme- 3-carboxamide:

[0785] The synthesis was carried out according to General Procedure C using 2-amino-3-iodopyridine (447 mg, 1.99 mmol) affording the title compound (710 mg, 91%) as a beige solid. LCMS Method C (m / z): [M+H]+ = 393.1, retention time = 1.27 min.

[0786] Step 2: Synthesis of 6-chloro-4-((3-(l-methoxycyclopropyl)pyridin-2-yl)amino)-N-(methy 1- d3 )pyridazine- 3-carboxamide:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0787] The synthesis was carried out according to General Procedure E using 1,3-dioxoisoindolin-2-yl 1 -methoxy cy cl opr opane-1 -carboxylate (106 mg, 408 umol) and 6-chloro-4-((3-iodopyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (100 mg, 255 umol) affording the title compound (45 mg, 52%) as a pale yellow solid. LCMS Method A (m / z):[M+H]+ = 337.3 retention time = 1.25 min.

[0788] Step 3: Synthesis of 6-(cyclopropanecarboxamido)-4-((3-(l-methoxycyclopropyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide:

[0789] The synthesis was carried out according to General Procedure F using 6-chloro-4-((3-(l-methoxycyclopropyl)pyridiii-2-yl)amiiio)-N-(methyl-d3)pyridazine-3-carboxamide (54.4 mg, 161 umol). The product was purified over normal phase flash chromatography (dry load) using IPA in DCM (0.1% - 10%) as an eluent. Fractions containing product were combined and the solvent removed under reduced pressure. The residue was further purified over reverse phase flash chromatography on Cl 8 column using MeCN in 10 mM AmB buffer (5% - 30%), Concentration of the pure fractions afforded the title compound (6.4 mg, 10%). LCMS Method C (m / z): [M+H]+ = 386.3, retention time = 2.08 min. 1 H NMR (500 MHz, acetone-d6) 8 12,08 (s, 1H), 10,04 (s, 1H), 9.93 (s, 1H), 8.46 (s, 1H), 8.23 (dd, J = 4.9, 1.9 Hz, 1H), 7.64 (dd, J = 7.4, 1.9 Hz, 1H), 6.91 (dd, J = 7.4, 4.9 Hz, 1H), 3.00 (s, 3H), 2.66 (s, 3H), 2.05 - 1.98 (m, 1H), 1.26 - 1.21 (m, 2H), 0.90 - 0.82 (m, 4H), 0,81 - 0.74 (m, 2H). Note: Peak (a) 2,66 ppm is the result of deuterium - proton exchange on the methyl amide.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 8A: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(l-methylcycIopropyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 8):NICI2(bpy), TMSCI Zn (dust), DMA, 0 °C, 2 h Step 1Step 2

[0790] Step 1: Synthesis of 6-chloro-N-(methyl-t / 3)-4-((3-(l-methylcyclopropyl)pyridin-2-yI)amino)pyridazine-3-carboxamide:

[0791] The synthesis was carried out according to General Procedure E using 1,3-dioxoisoindolin-2-yl 1 -methyl cyclopropane- 1 -carboxylate and 6-chloro-4-((3-iodopyridin-2-yl)amino)-N-(methyl- 3)pyridazine-3-carboxamide (100 mg, 255 umol) affording the title compound (70.0 mg, 57%) as a solid,

[0792] Step 2: Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-<: / 3)-4-((3-(l-methylcy cl opr opyl)pyri di n-2-y l)amino)pyri dazi ne-3 -carboxamide:

[0793] The synthesis was earned out according to General Procedure F using 6-chloro-N-(methyl-< / 3)-4-((3-(l-methylcyclopropyl)pyridin-2-yl)amino)pyridazine-3-carboxamide (54.4 mg, 161 umol). The product was purified by normal phase flash chromatography using IP A in DCM (0.1% - 10%) as an eluent. Fractions containing product were combined and the solvent removed under reduced pressure. The reside was further purified over reverse phase flash chromatography on Cl 8 column using ACN in 10 mM AmB buffer (5% - 30%). Concentration of the pure fractions afforded the title compound (6.4 mg, 10%). LCMS Method C (m / z): [M+H]+===:370.4, retention time === 2.60 min.1HNMR (500 MHz, DMSO-d6) 811.98 (s, HI), 11.27 (s, lH), 9.80 (s, III), 9.17ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(s, 1H), 8.20 (dd, J= 4.9, 1.9 Hz, 1H), 7.69 (dd, J= 7.4, 1.9 Hz, 1H), 7.00 (dd, J= 7.4, 4.9 Hz, 1H), 2.17 - 2.08 (m, 1H), 1.34 (s, 3H), 0.98 - 0.92 (m, 2H), 0.91 - 0.80 (m, 4H), 0.82 - 0.75 (m, 2H).Examples 8B-8P:

[0794] The following compounds were prepared in a similar fashion to that described for Compound 7 in Example 7 and Compound 8 in Example 8 ATable 3:(m / z)Ex. Compel MWStructure [M+H]+*H NMRNo No. (g / mol)(method)!H NMR (500 MHz, DMSOA>) 6 11.91 (s, 1H), 11.27 (s, 1H), 9.72 (s, 1H), 9.07 (s, 1H), 8.28 (dd, J = 4.9, 1.8 Hz, 1H), 7.73 (dd, J= 7.4, 400.3O 1.8 Hz, 1H), 7.04 (dd, 7 = 7.4, 4.9 8B 15 399.5D3C^ Hz, 1H), 3.28 - 3.25 (m, 2H), 2.163'hr o (G)- 2.08 (m, III), 1.29 - 1.21 (m, 2H), 0.96 (t, J ------ 7.0 Hz, 3H), 0.93 - 0.89 (m, 2H), 0.89 - 0.81 (m, 4H).’H NMR (500 MHz, DMSO-Je) 8 12.31 (s, 1H), 11.32 (s, 1H), 9.82Fx ) (s, HI), 9.19 (s, III), 8.38 (d, J --- 374.04.0 Hz, 1H), 7.89 (d, J = 7.3 Hz, 8C 19 373.4D3C. JL XA III), 7.12 - 7.00 (m, 1H), 2.16 -3 0(L)H 1 II 2.08 (m, 1H), 1.62 - 1.51 (m, 2H), A xA 1.19 - 1.09 (m, 2H), 0.93 - 0.78 H y(m, 4H).’ H NMR (500 MHz, DMSO-t / s) 8 11.29 (s, 1H), 11.07 (s, 1H), 9.15 400.3 (s, 1H), 8.01 (s, 1H), 7.51 -7.45 O8D 29 399.5 (m, 3H), 7.27 (ddd, J= 7.8, 5.3, D, C^ JL3n ° (D) 3.5 Hz, 1H), 2.10 -2.03 (m, 1H), H 1 II1.71 - 1.67 (m, 2H), 1.47 - 1.43 *N NH (m, 2H), 0.84 - 0.76 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-201441 NMR (500 MHz, DMSO-t / 6) 8 12.00 (s, 1H), 11.29 (s, 1H), 9.73 (s, 1H), 9.16 (s, 1H), 8.32 (dd, J = F / 406.3 4.8, 1.8 Hz, 1H), 7.76 (dd, J= 7.5, 0 HN NE 32 405.4 1.9 Hz, 1H), 7.08 (dd, J= 7.5, 4.9DSC" H^S^S ° (D) Hz, 1H), 5.93 (t, J= 56.0 Hz, 1H),2.11 (tt, J = 7.4, 5.2 Hz, 1H), 1.42 ’’N N V?H - 1.36 (m, 2H), 1.09- 1.02 (m,2H), 0.88 - 0.83 (m, 4H).41 NMR (500 MHz, DMSO-tk) 8 12.27 (s, 1H), 11.29 (s, 1H), 10.13 (s, 1H), 9.17 (s, 1H), 7.75 (dd, J = D 388.4 7.5, 1.3 Hz, 1H), 6.93 (d, J = 7.6 F 353C. JL 387.4(L) Hz, 1H), 2.51 -2.50 (m, 3H), 2.13 H I II (tt, J= 7.1, 5.5 Hz, 1H), 1.62- Jk JLN N Y”? 1.48 (tn, 2H), 1.14 - 1.06 (m, 2H), H0.90 - 0.83 (m, 4H).!H NMR (500 MHz, DMSO-Js) 8 12.37 (s, 1H), 10.77 (s, 1H), 9.80 (s, 1H), 9.27 (s, 1H), 8.39 (d, J = 0 KN^ YE 392.0 4.9 Hz, 1H), 7.91 (dt, J = 7.5, 1.8 G 38 391.4DSC'H^YSI ° (L) Hz, 1H), 7.11 (dd, J= 7.3, 5.1 Hz,1H), 1.63 - 1.53 (m, 2H), 1.53 - N> X JLN N 1.44 (m, 2H), 1.44 - 1.37 (m, 2H), H1.21 - 1.09 (m, 2H).’H NMR (500 MHz, DMSO-Je) 8 12.30 (s, 1H), 11.15 (s, 1H), 9.81 (s, 1H), 9.20 (s, 1H), 8.39 (dt, J = 4.9, 1.6 Hz, HI), 7.89 (dt, J= 7.5, O HN’'' j'T 402.1 1.9 Hz, HI), 7.09 (dd, J= 7.2, 5.2 H 39 401.5D3(E JI Jx. (L) Hz, 1H), 2.01 (dd, J 7.8, 5.5 Hz, N 78 01H), 1.57 (dt, J= 18.1, 6.9 Hz, 2H), 1.19- 1.12 (m, 8H), 1.05 (dd, J= 5.3, 4.1 Hz, 1H), 0.86 (dd, J = 7.8, 3.9 Hz, 1H).!H NMR (500 MHz, DMSO-Js) 8 = 12.17 (s, 1H), 11.29 (s, 1H), 9.74 (s, 1H), 9.16 (s, 1H), 8.23 (s, O HN' lT 388.31 40 387.4 1H), 7.74 (s, 1H), 2.28 (s, 3H), (D)3N 78 O 2.16-2.08 (m, 1H), 1.59 - 1.50 H! IIJk >k (m, 2H), 1.18 - 1.10 (m, 2H), 0.90 N N X”7H- 0.83 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014!H NMR (500 MHz, DMSO-t / 6) 8 12.31 (s, 1H), 10.08 (s, 1H), 9.74 o tan (s, 1H), 9.17 (s, 1H), 8.40 (d, 7 = / XZ 388.3 4.9 Hz, 1H), 7.93 - 7.86 (m, 1H), J 44 387.4yo= (L) 7.10 (dd, J= 7.2, 5.1 Hz, 1H), 1.63 / " Ti Z— - 1.50 (m, 2H), 1.47 (s, 3H), 1.23 \d iS \x_- 1.10 (m, 4H), 0.74 - 0.68 (m, *jr 2H).\Z= ’ H NMR (500 MHz, DMSO-t / s) 812.31 (s, 1H), 11.12 (s, 1H), 9.82 jZ _F (s, 1H), 9.19 (s, 1H), 8.41 (dt, J = F || 2.7, 1.6 Hz, 1H), 7.90 (dt, J= J A, D 0 HN'ZNr 400.1 1.7 Hz, 1H), 7.10 (dd, 7 = 7.2, 5.0 K 88 D^l II 1 399.4(L) Hz, 1H), 2.48 - 2.46 (m, 1H), 1.66 H I IIAN *> X< A - 1.49 (m, 2H), 1.45 (t, J = 3.8 Hz, N N A / H v 1H), 1.38 (dd, J--- 7.4, 3.4 Hz, HI), 1.18 - 1.12 (m, 2H), 0.95 - 0.83 (tn, 3H), 0.82 - 0.75 (m, HI).F!H NMR (500 MHz, DMSO-7e) 8 F \-711.93 (s, 1H), 11.30 (s, 1H), 9.69 (s, 1H), 9.22 (s, 1H), 8.30 (dd, J = JL. Jj 406.04.8, 1.7 Hz, 1H), 7.74 (d, J= 7.6 1, 54 0 HN N 405.4Hz, 1H), 7.08 (dd, 7= 7.5, 4.9 Hz, (L)1H), 2.15 -2.08 (m, 1H), 1.86 - %ANA0. 1.79 (tn, 2H), 1.53 (s, 3H), 0.90 - H \ / 0.84 (m, 4H).!H NMR (400 MHz, DMSO-7s) 8 11.93 (s, 1H), 11.32 (s, 1H), 9.50 (s, 1H), 9.16 (s, 1H), 8.45 - 8.28 (m, 1H), 7.83 (dt, 7= 7.5, 1.9 Hz,Fr il 414.01H), 7.20 - 7.03 (m, 1H), 2.85 - M 61 o HN'^N 413.52.73 (m, 1H), 2.26 -2.16 (m, 1H), (G)2.14-2.02 (m, 1H), 1.95 - 1.810N > x^X (tn, 1H), 1.79 - 1.63 (tn, 2H), 1.48 N N 3T“7H V - 1.32 (m, 2H), 1.24 (dd, 7= 19.6,7.8 Hz, 1 H), 0.91 - 0.72 (m, 4H).!H NMR (400 MHz, DMSO-76) 8 fr^ ^yX yCI F = 12.52 (s, 1H), 11.40 (s, 1H), ly xF458.3O HN N 9.78 (s, 1H), 9.25 (s, 1H), 8.47 (s, N 85 457.4D,<> 1H), 8.02 (s, 1H), 2.19 - 2.08 (m, N yX N-j 0 (G)1H), 1.66- 1.54 (m, 2H), 1.30- N N \ "7H A / 1.20 (m, 2H), 0.92 - 0.83 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014!H NMR (400 MHz, DMSO-t / 6) 8 11.99 (s, 1H), 10.80 (s, 1H), 9.41 457.3 (s, 1H), 8.67 (s, 1H), 8.60 (s, 1H), O HN N0 75 456.4 8.41 (s, 1H), 7.96 (s, 1H), 2.07- (C) 1.96 (m, 1H), 1.64 - 1.49 (m, 2H), nt M \ y 1.27- 1.14 (m, 2H), 0.87 - 0.75 H y (m, 4H).H NMR (400 MHz, DMSO-t / s) 8 12.35 (s, 1H), 11.32 (s, 1H), 9.71FX Y Y (s, 1H), 9.18 (s, 1H), 8.26 (s, 1H), O HN NP 72 439.4 440.3 7.79 (s, 1H), 7.26 (t, J = 73.7 Hz,D, C. JL Js.3 01H), 2.14-2.05 (m, 1H), 1.62- H 1 I]N N V7 1.48 (m, 2H), 1.23 - 1.14 (m, 2H), H V0.88 - 0.79 (m, 4H).Example 9A: methyl (6-((methyI-d3)carbamoyI)-5-((3-(l- (trifluoromethyl)cyclopropyI)pyridin-2-yl)amino)pyridazin-3-yl)carbamate (Compound 9):General Procedure FStep 2

[0795] Step 1: 6-chloro-N-(methyl-<73)-4-((3-(l -(trifluoromethyl)cyclopropyl)pyridin-2- yl)amino)pyridazine-3-carboxamide

[0796] The synthesis was carried out according to General Procedure C using 3-(l- (trifluoromethyl)cyclopropyl)pyridin-2-amine (450 mg, 2.3 mmol) and 4,6-dichloro-N-(methyl-ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014<73)pyridazine-3-carboxamide (558 mg, 2.78 mmol) to afford 6-chloro-N-(methyl- 3)-4-((3-(l- (trifluoromethyl)cyclopropyl)pyridin-2-yl)amino)pyridazine-3 -carboxamide (75 mg, 9%) as a white powder. LCMS Method F (m / z): [M+H]+ = 375.2, retention time = 1.41 min.

[0797] Step 2: Synthesis of methyl (6-((methyl-t / .?)carbamoyl)-5-((3-(l- (trifluoroniethyl)cyclopropyl)pyridin-2-yl)aniino)pyridazin-3-yl)carbamate

[0798] The synthesis was carried out according to General Procedure F using 6-chloro-N-(methyl- < / 3)-4-((3-(l-(trifluoromethyl)cy cl opropyl)pyndin-2-yl)amino)pyridazine-3 -carboxamide (32 mg, 104 umol) and methyl carbamate (32 mg, 104 umol) to afford the titled product (11.0 mg, 13 %). LCMS Method H (m / z): [M+H]+ = 414.2, retention time = 2.31 min.]H NMR (500 MHz, DMSO- de) 5 = 12.14 (s, 1H), 10.79 (s, 1H), 9.62 (s, 1H), 9.16 (s, 1H), 8.40 (dd, J =4.8, 1.8, 1H), 7.89 (dd, J =1.5, 1.8, 1H), 7.13 (dd, J =7.5, 4.8, 1H), 3.72 (s, 3H), 1.67 - 1.57 (m, 2H), 1.30 - 1.22 (m, 2H).Example 9B: 6-(3-isopropyI-2-oxoimidazoIidin-l-yI)-N-(methyI-d3)-4-((3-(l- (trifluoromethyl)cyclopropyI)pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 18):

[0799] The following compounds were prepared m a manner similar to that of Compound 9 described in Example 9 A using the corresponding amideZUTable 4: za(m / z)Compound wStructure [M+H]+Hl NMRNo. (g / mol)(method)1H NMR (500 MHz, DMSO-J6) 6 = 12.02 (s, 1H), 9.87 (s, 1H), 9.22 (s, 467.6 1H), 8.37 (dd, J=4.8, 1.8, 1H), 7.88 18466.5 (dd, J=7.5, 1.8, 1H), 7.11 (dd, J=7.5,(L) 4.8, 1H), 4.14 -4.08 (m, 3 H), 3.52 - 3.46 (m, 2H), 1.66 - 1.58 (m, 2H), 1.26- 1.24 (m, 211), 1.15 (d, 1 6.8. 6H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 10A: 6-(cyclopropanecarboxamido)-4-((3-(l-fIuoroethyI)pyridin-2-yI)amino)-N- (methyl-d3)pyridazine-3-carboxamide (Compound 10):

[0800] Step 1: Synthesis of l-(2-bromopyridin-3-yl)ethan-l-ol:

[0801] To a stirred solution of 3-acetyl-2-bromopyridine (335 mg, 1.64 mmol) in THF (8.00 mb) was added NaBH4 (110 mg, 2.79 mmol) at room temperature. Stirring continued for 90 minutes, and a sample was injected on LC (incomplete conversion). Additional quantity of NaBH4 (112 nig, 2.84 mmol) was added and stirring continued for another 20 h. Water (10 niL) was slowly added followed by satd. aq. NH4C1 (10 niL) and DCM (10 mb). The mixture was stirred for 1 h. The mixture was extracted with DCM (2 x 50 mb). The combined organics were washed with brine, dried over anh. Na2SO4, filtered and concentrated under reduced pressure to provide l-(2-bromopyridin-3-yl)ethan-l-ol (293 mg, 88%) as a yellow oil. LCMS Method K (m / z): 204.0, retention time = 1.01 mm. 1H NMR (400 MHz, DMSO-d6) 58.26 (d, J = 4.6 Hz, 1H), 7.98 - 7.90 (m, 1H), 7.47 (dd, J = 7.6, 4.6 Hz, 1H), 5.57 (d, J = 4.2 Hz, 1H), 4.92 - 4.83 (m, 1H), 1.32 (d, J = 6.4 Hz, 3H).

[0802] Step 2: Synthesis of 2-bromo-3-(l-fluoroethyl)pyndine:

[0803] The title compound was synthesized according to General Procedure H To a solution of l-(2-bromopyridin-3-yl)ethan-l-ol (290 mg, 1,44 mmol) in DCM (20,0 mL) was addedATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(Diethylamino)sulfur trifluoride (701 uL, 5.38 mmol). The solution was stirred at rt for 40 mm. The mixture was added dropwise to a stirred aq. NaHCOS sat. at 0 °C and stirred for 1 h. The mixture was extracted with DCM (2x 50 niL). The combined organic solution was washed with NaHCCh sat. (2x), NH4Q sat., brine, dried over anh. Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (179 mg, 61 %) as a brown oil. LCMS Method C (m / z): [M+H]+ = 206.1, retention time = 1.68 min. 1H NMR (400 MHz, DMSO-d6) 58.39 (d, J = 3.9 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.55 (dd, J = 7.7, 4.7 Hz, 1H), 5.85 (dq, J = 46.4, 6.3 Hz, 1H), 1.62 (dd, J= 24.3, 6.4 Hz, 3H).

[0804] Step 3: 6-(cyclopropanecarboxamido)-4-((3-(l-fluoroethyl)pyridin-2-yl)amino)-N-(methyl-d3)pyndazine-3-carboxamide:

[0805] The title compound was synthesized according to General Procedure A. To a degassed mixture of 2-bromo-3-(l-fluoroethyl)pyridine (222 mg, 999 umol), XantPhos (51.0 mg, 86.4 umol), 4-amino-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (98,0 mg, 411 umol) and K2CO3 (157 mg, 1.11 mmol) in dioxane (1.50 m ) was added Pd2(dba)3 (41.4 mg, 45.2 umol). Nitrogen was immediately bubbled to the mixture for 2 min and was stirred at 65 °C for 1 h, then at 75 °C for 16 h. The mixture was removed from the heating source, more Pd2(dba)3 (103 mg, 109 umol) and XantPhos (59.5 mg, 101 umol) were added and nitrogen was immediately bubbled to the mixture for 2 min. The mixture was heated again to 80°C for 8 h. The mixture was cooled, diluted with EtOAc and filtered on Celite®. The Celite® cake was rinsed with DCM and EtOAc and the combined organic was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% 1P / ADCM) to provide a solid. The residue was sonicated with ACN and concentrated to provide the title compound (36.9 mg, 23 %). LCMS Method C (m / z): [M+H]+::::362.4, retention time:::2.05 mm. 1H NMR (500 MHz, DMSO-d6) 5 11.94 (s, 1H), 11.32 (s, 1H), 9.56 (s, 1H), 9.24 (s, 1H), 8.36 (d, J === 4.8 Hz, 1H), 7.87 (d, J === 7.6 Hz, 1H), 7.15 (dd, J - 7.5, 5.0 Hz, 1H), 5.93 (dq, J === 46.8, 6.4 Hz, 1H), 2.15 - 2,08 (m, 1H), 1.71 (dd, J = 24.0, 6.4 Hz, 3H), 0.91 - 0.81 (m, 4H).Example lOB: Synthesis of l-(2-chIoro-4-fluoropyridin-3-yl)ethan-l-one (Compound 101)

[0806] Pyridyl ketones that were not commercially available were synthesized in a two step, on pot procedure as follows:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Bu3Sn-^Pd(PPh3)4OEtPhMe, 95 °C>2) cone HCI, RTStep 1, 2

[0807] Steps 1, 2: Synthesis of l-(2-chloro-4-fluoropyridin-3-yl)ethan-l-one:

[0808] 2-Chloro-4-fluoro-3-iodopyridine (1.10 g, 4.19 mmol) and Tributyl(l-ethoxyvinyl)tin (1.75 g, 4.61 mmol) were dissolved in toluene (22.0 mL) and Tetrakis(tnphenylphosphine)palladium(0) (370 mg, 314 urnol) was added. Nitrogen was bubbled through the mixture for 5 mins, the vial was sealed and heated to 80 °C for 36 h with stirring. Reaction incomplete so more Tetrakis(triphenylphosphine)palladium(0) (370 mg, 314 umol) was added and the heat increased to 95 °C and the mixture was left to stir additional 24 h at which point full conversion was observed by LCMS. The reaction was cooled to room temperature and cone HC1 (523 uL, 6.28 mmol) was added and the mixture stirred for 1 h. The reaction was poured over ca. 15 mL of saturated sodium bicarbonate, and the aqueous layer was extracted with EtOAc. The combined organic portions were washed with saturated sodium bicarbonate and brine, dried over anh. Na2SO4, filtered and adsorbed onto silica gel. Purified by normal phase flash chromatography (Dry Pack) (SiO2 with Heptanes / EtOAc: 0% - 100%), the fractions containing product were combined and the solvent removed in vacuo affording the title compound (475 mg, 65 %) a pale yellow oil. LCMS Method Q (m / z): [M+H]+ = 174.4, retention time = 0.76 min.

[0809] The following example was prepared in a manner similar to Compound 10 described in Example 10A from their corresponding acetylpyridines.(m / z)Cmpd MWStructure [M+H]+*HNMR No. (g / mol)(method)ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014-INMR (400 MHz, DMSO-t / e) 5 12.04 (ci., / 3.1 Hz, 1H), 11.36 (s, 1H), 9.53 (s, 1H), 9.24 (s, 1H),8.36 (dd, ■ / 8.1, 5.8 Hz, HI), 7.07 101 379.4(dd, ■ / 9.4, 5.6 Hz, HI), 6.13 (dq, J--- 45.5, 6.6 Hz, 1H), 2.16 -- 2.08 (m, 1H), 1.76 (dd, J ----- 23.1, 6.6 Hz, 3H), 0.95 - 0.77 (m, 4H).Example HA: 6-(cyclopropanecarboxamido)-4-((3-(l,l-difluoroethyI)pyridin-2-yI)amino)- N-(methyl-d3)pyridazine-3-carboxamide (Compound 11):General Procedure H General Procedure A Step 1Step 2

[0810] Step 1: Synthesis of 2-bromo-3-(l,l-difluoroethyl)pyridine:

[0811] The title compound was synthesized according to General Procedure H. To a solution of 3-acetyl-2-bromopyridine (1.03 mb, 7.76 mmol) in DCM (4.00 mb), was added (diethylamino)sulfur trifluoride (3.59 mb, 27.5 mmol). The solution was stirred at 50 °C for 24 h. The mixture was added drop wise to a stirring solution of ice-cold satd. aq. NaHCO3, stirring continued for an hour, and was extracted with DCM (50 mb). The organic layer was washed with satd. aq. NH4C1, followed by brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (1.43 g, 83%) as a yellow oil. LCMS Method K (m / z): [M+H]+ = no-iomzation, retention time = 1.97 mm. 1H NMR (400 MHz, DMSO-d6) 58.51 (d, J = 4.4 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.59 (dd, J = 7.7, 4.7 Hz, 1H), 2.09 (t, J = 19.1 Hz, 3H).

[0812] Step 2: Synthesis of 6-(cyclopropanecarboxamido)-4-((3-(l,l-difluoroethyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide:

[0813] The title compound was prepared according to General Procedure A. To a degassed mixture of 2-bromo-3-(l,l-difluoroethyl)pyridine (222 mg, 999 umol), XantPhos (51.0 mg, 86.4 umol), 4-amino-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (98.0 mg, 411 umol) and K2CO3 (157 mg, 1.11 mmol) in dioxane (1.50 mb), was added Pd2(dba)3ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(41.4 mg, 45.2 umol). Nitrogen was immediately bubbled through mixture for 2 min and was stirred at 65 °C for 1 h, then at 75 °C for 16 h. The mixture was removed from the heating source, more Pd2(dba)3 (103 mg, 109 umol) and XantPhos (59.5 mg, 101 umol) were added and nitrogen was immediately bubbled through mixture for 2 min. The mixture was heated again at 80 °C for 8 h. The mixture was cooled, diluted with EtOAc and filtered on Celite® and the Celite® cake was XO=rinsed with DCM and EtOAc and the combined organics were concentrated under reduced V / "yi.pressure. The residue was purified over normal phase flash chromatography using IPA in DCM (0-10%) as an eluent. Fractions contai zn y izing product were concentrated under reduced pressure to afford a solid, which was sonicated in ACN / water mixture and lyophilized to provide the title compound (36.9 mg, 23%) as an off-white solid. LCMS Method C (m / z): [M+H]+ = 380.3, retention time = 2.05 min. 1H NMR (500 MHz, DMSO-d6) 8 11.99 (s, 1 H), 11.34 (s, 1H), 9.52 (s, 1H), 9.20 (s, 1H), 8.49 - 8.43 (m, 1H), 7.97 (dd, J = 7.8, 1.7 Hz, 1H), 7.20 (dd, J = 7.7, 4.8 Hz, 1H), 2.15 - 2.08 (m, 1H), 2.07 (t, J = 19.2 Hz, 3H), 0.88 - 0.81 (m, 4H).Examples 11B-12H:

[0814] The following examples were prepared in a manner similar to Example 11 A from their corresponding commercially available 2-halo, 3-acetylheteroarenes.Table 5:(m / z)Ex. CompdStructure MW [M+H]+1H NMR No. No.(method)5H NMR (500 MHz, F F DMSO-D6) 8 11.99 (s, 1H), 11.35 (s, 1H), 9.33 398.30 (s, 1H), 9.21 (s, 1H), 8.50 IIB 12 D O 397.38M II 1 (D) (d, J= 2.9 Hz, 1H), 7.96D^H^V || ° (dd, J = 8.9, 2.9 Hz, 1H),N>. JL JL 2.14-2.03 (m, 4H), 0.87 H - 0.83 (m, 4H).JH NMR (500 MHz, DMSO-t / o) 8 = 11.29 (s, 1H), 10.86 (s, 1H), 9.11 375.3 (s, 1H), 7.91 (s, 1H), 7.66 11C 374.3916 (K) (dd, J=7.9, 1.2, 1H), 7.60-7.53 (m, 1H), 7.41 - 7.34 (m, 1H), 2.11 - 2.01(m, 1H), 1.92 (t, JH-FATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014=19.1, 3H), 0.91 - 0.74 (m, 4H).Hi NMR (500 MHz, F F DMSO-Jfi) 5 12.00 (s,1H), 11.31 (s, 1H), 9.88 (s, 1H), 9.18 (s, 1H), 7.82 O 394.3 (d, J = 7.9 Hz, 1H), 7.03 11D 393.428 D3C, (H) (d, J = 7.8 Hz, 1H), 2.50 N J' |1 0 (submerged s, 3H), 2.17 - N A Js, 2.11 (m, 1H), 2.05 (t, J = H Y719.1 Hz, 3H), 0.88 - 0.83 (m, 4H).JH NMR. (500 MHz, \DMSO-t / e) 8 11.85 (s, Z z zx 1H), 11.31 (s, 1H), 9.40 / / % / (s, 1H), 9.17 (s, 1H), 8.30 394.3HE 393.41 (d, J === 1.3 Hz, 1H), 7.8149 X\ iX * (H)(d, J === 1.7 Hz, 1H), 2.32 (s, 3H), 2.11 (m, 1H), 2.05 zz (t, J === 19.2 Hz, 3H), 0.84 uQ (m, 4H).F F ’H NMR (400 MHz,DMSO4) 8 11.46 (s, 1H), 10.76 (s, 1H), 8.85 o HN'^N (s, 1H), 8.64 (s, 1H), 8.57397.3HE 396.38 (s, 1H), 8.45 (d, J =2.877 D3C. JL Js. (D)Hz, 1H), 7.91 (dd, J= 8.8, H 1 11 »2.9 Hz, 1H), 2.12- 1.96 H V7 (m, 4H), 0.82 -0.74 (m,4H).5H NMR (400 MHz, F F DMSO-t / 6) 8 12.20 (s,1H), 11.00 (s, 1H), 9.31 (s, 1H), 8.98 (s, 1H), 8.55 0 HN'^N 376.1 (s, 1H), 8.32 (d, J = 2.0 11G 65 375.38(G) Hz, 1H), 3.15 (q, J= 7.1Xs^Xps|i0Hz, 2H), 2.13 (t, J= 19.7 *^N N **’ A^ Hz, 3H), 2.08 - 2.03 (ni, H vZ 1H), 1.11 (t, J = 7.1 Hz,3H), 0.86 -0.81 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014JH NMR (400 MHz, DMSO-Js) 8 12.35 (s, 1H), 11.44 (s, 1H), 9.56 405.1 (s, 1H), 9.29 (s, 1H), 8.14 (T) (d,.7= 7.8 Hz, 1H), 7.79(d, J = 7.8 Hz, 1H), 2.19 - 1.98 (m, 4H), 0.92 -0.79 (m, 4H).Example 12: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(oxetan-3-yl)pyridin-2- yl)amino)pyridazine-3-carboxamide (Compound 13):General procedure A Step 2

[0815] Step 1: Synthesis of 2-bromo-3-(oxetan-3-yl)pyridine:

[0816] To a degassed solution of (2-bromopyridin-3-yl)boronic acid (1.80 g, 8.85 mmol), nickel (II) iodide (174 mg, 557 umol) and tra -2-aminocyclohexanol hydrochloride (87.8 mg, 579 umol), in t-BuOH (6.21 niL), was added NaHMDS in THF (10.5 mL, 10.5 mmol) followed by 3- iodooxetane (0.500 mL, 5.57 mmol). Nitrogen was immediately bubbled through the mixture for 2 mm, and then heated at 70 °C for 6.5 h. The mixture was diluted with DCM, filtered through Celite®, washed with DCM, and the filtrate was concentrated under reduced pressure and the residue was triturated with 0.5 mL of dioxane to afford 2-bromo-3-(oxetan-3-yl)pyridine (40.0 mg, 3,4%), which was used as-is in the next step, LCMS Method C (m / z): [M+H]+ = no-ionization, retention time = 0.98 min.:H NMR (400 MHz, DMSO-De) 88.29 (d, J= 4.2 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.51 (dd, J= 7.2, 4.8 Hz, 1 H), 4.98 -4.91 (m, 2H), 4.69 (t,.7= 6.6 Hz, 2H), 4.50 - 4.38 (m, 1H).

[0817] Step 2: Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-<73)-4-((3-(oxetan-3- yl)pyridin-2-yl)amino)pyridazine-3-carboxannde:

[0818] Synthesized according to General Procedure A. To a degassed solution of 2-bromo-3- (oxetan-3-yl)pyridine (40.0 mg, 187 umol), 4-amino-6-(cyclopropanecarboxamido)-N-(methyl-ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014<73)pyridazine-3-carboxamide (44.5 mg, 187 umol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22.1 mg, 37.4 umol), and CS2CO3 (154 nig, 467 umol) in dioxane (934 uL), was added tris(dibenzylideneacetone)dipalladium(0) (17.1 mg, 18.7 umol). Nitrogen was immediately bubbled through the mixture for 2 min, and then heated at 100 °C for 1.25 h. The mixture was cooled, diluted with EtOAc, and filtered through Celite®, rinsed with a mixture of MeOH and EtOAc (25% MeOH, 4x 50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase flash chromatography using IPA in DCM (0 - 20%) as an eluent to provide 24 mg of a mixture of 39% purity. The residue was further purified over Prep-HPLC to provide 6-(cyclopropanecarboxamido)-N-(methyl-t / 3)-4-((3-(oxetan-3-yl)pyridin-2-yl)amino)pyridazine-3-carboxamide (2,50 mg, 8.1%). LCMS Method K (m / z):[M+H]+ = 372.2, retention time = 1.90 mm. 'H NMR (500 MHz, DMSO-D6) 8 11.63 (s, 1H), 11.30 (s, 1H), 9.64 (s, 1H), 9.29 (s, 1H), 8.26 (dd,.7= 4.9, 1.5 Hz, 1H), 7.90 (d,.7 = 7.7 Hz, 1H), 7.13 (dd, J= 7.5, 4.9 Hz, 1H), 5.06 (dd,.7= 8.2, 6.1 Hz, 2H), 4.75 -4.70 (m, 2H), 4.52-4.43 (m, 1H), 2.12 (ddd, = 12.4, 7.4, 5.1 Hz, 1H), 0.91 - 0.80 (m, 4H).Example 13: 6-(cyclopropanecarboxamido)-4-((3-(2-methoxypropan-2-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 30)MeMgCI NaH, Mel THF DMF Step 1 Step 2Step 3

[0819] Step 1: Synthesis of 2-(2-chloropyndin-3-yl)propan-2-ol

[0820] Synthesized according to general procedure G. To a solution of methyl -2-chloropyridine-3-carboxylate (2.28 mL, 17.5 mmol) in THF (69.9 mL) was added 3.0 M methylmagnesiumATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014chloride in THF (17.5 mb, 52.5 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was quenched with sat. aq. NH4CI then extracted with ethyl acetate. The combined organic layers were dried over anh. Na^SCU, filtered and concentrated under reduced pressure. The residue was dry-loaded onto silica and purified by normal phase chromatography (0-50% EtOAc / Heptanes) to afford 2-(2-chloropyridm-3-yl)propan-2-ol (2.71 g, 90 %) as a colorless oil. LCMS Method B (m / z): [M+H]4= 172.2, retention time = 0.87 min.

[0821] Step 2: Synthesis of 2-chloro-3-(2-methoxypropan-2-yl)pyridine

[0822] 2-(2-chloropyridin-3-yl)propan-2-ol (240 mg, 1.40 mmol) and DMF (2.80 mL) ’ere cooled in an ice bath and sodium hydride 60% in dispersion in mineral oil (83.9 mg, 2.10 mmol) was added and stirred for 15 minutes in an ice bath. To this mixture was added iodomethane (132 uL, 2.10 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. To this mixture was added sat. aq. NH4Q, extracted with DCM and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dry-loaded onto silica and purified by normal phase chromatography (0-20% EtO c / Heptanes) to afford 2-ch loro-3 -(2-methoxypropan-2-yl)pyridine (203 mg, 78 %) as a colorless oil. LCMS Method B (m / z): [M+H]4=186.2, retention time = 0.93 min.

[0823] Step 3: Synthesis of 6-(cyclopropanecarboxamido)-4-((3-(2-methoxypropan-2-yl)pyridin-2-yl)amino)-A7-(methyl-t / 3)pyridazine-3-carboxamide

[0824] The title compound was synthesized according to general procedure A

[0825] LCMS Method D (m / z): [M+H]4= 388.3, retention time = 2.14 min.1H NMR (500 MHz, DMSO-t / s) 8 = 11.59 (s, 1H), 11.23 (s, 1H), 9.30 (s, 1H), 8.96 (s, 1H), 8.24 (dd, J=4.8, 1.7, 1H), 7.73 (dd, J=7.8, 1.8, 1H), 7.09 (dd, J=7.7, 4.8, 1H), 3.11 (s, 3H), 2.13 -2.06 (m, 1H), 1.54 (s, 6H), 0.90-0.79 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 14: 6-(cyclopropanecarboxamido)-N-(methyI-d3)-4-((3-(perfluoroethyI)pyridin-2-yl)amino)nicotinamide (Compound 31)General Procedure A

[0826] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(perfluoroethyl)pyridin-2-yl)amino)ni cotinamide:

[0827] Prepared from commercially available pyridine according to General Procedure A

[0828] A flame-dried 2-5 mL microwave vial equipped with a Teflon®-coated stir bar and rubber septum was charged with 4-amino-6-(cyclopropanecarboxamido)-A-(methyl-<73)pyridazine-3-carboxamide (100 mg, 420 umol), followed by XantPhos (99.1 mg, 168 umol), K3PO4 (364 mg, 1.68 mmol), 2-chloro-3-(pentafluoroethyl)pyridine (256 mg, 1.05 mmol), and dioxane (1.40 mL). The heterogeneous reaction mixture was degassed by bubbling with nitrogen gas (balloon) for five minutes, and then Pd2(dba)3 (76.9 mg, 83.9 umol) was added. The vial was sealed with a crimp cap with PTFE septum in it, placed in a pre-heated oil bath (105 °C), stirring continued for 4 h, and a sample was injected on LCMS (complete conversion). The reaction mixture was diluted in DCM (100 mL), adsorbed on silica gel (~25 g) via concentration under reduced pressure, purified over normal phase flash chromatography (SiCh, 0-100% EtOAc in heptanes mobile phase) to afford the title compound (25.0 mg, 14 %). LCMS Method D (m / z): [M+H]+= 434.3, retention time = 2.44 min. 'H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 11.41 (s, 1H), 9.47 (s, 1H), 9.25 (s, 1H), 8.64 (d, J= 3.6 Hz, 1H), 8.15 (d, J= 6.7 Hz, 1H), 7.33 (dd, J= 7.8, 4.8 Hz, 1H), 2.16 -2.08 (m, 1H), 0.88 - 0.836 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 15: 4-((3-(1-cyanocyclobutyl)pyridin-2-yI)amino)-6-(cyclopropanecarboxamido)- N-(methyl-d3)pyridazine-3-carboxamide (Compound 14)

[0829] Step 1: l-(2-chloropyridin-3-yl)cyclobutane-1-carbonitrile:

[0830] (2-Chloropyridin-3-yl)acetonitrile (0.500 g, 3.18 mmol) and DMF (7.50 mL) were cooled in an ice bath and NaH (636 mg, 15.9 mmol) was added with stirring. The reaction was stirred at room temperature for 15 mins then 1,3 -Dibromopropane (358 uL, 3.50 mmol) was added dropwise. The reaction was stirred at room temperature for 2 h. The excess NaH was quenched with slow addition of methanol until gas evolution ceased then the mixture was concentrated to near-dryness in vacuo The residue was taken up in EtOAc and washed with brine. The organic portion was dried over anh. Na2SO4, filtered and adsorbed onto silica gel. Purified by normal phase flash chromatography (Dry Pack) (SiCh with Heptanes / EtOAc: 5% - 100%), the fractions containing product were combined and the solvent removed in vacuo affording the title compound (280 mg, 46%) as a pale brown oil. LCMS Method A (m / z): no ionization, retention time = 1.00 min.

[0831] Step 2: 4-((3 -( 1 -cyanocyclobuty l)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamideATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0832] The title compound was prepared according to General Procedure A using 4-amino-6-(cyclopropanecarboxamido)-V-(methyl- 3)pyridazine-3-carboxamide (88.4 mg, 371 umol) and 1-(2-chloropyndin-3-yl)cyclobutane-l -carbonitrile (65.0 mg, 337 umol). The product was purified over reverse phase flash chromatography on Cl 8 column using MeCN in 10 mM AmB buffer (25% - 60%) as an eluent to afford the title compound (10.0 nig, 9.5%). LCMS Method F (m / z):[M+H]+= 395.3, retention time = 1.84 min. 1H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 11.34 (s, 1H), 9.32 (s, 1H), 9.25 (s, 1H), 8.38 (dd, J= 4.8, 1.7 Hz, 1H), 7.85 (dd, J= 7.8, 1.7 Hz, 1H), 7.22 (dd, J= 7.7, 4.8 Hz, 1H), 3.05 - 2.97 (m, 2H), 2.74 - 2.65 (m, 2H), 2.40 - 2.29 (m, 1H), 2.14 - 2.08 (m, 1H), 1.98 - 1.90 (m, 1H), 0.87 -0.82 (m, 4H).Example 16A: 4-((3-(1-cyanocyclopropyl)-4-methylpyridin-2-yl)amino)-6- (cyclopropanecarboxamido)-N-(methyl-d3)nicotinamide (Compound 34)o NH2

[0833] Step 1: Synthesis of 2-chloro-3-(chloromethyl)-4-methylpyridme hydrochloride:

[0834] (2-Chloro-4-methylpyridin-3-yl)methanol (361 mg, 2.22 mmol) was stirred in neatthionyl chloride (9.77 mL, 133 mmol) at 40 °C for 20 mins. Full conversion observed - the thionyl chloride was removed under a stream of compressed air affording the title compound (320 mg, 68 %) as a white solid which was carried forward without purification. LCMS Method B (m / z): [M+H]+= 176.2, retention time = 1.05 min.

[0835] Step 2: Synthesis of 2-(2-chloro-4-methylpyri din-3 -yl)acetomtrile:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0836] 2-chloro-3-(chloromethyl)-4-methylpyridine hydrochloride (400 mg, 1.88 mmol), sodium cyanide (266 mg, 5.27 mmol), ethanol (8.00 mL) and water (4.00 mL) were stirred at 90 °C for 18 h. The reaction was cooled to ambient temperature and the ethanol was removed under vacuum. The aqueous layer was diluted with water extracted with EtOAc. The combined organics were washed with brine, dried over anh. Na2SC>4, filtered and concentrated under vacuum. The residue was taken up in DMSO and purified by reverse phase flash chromatography (Cl 8 silica with lOmM Ammonium Bicarbonate buffer / ACN: 5% - 30%), the fractions containing product were combined and lyophilized affording the title compound (90.0 mg, 29 %) as a colorless oil. LCMS Method B (m / z): [M+H]+= 165.0, retention time = 0.67 min.

[0837] Step 3: Synthesis of l-(2-chloro-4-methylpyridin-3-yl)cyclopropane-1-carbonitrile

[0838] 2-(2-chloro-4-methylpyridin-3-yl)acetonitrile (285 mg, 1.71 mmol) and DMF (4.04 mL) were cooled in an ice bath and NaH (342 mg, 8.55 mmol) was added with stirring. The reaction was stirred at room temperature for 15 mins then 1,2-dibromoethane (164 uL, 1.88 mmol) was added dropwise. The reaction was stirred for 1 h at room temperature and the excess NaH was quenched with slow addition of methanol until gas evolution ceased. The mixture was concentrated to near dryness in vacuo. The residue was taken up in EtOAc and washed with brine. The organic portion was dried over anh. Na2SO4, filtered and concentrated under vacuum. The residue was taken up in DMSO and purified by reverse phase flash chromatography (Cl 8 silica with lOmM Ammonium Bicarbonate buffer / MeCN: 5% - 30%), the fractions containing product were combined and extracted with EtOAc. The organic portion was separated and washed with water and brine and isolated affording the title compound (190 mg, 58 %) as a pale yellow semi-solid. LCMS Method B (m / z): [M + H]+= 193.0, retention time = 0.84 min.

[0839] Step 4: 4-((3 -( 1 -cyanocyclobuty l)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-A-(methyl-<73)pyridazine-3-carboxamide

[0840] The title compound was prepared according to General Procedure A using 4-amino-6-(cyclopropanecarboxamido)-A-(methyl- 3)pyridazine-3-carboxamide (117 mg, 493 umol) and 1-(2-chloropyridin-3-yl)cyclobutane-1-carbonitrile (95 mg, 493 umol). The product was purified over reverse phase flash chromatography on Cl 8 column using MeCN in 10 mM AmB buffer (25% - 60%) as an eluent to afford the title compound (10.0 mg, 9.5%). LCMS Method G (m / z):[M+H]+= 395.2, retention time = 2.03 min. 1H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 11.32ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(s, 1H), 9.75 (s, 1H), 9.26 (s, 1H), 8.22 (d, J= 5.0 Hz, 1H), 7.00 (d, J= 5.0 Hz, 1H), 2.49 (s, 3H), 2.19 -2.08 (m, 1H), 2.06 - 1.94 (m, 2H), 1.50- 1.39 (m, 2H), 0.94 - 0.80 (m, 4H).Examples 16B-16C:

[0841] The following compounds were prepared in a similar manner to Compound 34 described in example 16A.Table 6:(m / z)Cmpd MWEx. No. Structure [M+H]+1H NMRNo. (g / mol)(method)jZ F Tl NMR (500 MHz, DMSO-d6) δ NC12.59 (s, 1H), 11.47 (s, 1H), 9.94 399.3O (s, 1H), 9.32 (s, 1H), 8.86 (s, 1H), 16B 33 398.438.65 (s, 1H), 2.20-2.08 (m, 1H), T O (G)1.62 (s, 2H), 1.34 (s, 2H), 0.96 - 0.81 (m, 4H).1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 11.32 (s, 1H), 10.07 395.3 (s, 1H), 9.26 (s, 1H), 7.72 (d,.7 = 16C 27 394.5 7.7 Hz, 1H), 6.93 (d, J= 7.7 Hz,(G) 1H), 2.48 (s, 3H), 2.19 -2.08 (m,1H), 1.92 - 1.78 (m, 2H), 1.53 -1.41 (m, 2H), 0.92 - 0.81 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 17A: 6-(cyclopropanecarboxamido)-4-((3-(l-fluorocycIopropyl)pyridin-2-yl)amino)-7V-(methyl-d3)pyridazine-3-carboxamide (Compound 17)General Procedure A Step 3

[0842] Step 1: Synthesis of 2-(2-chloropyridin-3-yl)propan-2-ol|0843] The title compound was prepared according to General Procedure G. To a solution of methyl-2-chloropyridine-3-carboxylate (761 uL, 5.83 mmol) in THF (23.3 mL) was added 3.0 M methylmagnesium chloride in THF (5.83 mL, 17.5 mmol) at 0 °C. The solution was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aq. NHrCl and then extracted with DCM. The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. This residue was purified using flash chromatography (dry load silica, Biotage, 40 g, silica gel column, 0 to 100% EtOAc / Heptanes) (DP came out at 50% EtOAc). The appropriate fractions that contained product were concentrated under vacuum to obtain the title compound (514 mg, 51 %) as a brown liquid. LCMS Method B (m / z): [M+H]+= 172.2, retention time = 0.77 min.

[0844] Step 2: Synthesis of 2-chloro-3-(2-fluoropropan-2-yl)pyndine

[0845] The title compound was prepared according to General Procedure H To a solution of 2-(2-chloropyridin-3-yl)propan-2-ol (360 mg, 2.10 mmol) in DCM (4.20 mL) was added (Diethylamino)sulfur trifluoride (328 uL, 2.52 mmol) at -78 °C. The solution was stirred at room temperature for 30 min. The mixture was added dropwise to a stirred sat. aq. NaHCOs solution and stirred for 10 min. The mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. This residue was purifiedATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014using flash chromatography (dry load silica, Biotage, 40 g, silica gel column, 0 to 70% EtOAc / Heptanes). The appropriate fractions that contained product were concentrated to obtain the title compound (214 mg, 59 %) as a brown liquid. LCMS Method B (m / z): [M+H]+= 174.3, retention time = 1.15 min.

[0846] Step 3: Synthesis of 6-(cyclopropanecarboxamido)-4-((3-(l-fluorocyclopropyl)pyridin-2- yl)amino)-A’-(methyl-<73)pyridazine-3-carboxamide

[0847] The title compound was prepared according to General Procedure A. To a mixture of 4- amino-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (125 mg, 525 umol), 2-chloro-3-(2-fluoropropan-2-yl)pyridine (137 mg, 787 umol), Pd2(dba)3 (96.1 mg, 105 umol), XantPhos (124 mg, 210 umol) and K2CO3 (148 mg, 1.05 mmol) was added dioxane (1.91 mL). The reaction mixture was stirred at 100 °C for 5 h under N2 atmosphere. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase flash chromatography using MeOH in DCM (0 - 100%) as an eluent. The residue was further purified over Prep-HPLC to provide the title compound (10.0 mg, 5.1 %). LCMS Method H (m / z): [M+H]+= 376.3, retention time = 1.95 min. 1H NMR (500 MHz, DMSO-d6) δ = 11.68 (d, J=7.3, 1H), 11.28 (s, 1H), 9.36 (s, 1H), 9.12 (s, 1H), 8.33 - 8.29 (m, 1H), 7.85 - 7.81 (m, 1H), 7.16-7.12 (m, 1H), 2.14-2.08 (m, 1H), 1.79 (d, JH-F=22.1, 6H, ), 0.87-0.82 (m, 4H).Examples 17B-17J:

[0848] The following examples were prepared in a manner similar to Compound 17 disclosed in Example 17A from their corresponding substituted 2-haloheteroarenes and 4-aminoheteroarenes:Table 7:(m / z)Ex. Cmpd MWStructure [M+H]+’HNMR No. No. (g / mol)(method)ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014F ’H NMR (400 MHz, DMSO-Je) 8 = F ||11.67 (d, J=6.8, 1H), 11.31 (s, 1H), 394.49.17 (s, 1H), 9.14 (s, 1H), 8.35 (d, 17B 23 393.4J=2.7, 1H), 7.84 - 7.76 (m, 1H), \ J NX HO^o= 0O= l II (L)A 2.15 - 2.06 (m, 1H), 1.79 (d, / ( T1 n.... „..V\ / V f< xX \X^zy z X z ' z z"—J z— - J=22.2, 6H), 0.90 -• 0.80 (m, 4H). z / X. H \71H NMR (400 MHz, DMSO-d6) δ 11.90 (d,.7= 9.1 Hz, 1H), 10.95 (s, 1H), 9.15 (s, 1H), 8.95 (s, 1H), 8.38 372.1^17C 62 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = C 371.422.5, 0.9 Hz, 1H), 3.13 (q, J= 7.2 (S)Hz, 2H), 2.09 - 2.02 (m, 1H), 1.79 (d, J =22.1 Hz, 6H), 1.10 (t, J = 7.2 Hz, 3H), 0.82 (d, J = 6.2 Hz, 4H). 1H NMR (400 MHz, DMSO-d6) δ 11.60 (d, J = 8.0 Hz, 1H), 10.84 (s, 1H), 8.90 (s, 1H), 8.90 (s, 1H), 8.33 17D 89 371.6 (d, J= 4.6 Hz, 1H), 7.83 (d, J= 7.8 D 370.43 Hz, 1H), 7.16 (ddd, J= 7.7, 4.8, 1.3Q(0) Hz, 1H), 3.11 (q, J= 7.2 Hz, 2H), ^N>^N'Z>V, 2.08 - 1.98 (m, 1H), 1.77 (d, J = H \7 22.0 Hz, 6H), 1.09 (t, J= 7.2 Hz,3H), 0.88 -• 0.71 (m, 4H).’H NMR (400 MHz, DMSO-Je) 8 11.89 (d, J= 10.1 Hz, 1H), 10.94 (s, 1H), 9.15 (s, 1H), 8.94 (s, 1H), 90 386.6 8.37 (d, J = 2.4 Hz, 1H), 8.32- E 385.44 8.26 (m, 1H), 3.13 (q, J= 7.2 Hz,(0) 4H), 2.30 - 2.06 (m, 2H), 2.06 - 1.98 (m, 1H), 1.75 (d, J = 22.9 Hz, 3H), 0.98 (dt, J = 90.7, 7.3 Hz, 3H), 0.82 (d, J = 6.1 Hz, 4H).1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.36 (d, J = 9.9 Hz, 1H), 9.37 (s, 1H), 8.34 (d, J = 4.6 91 372.3 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), F 371.42 7.24 - 7.13 (m, 1H), 3.34 (q, J = (S) 7.3 Hz, 3H), 2.19 -2.09 (m, 1H),1.79 (d, J = 22.1 Hz, 6H), 1.12 (t, J = 7.3 Hz, 3H), 0.85 (d, J= 7.4 Hz,4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20141H NMR (400 MHz, DMSO-d6) δ 11.63 (d, J = 10.6 Hz, 1H), 11.58 (s, 1H), 9.54 (s, 1H), 8.41 (d, J= 92 373.32.4 Hz, IH), 8.31 (d,.7 = 1.6 Hz, G 372.4IH), 3.36 (q, 2H), 2.16-2.08 (m, (S)IH), 1.81 (d, 7= 22.4 Hz, 6H), 1.13 (t, J= 7.3 Hz, 3H), 0.93 - 0.85 (m, 4H).1H NMR (400 MHz, DMSO-d6) δ 11.63 (d, J = 11.8 Hz, 1H), 11.57 (s, 1H), 9.54 (s, IH), 8.40 (d, J = 2.4 Hz, IH), 8.33 (d, J= 1.4 Hz, 93FX ) 387.5IH), 3.38 - 3.34 (m, 2H)*, 2.32 - H O HN N 386.432.00 (m, 2H), 2.18 -2.07 (m, IH), o (G)1.76 (d, 7=23.1 Hz, 3H), 1.13 (t, J N> A*., JLN = 7.3 Hz, 3H), 0.90 - 0.85 (m, 7H).H* under water peak (expecting q, J ------ 7.3 Hz, 2H)\ / \ / / JH NMR (400 MHz, DMSO-7e) 811.91 (d, J = 9.1 Hz, IH), 10.99 (s, IH), 9.15 (s, IH), 8.96 (s, IH), 8.40 / u.Z“(d, J = 2.0 Hz, 1H), 8.28 (dd, J =2.5, 0.9 Hz, IH), 4.93 (dtd, J ------ 17I 94 390.266.1, 6.2, 3.8 Hz, 1H), 3.14 (q, J = 7.2 Hz, 2H)7.2 Hz, 2H), 2.24 (dtd, 7 = 8.9, (S)N 7.0,45.0 Hz, IH), 1.80 (dd, J = H 22.1, 2.7 Hz, 6H), 1.63 (dtd, J =23.4, 6.8, 3.8 Hz, IH), 1.17 (ddd, J = 12.4, 6.2, 2.8 Hz, IH), 1.10 (t, J = 7.2 Hz, 3H).1H NMR (400 MHz, DMSO-d6) δ 12.09 (d,.7= 8.3 Hz, IH), 11.39 (s, 95 0 HN'^N'^ 377.1 IH), 9.54 (s, IH), 9.18 (s, IH), 8.37 J D, C. JL x*s. 376.41 (d, 7= 2.3 Hz, IH), 8.26 (d,.7= 1.83n oH I / / (S) Hz, IH), 2.16 -2.06 (m, IH), 1.80 N «. JJ JIH N H (d, J = 22.0 Hz, 6H), 0.89 - 0.84V7(m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 18A: 6-(cyclopropanecarboxamido)-4-((5-fluoro-3-(l-fluorocycIopropyl)pyridin-2-yl)amino)-N-(methyI-d3)pyridazine-3-carboxamide (Compound 20)

[0849] Step 1: 6-chloro-4-((5-fluoro-3-iodopyridin-2-yl)amino)-Ar-(methyl-c / 3)pyridazine-3-carboxamide

[0850] The synthesis was carried out according to General Procedure C using 5-fluoro-3-iodo-pyridin-2-ylamine (I g, 403 uinol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (1.01 g, 484 umol) affording the title compound (1.49 g, 90%) as a tan powder. LCMS Method B (m / z): [M+H]+= 411.1, retention time = 1.35 min.

[0851] Step 2: 6-chloro-4-((5-fluoro-3-(l -fluorocyclopropyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0852] The synthesis was carried out according to General Procedure E using 6-chloro-4-((5-fluoro-3-iodopyridin-2-yl)amino)-A7-(methyl- 3)pyridazine-3-carboxamide (4.02 g, 9.79 mmol) and l,3-dioxoisoindolin-2-yl 1 -fluorocyclopropane- 1 -carboxylate (7.32 g, 29.4 mmol). The reaction mixture was flushed through a silica plug with EtOAc (200 mL), dried and redissolved in DCM, washed with IM NaOH (aq.) (200 mL) (discarding the aqueous layer), purified by flash column chromatography (0 - 10% iPrOH in DCM) and finally by recrystallization from hot iPrOH to afford the title compound (1.8 g, 35%) as an off-white solid. LCMS Method B (m / z): [M+H]4= 325.3, retention time = 1.33 mm.!H NMR (400 MHz, DMSO- s) 6 12.55 (s, 1H), 9.46 (s, 1H), 9.09 (s, 1H), 8.53 (s, 1H), 8.00 (d,.7= 7.8 Hz, 1H), 1.64 - 1.53 (m, 2H), 1.28 - 1.19 (m, 2H).

[0853] Step 3: tert-butyl (5-((5-fluoro-3-(l-fluorocyclopropyl)pyridm-2-yl)amino)-6-((methyl- c / 3)carbamoyl)pyridazin-3-yl)carbamate:

[0854] The synthesis was carried out according to General Procedure F using 6-chloro-4-((5- fluoro-3-(l-fluorocyclopropyl)pyridin-2-yl)amino)-Ar-(methyl-<73)pyridazine-3-carboxamide (686 mg, 2.00 mmol), tert-Butyl carbamate (598 mg, 5.00 mmol), Pd2(dba)3 (289 mg, 300 umol), dppf (364 mg, 600 umol), K3PO4 (1.73 g, 8,01 mmol) in dry dioxane (15.5 mL). After heating the reaction mixture at 110 °C for 3.5 h, LCMS indicated the reaction had completed. The reaction mixture was flushed through a silica plug with EtOAc (200 ml.) and evaporated to dryness under reduced pressure to give a brown residue, which was used in the next step without further purification. LCMS Method (m / z): [M+H]4:::424.1, retention time::::1.70 min.

[0855] Step 4: 6-amino-4-((5-fluoro-3-(l -fluorocyclopropyl)pyridin-2-yl)amino)-2V-(methyl-t / 3)pyridazine-3 -carboxami de:

[0856] To this brown residue obtained from the previous step was added HTTP (25.2 mL) followed by TFA (1.53 mL, 20.0 mmol), and the mixture was stirred for 16 h at 25 °C, after which LCMS indicated the second step had completed. The reaction mixture was evaporated to dryness under reduced pressure m a room temperature water bath. DCM was added and evaporated several times to remove residual TFA. The residue was partitioned between DCM (130 mL) and saturated NaFICCh solution (150 mL). The aqueous layer was extracted further with DCM (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (Normal phase: 0-5% MeOH in DCM, followed by Reversed phase: 20-50% MeCN in lOmM AmB) to yield the title compound (393 mg, 61 % overATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014two steps) as a white powder. LCMS Method J (m / z): [M+H]+= 324.1, retention time = 1.24 min. 'H NMR (400 MHz, DMSC >) 6 12.21 (s, 1H), 8.93 (s, 1H), 8.35 (dd, J= 2.5, 1.7 Hz, 1H), 8.09 (s, 1H), 7.90 (dt, J= 8.6, 2.2 Hz, 1H), 6.72 (s, 2H), 1.64 - 1.51 (m, 2H), 1.23 - 1.14 (m, 2H).

[0857] Step 5: Synthesis of 6-(cyclopropanecarboxamido)-4-((5-fluoro-3-(l- fluorocyclopropyl)pyridm-2-yl)amino)-A’-(methyl-<73)pyndazine-3-carboxamide:

[0858] The synthesis was carried out according to General Procedure J. In a first vial, to a mixture of Cyclopropanecarboxylic acid (31.1 uL, 371 umol), NMI (74.7 uL, 928 umol) and DMF (160 uL) was added TCFH (268 mg, 928 umol). The mixture was stirred at room temperature for 10 minutes.

[0859] In a second vial, 6-amino-4-((5-fluoro-3-(l-fluorocyclopropyl)pyridm-2-yi)ammo)vV- (methyl- 3)pyridazine-3-carboxamide (30.0 mg, 92.8 umol) was dissolved in DMF (140 uL) and NMI (187 uL, 2.32 mmol) was added. Then the activated acid mixture (first vial) was added to the second vial. The mixture was stirred at room temperature for 90 minutes, then heated to 40 °C for 90 minutes. Product was precipitated with addition of water and washed with 5x2 mL of 1:1 MeCN: HzO to give the title compound (22.0 mg, 61 %). LCMS Method L (m / z): [MEH] = 392.1, retention time = 2.58 min. 'H NMR (500 MHz, DMSO- e) 812.32 (s, 1H), 11.33 (s, 1H), 9.67 (s, 1H), 9.20 (s, 1H), 8.40 (dd, = 2.7, 1.5 Hz, 1H), 7.93 (ddd, J= 8.6, 2.6, 1.8 Hz, 1H), 2.17 -2.07 (m, 1H), 1.62- 1.51 (m, 2H), 1.26- 1.18 (m, 2H), 0.91 -0.82 (m, 4H).Example 18B: 4-((5-fluoro-3-(l-fluorocyclopropyl)pyridin-2-yl)amino)-6-((lS,2S)-2- fluorocyclopropane-l-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 21)

[0860] The following examples were prepared in a similar manner to Compound 20 described in Example 18 A, using the corresponding chloropyridazines or chloropyridines and commercially available carboxylic acidsTable 8: Synthesis of compound 21A(m / z)Cmpd General MWStructure [M+H|lH NMR No. Procedures (g / mol)+(method)ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014NMR (400 MHz, DMSO4) 8 12.34 (s, 1H), 11.39 (s, 1H), 9.66 (s, 1H), 9.22 (s, 1H), 8.42 (s, 1H), 410.31A 409.4 7.94 (d, J = 8.4 Hz, (L)1H), 4.96 (d, J = 66.2 Hz, 1H), 2.37-2.25 (m, 1H), 1.73 - 1.47 (m, 3H), 1.27 - 1.15(m, 3H).Example 19: 6-(l-fhiorocycIopropane-l-carboxamido)-4-((3-(l-fIiiorocyclopropyI)pyridin-2-yl)amino)-N-(methyl-d3)nicotinamide (Compound 84) - D3C.N H Pd2(dba)3, NaOtBu tBuDavePhos, dioxane D, C.NGeneral Procedure B HStep 2

[0861] Step 1: Synthesis of 3-(l-fluorocyclopropyl)pyridin-2-amine:

[0862] In a pressure tube, to a mixture of Pd2(dba)s (27.7 mg, 30.3 umol), tBuDavePhos (21.1 mg, 60.6 umol) and sodium tert-butoxide (36.0 mg, 364 umol) was added dioxane (2.55 mL). This reaction mixture was bubbled with nitrogen for 5 mm. To this mixture was then added 2-chloro-3-(l-fluorocyclopropyl)pyridine (100 mg, 303 umol) and Ammonia (3.79 mL, 1.52 mmol) 0.4 M solution in dioxane, the vial was sealed and stirred at 80 °C for 3 h. This residue was directly purified using flash chromatography (dry load silica, Biotage, 40 g, silica gel column, 0 to 10% DCM / MeOH). The appropriate fractions that were concentrated to obtain the title compound (35,0 mg, 39 %) as a pale brown oil. LCMS Method B (m / z): [M+H]+= 153.3,

[0863] Step 2: Synthesis of 6-(l -fluorocyclopropane- 1 -carboxamido)-4-((3-(l-fluorocyclopropyl)pyridin-2-yl)ammo)-A’-(methyl-<73)nicotmamide:

[0864] The title compound was prepared according to General Procedure B using [l,l'-Bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (22.5 mg, 29.1 umol) and cesium carbonate (119 mg, 364 umol). LCMS Method D (m / z): [M+H]+= 391.3, retention time = 1.97 mm. I NMRATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(500 MHz, DMSO-t / 6) 8 = 11.82 (s, 1H), 10.05 (s, 1H), 9.46 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 8.38 - 8.32 (m, 1H), 7.88 - 7.83 (m, 1H), 7.07 - 7.00 (m, 1H), 1.60 - 1.50 (m, 2H), 1.49 - 1.40(m, 2H), 1.39- 1.32 (m, 2H), 1.16- 1.08 (m, 2H).Example 20: (lS,2S)-2-fhioro-N-(4-((3-(l-fIuorocycIopropyl)pyridin-2-yI)amino)-5-propionylpyridin-2-yl)cydopropane-l-carboxamide (Compound 76A)

[0865] The title compound was prepared according to General Procedure B using [l,l'-Bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (22.9 mg, 29.6 umol), K3PO4 (128 mg, 591 umol), LCMS Method C (m / z): [M+H]+= 387.4, retention time = 2,24 min,!H NMR (500 MHz, DMSO-t / s) 512.18 (s, 1H), 10.94 (s, 1H), 9.56 (s, 1H), 8.95 (s, 1H), 8.48 - 8.35 (m, 1H), 7.89 (dt,.7 = 7.5, 2.0 Hz, 1H), 7.10 (dd,.7= 6.7, 5.0 Hz, 1H), 4.93 (dtd, J = 66.1, 6.2, 3.8 Hz, 1H), 3.15 (q,J= 7.2 Hz, 2H), 2.32 - 2.19 (m, 1H), 1.73 - 1.52 (m, 3H), 1.24 - 1.08 (m, 6H).Example 21A: 6-(cyclobutanecarboxamido)-4-((3-(l-fluorocycIopropyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 51)ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0866] Step 1: Synthesis of 6-((2,4-diniethoxybenzyl)amino)-4-((3-iodopyridm-2-yl)ammo)- '-(methyl- 3)pyridazine-3-carboxamide:

[0867] 6-Chloro-4-((3-iodopyridin-2-yl)amino)-A-(methyl-<73)pyridazine-3 -carboxamide (1.20 g, 3.06 mmol), 2,4-dimethoxybenzylamine (2.32 mL, 15.3 mmol), potassium fluoride (533 mg, 9.17 mmol) and DMSO (28.8 mL) were stirred at 120 °C for 6 h. The reaction was cooled to ambient temperature and poured over ca. 100 mL of water. The resulting precipitate was isolated by vacuum filtration and suction-dried affording the title compound (1.25 g, 78 %) as a white solid. LCMS Method B (m / z): [M+H]+= 524.2, retention time = 1.39 min.

[0868] Step 2: Synthesis of 6-amino-4-((3-iodopyridin-2-yl)amino)-2V-(methyl- 3)pyridazine-3-carboxamide:

[0869] 6-((2,4-diniethoxybenzyl)amino)-4-((3-iodopyridin-2-yl)amino)-A’-(methyl-<73)pyridazine-3-carboxamide (1.25 g, 2.39 mmol) and TFA (185 uL, 2.39 mmol) were stirred at room temperature for 45 mins and the TFA was removed under a stream of compressed air. The resulting red solid was stirred between EtOAc and NaHCOs (sat.) for 30 mins sonicating intermittently to break up the solid. The organic portion was washed with NaHCOs (sat.) and brine and the aqueous portion was back extracted with EtOAc. The combined organics were dried over anh, N 2SOr, filtered and adsorbed onto silica gel. Purified by normal phase flash chromatography (Dry Pack) (SiO2 with DCM / IPA in DCM): 0% - 10%), the fractions containing product were combined and the solvent removed in vacuo affording the title compound (620 mg, 70 %) a yellow solid. LCMS Method B (m / z): [M+H]+= 374.0, retention time = 0.75 min,

[0870] Step 3: Synthesis of 6-amino-4-((3-(l-fluorocyclopropyl)pyridin-2-yl)amino)-2V-(methyl-c / 3)pyndazine-3 -carboxamide:

[0871] The title compound was prepared according to General Procedure E

[0872] 6-((2,4-dimethoxybenzyl)amino)-4-((3-iodopyridin-2-yl)amino)- / V-(methyl-t / 3)pyridazine-3-carboxamide (800 mg, 2,14 mmol) and l,3-dioxoisoindolin-2-yl 1-fluorocyclopropane- 1 -carboxylate (1,60 g, 6,43 mmol) were dissolved in DMA (8,00 mL) and the solution was degassed with nitrogen for 10 mins while cooling in a brine / ice bath. In a separated flask fitted with a stir bar. Zinc (1.12 g, 17.2 mmol) and NiChbpy (124 mg, 429 nmol) were addedATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014and the flask was purged with nitrogen 10 mins while cooling in a brine / ice bath. The DMA solution was cannulated into the flask containing BIPY and zinc, and chlorotrimethylsilane (972 uL, 7.50 mmol) was added concurrently with vigorous stirring. The reaction was stirred for 30 mins then opened to air and filtered through ca. 25 g of silica gel topped with Celite® using EtOAc as eluent. The filtrate was concentrated to near-dryness under vacuum and loaded directly onto the flash column. Purified by reverse phase flash chromatography (Cl 8 silica with lOmM ammonium formate buffer / ACN: 5% - 50%), the fractions containing product were combined and extracted into EtOAc. The organic portion was washed with water and brine and isolated affording the title compound (295 mg, 23 %) as a yellow solid which was carried forward without further purification. LCMS Method C (m / z): [M+H]h= 306.3, retention time = 1.52 min,

[0873] Step 4: Synthesis of 6-(cyclobutanecarboxamido)-4-((3-(l-fluorocyclopropyl)pyridin-2-yl)amino)-A7-(methyl-t / 3)pyridazine-3-carboxamide:

[0874] The title compound was prepared according to general procedure J

[0875] Cyclobutanecarboxylic acid (31.3 uL, 328 umol), 1 -metliylimidazole (68.0 uL, 819 umol) and TCFH (232 mg, 819 umol) were stirred in MeCN (4.17 mL) at ambient temperature for 15 mins then 6-amino-4-((3-(l -fluorocyclopropyl)pyridin-2-yl)amino)-2V-(methyl-<73)pyridazine-3-carboxamide (25.0 mg, 81.9 umol) in MeCN (4.17 mL) was added and the reaction stirred at 50 °C for 2 h. The reaction was concentrated to ca. 1 mL under vacuum and injected directly into the purification system. Purification using Buchi C-850 Benchtop Prep chromatography (5-100% lOmM AMB buffer in MeCN) afforded the title compound (7.40 mg, 23 %). LCMS Method C (m / z): [M+H]+=== 388.3, retention time === 1.52 mm.NMR (400 MHz, DMSO ) 8 12.32 (s, 1H), 10.85 (s, III), 9.88 (s, 1H), 9.19 (s, 1H), 8.44 (d, J --- 4.8 Hz, 1H), 7.90 (d, J--- 7.5 Hz, III), 7.11 (dd, J ------ 7.2, 5.2 Hz, 1 H), 3.53 - 3.41 (m, 1H), 2.31 - 2.19 (m, 211), 2.19 - 2.08 (m, 2H), 2.02 - 1.88 (m, III), 1.88 - 1.74 (m, 1H), 1.64 -• 1.50 (m, 211), 1.21 - 1.10 (m, 2H).Examples 21B-21R:

[0876] The following examples were prepared in a similar manner to Compound 51 described in Example 21 A using the corresponding chloropyridazines or chloropyridines and commercially available carboxylic acidsATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Table 9:(m / z)Ex. Cmpd General MWStructure [M+H]+ lH NMR No. No. Proc. (g / mol)(method)'H NMR (400 MHz, DMSO-tfc) 5 12.37 (s, IH), 11.54 (s, IH), 9.84 (s, IH), 9.25 (s, IH), 8.40 410.2 (d,,7= 4.8 Hz, IH), 7.90 O21B 53 D, C. JI JL E, K 409.4 (d, <7= 7.4 Hz, IH), 7.11N?! 0H 1 II F (L) (dd, J= 7.2, 5.2 Hz, IH), JL JL / N N / F 3.11 (ddd, <7 = 13.5, 10.7, H8.2 Hz, IH), 2.15 - 1.99 (m, 2H), 1.64- 1.51 (m, 2H), 1.21 - 1.09 (m, 2H).!H NMR (400 MHz, DMSO-Je) 8 12.34 (s, IH), 11.38 (s, IH), 9.84 s(=X(s, IH), 9.22 (s, IH), 8.41 >r (d, <7= 4.9 Hz, IH), 7.91392.3oZ:= (d, <7 = 7.5 Hz, IH), 7.11 21 C 36A E, K 391.4(dd, 7 = 7.4, 5.0 Hz, IH), (G)Q 5.18 -4.73 (m, IH), 2.36-2.29 (m, IH), 1.76 - 1.65 (m, IH), 1.63 - 1.53 (m, 2H), 1.29 - 1.20 (m, IH), 1.20 - 1.13 (m, 2H).1H NMR (400 MHz, DMSO-d6) 8 12.33 (s, IH), 11.37 (s, IH), 9.83 (s, IH), 9.21 (s, IH), 8.44 - 8.36 (m, IH), 7.90 (dt, J 392.2O HN''’ O'T = 7.6, 1.9 Hz, IH), 7.10 1D 96 O3CxJs. E, K 391.4N NzN 0 (dd,<7= 7.3, 5.0 Hz, IH), H 1 || (G)N> JA. JL < F 5.07-4.86 (m, IH), 2.35 N NH -2.30 (m, IH), 1.75 - 1.65 (m, IH), 1.63 - 1.52 (m, 2H), 1.28 - 1.19 (m,IH), 1.19- 1.12 (m, 2H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014NMR (400 MHz, DMSO-Je) 8 12.23 (s, C3 w0 1H), 11.14 (s, 1H), 9.74 / (s, 1H), 9.12 (s, 1H), 8.39 teo - 8.23 (m, 1H), 7.83 (dt, J / Z “H““T | Z X V““ 388.3 = 7.5, 1.9 Hz, 1H), 7.02 E 41A E, K 387.4 (dd, J = 7.2, 5.1 Hz, 1H),xz Z (G) 2.12-2.02 (m, 1H), 1.57~ 1.43 (m, 2H), 1.31 - 1.20 (m, 1H), 1.13 - 1.07 (m, 2H), 1.06 (d, J= 6.2 Hz, 3H), 0.98 - 0.91 (m, 1H), 0.82-0.74 (m, 1H).lH NMR (400 MHz, DMSO-6 / 6) 8 12.27 (s, u. 1H), 11.43 (s, 1H), 9.76(s, 1H), 9.16 (s, 1H), 8.31F^ |^SS|| (d, J = 4.9 Hz, 1H), 7.83424.3o HN' IT (d, J= 7.5 Hz, 1H), 7.03 F 42A D3C. JL JL C\ Z ZZ E, K 423.4N?| / / V* / 0 F (dd, J = 7.2, 5.1 Hz, 1H), H 1 II I (G)N.'x P z^ z— Jk Jk 5.96 (td,.7= 56,7, 4.6 Hz, >z kk,— N N FH A / 1H), 2.41 -2.34 (m, 1H),1.91 - 1.77 (m, 1H), 1.56 Z3C / - 1.45 (m, 2H), 1.18 - w u£S 1.06 (m, 4H).!H NMR (400 MHz, DMSO-Je) 8 12.27 (s, 1H), 11.42 (s, 1H), 9.75 (s, 1H), 9.15 (s, 1H), 8.37 - 8.21 (m, 1H), 7.82 (dt, J 392.2= 7.5, 1.9 Hz, 1H), 7.02 G 97A E, K 391.4(dd, J = 7.3, 5.1 Hz, 1H), (G)5.00-4.75 (m, 1H), 2.65 -2.55 (m, 1H), 1.67 - 1.41 (m, 3H), 1.29 - 1.19 (m, 1H), 1.12 - 1.04 (m,2H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014NMR (400 MHz, DMSO-Je) 8 12.27 (s, 1H), 11.41 (s, 1H), 9.75 (s, 1H), 9.15 (s, 1H), 8.30 F(d, <7= 4.9 Hz, 1H), 7.82 392.3(d, J= 7.5 Hz, 1H), 7.02 H 97B E, K 391.4D, C, Uk. JL (dd, J = 7.3, 5.0 Hz, 1H),(G)HJk. 4.99-4.78 (m, 1H), 2.68 N N ^~TH -2.53 (m, 1H), 1.57 - 1.43 (m, 3H), 1.30 - 1.19 (m, 1H), 1.14 - 1.03 (m, 2H).’H NMR (400 MHz, DMSO-rfe) 8 12.32 (s, 1H), 10.77 (s, 1H), 9.83FX^sT^sil (s, 1H), 9.16 (s, 1H), 8.41 0 HN'Z*!!\r 400.4(d,.7= 4.9 Hz, 1H), 7.90 1 47 E, J 399.4D, CK Js. JL (d, J = 7.5 Hz, 1H), 7.10 N a OH 1 II (G)N > Jv J“L _ (dd,.7= 7.3, 5.1 Hz, III), N N 2,46 (s, 1H), 2,16 (s, 6H), H \S*1.65 - 1.50 (m, 2H), 1,22 - 1.09 (m, 2H).NMR (400 MHz, DMSO-t76) 8 12.31 (s, 1H), 11.03 (s, 1H), 9,80 (s, 1H), 9.16 (s, 1H), 8.40 O HN’’' j»r 418.3(d, J= 4.9Hz, 1H), 7.89 J 48 EJjC. 'v, E, J 417.4N TJ o (d,.7= 7.5 Hz, 1H), 7.09 H 1 II II (C)N> _ (dd, J= 7.3, 5.1 Hz, 1H), N N H N Kr'AAV2.47 (d, J=2.3 Hz, 6H), "^'F1.65 - 1.51 (m, 2H), 1.22 - 1.09 (m, 2H).!H NMR (400 MHz, DMSO-t / 6) 8 12.27 (s, 1H), 11.16 (s, 1H), 9.74 (s, 1H), 9.17 (s, 1H), 8.34 414.4o HNX*^’N'^ (d, J= 4.9Hz, 1H), 7.86 K 52 DJC E, J 413.5N 7» o (d, J= 7.5 Hz, 1H), 7.05 H 1 || (C)N> JL JL / ? (dd, J = 7.2, 5.1 Hz, 1H), N N N-”jMH y 2.25 -2.14 (m, 1H), 2.14- 1.88 (m, 6H), 1.62 -1.44 (m, 2H), 1.19 - 1.05ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014(m, 3H), 1.06 - 0.95 (m, IH).lH NMR (400 MHz, DMSO-<7>) 5 12.30 (s, IE), 11.59 (s, IE), 9.77 (s, IE), 9.19 (s, IE), 8.35 (d, <7= 4.8 Hz, 1H), 7.87 399.0o (d,.7= 7.5 Hz, IE), 7.07 1L 55A D3C. E, J 398.4N 7| o (dd, <7= 7,2, 5.1 Ez, 1H), H 1 II (K)N> JK. > L ACN 2.60 (dd,.7 = 14.5, 7.6 Hz, N N H A / 1H), 2.26 (dd, <7= 15.4,8.2 Hz, IH), 1.62 - 1.38 (m, 4H), 1.19- 1.07 (m, 2H).1H NMR (400 MHz, DMSO-Je) 5 12.37 (s, 1H), 10.51 (s, IH), 9.92 (s, 1H), 9.24 (s, IH), 8.41 (d,.7= 4.9 Hz, 1H), 7.89 o HN','' Nr 390.3 (d, <7= 7.5 Hz, 1H), 7.11 1M 57 D, C. JI JL E, J 389.4 (dd, J = 6.8, 5.0 Hz, 1H),(K) 5.26 (dd, J = 8.9, 6.7 Hz, N N IH), 4.64 (t, J --- 7.8 Hz, H \ \O-* 2H), 3.02 - 2.88 (m, IH),2.76-2.62 (m, IH), 1.65 - 1.46 (m, 2H), 1.18 - 1.10 (m, 2H).lH NMR (400 MHz, DMSCWo) 5 12.30 (s, IH), 10.90 (s, IH), 9.86 (s, IE), 9.17 (s, IH), 8.39 (d, <7= 4.9 Hz, IH), 7.88 O HN^^T 388.5 (dd,<7= 5.7, 3.7 Hz, IH), IN 58 / JK. E, K 387.4 7.09 (dd, J= 7.1, 5.2 Hz,H(K) IH), 2.35 (d, J = 1.1 Hz, J.- N 1 N A N 2H), 1.61 - 1.49 (m, 2H),A 1.18 - 1.11 (m, 2H), 1.11- 1.00 (m, IH), 0.52 - 0.42 (m, 2H), 0.24 -0.13(m, 2H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014NMR (400 MHz, DMSO-Je) 8 12.32 (s, 1H), 10.97 (s, 1H), 9.87 (s, 1H), 9.19 (s, 1H), 8.42 376.4O HN' IT (dd, J = 3.2, 1.7 Hz, 1H), 0 59 E, J 375.4N o 7.90 (dt, 7= 7.5, 1.9 Hz,(C)HJ.- 1H), 7.11 (dd, J = 7.0, 5.1 N X N JO NrH| Hz, 1H), 2.92 -2.80 (m,1H), 1.64 - 1.50 (m, 2H), 1.20- 1.06 (m, 8H). ’H NMR (400 MHz, DMSO-Je) 8 12.31 (s, 1H), 11.12 (s, 1H), 9.83 (s, 1H), 9.19 (s, 1H), 8.41pX(d, 7= 4.9 Hz, 1H), 7.90 |^Sjl400.4 (d, J 7.5 Hz, 1H), 7.10 o HN' ITP 60B E, J 399.4 (dd, 7= 7.1, 5.2 Hz, 1H),N Nf^ H o (G) 2.49 -2.44 (m, 1H), 1.57 - (dt, 7= 18.2, 7.0 Hz, 2H),1.45 (t,.7= 3.7 Hz, 1H), 1.38 (dd, J = 7.4, 3.4 Hz, 1H), 1.15 (q, J = 8.4 Hz, 2H), 0.97 - 0.72 (m, 4H).NMR (400 MHz, DMSO-Je) 8 12.31 (s, 1H), 11.12 (s, 1H), 9.83 (s, 1H), 9.19 (s, 1H), 8.41Fxl^?sjl (d,.7=4,9 Hz, 1H), 7.90400.4 (d, J = 7.5 Hz, 1H), 7.10 0 HN'NTQ 60A 03CxJL A. E, k 399.4 (dd, 7= 7.1, 5.2 Hz, 1H),N il o (H) 2.49-2.44 (m, 1H), 1.57(dt,7= 18.2, 7.0 Hz, 2H), 1.45 (t, 7= 3.7 Hz, 1H), 1.38 (dd, 7= 7.4, 3.4 Hz, 1H), 1.15 (q, 7= 8.4 Hz, 2H), 0.97 - 0.72 (m, 4H).lH NMR (400 MHz, DMSO-76) 8 12.36 (s, 1H), 11.06 (s, 1H), 9.94 o HNXJ'T 390.3R 80 E, K 389.4 (s, 1H), 9.22 (s, 1H), 8.45N H N 1^ N o II (G) (d, 7= 4.9 Hz, 1H), 7.91 N> JA. JL _N N N-'A (d, 7= 7.5 Hz, 1H), 7.12Hto (dd,7 = 7.1, 5.3 Hz, 1H),ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20144.76 - 4.67 (m, 4H), 4.21 -4.11 (m, 1H), 1.64 - 1.51 (m, 2H), 1.21 - 1.12(m, 2H).Example 22A: 4-((5-chIoro-3-(l-fluorocyclopropyl)pyridin-2-yl)amino)-6-((ll?,21?)-2- fluorocycIopropane-l-carboxamido)-r-(methyl-d3)pyridaziiie-3-carboxamide (Compound 46A)N-Chlorosuccinlmlde, DMF, RT

[0877] Synthesis of 4-((5-chloro-3-(l -fluorocyclopropyl)pyridin-2-yl)amino)-6-((lA,2A)-2- fluorocyclopropane- 1 -car boxamido)-A-(methyl-<73)pyridazine-3 -carboxamide:

[0878] 6-((l i,2 / J)-2-fluorocyclopropane-l-carboxamido)-4-((3-(l-fluorocyclopropyl)pyridin-2- yl)amino)-V-(niethyl-t / 3)pyridazine-3-carboxamide (30.0 mg, 76.6 umol), A-chlorosuccinimide (11.5 mg, 84.3 umol) and DMF (1.00 mL) were stirred at 50 °C 18 h, no reaction observed so more JV-Chlorosuccinimide (11.5 mg, 84.3 umol) was added. The reaction was stirred an additional 3 h then cooled to ambient temperature and injected directly into the purification system. Purification using Buchi Pure C850 Benchtop Semi-Prep (CT8 silica with 10 mM Ammonium Bicarbonate Buffer pH 10.3 / MeCN 5% - 95%) afforded the title compound (2.01 mg, 6.2 %). LCMS Method D (m / z): [M+H]+= 426.3, retention time = 2.63 mm. H NMR (400 MHz, DMSO-^) 8 12.43 (s, 1H), 11.42 (s, 1H), 9.71 (s, 1H), 9.24 (s, 1H), 8.43 (dd, J= 2.4, 1.6 Hz, 1H), 8.07 - 8.00 (m, 1H), 5.08 - 4.87 (m, 1H), 2.35 - 2.29 (m, 1H), 1.76 - 1.63 (m, 1H), 1.62 - 1.50 (m, 2H), 1.29 - 1.17 (m, 3H).Example 22B-22C:

[0879] The following compounds were prepared in a similar fashion as Compound 46A described in Example 22A using the corresponding N-halosuccinimides:ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Table 10:(m / z)Ex. Cmpd wStructure [M+Hf H 1 NMR No. No. (g / mol)(method)’H NMR (500 MHz, DMSO-Je) 8 = 12.41 (s, 1H), 11.37 (s, 1H), 9.70 (s, 1H), 9.22 (s, HI), 8.43 - O HN N 408.222B 45 D3C. JL Js. 407.9 8.40 (m, 1H), 8.04- 8.01(D)(m, 1H), 2.15 -2.09 (m, re N 1H), 1.61 - 1.52 (m, 2H), H V 1.26- 1.20 (m, 2H), 0.91 - 0.83 (m, 4H)452.2,O 454.222C INT-X D3(X 452.3 NN JL JL D O O MA (B)H V,Example 23: 4-((5-cyano-3-(l-fluorocycIopropyl)pyridin-2-yI)amino)-6- (cycIopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 56)

[0880] To a mixture of 4-((5-bromo-3-(l-fluorocyclopropyl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-JV-(methyl-d3)pyridazine-3-carboxamide (16.0 mg, 35.4 umol), tetrakis(tnphenylphosphine)palladium(0) (4.17 mg, 3.54 umol) and zinc cyanide (21.2 mg, 177 umol) was added DMF (800 uL). The reaction mixture was purged with N2 for 10 minutes and then allowed to stir at 135 °C for 6 h. The mixture was directly purified by reverse phase flash chromatography (Cl 8 silica with lOmM Ammonium Bicarbonate buffer / MeCN: 10% - 100%) to afford 4-((5-cyano-3-(l-fluorocyclopropyl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014JV-(methyl-<: / 3)pyridazine-3-carboxamide (2.01 nig, 13 %). LCMS Method D (m / z): [M+H]+= 399.3, retention time = 2.07 mm. 1H NMR (400 MHz, DMSO) 5 = 12.79 (s, 1H), 11.47 (s, 1H), 9.85 (s, 1H), 9.31 (s, 1H), 8.81 (s, 1H), 8.37 - 8.33 (m, 1H), 7.66 - 7.51 (m, 1H), 2.19 -2.10 (m, 1H), 1.63 - 1.54 (m, 2H), 1.29 - 1.20 (m, 2H, grease overlap), 0.92 - 0.84 (m, 4H).Example 24: 6-(cyclopropanecarboxamido)-4-((3-(l-fluorocyclopropyI)-5-(l-methyl-lH-pyrazoI-3-yl)pyridin-2-yI)amino)-N-(methyI-d3)pyridazine-3-carboxamide (Compound 81)

[0881] To a mixture of 4-((5-bromo-3-(l-fluorocyclopropyl)pyridm-2-yl)ammo)-6-(cyclopropanecarboxamido)-A’-(methyl-<73)pyridazine-3-carboxamide (15.0 mg, 33.2 umol), (1-methyl-l / 7-pyrazol-3-yl)boronic acid (8.79 mg, 66.3 umol), NaiCCh (10.8 mg, 99.5 umol) and tetrakis(tnphenylphosphine)palladium(0) (3.87 mg, 3.32 umol) was added dioxane (750 uL) and water (75.0 uL) in a pressure vial fitted with a stir bar. The reaction mixture was purged with N2 for 10 minutes and then allowed to stir at 110 °C for 1 h. The mixture was directly purified by reverse phase flash chromatography (Cl 8 silica with lOmM Ammonium Bicarbonate buffer / ACN: 10% - 100%) to afford 6-(cyclopropanecarboxamido)-4-((3-(l-fluorocyclopropyl)-5-(l-methyl-lH-pyrazol-3-yl)pyridin-2-yl)amino)-A-(metliyl-<73)pyridazine-3-carboxamide (2.42 mg, 16 %). LCMS Method D (m / z): [M+H]^ = 454.3, retention time = 2.09 min. 'H NAIR (400 MHz, DMSO-6) 8 = 12.37 (s, 1H), 11.34 (s, 1H), 9.86 (s, 1H), 9.21 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.77 (d, J=2.2, 1H), 6.87 (d, J=2.2, lH), 3.90 (s, 3H), 2.17-2.10 (m, 1H), 1.65 - 1.55 (m, 2H), 1.29- 1.17 (m, 2H), 0.93 - 0.82 (m, 4H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 25A: 4-((3-(l,l-difluoroethyI)-5-fluoropyridin-2-yl)amino)-6-(l- fluorocycIopropane-l-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (Compound70)

[0882] Step 1: Synthesis of 2-6-amino-4-((3-(l,l-difluoroethyl)-5-fluoropyridin-2-yl)amino)vV- (methyl-r / 3)pyridazine-3-carboxamide:

[0883] To a solution of 6-(cyclopropanecarboxamido)-4-((3-(l,l-difluoroethyl)-5-fluoropyridin- 2-yl)amino)-V-(methyl- 3)pyridazine-3-carboxamide (100 mg, 0.234 mmol) in THF (851 uL) MeOH (426 uL) and Water (426 uL) was added aqueous 5 M NaOH (468 uL, 2.34 mmol). The mixture was allowed to stir at room temperature for 96 h. The organics were removed under vacuum and the mixture was diluted with 10% MeOHZDCM solution and was transferred into a separatory funnel. The organic layer was washed with water (2 ), dried over anh. Na2SO4, filtered, and concentrated under vacuum to afford crude 6-amino-4-((3-(l,l-difluoroethyl)-5- fluoropyridin-2-yl)amino)-A7-(methyl-t / 3)pyridazine-3-carboxamide (70.0 mg, 91 %) as an off- white solid. Used as-is without further purification. LCMS Method R (m / z): [M+H]+= 330.3, retention time = 0.92 min.

[0884] Step 2: Synthesis of 4-((3-(l,l-difluoroethyl)-5-f]uoropyridin-2-yl)amino)-6-(l- fluorocyclopropane-l-carboxamido)-7V-(methyl- 3)pyridazine-3-carboxamide:

[0885] The synthesis was carried out according to General Procedure J, In a vial, to a mixture of 1 -fluorocyclopropanecarboxylic acid (117 uL, 1.21 mmol), NMI (245 uL, 3.04 mmol) and DMF (525 uL) was added TCFH (878 mg, 3.04 mmol). The mixture was stirred at room temperature for 10 minutes.

[0886] In a second vial, 6-amino-4-((3-(l,l-difluoroethyl)-5-fluoropyridin-2-yl)amino)-jV- (methyl-r / 3)pyndazme-3 -carboxamide (100 mg, 304 umol) was dissolved in DMF (457 uL) and NMI (611 uL, 7.59 mmol) was added. Then the activated acid mixture (first vial) was added to the second vial.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0887] After 40 minutes, LCMS analysis indicated the reaction had completed. The product was precipitated by adding water (8 mL) and washed with water (2 x 8 mL). then purified by Cl 8 reversed phased column chromatography (10 - 100% MeCN in 10 mM AmB ( aq.)) to give the title compound (85.0 nig, 67 %). LCMS Method L (m / z): [M+H]+= 416.2, retention time = 2.99 mm. ’H NMR (400 MHz, DMSO- s) 5 12.06 (s, 1H), 10.87 (s, 1H), 9.30 (s, 1H), 9.28 (s, 1H), 8.51 (d, J= 2.8 Hz, 1H), 7.98 (dd, = 8.9, 2.9 Hz, 1H), 2.09 (t, J= 19.3 Hz, 3H), 1.54 - 1.43 (m, 2H), 1.43 - 1.33 (m, 2H).19F NMR (376 MHz, DMSO-r / e) 5 -85.72 (q, J= 19.3 Hz, 2F), -134.22 (d, J= 8.9 Hz, IF), -195.32 (s, IF).Example 25B-25F:

[0888] The following examples were prepared in a similar manner to Compound 70 described in Example 25A using the corresponding commercially available carboxylic acids:Table 11:(m / z)Ex. Cmpd General MWStructure [M+H]+I NMR No. No. Proc. (g / mol)(method)’H NMR (400 MHz, DMSO-Je) 8 12.03 (s, 1H), 11.52 (s, 1H), 9.31 F F(s, 1H), 9.24 (s, 1H), 8.48 (d, J= 2.6Hz, 1H), 416.1o 7.96 (dd, J --- 8.9, 2.8 25B 86 J 415.4Jk..N % o Hz, 1H), 4.91 (d, J ------ (K)HXV65.3 Hz, III), 2.76 - F2.57 (m, 1H), 2.08 (t, J = 19.3 Hz, 3H), 1.67- 1.49 (m, 1H), 1.27 (dq, J= 13.0, 6.4 Hz, 1H).rH NMR (400 MHz, F F DMSO-t / e) 8 12.02 (s,1H), 11.52 (s, 1H), 9.31 416.1 (s, 1H), 9.23 (s, 1H), O HN'' Tr25C 67A J 415.4 8.48 (d, J = 2.8 Hz, 1H),JL Js.(K) 7.96 (dd, J = 8.9, 2.8HJk, JL Hz, 1H), 5.02-4.80 (m,H 1H), 2.66 (ddd, J =17.9, 10.4, 7.2 Hz, 1H),ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20142.08 (t, 7 = 19.3 Hz, 3H), 1.57 (dddd, 7 = 13.7, 10.0, 6.4, 3.2 Hz, 1H), 1.27 (tt, 7 = 10.8, 5.4 Hz, 1H).F FrH NMR (400 MHz, DMSO-Je) 8 11.99 (s, 1H), 10.99 (s, 1H), 9.22 (s, 1H), 9.12 (s, 1H), o HN'zjr 423.2D 66 J 422.4 8.51 (d,.7= 2.6 Hz, 1H),D 3Cs(H)N O 7.96 (dd, 7= 8.9, 2.7 H I IIN > J> L Hz, 1H), 2.09 (t, J = N N X-7 19.3 Hz, 3H), 1.76-HNC V1.59 (m, 4H).1H NMR. (400 MHz, DMSO-Je) 8 11.99 (s, F F 1H), 11.16 (s, 1H), 9.33xXx^z,ss-. F (s, 1H), 9.20 (s, 1H),8.53 (d, 7= 2.9 Hz, 1H), 424.20 HNZ' JT 7.97 (dd, 7= 8.9, 2.9 E 71 A J 423.4D,(K J-L JL Hz, 1H), 2.46 (dd, 7 = (C)7.4, 4.3 Hz, 1H), 2.08 (t, "-'AA^A J --- 19.3 Hz, 311), 1.44 - 1.40 (m, 1H), 1.40 - 1.34 (m, 1H), 0.92- 0.77 (m, 4H).XH NMR. (400 MHz, DMSO-76) 8 12.01 (s, F F 1H), 11.41 (s, 1H), 9.33(d, 7= 2.6 Hz, 1H), 9.23 416.3 (s, 1H), 8.53 (s, 1H), 0F 98 A J 415.4 7.97 (dt, 7=4.6, 2.5 Hz, DSC%J-L A.N A O (L) 1H), 5.08 -4.86 (m, H 1 IIJA J< L ^F 1H), 2.36-2.27 (m, N N A™ZH v 1H), 2.15 -2.03 (m,4H), 1.73 - 1.58 (m,1H).ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014Example 26 A: 6-(cyclopropanecarboxamid o)-4-((3-(l-fhiorospiro [2.2] pentan- l-yl)pyrid in- 2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 83)

[0889] Step 1: Synthesis of ethyl 2-(2-chloropyridin-3-yl)acrylate:

[0890] Dry toluene (98.2 mL) was added to a mixture of ethyl 2-(2-chl oropyri din-3 -yl)acetate (1.00 g, 4.91 mmol), K2CO3 (2.22 g, 15.7 mmol), tetrabutylammonium iodide (92.5 mg, 0.245 mmol) and paraformaldehyde (3.49 g, 110 mmol). The mixture was stirred at 90 °C 18 h. The mixture was then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and adsorbed onto silica gel. Purified by column chromatography on silica (0- 100% EtOAc) to obtain ethyl 2-(2-chloropyndin-3-yl)acrylate (800 mg, 77 %) as a colourless oil. LCMS Method B (m / z): [M+H]4= 212,2, retention time = 0.92 min.

[0891] Step 2: Synthesis of ethyl l-(2-chloropyndin-3-yl)spiro[2.2]pentane-l -carboxylate:

[0892] Ethyl 2-(2-chloropyridin-3-yl)acrylate (700 mg, 3.31 mmol) and cyclopropyl diphenylsulfonium tetrafluoroborate (1.59 g, 4.96 mmol) were suspended in dry THF (16.5 mL) and flask was purged with nitrogen and sonicated 2 mins. The mixture was cooled in an ice bath with stirring under nitrogen and NaHMDS (4.96 mL, 4.96 mmol) 1 M in THF was added dropwise. The reaction was complete within 10 mins after base addition and quenched withATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014saturated NH4CI. The mixture was extracted with EtOAc, the combined organics were washed with brine, dried over anh. Na2SO4 filtered and concentrated under vacuum. The residue was taken up in DCM and filtered through 30 g of silica gel using Heptanes as eluent, this removed most of the diphenyl sulfide byproduct. The column was flushed with 50 / 50 Heptanes / DCM to remove the desired product. This filtrate was concentrated under vacuum to afford ethyl l-(2-chloropyndin-3-yl)spiro[2.2]pentane-l -carboxylate (720 mg, 86 %) as a pale yellow oil which was used as is m the next step without further purification. LCMS Method B (m / z): [M+H]+= 252.2, retention time = 1.09 min.

[0893] Step 3: Synthesis of l-(2-chloropyridin-3-yl)spiro[2.2]pentane-l-carboxylic acid:

[0894] To a solution of ethyl l-(2-chloropyridin-3-yl)spiro[2.2]pentane-l -carboxylate (720 mg, 2.86 mmol) in THF (9.53 mL), water (4.77 mL), and MeOH (4.77 mb) was added 5 M aq. NaOH (5.72 mL, 28.6 mmol). The reaction mixture was stirred at 40 °C for 16 h. 1 M aq. HC1 was added and brought pH ~ 1-3 and the aqueous portion was extracted with DCM: MeOH (4:1). The combined organic layers were dried over NaaSCL, filtered and concentrated under reduced pressure to afford l-(2-chloropyndin-3-yl)spiro[2,2]pentane-l -carboxylic acid (630 mg, 98 %) as a white solid. The residue was used as it is m the next step without any further purification. LCMS Method F (m / z): [M+H]+= 224.1, retention time = 0.40 min.

[0895] Step 4: Synthesis of 2-chloro-3-(l-fluorospiro[2,2]pentan-l-yl)pyridine:

[0896] To a mixture of l-(2-chloropyridin-3-yl)spiro[2.2]pentane-l-carboxylic acid (630 mg, 2.82 mmol), Selectfluor® (3.19 g, 9.01 mmol), and K2HPO4 (1,05 g, 5.92 mmol) was added water (11.3 mL) / MeCN (11.3 mb). The reaction mixture was degassed with nitrogen for 5 min. To this mixture was then added 2,3-butanedione (25.0 mg, 0.282 mmol) and stirred for 1 h under the irradiation of 440 nm LED. The reaction mixture was extracted with DCM and washed with sat. aq. NaHCOs The combined organic layers were dried over Na2S(>4, filtered and concentrated under reduced pressure to afford 2-chloro-3-(l-fluorospiro[2.2]pentan-l-yl)pyridine (400 mg, 72 %) as a pale yellow oil. This residue was used as it is in the next step without any further purification. LCMS Method F (m / z): [M+H]’ = no ionization, retention time = 1.13 min.

[0897] Step 5: Synthesis of 6-(cyclopropanecarboxamido)-4-((3-(l-fluorospiro[2.2]pentan-l-yi)pyridin-2-yl)amino)- / V-(methyl-<73)pyridazine-3-carboxamideATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014

[0898] The title compound was prepared according to General Procedure A.

[0899] To a degassed mixture of 2-chloro-3-(l-fluorospiro[2.2]pentan-l-yl)pyridine (99.5 mg, 0.504 mmol), 4-amino-6-(cyclopropanecarboxamido)-7V-(methyl- <73)pyridazine-3 -carboxamide (100 mg, 0.420 mmol), dppf (102 mg, 0.168 mmol), and K3PO4 (364 mg, 1.68 mmol) in dioxane (4.20 mL) was added Pd2(dba)s (76.9 mg, 0.0839 mmol). Nitrogen was immediately bubbled to the mixture for 2 min and the reaction was stirred at 120 °C for 1 h. The mixture was cooled, diluted with 50%EtOAc / MeOH and filtered on Celite®. The C elite® cake was rinsed with EtOAc and the combined organic was concentrated under reduced pressure. The residue was purified by normal phase chromatography (0-20% zPrOH'DCM) to afford racemic 6- (cyclopropanecarboxamido)-4-((3-(l -fluorospiro [2.2] pentan- 1 -yl)pyridin-2-yl)amino)-Ar-(methyl-r / 3)pyndazine-3 -carboxamide (57.5 mg, 34 %). LCMS Method D (m / z): [M+H] = 400.3, retention time = 2.27 m...

Claims

ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014CLAIMS1. A compound of F ormula (I):or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof; wherein:R1is -H, -halo, -CN, -C1-6 alkyl, -C1-6 alkenyl, -Ci-6 alkynyl, -C3-6 cycloalkyl, -OH, -OCi-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(C1-6 alkyl)(C3-6 cycloalkyl); wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -Oheterocyclyl, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-6 cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R2is -H, -halo, -CN, -Ci-e alkyl, -OC1-6 alkyl, -Ci-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl; wherein the -C1-6 alkyl, -OCi-e alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or heterocyclyl are each independently optionally substituted with 1 or more halo, - CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;or R1and R2are taken together to form a carbocyclyl or saturated or partially unsaturated heterocyclyl, wherein the carbocyclyl or saturated or partially unsaturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OC1-6 alkyl, -C1-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;R3is -H, -halo, -C1-6 alkyl, -O-C1-6 alkyl, or -CN; wherein the -C1-6 alkyl or -OC1-6 alkyl, are each independently optionally substituted with 1 or more halo, -CN, -OC1-6 alkyl, -OC1-6 haloalkyl, or -CO2alkyl;ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014each R4is independently -H or -D;X1is CH or N;X2is C(R8)2or NH;each R8is independently H, halo, -C1-6 alkyl, -C1-6 haloalkyl, -O-C1-6 alkyl, or -CN;Y is N or CRYA;Y1is N or CRYB;Y2is N or CRYC; andY3is N or CRYD;RYA, RYB, RYC, and RYDare each independently -H, -CN, -halo, -NRARB, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl, wherein the, -C1-6 alkyl, -OC1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, heterocyclyl, or aryl are each optionally substituted with -halo, -C1-6 alkyl, -C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN;RAand RBare each independently -H, -C1-C6 alkyl, cycloalkyl, or heterocyclyl;U is H;Z is -ORZ, -C1-6alkyl, -(CH2)0-3-(C3-6 cycloalkyl), or -(CH2)0-3-(C3-C4 heterocyclyl), and wherein the -C1-6alkyl, -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1 or more substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl; orU and Z are taken together to form a heterocyclyl optionally substituted with 1 or more substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl; andRZis -C1-6 alkyl, or -C3-6 cycloalkyl;and provided the compound is not:3 -pyridinecarboxamide, 6-[(cyclopropylcarbonyl)amino]-4-[[2-(l-hydroxy-l-methylethyl)phenyl]amino]-N-methyl-; or6-( cyclopropanecarboxamido)-4-((2-( 1 -hydroxy ethyl)-3 -(1 -methyl- 1 H- 1,2,4-triazol-3 -yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-20142. The compound of claim 1, wherein Z is -ORZ, -(CH2)o-3-(C3-Ce cycloalkyl), -C3-6 cycloalkyl, or -C3-C4 heterocyclyl wherein the -C3-6 cycloalkyl or -C3-C4 heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN or two substituents are taken together to form a carbocyclyl.

3. The compound of claim 1 or 2, wherein Z is -ORZ, -(CH2)-cyclopropyl, cyclopropyl, cyclobutyl, bicyclo[l.l.l]pentyl, spiro[2.3]hexyl, spiro[2.2]pentyl, or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclofl. l.l]pentyl, spiro[2.3]hexyl, spiro[2.2]pentyl, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -Ci-e alkyl, -C1-6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN, or two substituents are taken together to form a carbocyclyl.

4. The compound of claim 3, wherein Z is -ORZ, cyclopropyl, cyclobutyl,bicyclofl. l.l]pentyl, spiro[2.3]hexyl, spiro[2.2]pentyl„ or oxetanyl, wherein the cyclopropyl, cyclobutyl, bicyclofl.1.1 Jpentyl, spiro [2.3] hexyl, spiro [2.2] pentyl, or oxetanyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -halo, -C1-6 alkyl, -Ci -6 haloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, or -CN.

5. The compound of claim 1, wherein Z is -(CH2)o-3-(C3-C6 cycloalkyl).

6. The compound of claim 1, wherein Z is -(CH2)-(C3-C6 cycloalkyl).

7. The compound of any one of claims 1 -6, wherein U is H.

8. The compound of claim 1, wherein U and Z are taken together to form a 5-8 membered heterocyclyl, wherein the 5-8 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -halo, -C1-6 alkyl, or -OC1-6 alkyl.

9. The compound of claim 8, wherein U and Z are taken together to form a 5-membered saturated heterocyclyl, wherein the 5 -membered saturated heterocyclyl is optionally substituted with -Ci-6 alkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-201410. The compound of claim 9, wherein the 5 -membered saturated heterocyclyl is substituted with -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.

11. The compound of claim 1, having a structure of Formula (IA):or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

12. The compound of claim 1, having a structure of Formula (IB):(IB)or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof;wherein R3, R6and R7are each independently selected from the group consisting of -H, -CN, -halo, -C1-6 alkyl, -Cue haloalkyl, -OC1-6 alkyl, or -OC3-6 cycloalkyl, or R6and R7are taken together to form a carbocyclyl.

13. The compound of any one of claims 1-12, wherein Y, Y1, Y2, and YJare not all CH.

14. The compound of any one of claims 1-13, wherein at least one of Y, Y1, Y2, and Y3is N.

15. The compound of any one of claims 1-14, wherein Y is N.16, The compound of any one of claims 1 -15, wherein one or two of Y1, Y2, and Y3is N.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-201417. The compound of any one of claims 1-13, wherein Y is N and Y2is N.

18. The compound of any one of claims 1-13, wherein Y is N and Ydis N.

19. The compound of any one of claims 1-12, wherein:(i)Y is N and Y2is CYCwherein RYCis -CHs, -CN, -F, or -Cl; or(ii) Y is N and Y3is CR'IDwherein RYDis -CEF, -CN, -F, or -Cl.

20. The compound of any one of claims 1-7 or 12-15, having a structure of Formula (II A) orHor a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

21. The compound of any one of claims 12-20, w’herein R5is -H, -Cue alkyl, -CN, or halo.

22. The compound of any one of claims 12-20, wherein R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-e alkyl, -Ci-6 haloalkyl, or -OCi-6 alkyl, or R° and R7are taken together to form a C3-6cycloalkyl.

23. The compound of claim 22, wherein R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-6 alkyl, or R6and R7are taken together to form a cyclopropyl or cyclobutyl.

24. The compound of claim 23, wherein R6and R7are each independently selected from the group consisting of -H, -halo, -Ci-6 alkyl, or -OCi-6 alkyl.

25. The compound of any one of claims 12-21, wherein R5, R6and R7are H.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-201426. The compound of any one of claims 1-18 or 20-25, wherein RYA, RYB, and RYCare each independently -H, -CN, -halo, -N(Ci-e alkyl)(saturated heterocyclyl), -Ci-6 alkyl, -Cue alkenyl, - Ci-6 alkynyl, -OCi-6 alkyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl, wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -OC1-6 alkyl, -C3-6 cycloalkyl, saturated heterocyclyl, aryl, or heteroaryl are optionally substituted with -F, -Cue alkyl, or -OC1-6 alkyl and RYDis -H, - CN, -halo, -C1-6 alkyl, -Ci-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, a saturated heterocyclyl, or aryl.

27. The compound of claim 26, wherein RYB, RYC, and RYDare each independently -H, - N(Ci-e alkyl)(saturated heterocyclyl), -Ci-e alkyl, -OC1-6 alkyl, -CN, halo, saturated heterocyclyl, or heteroaryl, wherein the -Ci-e alkyl, -OCi-e alkyl, saturated heterocyclyl, or heteroaryl are optionally substituted with -F, -Ci-e alkyl, or -OCi-e alkyl.

28. The compound of claim 27, wherein RYBand RDare each independently -H, -F -CN, or29. The compound of claim 27, wherein two or three of RB, R'c, and Rware -H.

30. The compound of any one of claims 1-29, wherein:R1is -H, -halo, -CN, -Ci-e alkyl, -Cue alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, -NH2, -NH(Cne alkyl), -N(Ci-e alkylh, - NH(C3-6 cycloalkyl), or -N(CI-6 alkyl)(C3-e cycloalkyl); wherein the -Ci-e alkyl, -Cue alkenyl, - C1-6 alkynyl, -C3-6 cycloalkyl, -OC1-6 alkyl, -OC3-6 cycloalkyl, -O-saturated heterocyclyl, - NH(CJ-6 alkyl), -N(CI-6 alkyl)2, -NH(C3-6 cycloalkyl), or -N(Ci-e alkyl)(C3-e cycloalkyl) are each independently optionally substituted with 1 or more halo, -CN, -OCi-e alkyl, -OCi-e haloalkyl, or -CO2alkyl;R2is -H, -halo, -Ci-e alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or a saturated heterocyclyl; wherein the -C1-6 alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturatedATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014heterocyclyl are each independently optionally substituted with 1 or more halo, -CN, -OCi-s alkyl, -OCi-6 haloalkyl, or -CChalkyl;or R1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are each independently optionally substituted with 1 or more halo, -OCi-6 alkyl, -Ci-6 alkyl, -C3-6 cycloalkyl, or -CN; wherein the -C1-6 alkyl or -C3-6 cycloalkyl, are each independently optionally substituted with 1 or more -CN, -OC1-6 alkyl, - OCi-6 haloalkyl, or -CChalkyl.

31. The compound of any one of claims 1 -29, wherein:R1is -H, -halo, -OH, -CN, -Cue alkyl, -C1-6 alkenyl, -Cue alkynyl, -C3-6 cycloalkyl, -OCi-6 alkyl, -OC3-6 cycloalkyl, or -O-saturated heterocyclyl;R2is -H, -halo, -Ci-e alkyl, -C1-6 alkenyl, -C1-6 alkynyl, -C3-6 cycloalkyl, or saturated heterocyclyl; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl,32. The compound of any one of claims 1-31, wherein:R1is -C1-6 alkyl or -C3-6 cycloalkyl optionally substituted with 1 or more halo;R2is -H, -Ci-e alkyl, or -halo; orR1and R2are taken together to form a carbocyclyl or saturated heterocyclyl, wherein the carbocyclyl or saturated heterocyclyl are optionally substituted with 1 or more halo.

33. The compound of any one of claims 1-32, wherein R1is Ci-e alkyl.

34. The compound of claim 33, wherein R1is -CH3.

35. The compound of any one of claims 1-32, wherein R1and R2are taken together to form a carbocyclyl.

36. The compound of any one of claims 1-32, wherein R1and R2are taken together to form a -C’3-6 cycloalkyl or saturated heterocyclyl.

37. The compound of claim 35 or 36, wherein R1and R2are taken together to form a -C3-6 cycloalkyl.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-201438. The compound of claim 32, wherein R1and R2are taken together to form a cyclopropyloptionally substituted with 1 or 2 -F, oxetanyl, cyclobutyl,39. The compound of any one of claims 32-35, wherein R1and R2are taken together to forma cyclopropyl or40. The compound of any of claims 35-39, wherein the carbocycle or heterocycle is substituted with -CI I2OCII3.

41. The compound of claim 35, wherein R1and R2are taken together to form a Cs-s bicyclic cycloalkyl.

42. The compound of any one of claims 1 -36, wherein R2is -H, -Ci-s alkyl or -halo.

43. The compound of claim 42, wherein R2is -H44. The compound of claim 42, wherein R2is halo.

45. The compound of claim 42, wherein R2is F.

46. The compound of any one of claims 1-45, wherein R3is -H, -halo, -C1-6 alkyl, -C1-6 haloalkyl, -O-C1-6 alkyl, or CN, wherein the -Ci-s alkyl is optionally substituted with 1 or more OC1-6 alkyl.

47. The compound of any one of claims 1-46, wherein R3is -halo, -C1-6 alkyl, -C1-6 haloalkyl, or CN.ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-201448. The compound of any one of claims 1-47, wherein R3is Ci-6 haloalkyl, -OCi-6 alkyl, or CN.

49. The compound of any one of claims 1-48, wherein R3is C1-3 haloalkyl, -OC1-3 alkyl, or CN.

50. The compound of claim 46, wherein R3is -H, -F, -Cl, -CH3, -CH2F, -CHF?., -CFs, -OCH3, -OCH2CH3, -CH2CH3, -CH2OCH3 or CN.

51. The compound of claim 46, wherein R3is -F, -CH3, -CFs, -OCH3, -OCH2CH3, or CN.

52. The compound of claim 51, wherein R3is -CH?, -CF3, -OCH3, -OCH2CH3, or CN.

53. The compound of claim 46, wherein RJis FI, F, or Cl.

54. The compound of claim 53, wherein R3is F,55. The compound of any one of claims 1 -54, wherein X2is CHR8.

56. The compound of any one of claims 1-55, w’herein X2is CH2.

57. The compound of any one of claims 1-54, wherein X2is NH.

58. The compound of any one of claims 1-57, wherein each R4is -H.

59. The compound of any one of claims 1-57, wherein each R4is -D.

60. The compound of any one of claims 1 -59, wherein X1is CH.

61. The compound of any one of claims 1-59, wherein X1is N.

62. A compound selected from the group consisting of”ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014ATTORNEY DOCKET NO.: TTTI-003 / 03WO 354643-2014or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof.

63. A pharmaceutical composition comprising a compound of any one of claims 1-62, or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

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