JAK2 INHIBITOR COMPOUNDS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/373,156, filed August 22, 2022, which is incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] Described herein are compounds that modulate the activity of a Janus kinase, particularly Janus kinase 2 (JAK2), methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulating Janus kinase 2 (JAK2) activity. BACKGROUND OF THE INVENTION [0003] Janus kinases (JAKs) are a family of non-receptor tyrosine kinases that includes JAK1, JAK2, JAK3, and TYK2, and which are implicated in the transduction of cytokine signaling pathways (e.g., the JAK-STAT pathway). Perturbations in the JAK-STAT pathway may lead to a variety of diseases, including some skin conditions, cancers, immune disorders, or inflammatory conditions. Certain mutations in JAK2 genes (e.g., V617F), or overactivity in JAK2 activity, may be implicated in blood disorders such as, for example, myeloproliferative neoplasms (MPNs), such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia; and hematological malignancies such as lymphomas or leukemias. Modulators of JAK2 activity (e.g., inhibitors (e.g., selective inhibitors)) may be attractive for their use in the treatment of, or in the preparation of a medicament for treating, certain conditions, diseases, or disorders that would benefit from modulating JAK2 activity. SUMMARY OF THE INVENTION [0004] Compounds described herein are inhibitors of JAK2. In some embodiments, the compounds described herein are used in the treatment or prevention of diseases or conditions in which JAK2 activity contributes to the symptomology or progression of the disease or condition, such as, for example, hematological malignancies and/or myeloproliferative neoplasms. [0005] In one aspect, described herein is a compound of Formula (I):

Formula I or a pharmaceutically acceptable salt thereof wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl; X is -NH-L-; L is absent or -C(=O)-; Ring B is selected from the group consisting of C3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, - OR ¹⁰ , -N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; Ring D is a 5- or 6-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C _1-6 alkoxy; wherein each substituted C _1-6 alkyl and substituted C _1-6 alkoxy is substituted with 1-5 instances of R ¹² ; Ring E is a substituted or unsubstituted C _7-12 bicyclic carbocycle, or a substituted or unsubstituted 7- to 12-membered bicyclic heterocycle; R ¹ is hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(O)OH, -C(O)OC1-6 alkyl, -C(O)C1-6 alkyl, -C(O)NH2, -C(O)NHC1-6 alkyl, - C(O)N(C _1-6 alkyl) ₂ , -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -OH, OC _1-6 alkyl, -SH, - SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; p is 0, 1, 2, 3, or 4; q is 0, 1 or 2; and r is 0, 1, 2, 3, 4 or 5. [0006] In some embodiments, the compound of Formula (I), is a compound of Formula (II): Formula II wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl; L is absent or -C(=O)-; Ring B is selected from the group consisting of C3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, - OR ¹⁰ , -N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; D ² , D ⁴ , and D ⁵ are each independently selected from N and CR ^d each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C _1-6 alkoxy; wherein each substituted C _1-6 alkyl and substituted C _1-6 alkoxy is substituted with 1-5 instances of R ¹² ; R ¹ is hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C _3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C _1-6 alkyl, C _1- 6 alkoxy, and C1-6 haloalkyl; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(=O)OH, -C(=O)OC1-6 alkyl, -C(=O)C1-6 alkyl, -C(=O)NH2, -C(=O)NHC1-6 alkyl, -C(=O)N(C _1-6 alkyl) ₂ , -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -OH, OC _1-6 alkyl, - SH, -SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; m is 1, 2, or 3; r is 0, 1, 2, 3, 4 or 5; and t is 1, 2, 3, or 4. [0007] In some embodiments, the compound of Formula (I) is a compound of Formula (III): Formula III wherein: A ¹ and A ² are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C _1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; each R ^d is independently hydrogen, halogen, -CN, C _1-6 alkyl, or C _1-6 alkoxy; R ¹ is -CN, -OCH ₃ , or -OCF ₃ ; R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C _3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl, wherein the substituted C _3-6 cycloalkyl and the substituted C _2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; m is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, or 4. [0008] In some embodiments, the compound of Formula (I) is a compound of Formula (IV): Formula IV wherein: A ¹ and A ² are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C _1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; each R ^d is independently hydrogen, halogen, -CN, C1-6 alkyl, or C1-6 alkoxy; R ¹ is -CN, -OCH ₃ , or -OCF ₃ ; R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C _3-6 cycloalkyl and the substituted C _2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C1-6 haloalkyl; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; m is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, or 4. [0009] In some embodiments,the compound of Formula (I) is: 节 PS

, , , , or a pharmaceutically acceptable salt thereof, or a stereoisomer or a mixture of stereoisomers thereof. [0010] In some embodiments, provided herein is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; A ³ is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, and C _1-6 haloalkyl; X is -NH-L-; L is absent or -C(=O)-; Ring B is selected from the group consisting of C _3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , - OR ¹⁰ , -N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; Ring D is a 5-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; Ring F is a substituted or unsubstituted C _3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -C(O)NH ₂ , -C(O)NHC _1-6 alkyl, - C(O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, -OC1-6 alkyl, -SH, - SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; p is 0, 1, 2, 3, or 4; q is 0, 1 or 2; r is 0, 1, 2, 3, 4 or 5; and x is 0, 1, 2, 3, or 4. [0011] In some embodiments, the compound of Formula (V) is of Formula (VI): or a pharmaceutically acceptable salt thereof; wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; A ³ is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl; L is absent or -C(=O)-; Ring B is selected from the group consisting of C _3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , - OR ¹⁰ , -N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; D ² , D ⁴ , and D ⁵ are each independently selected from N and CR ^d ; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; Ring F is a substituted or unsubstituted C3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, -C(=O)OH, -C(=O)OC _1-6 alkyl, -C(=O)C _1-6 alkyl, -C(=O)NH ₂ , -C(=O)NHC _1-6 alkyl, -C(=O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, - SH, -SC _1-6 alkyl, -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, or -SO ₂ NHC _1-6 alkyl; q is 0, 1, 2, or 3; r is 0, 1, 2, 3, 4 or 5; and x is 0, 1, 2, 3, or 4. [0012] In some embodiments, the compound of Formula (V) is of Formula (VII): or a pharmaceutically acceptable salt thereof; wherein: A ¹ , A ² , and A ³ are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C _1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; each R ^d is independently hydrogen, halogen, -CN, C _1-6 alkyl, or C _1-6 alkoxy; R ¹ is -CN, -OCH ₃ , or -OCF ₃ ; Ring F is a substituted or unsubstituted C3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; R ¹² is selected from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, -C(=O)OH, - C(=O)OC1-6 alkyl, -C(=O)C1-6 alkyl, -C(=O)NH2, -C(=O)NHC1-6 alkyl, -C(=O)N(C1- 6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, -SH, -SC1-6 alkyl, - SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, or -SO ₂ NHC _1-6 alkyl; r is 0, 1, 2, 3, 4, or 5; and x is 0, 1, 2, 3, or 4. [0013] In some embodiments, the compound of Formula (V) is of Formula (VIII): or a pharmaceutically acceptable salt thereof; wherein: A ¹ , A ² , and A ³ are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C _1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; or two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; each R ^d is independently hydrogen, halogen, -CN, C1-6 alkyl, or C1-6 alkoxy; R ¹ is -CN, -OCH ₃ , or -OCF ₃ ; Ring F is a substituted or unsubstituted C3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; R ¹² is selected from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, -C(=O)OH, - C(=O)OC1-6 alkyl, -C(=O)C1-6 alkyl, -C(=O)NH2, -C(=O)NHC1-6 alkyl, -C(=O)N(C1- 6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, -SH, -SC1-6 alkyl, - SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, or -SO ₂ NHC _1-6 alkyl; r is 0, 1, 2, 3, 4, or 5; and x is 0, 1, 2, 3, or 4. [0014] In some embodiments, the compound of Formula (V) is:

pharmaceutically acceptable salt thereof, or a stereoisomer or a mixture of stereoisomers thereof. [0015] In another embodiment, provided herein is a compound having the structure: pharmaceutically acceptable salt thereof, or a stereoisomer or a mixture of stereoisomers thereof. [0016] In another embodiment is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII), or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. [0017] In another embodiment is a method of modulating JAK2 activity in a mammal comprising administering to the mammal a compound disclosed herein, or a pharmaceutically acceptable salt, or solvate thereof. In another embodiment is a method of treating a disease, disorder, or condition in a mammal that would benefit from the modulation of JAK2 activity comprising administering to the mammal a compound disclosed herein (e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII), or a pharmaceutically acceptable salt, or solvate thereof. In another embodiment is a method of manufacturing a pharmaceutical composition (alternatively, a medicament) comprising a compound disclosed herein (e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII), or a pharmaceutically acceptable salt thereof, for treating a disease, disorder, or condition in a mammal. In some embodiments, the disease, disorder, or condition is a disease, disorder, or condition in which aberrant JAK2 expression or activity contributes to the symptomology or progression of the disease. In some embodiments, the disease, disorder, or condition is a hyperproliferative disease. In some embodiments, the disease, disorder, or condition is a cancer. In some embodiments, the disease, disorder, or condition is a hematological malignancy and/or a myeloproliferative neoplasm. [0018] Other objects, features, and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION [0019] Janus kinases (JAK1, JAK2, JAK3, and TYK2) are a family of non-receptor tyrosine kinases that may have important roles in the regulation of hematopoeisis, the immune system, and cellular metabolism. JAKs can interact with certain cytokine receptors and can couple cytokine binding to cytoplasmic signaling cascades, including the signal transducers and activators of transcription (STAT) pathway. In addition to a canonical tyrosine kinase domain (JH1) located in the C-terminal region, JAK proteins also contain a pseudokinase domain (JH2). [0020] Both JH1 and JH2 contain an ATP binding site, but catalytic activity is believed to come predominantly from JH1, as JH2 lacks essential residues for phosphorylation catalysis. However, JH2 mediates critical regulatory functions in JAKs and is believed to primarily serve to inhibit basal JH2 activity. Mutations to JH2 may therefore, in some instances, lead to kinase hyperactivity. For example, a V617F mutation to the JH2 domain of JAK2 may promote constitutive activation of the JAK-STAT pathway, and may play a causative role in various myeloproliferative disorders. The V617F mutation is found 95% of patients with polycythemia vera, as well as ~60% of patients with essential thrombocythemia and primary myelofibrosis. JAK2 hyperactivation is also associated with several leukemias and lymphomas. [0021] A modulator of JAK2 kinase activity (e.g., a JAK2 inhibitor disclosed herein) may be effective in treating a disease associated with JAK-STAT hyperactivity. Therefore, a JAK2 modulator capable of reducing JH1 activity and/or promoting JH2 regulatory function could be useful in restoring or treating aberrant JAK2-mediated signaling, and in treating diseases associated therewith. [0022] Provided herein, in one aspect, is a compound that inhibits JAK2 kinase activity (i.e., a JAK2 inhibitor). In some embodments, the compound is a selective JAK2 inhibitor. In some embodiments, the compound is a non-selective inhibitor of JAKs. In some embodiments, the compound inhibits JAK2 kinase activity with selectivity over another member of the JAK family. For example, in some embodiments, a compound may be selective for JAK2 over JAK1, but not JAK3 or TYK2. In some embodiments, a compound disclosed herein is selective for JAK2 over JAK1, JAK3, and TYK2. In some embodiments, a compound disclosed herein is at least about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more selective for JAK2 over JAK1, JAK3, and/or TYK2. [0023] In some embodiments, the compound is a small molecule inhibitor of JAK2. In some embodiments, the compound modulates JH1 activity. In some embodiments, the compound modulates JH2 activity. In some embodiments, the compound binds a kinase domain (JH1). In some embodiments, the compound binds a pseudokinase domain (JH2). In some embodiments, the compound is a selective JH2 modulator. In some embodiments, the compound is a selective JAK2 JH2 modulator. In some embodiments, the compound is selective for JH2 over JH1. In some embodiments, the compound is at least about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20- fold, 50-fold, 100-fold, 1000-fold, or more selective for JH2 over JH1. In some embodiments, the compound is selective for the JH2 of JAK2 over the JH2 of JAK1, JAK3, or TYK2. [0024] In some embodiments, the compound comprises 5 or more rings (e.g., Ring A, Ring B, Ring C, Ring D, and Ring E, etc.), wherein each ring is a substituted or unsubstituted monocyclic carbocycle or a substituted or unsubstituted monocyclic heterocycle. In some embodiments, the compound comprises 5 or more rings, wherein one or more rings is a substituted or unsubstituted bicyclic carbocycle or a substituted or unsubstituted bicyclic heterocycle. In some embodiments, the bicyclic carbocycle or bicyclic heterocycle promotes binding to JAK2 JH2, and/or diminishes binding to JH1 and/or JH2 of JAK1, JAK3, and/or TYK2. In some embodiments, provided herein is a selective JAK2 inhibitor. In some embodiments, provided herein is a selective JAK2 pseudokinase domain (JH2) inhibitor. In some embodiments, provided herein is a compound having the structure of any one or more of the formulae disclosed herein, or a pharmaceutically acceptable salt thereof. Compounds [0025] Provided herein, in one aspect, is a compound having the structure of any one of the formulae disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure of Formula (0) or (00) disclosed herein. In some embodiments, the compound has the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-C), Formula (I-D), Formula (I-E), Formula (I-F), Formula (I-G), Formula (I-H), Formula (II), Formula (III), or Formula (IV). In some embodiments, the compound has the structure of Formula (V), Formula (V-A), Formula (V-B), Formula (V-C), Formula (V-D), Formula (VI), Formula (VII), Formula (VIII), Formula (VIII-A), or Formula (VIII-B). [0026] In another aspect, provided herein is a compound that is a JAK2 inhibitor. In some embodiments, the compound is a JAK2 pseudokinase domain (JH2) inhibitor. In some embodiments, the compound has the structure of any one of the formulae disclosed herein, or a pharmaceutically acceptable salt thereof. [0027] In one embodiment, provided herein is a compound of Formula (0):

or a pharmaceutically acceptable salt thereof; wherein: Ring A is a substituted or unsubstituted monocyclic heteroaryl; Ring B is a substituted or unsubstituted monocyclic carbocycle or a substituted or unsubstituted monocyclic heterocycle; Ring C is a substituted or unsubstituted monocyclic aryl or a substituted or unsubstituted monocyclic heteroaryl; Ring D is a substituted or unsubstituted heterocycle; Ring E is a substituted or unsubstituted bicyclic carbocycle, or a substituted or unsubstituted bicyclic heterocycle; X is -NH-L-; and L is absent or -C(=O)-. [0028] In another embodiment, provided herein is a compound of Formula (0), or a pharmaceutically acceptable salt thereof, wherein: Ring A is a substituted or unsubstituted 6-membered monocyclic heteroaryl; Ring B is a substituted or unsubstituted C _3-6 cycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered heteroaryl; Ring C is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 6- membered monocyclic heteroaryl; Ring D is a substituted or unsubstituted 5- or 6-membered heterocycle; and Ring E is a substituted or unsubstituted bicyclic spirocyclic C7-12 cycloalkyl, or a substituted or unsubstituted bicyclic spirocyclic 7- to 12-membered heterocycloalkyl; or Ring E is a substituted or unsubstituted bridged bicyclic C _7-12 cycloalkyl, or a substituted or unsubstituted bridged bicyclic 7- to 12-membered heterocycloalkyl; or Ring E is a substituted or unsubstituted fused bicyclic C7-12 cycloalkyl, or a substituted or unsubstituted fused bicyclic 7- to 12-membered heterocycloalkyl; X is -NH-L-; and L is absent or -C(=O)-. [0029] In some embodiments, X is -NH- (i.e., L is absent). In some embodiments, X is - NHC(=O)-. [0030] In some embodiments, Ring A is a substituted or unsubstituted monocyclic heteroaryl. In some embodiments, Ring A is a substituted or unsubstituted 6-membered monocyclic heteroaryl. In some embodiments, Ring A is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, a substituted or unsubstituted pyridazine, or a substituted or unsubstituted pyrazine. In some embodiments, Ring A is a substituted or unsubstituted pyridine. In some embodiments, Ring A is a substituted or unsubstituted pyrimidine. In some embodiments, Ring A is a substituted or unsubstituted pyridazine. In some embodiments, Ring A is a substituted or unsubstituted pyrazine. In other embodiments, Ring A is a substituted or unsubstituted phenylene. [0031] In some embodiments, Ring A is: . ^[0032] In some embodiments, A ¹ is N or CR ^a . In some embodiments, A ¹ is N. In some embodiments, A ¹ is CR ^a . In some embodiments, A ² is N or CR ^a . In some embodiments, A ² is N. In some embodiments, A ² is CR ^a . In some embodiments, each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R ^a is independently hydrogen, deuterium, halogen, -CN, or methyl. In some embodiments, each R ^a is hydrogen. In some embodiments, A ¹ is CH. In some embodiments, A ² is CH. [0033] In some embodiments, Ring A is: wherein: A ¹ is CH; and A ² is CH; or A ¹ is CH; and A ² is N; or A ¹ is N; and A ² is CH. [0034] In some embodiments, A ¹ is CH; and A ² is CH. In some embodiments, A ¹ is CH; and A ² is N. In some embodiments, A ¹ is N; and A ² is CH. In some embodiments, A ¹ is N; and A ² is N. In some embodiments, Ring A is (A1), (A2), or (A3): [0035] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: Ring C is a substituted or unsubstituted phenylene, wherein if Ring C is substituted, then it is substituted with R ¹ and q instances of R ² ; R ¹ is hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; and q is 0, 1, or 2. [0036] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, provided herein is a compound of Formula (0), or a pharmaceutically acceptable salt thereof; wherein: Ring C is a substituted phenylene; R ¹ is halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, or -OR ¹⁰ ; each R ² is independently halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, or -OR ¹⁰ ; each R ¹⁰ is independently a substituted or unsubstituted C _1-6 alkyl; and q is 1 or 2. [0037] In some embodiments, provided herein is a compound wherein: Ring C is a substituted phenylene; R ¹ is halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, or -OR ¹⁰ ; each R ¹⁰ is independently a substituted or unsubstituted C _1-6 alkyl; and q is 0. ^[0038] In some embodiments, R ¹ is halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, or -OR ¹⁰ ; and R ¹⁰ is a substituted or unsubstituted C _1-6 alkyl. In some embodiments, R ¹ is -CN or -OR ¹⁰ ; and R ¹⁰ is a substituted or unsubstituted C1-6 alkyl. In some embodiments, R ¹ is -CN, -O(C1-6 alkyl); wherein the C1-6 alkyl is unsubstituted or is substituted with 1, 2, or 3 halogen atoms. In some embodiments, R ¹ is -CN, -O(C _1-6 alkyl), or -O(C _1-6 haloalkyl). In some embodiments, R ¹ is -CN. In some embodiments, R ¹ is -O(C _1-6 alkyl) or -O(C _1-6 haloalkyl). In some embodiments, R ¹ is - O(C1-6 alkyl). In some embodiments, R ¹ is -O(C1-6 haloalkyl). In some embodiments, R ¹ is - OCH ₃ , -OCH ₂ F, -OCHF ₂ , or -OCF _3. In some embodiments, R ¹ is -OCH ₃ or -OCF _3. In some embodiments, R ¹ is -OCF _3. In some embodiments, R ¹ is -OCH ₃ . _. [0039] In some embodiments, Ring C is: wherein: R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; and q is 0, 1, or 2. [0040] In some embodiments, Ring C is: wherein R ¹ is -CN, -O(C1-6 alkyl), or -O(C1-6 haloalkyl); and q is 0. [0041] In some embodiments, Ring C is (C1), (C2), or (C3): [0042] In another aspect, provided herein is a compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, and C _1-6 haloalkyl; X is -NH-L-; L is absent or -C(=O)-; Ring B is selected from the group consisting of C3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, - OR ¹⁰ , -N(R ¹⁰ ) ₂ , -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C _3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; Ring D is a 5- or 6-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; Ring E is a substituted or unsubstituted C _7-12 bicyclic carbocycle, or a substituted or unsubstituted 7- to 12-membered bicyclic heterocycle; R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -C(O)NH ₂ , -C(O)NHC _1-6 alkyl, - C(O)N(C _1-6 alkyl) ₂ , -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -OH, OC _1-6 alkyl, -SH, - SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; p is 0, 1, 2, 3, or 4; q is 0, 1 or 2; and r is 0, 1, 2, 3, 4 or 5. [0043] In some embodiments, Ring E is a substituted or unsubstituted C7-12 bicyclic carbocycle, or a substituted or unsubstituted 7- to 12-membered bicyclic heterocycle. [0044] In some embodiments, Ring E is a substituted or unsubstituted C7-12 spirocyclic bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered spirocyclic bicyclic heterocycle; or Ring E is a substituted or unsubstituted C _7-12 bridged bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered bridged bicyclic heterocycle; or Ring E is a substituted or unsubstituted C7-12 fused bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered fused bicyclic heterocycle. [0045] In some embodiments, Ring E is a substituted or unsubstituted C _7-12 fused bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered fused bicyclic heterocycle. In some embodiments, Ring E is a substituted or unsubstituted C7-12 spirocyclic bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered spirocyclic bicyclic heterocycle; or Ring E is a substituted or unsubstituted C7-12 bridged bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered bridged bicyclic heterocycle. In some embodiments, Ring E is a substituted or unsubstituted C _7-12 bridged bicyclic cycloalkyl or a substituted or unsubstituted 7- to 12-membered bridged bicyclic heterocycloalkyl. In some embodiments, Ring E is a substituted or unsubstituted C7-12 spirocyclic bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered spirocyclic bicyclic heterocycle. In some embodiments, Ring E is a substituted or unsubstituted C _7-12 spirocyclic cycloalkyl, or a substituted or unsubstituted 7- to 12-membered spirocyclic heterocycloalkyl. [0046] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: Ring E is a spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, or spiro[5.5]undecane; or Ring E is a 1-oxaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 5-oxaspiro[3.4]octane, 6- oxaspiro[3.4]octane, 5-oxaspiro[3.5]nonane, 6-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 1-oxaspiro[3.4]octane, 2-oxaspiro[3.4]octane, 1- oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 5-oxaspiro[3.5]nonane, 6- oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 6-oxa-spiro[4.5]decane, 7-oxa- spiro[4.5]decane, 8-oxa-spiro[4.5]decane, 1-oxaspiro[5.5]undecane, 2- oxaspiro[5.5]undecane, or 3-oxaspiro[5.5]undecane; or Ring E is a 1-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 5-azaspiro[3.4]octane, 6- azaspiro[3.4]octane, 5-azaspiro[3.5]nonane, 6-azaspiro[3.5]nonane, 7- azaspiro[3.5]nonane, 1-azaspiro[3.4]octane, 2-azaspiro[3.4]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 5-azaspiro[3.5]nonane, 6- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 6-azaspiro[4.5]decane, 7-aza- spiro[4.5]decane, 8-aza-spiro[4.5]decane, 1azaspiro[5.5]undecane, 2- azaspiro[5.5]undecane, or 3-azaspiro[5.5]undecane; wherein Ring E is substituted or unsubstituted. [0047] In some embodiments, provided herein is a compound wherein Ring E is a substituted or unsubstituted spiro[3.3]heptane, a substituted or unsubstituted spiro[3.4]octane, a substituted or unsubstituted spiro[3.5]nonane, a substituted or unsubstituted spiro[4.4]nonane, a substituted or unsubstituted spiro[4.5]decane, or a substituted or unsubstituted spiro[5.5]undecane. [0048] In some embodiments, provided herein is a compound wherein Ring E is a substituted or unsubstituted 1-oxaspiro[3.3]heptane, a substituted or unsubstituted 2-oxaspiro[3.3]heptane, a substituted or unsubstituted 5-oxaspiro[3.4]octane, a substituted or unsubstituted 6- oxaspiro[3.4]octane, a substituted or unsubstituted 5-oxaspiro[3.5]nonane, a substituted or unsubstituted 6-oxaspiro[3.5]nonane, a substituted or unsubstituted 7-oxaspiro[3.5]nonane, a substituted or unsubstituted 1-oxaspiro[3.4]octane, a substituted or unsubstituted 2- oxaspiro[3.4]octane, a substituted or unsubstituted 1-oxaspiro[3.5]nonane, a substituted or unsubstituted 2-oxaspiro[3.5]nonane, a substituted or unsubstituted 5-oxaspiro[3.5]nonane, a substituted or unsubstituted 6-oxaspiro[3.5]nonane, a substituted or unsubstituted 7- oxaspiro[3.5]nonane, a substituted or unsubstituted 6-oxa-spiro[4.5]decane, a substituted or unsubstituted 7-oxa-spiro[4.5]decane, a substituted or unsubstituted 8-oxa-spiro[4.5]decane, a substituted or unsubstituted 1-oxaspiro[5.5]undecane, a substituted or unsubstituted 2- oxaspiro[5.5]undecane, or a substituted or unsubstituted 3-oxaspiro[5.5]undecane. [0049] In some embodiments, provided herein is a compound wherein Ring E is a substituted or unsubstituted 1-azaspiro[3.3]heptane, a substituted or unsubstituted 2-azaspiro[3.3]heptane, a substituted or unsubstituted 5-azaspiro[3.4]octane, a substituted or unsubstituted 6- azaspiro[3.4]octane, a substituted or unsubstituted 5-azaspiro[3.5]nonane, a substituted or unsubstituted 6-azaspiro[3.5]nonane, a substituted or unsubstituted 7-azaspiro[3.5]nonane, a substituted or unsubstituted 1-azaspiro[3.4]octane, a substituted or unsubstituted 2- azaspiro[3.4]octane, a substituted or unsubstituted 1-azaspiro[3.5]nonane, a substituted or unsubstituted 2-azaspiro[3.5]nonane, a substituted or unsubstituted 5-azaspiro[3.5]nonane, a substituted or unsubstituted 6-azaspiro[3.5]nonane, a substituted or unsubstituted 7- azaspiro[3.5]nonane, a substituted or unsubstituted 6-azaspiro[4.5]decane, a substituted or unsubstituted 7-aza-spiro[4.5]decane, a substituted or unsubstituted 8-aza-spiro[4.5]decane, a substituted or unsubstituted 1-azaspiro[5.5]undecane, a substituted or unsubstituted 2- azaspiro[5.5]undecane, or a substituted or unsubstituted 3-azaspiro[5.5]undecane. [0050] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: ^; wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C1-6 haloalkyl; R ⁶ is selected from hydrogen, deuterium, halogen, -OH, CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C _1-6 haloalkoxy; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. [0051] In some embodiments, R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl. [0052] In some embodiments, R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a Ring E’, wherein Ring E’ is a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl; wherein the substituted C _3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ . [0053] In some embodiments, Ring E’ is a substituted or unsubstituted C3-6 cycloalkyl. In some embodiments, Ring E’ is a substituted or unsubstituted cyclopropane. In some embodiments, Ring E’ is a substituted or unsubstituted cyclobutane. In some embodiments, Ring E’ is a substituted or unsubstituted cyclopentane. In some embodiments, Ring E’ is a substituted or unsubstituted cyclohexane. In some embodiments, Ring E’ is a substituted or unsubstituted C _2-6 heterocycloalkyl. In some embodiments, Ring E’ is a substituted or unsubstituted 4-, 5-, or 6-membered heterocycloalkyl. [0054] In some embodiments, Ring E’ is a substituted or unsubstituted 4-membered heterocycloalkyl. In some embodiments, Ring E’ is a substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted thietane, substituted or unsubstituted 1,3-diazetidine, or a substituted or unsubstituted 1,3-dioxetane. In some embodiments, Ring E’ is a substituted or unsubstituted azetidine. In some embodiments, Ring E’ is a substituted or unsubstituted oxetane. [0055] In some embodiments, Ring E’ is a substituted or unsubstituted 5-membered heterocycloalkyl. In some embodiments, Ring E’ is a substituted or unsubstituted pyrrolidine, substituted or unsubstituted tetrahydrofuran, substituted or unsubstituted tetrahydrothiophene, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazolidine, substituted or unsubstituted oxazolidine, substituted or unsubstituted isoxazolidine, or a substituted or unsubstituted dioxolane. In some embodiments, Ring E’ is a substituted or unsubstituted tetrahydrofuran. In some embodiments, Ring E’ is a substituted or unsubstituted dioxolane. [0056] In some embodiments, Ring E’ is a substituted or unsubstituted 6-membered heterocycloalkyl. In some embodiments, Ring E’ is a substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted piperazine, substituted or unsubstituted morpholine, or a substituted or unsubstituted dioxane, (e.g., 1,3-dioxane, 1,4- dioxane, etc.). In some embodiments, Ring E’ is a substituted or unsubstituted tetrahydropyran. In some embodiments, Ring E’ is a substituted or unsubstituted 1,3-dioxane. [0057] In some embodiments, Ring E’ is a substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted thietane, substituted or unsubstituted 1,3- diazetidine, substituted or unsubstituted 1,3-dioxetane, substituted or unsubstituted pyrrolidine, substituted or unsubstituted tetrahydrofuran, substituted or unsubstituted tetrahydrothiophene, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazolidine, substituted or unsubstituted oxazolidine, substituted or unsubstituted isoxazolidine, substituted or unsubstituted dioxolane, substituted or unsubstituted piperidine, substituted or unsubstituted tetrahydropyran, substituted or unsubstituted piperazine, substituted or unsubstituted morpholine, or a substituted or unsubstituted dioxane, (e.g., 1,3-dioxane, 1,4-dioxane, etc.). [0058] In some embodiments, each R ⁵ is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C _1-6 alkyl, C _1-6 alkoxy, and C _1-6 haloalkyl. In some embodiments, each R ⁵ is independently hydrogen, deuterium, halogen, -CN, -CH3, or -CF3. In some embodiments, each R ⁵ is independently hydrogen, halogen, -CN, or -CH3. In some embodiments, each R ⁵ is independently hydrogen, halogen, C _1-6 alkyl, or C _1-6 haloalkyl. In some embodiments, each R ⁵ is independently hydrogen, halogen, -CH3, or -CF3. In some embodiments, each R ⁵ is independently hydrogen, halogen, or -CH3. In some embodiments, each R ⁵ is independently hydrogen or halogen. In some embodiments, each R ⁵ is hydrogen. In some embodiments, each R ⁵ is halogen. In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is halogen. In some embodiments, R ⁵ is -F. In some embodiments, R ⁶ is halogen. In some embodiments, R ⁶ is fluorine. In some embodiments, R ⁶ is selected from C _1-6 alkoxy and C _1-6 haloalkoxy. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ⁶ is -OCH ₃ . In some embodiments, R ⁶ is -OCD3. In some embodiments, R ⁶ is -OCF3. [0059] In some embodiments, t is 0, 1, or 2. In some embodiments, t is 2. In some embodiments, t is 0 or 1. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2 and each R ⁵ is independently halogen or -CH ₃ . In some embodiments, t is 1 and R ⁵ is halogen, -CN, or -CH3. In some embodiments, t is 0. [0060] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: m is 0, 1, 2, or 3; and n is 0, 1, or 2. [0061] In some embodiments, Ring E is: wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; R ⁶ is selected from hydrogen, deuterium, halogen, -OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; m is 0, 1, 2, or 3; and n is 0, 1, or 2. [0062] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1 or 2. In some embodiments, m is 0, 1, or 2; and n is 1 or 2. [0063] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: m is 0, 1, 2, or 3; and n is 2. [0064] In some embodiments, m is 0 or 1; and n is 2. In some embodiments, m is 0; and n is 2. In some embodiments, m is 1; and n is 2. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C _3-6 cycloalkyl and the substituted C _2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; m is 0 or 1; and t is 0, 1, 2, 3, or 4. [0065] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: m is 0, 1, 2, or 3; and n is 1. [0066] In some embodiments, m is 0, 1, or 2; and n is 1. In some embodiments, m is 1 or 2; and n is 1. In some embodiments, m is 1; and n is 1. In some embodiments, m is 2; and n is 1. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C _3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl, wherein the substituted C _3-6 cycloalkyl and the substituted C _2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; m is 0, 1, or 2; and t is 0, 1, 2, 3, or 4. [0067] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: n is 0. [0068] In some embodiments, m is 0, 1, 2, or 3; and n is 0. In some embodiments, m is 0, 1, or 2; and n is 0. In some embodiments, m is 1, 2, or 3; and n is 0. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C _3-6 cycloalkyl and the substituted C _2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; m is 0, 1, 2, 3, or 4; and t is 0, 1, 2, 3, or 4. [0069] In some embodiments, the compound is a compound of Formula (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof; wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl; X is -NH-L-; L is absent or -C(=O)-; Ring B is selected from the group consisting of C _3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , - OR ¹⁰ , -N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; Ring D is a 5- or 6-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from deuterium, halogen, CN, C _1-6 alkyl, C _1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -OH, and -OR ¹⁰ ; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -C(O)NH ₂ , -C(O)NHC _1-6 alkyl, - C(O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, -SH, - SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0, 1 or 2; r is 0, 1, 2, 3, 4 or 5; and t is 0, 1, 2, 3, or 4. [0070] In some embodiments, the compound is a compound of Formula (I-A’) or (I-B’):

or a pharmaceutically acceptable salt thereof. [0071] In some embodiments, n is 0. In some embodiments, the compound is a compound of Formula (I-C) or (I-D), or a pharmaceutically acceptable salt thereof: . [0072] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is (i.e., is): wherein: each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; m is 0, 1, 2, or 3; t is 0, 1, 2, 3, or 4; u is 1, 2, or 3; v is 0, 1, or 2; and w is 0, 1, 2, or 3. [0073] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C1-6 haloalkyl; m is 0, 1, 2, or 3; t is 0, 1, 2, 3, or 4; v is 0, 1, or 2; and w is 0, 1, 2, or 3. [0074] In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0. In some embodiments, v is 1 or 2. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, w is 0, 1, 2, or 3. In some embodiments, w is 0. In some embodiments, w is 1, 2, or 3. In some embodiments, w is 3. In some embodiments, w is 1 or 2. In some embodiments, w is 1. In some embodiments, w is 2. [0075] In some embodiments: m is 1; v is 0; and w is 1; or m is 1; v is 0; and w is 2; or m is 1; v is 0; and w is 3; or m is 2; v is 0; and w is 1; or m is 2; v is 0; and w is 2; or m is 2; v is 0; and w is 3; or m is 3; v is 0; and w is 1; or m is 3; v is 0; and w is 2; or m is 3; v is 0; and w is 3. [0076] In some embodiments: m is 1; v is 1; and w is 0; or m is 1; v is 1; and w is 1; or m is 1; v is 1; and w is 2; or m is 2; v is 1; and w is 0; or m is 2; v is 1; and w is 1; or m is 2; v is 1; and w is 2; or m is 3; v is 1; and w is 0; or m is 3; v is 1; and w is 1; or m is 3; v is 1; and w is 2. [0077] In some embodiments: m is 1; v is 2; and w is 0; or m is 1; v is 2; and w is 1; or m is 2; v is 2; and w is 0; or m is 2; v is 2; and w is 1; or m is 3; v is 2; and w is 0; or m is 3; v is 2; and w is 1. [0078] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; m is 0, 1, 2, or 3; and t is 0, 1, 2, 3, or 4. [0079] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: [0080] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: [0081] In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 2; and t is 0 or 1. In some embodiments, m is 1 or 2; and t is 0. In some embodiments, m is 1; and t is 0. [0082] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is (E1): . [0083] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: . [0084] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: [0085] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: . [0086] In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 2; and t is 0 or 1. In some embodiments, m is 1 or 2; and t is 0. In some embodiments, m is 1; and t is 0. [0087] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: [0088] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: . [0089] In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 2; and t is 0 or 1. In some embodiments, m is 1 or 2; and t is 0. In some embodiments, m is 1; and t is 0. [0090] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: [0091] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: . [0092] In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 2; and t is 0 or 1. In some embodiments, m is 1 or 2; and t is 0. In some embodiments, m is 1; and t is 0. In some embodiments, m is 2; and t is 0. [0093] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: [0094] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is (E2), (E3), or (E4): [0095] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is:

[0096] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: wherein: each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C _1-6 alkyl, C _1- 6 alkoxy, and C1-6 haloalkyl; m is 0, 1, 2 or 3; t is 0, 1, 2, 3, or 4; and u is 1 or 2. [0097] In some embodiments, u is 1 or 2. In some embodiments, u is 1. In some embodiments: m is 1; and u is 1; or m is 1; and u is 2; or m is 2; and u is 1; or m is 2; and u is 2; or m is 3; and u is 1; or m is 3; and u is 2. [0098] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: wherein: each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; m is 0, 1, 2, or 3; and t is 0, 1, 2, 3, or 4. [0099] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: [00100] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is (E5) or (E6): [00101] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: . [00102] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: , [00103] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C _3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl, wherein the substituted C _3-6 cycloalkyl and the substituted C _2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; m is 0, 1, 2, or 3; n is 0, 1, or 2; and t is 0, 1, 2, 3, or 4. [00104] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C _3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C _1-6 alkyl, C _1- 6 alkoxy, and C1-6 haloalkyl; m is 0, 1, or 2; and t is 0, 1, 2, 3, or 4. [00105] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. [00106] In some embodiments, R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C _3-6 cycloalkyl; wherein the substituted C3-6 cycloalkyl is substituted with t instances of R ⁵ . In some embodiments, R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cyclopropyl; wherein the substituted cyclopropyl is substituted with t instances of R ⁵ . [00107] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: (e.g., or ). [00108] In some embodiments, Ring E is (E7): . [00109] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: ( g, ) [00110] In some embodiments, Ring E is (E8): . (E8) [00111] In some embodiments, Ring E is: wherein: R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C1-6 haloalkyl; R ⁶ is selected from deuterium, halogen, -OH, CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C1-6 haloalkoxy; m is 0, 1, 2, or 3; [00112] In some embodiments, wherein: each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; R ⁶ is selected from deuterium, halogen, -OH, CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C1-6 haloalkoxy; m is 0, 1, 2, or 3; t is 0, 1, 2, 3, or 4; v is 0, 1, or 2; and w is 0, 1, 2, or 3. [00113] In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0. In some embodiments, v is 1 or 2. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, w is 0, 1, 2, or 3. In some embodiments, w is 0. In some embodiments, w is 1, 2, or 3. In some embodiments, w is 3. In some embodiments, w is 1 or 2. In some embodiments, w is 1. In some embodiments, w is 2. [00114] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring E is: , , , [00115] In some embodiments, Ring E is a substituted or unsubstituted C7-12 bridged bicyclic carbocycle or a substituted or unsubstituted 7- to 12-membered bridged bicyclic heterocycle. In some embodiments, Ring E is a substituted or unsubstituted C _7-12 bridged bicyclic carbocycle. In some embodiments, Ring E is a substituted or unsubstituted C _7-12 bridged bicyclic cycloalkyl. In some embodiments, Ring E is a substituted or unsubstituted 7- to 12-membered bridged bicyclic heterocycle. In some embodiments, Ring E is a substituted or unsubstituted 7- to 12-membered bridged bicyclic heterocycloalkyl. [00116] In some embodiments, Ring E is a substituted or unsubstituted C7-12 fused bicyclic carbocycle. In some embodiments, Ring E is a substituted or unsubstituted C7-12 fused bicyclic cycloalkyl. In some embodiments, Ring E is a substituted or unsubstituted 7- to 12-membered fused bicyclic heterocycle. In some embodiments, Ring E is a substituted or unsubstituted 7- to 12-membered fused bicyclic heterocycloalkyl. [00117] In some embodiments, Ring E is: . In some embodiments, Ring E is [00118] In some embodiments, Ring D is a substituted or unsubstituted 5- or 6-membered heterocycloalkyl, or a substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, Ring D is an unsubstituted 5- or 6-membered heterocycloalkyl, or an unsubstituted 5- or 6-membered heteroaryl. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: Ring D is a substituted 5- or 6-membered heterocycloalkyl, or a substituted 5- or 6- membered heteroaryl; wherein the substituted 5- or 6-membered heterocycloalkyl and the substituted 5- or 6- membered heteroaryl are each substituted with p instances of R ^d ; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; each R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, - C(O)OH, -C(O)OC1-6 alkyl, -C(O)C1-6 alkyl, -C(O)NH2, -C(O)NHC1-6 alkyl, - C(O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, -SH, - SC _1-6 alkyl, -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, or -SO ₂ NHC _1-6 alkyl; and p is 0, 1, 2, 3, or 4. [00119] In some embodiments, Ring D is a substituted or unsubstituted 5- or 6-membered heterocycloalkyl. In some embodiments, Ring D is a substituted or unsubstituted 5- or 6- membered heteroaryl. In some embodiments, Ring D is a substituted or unsubstituted 6- membered heterocycloalkyl, or a substituted or unsubstituted 6-membered heteroaryl. In some embodiments, Ring D is a substituted or unsubstituted 5-membered heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. [00120] In some embodiments, Ring D is a substituted or unsubstituted 5-membered heterocycloalkyl. In some embodiments, Ring D is a substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazolidine, or substituted or unsubstituted tetrahydrofuran. [00121] In some embodiments, Ring D is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, Ring D is a substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted triazole, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted thiazole, or a substituted or unsubstituted thiadiazole. In some embodiments, Ring D is a substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, or a substituted or unsubstituted thiazole. In some embodiments, Ring D is a substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, or a substituted or unsubstituted thiazole. In some embodiments, Ring D is a substituted or unsubstituted thiazole. In some embodiments, Ring D is a substituted or unsubstituted pyrazole, or a substituted or unsubstituted imidazole. In some embodiments, Ring D is a substituted or unsubstituted pyrazole. In some embodiments, Ring D is a substituted or unsubstituted imidazole. [00122] In some embodiments, Ring D is: wherein each of D ¹ , D ² , D ³ , D ⁴ , and D ⁵ are selected from C, N, O, and S, each of which may be further substituted by R ^d . [00123] In some embodiments, Ring D is: wherein: D ² is CR ^d or N; D ⁴ is CR ^d or N; and D ⁵ is CR ^d or N. [00124] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: wherein: D ² , D ⁴ , and D ⁵ are each independently selected from N and CR ^d ; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; each R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, - C(O)OH, -C(O)OC1-6 alkyl, -C(O)C1-6 alkyl, -C(O)NH2, -C(O)NHC1-6 alkyl, - C(O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, -SH, - SC _1-6 alkyl, -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, or -SO ₂ NHC _1-6 alkyl; and p is 0, 1, or 2. [00125] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: wherein: each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² . [00126] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: wherein: D ² is CR ^d ; D ⁴ is CR ^d ; and D ⁵ is CR ^d ; or D ² is N; D ⁴ is CR ^D ; and D ⁵ is CR ^d ; or D ² is CR ^d ; D ⁴ is N; and D ⁵ is CR ^d ; or D ² is CR ^d ; D ⁴ is CR ^d ; and D ⁵ is N; or D ² is N; D ⁴ is CR ^d ; and D ⁵ is N; and each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² . [00127] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: wherein: D ² is CR ^d ; and D ⁴ is CR ^d ; or D ² is N; and D ⁴ is CR ^d ; or D ² is CR ^d ; and D ⁴ is N; and each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² . [00128] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: wherein: D ² is N; and D ⁵ is CR ^d ; or D ² is CR ^d ; and D ⁵ is N; and each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² . [00129] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: wherein: D ² is NR ^d , O, or S; D ⁴ is CR ^d or N; D ⁵ is CR ^d or N; and each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² . [00130] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: , wherein: each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² . [00131] In some embodiments, . some embodiments, each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C _1-6 haloalkyl. In some embodiments, R ^d is substituted C _1-6 alkyl or substituted C _1-6 alkoxy. In some embodiments, R ¹² is hydrogen, deuterium, halogen, -CN, C _1-6 alkyl. In some embodiments, R ^d is C1-6 alkyl or C1-6 alkoxy. In some embodiments, R ^d is C1-6 alkyl or C1-6 alkoxy, wherein the C1-6 alkyl or C1-6 alkoxy are substituted with 1, 2, or 3 R ¹² ; and wherein each R ¹² is selected from deuterium, halogen, -CN, C _1-6 alkyl. In some embodiments, each R ^d is independently selected from hydrogen, halogen, -CN, and -CH3. In some embodiments, R ^d is hydrogen or halogen. In some embodiments, R ^d is hydrogen. In some embodiments, R ^d is halogen. In some embodiments, R ^d is fluorine. In some embodiments, R ^d is chlorine. In some embodiments, R ^d is -CN. In some embodiments, R ^d is methyl. [00132] In some embodiments, Ring D is: , , , . (D1) (D2) (D3) (D4) [00133] In some embodiments, the compound is a compound of Formula (I-E) or (I-F): [00134] In some embodiments, X is -NH-L-; and L is absent or -C(=O)-. In some embodiments, X is -NH- or -NH-C(=O)-. In some embodiments, L is absent. In some embodiments, X is -NH-. In some embodiments, X is -NH-L-; and L is absent. In some embodiments, X is -NH-; and Ring B is 6-membered heteroaryl or phenyl. In some embodiments, L is -C(=O)-. In some embodiments, X is -NH-L-; and L is -C(=O)-. In some embodiments, X is -NH-C(=O)-. In some embodiments, X is -NH-C(=O)-; and Ring B is C3-6 cycloalkyl. [00135] In some embodiments, X is -NH- and Ring B is 6-membered heteroaryl or phenyl; or X is -NHC(O)- and Ring B is C _3-6 cycloalkyl. In some embodiments, X is -NH- and Ring B is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, or a substituted or unsubstituted phenyl. In some embodiments, X is -NHC(O)- and Ring B is a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cyclohexyl. In some embodiments, X is -NH- and Ring B is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrimidine, or a substituted or unsubstituted phenyl; or X is -NHC(O)- and Ring B is a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a substituted or unsubstituted cyclohexyl. [00136] In some embodiments, the compound is a compound of Formula (II): Formula II or a pharmaceutically acceptable salt thereof; wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl; L is absent or -C(=O)-; Ring B is selected from the group consisting of C _3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, - OR ¹⁰ , -N(R ¹⁰ ) ₂ , -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C _3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C1-6 haloalkyl; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(=O)OH, -C(=O)OC _1-6 alkyl, -C(=O)C _1-6 alkyl, -C(=O)NH ₂ , -C(=O)NHC _1-6 alkyl, -C(=O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, - SH, -SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; m is 1, 2, or 3; q is 0, 1, or 2; r is 0, 1, 2, 3, 4 or 5; and t is 1, 2, 3, or 4. [00137] In some embodiments, Ring B is a substituted or unsubstituted monocyclic carbocycle or a substituted or unsubstituted monocyclic heterocycle. In some embodiments, Ring B is a substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or substituted or unsubstituted 5- to 6- membered heteroaryl. [00138] In some embodiments, Ring B is a substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted 6-membered heteroaryl. In some embodiments, Ring B is a substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, or a substituted or unsubstituted pyrazine. [00139] In some embodiments, Ring B is a substituted or unsubstituted C _3-6 cycloalkyl or a substituted or unsubstituted phenyl. In some embodiments, Ring B is a substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or a substituted or unsubstituted phenyl. [00140] In some embodiments, Ring B is a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridinyl, or a substituted or unsubstituted pyrimidinyl. In some embodiments, Ring B is a substituted or unsubstituted cyclpropyl, a substituted or unsubstituted cyclobutyl, or a substituted or unsubstituted phenyl. In some embodiments, Ring B is a substituted or unsubstituted cyclpropyl. In some embodiments, Ring B is a substituted or unsubstituted cyclobutyl. In some embodiments, Ring B is a substituted or unsubstituted phenyl. [00141] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring B is: wherein: B ¹ and B ² are each independently CH or N; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, - OR ¹⁰ , -N(R ¹⁰ ) ₂ , -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C _3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C _3-6 cycloalkyl; and r is 0, 1, 2, 3, 4 or 5. [00142] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: , , wherein: B ¹ and B ² are each independently CH or N; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , - OR ¹⁰ , -N(R ¹⁰ ) ₂ , -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C _3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; and r is 0, 1, 2, 3, 4 or 5. [00143] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: . [00144] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein B ¹ is CH; and B ² is CH; or B ¹ is N; and B ² is CH; or B ¹ is N; and B ² is N. In some embodiments, B ¹ is CH; and B ² is CH. In some embodiments, B ¹ is N; and B ² is CH. In some embodiments, B ¹ is CH; and B ² is N. In some embodiments, B ¹ is N; and B ² is N. In some embodiments is a compound of Formula (I-G) or (I-H), or a pharmaceutically acceptable salt thereof: wherein each variable is as defined in Formula I. [00145] In some embodiments, the compound is a compound of Formula (III): or a pharmaceutically acceptable salt thereof; wherein: A ¹ and A ² are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , -OR ¹⁰ , -N(R ¹⁰ ) ₂ , or -NHC(=O)R ¹⁰ ; each R ^d is independently hydrogen, halogen, -CN, C1-6 alkyl, or C1-6 alkoxy; R ¹ is -CN, -OCH3, or -OCF3; R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted C2-6 heterocycloalkyl, wherein the substituted C _3-6 cycloalkyl and the substituted C _2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1- 6 alkoxy, and C _1-6 haloalkyl; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; m is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, or 4. [00146] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: wherein: each R ^b is independently hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; and each R ¹⁰ is independently a substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. [00147] In some embodiments, each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, and -C(O)R ¹⁰ . In some embodiments, R ¹⁰ is a substituted or unsubstituted C3-6 cycloalkyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: wherein: R ^b is -C(=O)R ¹⁰ ; and R ¹⁰ is a substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. ^[00148] In some embodiments, R ¹⁰ is a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: wherein: R ^b is -C(=O)R ¹⁰ ; and R ¹⁰ is substituted or unsubstituted 3- to 6-membered heterocycloalkyl. [00149] In some embodiments, R ¹⁰ is a substituted or unsubstituted 5- or 6-membered heterocycloalkyl. In some embodiments, R ¹⁰ is a substituted or unsubstituted 6-membered heterocycloalkyl. In some embodiments, R ¹⁰ is a substituted or unsubstituted piperazinyl, a substituted or unsubstituted piperidinyl, or a substituted or unsubstituted morpholinyl. In some embodiments, R ¹⁰ is a substituted or unsubstituted piperazinyl. In some embodiments, R ¹⁰ is unsubstituted piperazinyl. In some embodiments, R ¹⁰ is methylpiperazinyl. In some embodiments, R ¹⁰ is a substituted or unsubstituted piperidinyl. In some embodiments, R ¹⁰ is unsubstituted piperidinyl. In some embodiments, R ¹⁰ is a substituted or unsubstituted morpholinyl. In some embodiments, R ¹⁰ is unsubstituted morpholinyl. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: . [00150] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein X is -NH-; L is absent; and Ring B is (B1): . [00151] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: . [00152] In some embodiments, the compound is a compound of Formula (IV): Formula IV or a pharmaceutically acceptable salt thereof; wherein: A ¹ and A ² are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C _1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; each R ^d is independently hydrogen, halogen, -CN, C _1-6 alkyl, or C _1-6 alkoxy; R ¹ is -CN, -OCH3, or -OCF3; R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C _3-6 cycloalkyl, or a substituted or unsubstituted C _2-6 heterocycloalkyl, wherein the substituted C3-6 cycloalkyl and the substituted C2-6 heterocycloalkyl are substituted with t instances of R ⁵ ; each R ⁵ is independently selected from hydrogen, deuterium, halogen, CN, C _1-6 alkyl, C _1- 6 alkoxy, and C1-6 haloalkyl; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; m is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, or 4. [00153] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein X is -NHC(=O)-; and Ring B is: each R ^b is independently hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; and each R ¹⁰ is independently a substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. [00154] In some embodiments, each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, and -C(O)R ¹⁰ . In some embodiments, each R ^b is independently selected from the group consisting of hydrogen, halogen, -CN, C1-6 alkyl, and -C(O)R ¹⁰ . In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring B is: each R ^b is independently hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl. ^[00155] In some embodiments, each R ^b is independently hydrogen, -F, -Cl, -CH3, or -CF3. In some embodiments, each R ^b is independently hydrogen, fluorine or methyl. In some embodiments, each R ^b is independently hydrogen or fluorine. In some embodiments, each R ^b is independently hydrogen or methyl. In some embodiments, R ^b is hydrogen. In some embodiments, R ^b is fluorine. In some embodiments, R ^b is methyl. [00156] In some embodiments, two R ^b taken together can form a 3- to 6-membered heterocycloalkyl or a C3-6 cycloalkyl. In some embodiments, two R ^b taken together form a C3-6 cycloalkyl. In some embodiments, two R ^b taken together form a cyclopropyl or cyclobutyl. In some embodiments, two R ^b taken together form a cyclopropyl. In some embodiments, two R ^b taken together form a cyclobutyl. In some embodiments, two R ^b attached to the same atom form a spirocyclic cyclopropane or cyclobutane. [00157] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein X is -NHC(=O)-; and Ring B is (B2), (B3), (B4), (B5), or (B6): , , , , . (B2) (B3) (B4) (B5) (B6) [00158] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring B is: [00159] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: . [00160] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein X is -NHC(=O)-; and Ring B is: wherein: each R ^b is independently hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; and each R ¹⁰ is independently a substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. [00161] In some embodiments, each R ^b is independently hydrogen, fluorine or methyl. In some embodiments, each R ^b is independently hydrogen or fluorine. In some embodiments, each R ^b is independently hydrogen or methyl. In some embodiments, R ^b is hydrogen. In some embodiments, R ^b is fluorine. In some embodiments, R ^b is methyl. In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein X is - NHC(=O)-; and Ring B is (B7): . [00162] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring B is: [00163] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein: [00164] In another aspect, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having a structure disclosed in Table 1 or Table 2. [00165] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00166] Exemplary compounds of Formula (I) include the compounds described in the following Tables 1 and 2: TABLE 1:

F j PS

[00167] Compounds in Table 1 are named: I-1: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-3-yl)-2- methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-2: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-4: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-5: 4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-6: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(2,2- difluorocyclopropane-1-carboxamido)nicotinamide; I-7: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-((trans)-3- methylcyclobutane-1-carboxamido)nicotinamide; I-8: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-9: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-((S)-2,2- dimethylcyclopropane-1-carboxamido)nicotinamide; I-10: 4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-11: 4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-((S)-2,2- dimethylcyclopropane-1-carboxamido)nicotinamide; I-12: 4-((3-(1-(5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-13: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (spiro[2.3]hexane-1-carboxamido)nicotinamide; I-14: 4-((3-(1-(5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-15: 4-((3-(1-(5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-16: 4-((3-(1-(1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-18: 4-((3-(1-(1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-19: 4-((3-(1-(5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-20: 4-((3-(1-(5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-21: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide; I-22: 4-((3-(1-(1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-23: 4-((3-(1-(5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-24: 4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide; I-26: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- (trifluoromethoxy)phenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-27: 4-((3-(1-(5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-28: 4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2- cyanophenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-29: 4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2- cyanophenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-30: 4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2- cyanophenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-33: 4-((3-(2-(1,4-dioxaspiro[4.4]nonan-6-yl)thiazol-5-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-34: 4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-3-yl)-2-met hoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-35: 4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-4-yl)-2-met hoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-54: 4-((3-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-55: 4-((3-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-59: 4-((3-(1-((1R,3r,5S)-8-oxabicyclo[3.2.1]octan-3-yl)-1H-pyraz ol-3-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-60: 4-((3-(1-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-61: 4-((3-(1-(1,4-dioxaspiro[4.5]decan-6-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-70: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2.4]he ptan-4-yl)-1H-pyrazol-4- yl)phenyl)amino)pyridazine-3-carboxamide; I-71: 4-((3-(1-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-72: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2.4]he ptan-4-yl)-1H-pyrazol-4- yl)phenyl)amino)nicotinamide; I-73: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2.4]he ptan-5-yl)-1H-pyrazol-4- yl)phenyl)amino)nicotinamide; I-74: 4-((3-(1-(4-oxaspiro[2.5]octan-7-yl)-1H-pyrazol-4-yl)-2-meth oxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-75: 4-((3-(1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-4-yl)-2-met hoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; and I-78: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(3-methoxyspi ro[4.4]nonan-2-yl)-1H-pyrazol-4- yl)phenyl)amino)nicotinamide. TABLE 2:

i

[00168] Compounds in Table 2 are named: I-1-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-1-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-2-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-3-yl )-2-methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-2-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-3-yl )-2-methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-4-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-4-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-5-a: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-5-b: (S)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-6-a: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- 2,2-difluorocyclopropane-1-carboxamido)nicotinamide; I-6-b: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((R)- 2,2-difluorocyclopropane-1-carboxamido)nicotinamide; I-6-c: 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((R)- 2,2-difluorocyclopropane-1-carboxamido)nicotinamide; I-6-d: 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- 2,2-difluorocyclopropane-1-carboxamido)nicotinamide; I-7-a: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- ((1r,3R)-3-methylcyclobutane-1-carboxamido)nicotinamide; I-7-b: 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- ((1r,3S)-3-methylcyclobutane-1-carboxamido)nicotinamide; I-8-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-8-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-9-a: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- 2,2-dimethylcyclopropane-1-carboxamido)nicotinamide; I-9-b: 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- 2,2-dimethylcyclopropane-1-carboxamido)nicotinamide; I-10-a: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-10-b: (S)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-11-a: 4-((3-(1-((R)-1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- 2,2-dimethylcyclopropane-1-carboxamido)nicotinamide; I-11-b: 4-((3-(1-((S)-1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- 2,2-dimethylcyclopropane-1-carboxamido)nicotinamide; I-12-a: 4-((3-(1-((1R,4S)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-12-b: 4-((3-(1-((1S,4R)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-13-a: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- spiro[2.3]hexane-1-carboxamido)nicotinamide; I-13-b: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((R)- spiro[2.3]hexane-1-carboxamido)nicotinamide; I-13-c: 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((R)- spiro[2.3]hexane-1-carboxamido)nicotinamide; I-13-d: 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-((S)- spiro[2.3]hexane-1-carboxamido)nicotinamide; I-14-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-imidazol-4-y l)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-14-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-imidazol-4-y l)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-15-a: 4-((3-(1-((1R,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-15-b: 4-((3-(1-((1S,4R)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-16-a: 4-((3-(1-((5R,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-16-b: 4-((3-(1-((5S,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-16-c: 4-((3-(1-((5S,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-16-d: 4-((3-(1-((5R,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-18-a: 4-((3-(1-((5S,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-18-b: 4-((3-(1-((5R,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-18-c: 4-((3-(1-((5R,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-18-d: 4-((3-(1-((5S,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-19-a: 4-((3-(1-((1R,4R)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-19-b: 4-((3-(1-((1S,4S)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-19-c: 4-((3-(1-((1S,4R)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-19-d: 4-((3-(1-((1R,4S)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-20-a: 4-((3-(1-((1R,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-20-b: 4-((3-(1-((1S,4R)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-20-c: 4-((3-(1-((1S,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-20-d: 4-((3-(1-((1R,4R)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-21-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide; I-21-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide; I-22-a: 4-((3-(1-((5S,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-22-b: 4-((3-(1-((5R,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-22-c; 4-((3-(1-((5S,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-22-d; 4-((3-(1-((5R,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-23-a: 4-((3-(1-((1R,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-23-b: 4-((3-(1-((1S,4R)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-23-c: 4-((3-(1-((1S,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-23-d: 4-((3-(1-((1R,4R)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide; I-24-a: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide; I-24-b: (S)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide; I-26-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- (trifluoromethoxy)phenyl)amino)-6-(cyclopropanecarboxamido)n icotinamide; I-26-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- (trifluoromethoxy)phenyl)amino)-6-(cyclopropanecarboxamido)n icotinamide; I-27-a: 4-((3-(1-((1S,4S)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-27-b: 4-((3-(1-((1R,4R)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-27-c: 4-((3-(1-((1R,4S)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-27-d: 4-((3-(1-((1S,4R)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-28-a: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-cyanophenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-28-b: (S)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-cyanophenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-29-a: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-cyanophenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-29-b: (S)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-cyanophenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-30-a: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-cyanophenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-30-b: (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-cyanophenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-33-a: (R)-4-((3-(2-(1,4-dioxaspiro[4.4]nonan-6-yl)thiazol-5-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-33-b: (S)-4-((3-(2-(1,4-dioxaspiro[4.4]nonan-6-yl)thiazol-5-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-34-a: (R)-4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-3-yl)-2 -methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-34-b: (S)-4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-3-yl)-2 -methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide ; I-35-a: (R)-4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-35-b: (S)-4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide; I-61-a: (R)-4-((3-(1-(1,4-dioxaspiro[4.5]decan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)- 6-(cyclopropanecarboxamido)pyridazine-3-carboxamide; I-61-b: (S)-4-((3-(1-(1,4-dioxaspiro[4.5]decan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)- 6-(cyclopropanecarboxamido)pyridazine-3-carboxamide I-70-a: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2. 4]heptan-4-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-70-b: (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2. 4]heptan-4-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-72-a: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2. 4]heptan-4-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-72-b: (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2. 4]heptan-4-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-73-a: (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2. 4]heptan-5-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-73-b: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2. 4]heptan-5-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-74-a: (R)-4-((3-(1-(4-oxaspiro[2.5]octan-7-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-74-b: (S)-4-((3-(1-(4-oxaspiro[2.5]octan-7-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-75-a: (R)-4-((3-(1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-75-b: (S)-4-((3-(1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-78-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2R,3R)-3-me thoxyspiro[4.4]nonan- 2-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-78-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2S,3S)-3-me thoxyspiro[4.4]nonan- 2-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-78-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2S,3R)-3-me thoxyspiro[4.4]nonan- 2-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide; and I-78-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2R,3S)-3-me thoxyspiro[4.4]nonan- 2-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide. [00169] In another embodiment, provided herein is a compound of Formula (00): Formula (00) or a pharmaceutically acceptable salt thereof; wherein: Ring A is a substituted or unsubstituted monocyclic heteroaryl; Ring B is a substituted or unsubstituted monocyclic carbocycle or a substituted or unsubstituted monocyclic heterocycle; Ring C is a substituted or unsubstituted monocyclic aryl or a substituted or unsubstituted monocyclic heteroaryl; Ring D is a 5- or 6-membered heteroaryl, or a 5-membered heterocycloalkyl; Ring F is a monocyclic carbocycle or a monocyclic heterocycle, each of which may be unsubstituted, or substituted with 0-4 groups selected from halogen, alkyl, and alkoxy, wherein each alkyl or alkoxy may be further substituted; X is -NH-L-; and L is absent or -C(=O)-. [00170] In some embodiments, Ring A is: . [00171] In some embodiments, A ¹ is N or CR ^a . In some embodiments, A ¹ is N. In some embodiments, A ¹ is CR ^a . In some embodiments, A ² is N or CR ^a . In some embodiments, A ² is N. In some embodiments, A ² is CR ^a . In some embodiments, each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, each R ^a is independently hydrogen, deuterium, halogen, -CN, or methyl. In some embodiments, each R ^a is hydrogen. In some embodiments, A ¹ is CH. In some embodiments, A ² is CH. [00172] In some embodiments, Ring A is: wherein: A ¹ is CH; and A ² is CH; or A ¹ is CH; and A ² is N; or A ¹ is N; and A ² is CH. [00173] In some embodiments, A ¹ is CH; and A ² is CH. In some embodiments, A ¹ is CH; and A ² is N. In some embodiments, A ¹ is N; and A ² is CH. In some embodiments, A ¹ is N; and A ² is N. In some embodiments, Ring A is (A1), (A2), or (A3): , , . (A1) (A2) (A3) [00174] In some embodiments, Ring C is a substituted or unsubstituted phenylene, a substituted or unsubstituted pyridinene, wherein if Ring C is substituted, then it is substituted with R ¹ and q instances of R ² . [00175] In some embodiments, Ring C is: [00176] In some embodiments, R ¹ is halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, or -OR ¹⁰ ; and R ¹⁰ is a substituted or unsubstituted C _1-6 alkyl. In some embodiments, R ¹ is -CN or -OR ¹⁰ ; and R ¹⁰ is a substituted or unsubstituted C _1-6 alkyl. In some embodiments, R ¹ is -CN, -O(C _1-6 alkyl); wherein the C1-6 alkyl is unsubstituted or is substituted with 1, 2, or 3 halogen atoms. In some embodiments, R ¹ is -CN, -O(C _1-6 alkyl), or -O(C _1-6 haloalkyl). In some embodiments, R ¹ is -CN. In some embodiments, R ¹ is -O(C _1-6 alkyl) or -O(C _1-6 haloalkyl). In some embodiments, R ¹ is - O(C1-6 alkyl). In some embodiments, R ¹ is -O(C1-6 haloalkyl). In some embodiments, R ¹ is - OCH3, -OCH2F, -OCHF2, or -OCF3. In some embodiments, R ¹ is -OCH3 or -OCF3. In some embodiments, R ¹ is -OCF _3. In some embodiments, R ¹ is -OCH ₃ . _. [00177] In some embodiments, Ring C is: wherein: R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; and q is 0, 1, or 2. [00178] In some embodiments, Ring C is: wherein R ¹ is -CN, -O(C1-6 alkyl), or -O(C1-6 haloalkyl); and q is 0. [00179] In some embodiments, Ring C is (C1), (C2), or (C3): ( ) ( ) ( ) ( ) [00180] In some embodiments, provided herein is a compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; A ³ is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl; X is -NH-L-; L is absent or -C(=O)-; Ring B is selected from the group consisting of C _3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , - OR ¹⁰ , -N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; Ring D is a 5-membered heterocycloalkyl, or a 5- or 6-membered heteroaryl; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C _1-6 alkoxy; wherein each substituted C _1-6 alkyl and substituted C _1-6 alkoxy is substituted with 1-5 instances of R ¹² ; Ring F is a substituted or unsubstituted C3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; R ¹ is hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, -C(O)OH, -C(O)OC1-6 alkyl, -C(O)C1-6 alkyl, -C(O)NH2, -C(O)NHC1-6 alkyl, - C(O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, -OC1-6 alkyl, -SH, - SC _1-6 alkyl, -SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, or -SO ₂ NHC _1-6 alkyl; p is 0, 1, 2, 3, or 4; q is 0, 1 or 2; r is 0, 1, 2, 3, 4 or 5; and x is 0, 1, 2, 3, or 4. [00181] In some embodiments, . [00182] In some embodiments, . [00183] In some embodimetns, each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 2. In some embodimetns, each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2. In some embodiments, q is 1. In some embodimetns, R ² is selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ . In some embodimetns, each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R ² is halogen or -CN. In some embodiments, q is 0. In some embodiments, A ³ is CH. In some embodiments, A ³ is CF. In some embodiments, A ³ is CR ^a . In some embodiments, A ³ is N. [00184] In some embodiments, . [00185] In some embodiments , [00186] In some embodiments, R ¹ is halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, or -OR ¹⁰ ; and R ¹⁰ is a substituted or unsubstituted C1-6 alkyl. In some embodiments, R ¹ is -CN or -OR ¹⁰ ; and R ¹⁰ is a substituted or unsubstituted C _1-6 alkyl. In some embodiments, R ¹ is -CN, -O(C _1-6 alkyl); wherein the C1-6 alkyl is unsubstituted or is substituted with 1, 2, or 3 halogen atoms. In some embodiments, R ¹ is -CN, -O(C1-6 alkyl), or -O(C1-6 haloalkyl). In some embodiments, R ¹ is -CN. In some embodiments, R ¹ is -O(C _1-6 alkyl) or -O(C _1-6 haloalkyl). In some embodiments, R ¹ is - O(C _1-6 alkyl). In some embodiments, R ¹ is -O(C _1-6 haloalkyl). In some embodiments, R ¹ is - OCH ₃ , -OCH ₂ F, -OCHF ₂ , or -OCF _3. In some embodiments, R ¹ is -OCH ₃ or -OCF _3. In some embodiments, R ¹ is -OCF3. In some embodiments, R ¹ is -OCH3. [00187] In some embodiments, Ring C is: wherein: A ³ is CH or N; R ¹ is hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; and q is 0, 1, or 2. [00188] In some embodiments, Ring C is: wherein R ¹ is -CN, -O(C _1-6 alkyl), or -O(C _1-6 haloalkyl); and q is 0. [00189] In some embodiments, is C1, C2, C3, or C4. ( ) ( ) ( ) ( ) [00190] In some embodiments, provided herein are compounds of Formula (V), wherein Ring F is a substituted or unsubstituted C _3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle. In some embodiments, Ring F is a substituted or unsubstituted C3-8 monocyclic carbocycle. In some embodiments, Ring F is a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle. In some embodiments, Ring F is a substituted or unsubstituted C _3-6 monocyclic carbocycle, or a substituted or unsubstituted 5- or 6-membered monocyclic heterocycle. In some embodiments, Ring F is a substituted or unsubstituted C3-6 monocyclic cycloalkyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heterocycloalkyl. In some embodiments, the 5- or 6-membered monocyclic heterocycloalkyl is a heterocycle comprising atoms selected from carbon, oxygen, and nitrogen. In some embodiments, the 5- or 6-membered monocyclic heterocycloalkyl is a heterocycle comprising atoms selected from carbon and oxygen. In some embodiments, Ring F is an unsubstituted cyclopropane, cyclobutene, cyclopentane, or cyclohexane. In some embodiments, Ring F is a cyclopropane, cyclobutene, cyclopentane, or cyclohexane, which is substituted with x instances of a substituent R ^f . In some embodiments, Ring F is an unsubstituted pyrrolidine, tetrahydrofuran, tetrahydropyran, or dioxane. In some embodiments, Ring F is a pyrrolidine, tetrahydrofuran, tetrahydropyran, or dioxane, which is substituted with x instances of a substituent R ^f . [00191] In some embodiments, x is 0, and Ring F is unsubstituted. In some embodiments, x is 1, and Ring F is substituted with one substituent R ^f . In some embodiments, Ring F is chiral. All stereoisomers are considered within the scope of the present invention, including both R and S configurations (or alternatively, D, and L isomers). In some embodiments, x is 2 and Ring F is disubstituted. In some embodimens, x is 0, 1, 2, or 3. In some embodiments, x is 0, 1, or 2. [00192] In some embodiments, x is 1 and R ^f is hydrogen, halogen, C1-6 alkoxy, C1-6 haloalkoxy, or C1-6 deuteroalkoxy. In some embodiments, x is 1 and R ^f is halogen, hydroxy, or alkoxy. In some embodiments, x is 1, and R ^f is unsubstituted alkoxy. In some embodiments, x is 1, and R ^f is alkoxy substituted with 1, 2, or 3 instances of R ¹² . In some embodiments, R ^f is selected from deuterium, halogen, -OCH3, -OCH2D, -OCHD2, -OCD3, -OCHF2, -OCH2F, -OCF3, or - OCH(CH ₃ ) ₂ . In some embodiments, R ^f is -F, -OCH ₃ , -OCD ₃ , -OCHF ₂ , or -OCF ₃ . In some embodiments, R ^f is -F. In some embodiments, R ^f is -OCH3. In some embodiments, R ^f is -OCD3. In some embodiments, R ^f is -OCHF2 or -OCF3. [00193] In some embodiments, Ring F is: o ; wherein: each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and C1-6 deuteroalkoxy; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; provided the sum of m and n is not greater than 5; and x is 0, 1, 2, 3, or 4. [00194] In some embodiments, the compound of Formula (V) is of Formula (V-A) or Formula (V-B): or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; provided the sum of m and n is not greater than 5 each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 deuterium or halogen; and x is 0, 1, 2, 3, or 4. [00195] In some embodiments, Ring F is: [00196] In some embodiments, Ring F is: [00197] In some embodiments, Ring F is: [00198] In some embodiments, Ring F is: [00199] In some embodiments, Ring F is: , wherein each R ^f is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 deuteroalkoxy. [00200] In some embodiments, Ring F is: ,

[00201] In some embodiments, Ring F is: ; wherein: each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, CN, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, and C _1-6 deuteroalkoxy. m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and x is 0, 1, 2, 3, or 4. [00202] In some embodiments, Ring F is: . [00203] In some embodiments, each R ^f is selected from -F, -CH ₂ OCH ₃ , -OCH ₃ , -OCD ₃ , -OCF ₃ , or -OCHF ₂ . [00204] In some embodiments, Ring F is: wherein: each R ^f is independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C1-6 deuteroalkoxy; and x is 0 or 1. [00205] In some embodiments, Ring F is: wherein: each R ^f is independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, and C _1-6 deuteroalkoxy; and x is 0 or 1. In some embodiments, each R ^f is selected from -F, -OCH3, -OCD3, - OCF3, or -OCHF2. [00206] In some embodiments, Ring F is: [00207] In some embodiments, Ring F is: [00208] In some embodiments, Ring F is: [00209] In some embodiments, the compound is of Formula (V-C) or Formula (V-D):

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, or 2; and R ^f is hydrogen, halogen, C1-6 alkoxy, C1-6 haloalkoxy, or C1-6 deuteroalkoxy. [00210] In some embodiments, Ring D is a substituted or unsubstituted 5-membered heterocycloalkyl, or a substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, Ring D is a substituted or unsubstituted 5-membered heterocycloalkyl or heteroaryl. In some embodiments, Ring D is a substituted 5-membered heterocycloalkyl or heteroaryl. In some embodiments, Ring D is an unsubstituted 5-membered heterocycloalkyl or heteroaryl. In some embodiments, Ring D is a substituted or unsubstituted 5-membered heterocycloalkyl. In some embodiments, Ring D is a substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazolidine, or substituted or unsubstituted tetrahydrofuran. [00211] In some embodiments, Ring D is a substituted or unsubstituted 5- or 6-membered heteroaryl. In some embodiments, Ring D is a substituted 5- or 6-membered heteroaryl. In some embodiments, Ring D is an unsubstituted 5- or 6-membered heteroaryl. In some embodiments, Ring D is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, Ring D is a substituted 5-membered heteroaryl. In some embodiments, Ring D is an unsubstituted 5- membered heteroaryl. [00212] In some embodiments, Ring D is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, Ring D is a substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted triazole, substituted or unsubstituted oxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted thiazole, or a substituted or unsubstituted thiadiazole. In some embodiments, Ring D is a substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, or a substituted or unsubstituted thiazole. In some embodiments, Ring D is a substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, or a substituted or unsubstituted thiazole. In some embodiments, Ring D is a substituted or unsubstituted thiazole. In some embodiments, Ring D is a substituted or unsubstituted pyrazole, or a substituted or unsubstituted imidazole. In some embodiments, Ring D is a substituted or unsubstituted pyrazole. In some embodiments, Ring D is a substituted or unsubstituted imidazole. In some embodiments, Ring D is a pyrrole, pyrazole, imidazole, triazole, oxazole, oxadiazole, thiazole, or a thiadiazol, each of which is unsubstituted or substituted. [00213] In some embodiments, Ring D is: wherein: D ² is CR ^d or N; D ⁴ is CR ^d or N; and D ⁵ is CR ^d or N. [00214] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring D is: wherein: D ² , D ⁴ , and D ⁵ are each independently selected from N and CR ^d ; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C _1-6 alkoxy; wherein each substituted C _1-6 alkyl and substituted C _1-6 alkoxy is substituted with 1-5 instances of R ¹² ; each R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, - C(O)OH, -C(O)OC _1-6 alkyl, -C(O)C _1-6 alkyl, -C(O)NH ₂ , -C(O)NHC _1-6 alkyl, - C(O)N(C _1-6 alkyl) ₂ , -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -OH, OC _1-6 alkyl, -SH, - SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; and p is 0, 1, or 2. [00215] In some embodiments, Ring D is: wherein: each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy. [00216] In some embodiments, the compound of Formula (V) is a compound of Formula (VI): o u a V or a pharmaceutically acceptable salt thereof; wherein: A ¹ is N or CR ^a ; A ² is N or CR ^a ; A ³ is N or CR ^a ; each R ^a is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, and C _1-6 haloalkyl; L is absent or -C(=O)-; Ring B is selected from the group consisting of C3-6 cycloalkyl, phenyl, 3- to 6- membered heterocycloalkyl, and 5- to 6-membered heteroaryl; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, - OR ¹⁰ , -N(R ¹⁰ ) ₂ , -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C _3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C3-6 cycloalkyl; D ² , D ⁴ , and D ⁵ are each independently selected from N and CR ^d ; each R ^d is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; Ring F is a substituted or unsubstituted C _3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C _1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; R ¹ is hydrogen, deuterium, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ ) ₂ ; each R ² is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, -OR ¹⁰ , or -N(R ¹⁰ )2; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C2-6 heterocycloalkyl; each R ¹¹ and R ¹² is independently selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(=O)OH, -C(=O)OC _1-6 alkyl, -C(=O)C _1-6 alkyl, -C(=O)NH ₂ , -C(=O)NHC _1-6 alkyl, -C(=O)N(C1-6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, - SH, -SC1-6 alkyl, -SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; q is 0, 1, 2, or 3; r is 0, 1, 2, 3, 4 or 5; and x is 0, 1, 2, 3, or 4. [00217] In some embodiments, Ring B is as defined herein with regard to Formula (I). [00218] In some embodiments, is: wherein: B ¹ and B ² are each independently CH or N; each R ^b is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , - OR ¹⁰ , -N(R ¹⁰ ) ₂ , -NR ¹⁰ C(=O)R ¹⁰ , substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and a substituted or unsubstituted 5- to 6-membered heteroaryl; wherein each substituted C _3-6 cycloalkyl, substituted phenyl, substituted 3- to 6- membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl is substituted with 0-5 instances of R ¹¹ ; and wherein two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C _3-6 cycloalkyl; and r is 0, 1, 2, 3, 4 or 5. [00219] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein B ¹ is CH; and B ² is CH; or B ¹ is N; and B ² is CH; or B ¹ is N; and B ² is N. In some embodiments, B ¹ is CH; and B ² is CH. In some embodiments, B ¹ is N; and B ² is CH. In some embodiments, B ¹ is CH; and B ² is N. In some embodiments, B ¹ is N; and B ² is N. [00220] In some embodiments, the compound of Formula (V) is a compound of Formula (VII): Formula VII or a pharmaceutically acceptable salt thereof; wherein: A ¹ , A ² , and A ³ are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ ) ₂ , -OR ¹⁰ , -N(R ¹⁰ ) ₂ , or -NHC(=O)R ¹⁰ ; each R ^d is independently hydrogen, halogen, -CN, C _1-6 alkyl, or C _1-6 alkoxy; R ¹ is -CN, -OCH3, or -OCF3; Ring F is a substituted or unsubstituted C _3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C _1-6 alkoxy; wherein each substituted C _1-6 alkyl and substituted C _1-6 alkoxy is substituted with 1-5 instances of R ¹² ; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; R ¹² is selected from hydrogen, deuterium, halogen, -CN, C1-6 alkyl, -C(=O)OH, - C(=O)OC1-6 alkyl, -C(=O)C1-6 alkyl, -C(=O)NH2, -C(=O)NHC1-6 alkyl, -C(=O)N(C1- 6 alkyl) ₂ , -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -OH, OC _1-6 alkyl, -SH, -SC _1-6 alkyl, - SOC1-6 alkyl, -SO2C1-6 alkyl, or -SO2NHC1-6 alkyl; r is 0, 1, 2, 3, 4, or 5; and x is 0, 1, 2, 3, or 4. [00221] In some embodiments, wherein: R ^b is -C(=O)R ¹⁰ ; and R ¹⁰ is substituted or unsubstituted 3- to 6-membered heterocycloalkyl. [00222] In some embodiments, R ^b is -C(=O)R ¹⁰ ; and R ¹⁰ is substituted or unsubstituted piperazinyl, a substituted or unsubstituted piperidinyl, or substituted or unsubstituted morpholinyl. [00223] In some embodiments, [00224] In some embodiments, [00225] In some embodiments, the compound of Formula (V) is a compound of Formula (VIII): or a pharmaceutically acceptable salt thereof; wherein: A ¹ , A ² , and A ³ are each independently N or CR ^a ; D ² , D ⁴ , and D ⁵ are each independently N or CR ^d ; each R ^a is hydrogen or C1-6 alkyl; each R ^b is independently hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, - C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)N(R ¹⁰ )2, -OR ¹⁰ , -N(R ¹⁰ )2, or -NHC(=O)R ¹⁰ ; or two R ^b taken together can form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl or a substituted or unsubstituted C _3-6 cycloalkyl; each R ^d is independently hydrogen, halogen, -CN, C1-6 alkyl, or C1-6 alkoxy; R ¹ is -CN, -OCH3, or -OCF3; Ring F is a substituted or unsubstituted C _3-8 monocyclic carbocycle, or a substituted or unsubstituted 3- to 8-membered monocyclic heterocycle; each R ^f is independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, substituted or unsubstituted C1-6 alkyl, and substituted or unsubstituted C1-6 alkoxy; wherein each substituted C1-6 alkyl and substituted C1-6 alkoxy is substituted with 1-5 instances of R ¹² ; each R ¹⁰ is independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted 5- to 6-membered heteroaryl; or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C _2-6 heterocycloalkyl; R ¹² is selected from hydrogen, deuterium, halogen, -CN, C _1-6 alkyl, -C(=O)OH, - C(=O)OC1-6 alkyl, -C(=O)C1-6 alkyl, -C(=O)NH2, -C(=O)NHC1-6 alkyl, -C(=O)N(C1- 6 alkyl)2, -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, -OH, OC1-6 alkyl, -SH, -SC1-6 alkyl, - SOC _1-6 alkyl, -SO ₂ C _1-6 alkyl, or -SO ₂ NHC _1-6 alkyl; r is 0, 1, 2, 3, 4, or 5; and x is 0, 1, 2, 3, or 4. [00226] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein X is -NHC(=O)-; and Ring B is: wherein each R ^b is independently hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl. [00227] In some embodiments, X is -NHC(=O)-; and Ring B is: [00228] In some embodiments, Ring B is ^b wherein each R is independently -F, -Cl, -CH3, or -CF3. In some embodiments, R ^b is -F. [00229] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein X is -NHC(=O)-; and Ring B is (B2), (B3), (B4), (B5), or (B6): , , , , . (B2) (B3) (B4) (B5) (B6) In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein Ring B is: . [00230] In some embodiments, [00231] In some embodiments, the compound of Formula (V) is a compound of Formula (VIII- A) or Formula (VIII-B): Formula VIII-A Formula VIII-B or a pharmaceutically acceptable salt thereof. [00232] In some embodiments, provided herein is a compound of Formula (VIII-A) or Formula (VIII-B), wherein: A ¹ , A ² , and A ³ are each independently N or CR ^a ; D ² and D ⁴ are each independently N or CH; R ¹ is -CN, -OCH ₃ , -OCD ₃ , or -OCF ₃ ; each R ^b is independently hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl, R ^d is hydrogen, -CN, or substituted or unsubstituted C1-6 alkyl; each R ^f is independently hydrogen, halogen, C _1-6 alkyl, or C _1-6 alkoxy; wherein the C _1-6 alkyl or C1-6 alkoxy is either unsubstituted, or is substituted with 1-3 halogen or 1-3 deuterium m is 0, 1, or 2; r is 0, 1, 2, 3, 4, or 5; and x is 0, 1, 2, 3, or 4. [00233] Exemplary compounds of Formula (V) include the compounds described in the following Tables 3 and 4: Table 3

人

[00234] Compounds in Table 3 are named: I-31: 6-(cyclopropanecarboxamido)-4-((3-(1-(2-(difluoromethoxy)cyc lopentyl)-1H-pyrazol-4- yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide; I-32: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(2-(trifluoro methoxy)cyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-36: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-3-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-38: 4-((3-(3-cyano-1-(2-methoxycyclohexyl)-1H-pyrazol-4-yl)-2-me thoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-39: 4-((3-(3-cyano-1-cyclohexyl-1H-pyrazol-4-yl)-2-methoxyphenyl )amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-40: (S)-4-((3-(5-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) -2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-41: (R)-4-((3-(5-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) -2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-42: 4-((3-(5-cyano-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) -2-methoxyphenyl)amino)- 6-(cyclopropanecarboxamido)pyridazine-3-carboxamide; I-43: 4-((3-(5-cyano-1-cyclohexyl-1H-pyrazol-4-yl)-2-methoxyphenyl )amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-44: 4-((3-(3-cyano-1-cyclohexyl-1H-pyrazol-4-yl)-2-methoxyphenyl )amino)-6- (cyclopropanecarboxamido)nicotinamide; I-45: 4-((3-(4-cyano-1-cyclohexyl-1H-pyrazol-3-yl)-2-methoxyphenyl )amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-46: 4-((3-(1-cyclohexyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)- 6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-47: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd rofuran-3-yl)-1H-pyrazol- 4-yl)phenyl)amino)pyridazine-3-carboxamide; I-48: (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd rofuran-3-yl)-1H-pyrazol- 4-yl)phenyl)amino)pyridazine-3-carboxamide; I-49: 4-((3-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)- 6- (cyclopropanecarboxamido)nicotinamide; I-50: 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-pyrazol- 4-yl)-2- methoxyphenyl)amino)nicotinamide; I-51: 4-((3-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)- 6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; I-52: 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-pyrazol- 4-yl)-2- methoxyphenyl)amino)pyridazine-3-carboxamide; I-53: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4R)-4-me thoxytetrahydrofuran-3- yl)-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide; I-56: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-phenyl-1H-pyr azol-3- yl)phenyl)amino)pyridazine-3-carboxamide; I-57: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-phenyl-1H-pyr azol-4- yl)phenyl)amino)pyridazine-3-carboxamide; I-58: 6-(cyclopropanecarboxamido)-4-((3-(5-ethyl-1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-3- yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide; I-62: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(1-(methoxyme thyl)cyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-63: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(1-(methoxyme thyl)cyclobutyl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-64: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(4-methoxytet rahydrofuran-3-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-65: 6-(cyclopropanecarboxamido)-4-((3-(1-((1r,3r)-3-fluorocyclob utyl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)nicotinamide; I-66: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd rofuran-3-yl)-1H-pyrazol- 4-yl)phenyl)amino)nicotinamide; I-67: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(2-methoxycyc lopentyl)-1H-pyrazol-4- yl)phenyl)amino)nicotinamide; I-68: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(4-(methoxy-d 3)tetrahydrofuran-3-yl)- 1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-69: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(4-(methoxy-d 3)tetrahydrofuran-3-yl)- 1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-76: 6-(cyclopropanecarboxamido)-4-((3-(1-(4-fluorotetrahydrofura n-3-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)nicotinamide; I-77: 6-(cyclopropanecarboxamido)-4-((3-(1-(2-fluorocyclopentyl)-1 H-pyrazol-4-yl)-2- methoxyphenyl)amino)nicotinamide; I-79: N-(4-((3-(1-(2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2-methoxy phenyl)amino)-5- methoxypyridin-2-yl)cyclopropanecarboxamide; I-80: 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1-(4-methoxytet rahydrofuran-3-yl)-1H- pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide; I-81: 4-((3-(3-cyano-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) -2-methoxyphenyl)amino)- 6-(cyclopropanecarboxamido)pyridazine-3-carboxamide; I-84: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-4-yl)-1H- pyrazol-3-yl)phenyl)amino)nicotinamide; I-85: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-3-yl)-1H- pyrazol-3-yl)phenyl)amino)nicotinamide; I-86: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-4-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-87: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-4-yl)-1H- pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide; I-88: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-4-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-89: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(4-methoxytet rahydrofuran-3-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-90: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(2-methoxycyc lopentyl)-1H-pyrazol-4- yl)phenyl)amino)pyridazine-3-carboxamide; I-91: (R)-4-((3-(3-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) -2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; and I-92: (S)-4-((3-(3-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) -2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide. Tabl le 4 已 0 5 中 2 O

Q

[00235] Compounds in Table 4 are named: I-31-a: 6-(cyclopropanecarboxamido)-4-((3-(1-((1R,2R)-2-(difluoromet hoxy)cyclopentyl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide ; I-31-b: 6-(cyclopropanecarboxamido)-4-((3-(1-((1S,2S)-2-(difluoromet hoxy)cyclopentyl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide ; I-31-c: 6-(cyclopropanecarboxamido)-4-((3-(1-((1S,2R)-2-(difluoromet hoxy)cyclopentyl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide ; I-31-d: 6-(cyclopropanecarboxamido)-4-((3-(1-((1R,2S)-2-(difluoromet hoxy)cyclopentyl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)pyridazine-3-carboxamide ; I-32-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1S,2S)-2- (trifluoromethoxy)cyclopentyl)-1H-pyrazol-4-yl)phenyl)amino) pyridazine-3-carboxamide; I-32-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1R,2R)-2- (trifluoromethoxy)cyclopentyl)-1H-pyrazol-4-yl)phenyl)amino) pyridazine-3-carboxamide; I-32-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1S,2R)-2- (trifluoromethoxy)cyclopentyl)-1H-pyrazol-4-yl)phenyl)amino) pyridazine-3-carboxamide; I-32-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1R,2S)-2- (trifluoromethoxy)cyclopentyl)-1H-pyrazol-4-yl)phenyl)amino) pyridazine-3-carboxamide; I-36-a: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd ro-2H-pyran-3-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-36-b: (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd ro-2H-pyran-3-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-38-a: 4-((3-(3-cyano-1-((1S,2S)-2-methoxycyclohexyl)-1H-pyrazol-4- yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; I-38-b: 4-((3-(3-cyano-1-((1R,2R)-2-methoxycyclohexyl)-1H-pyrazol-4- yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; I-38-c: 4-((3-(3-cyano-1-((1S,2R)-2-methoxycyclohexyl)-1H-pyrazol-4- yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; I-38-d: 4-((3-(3-cyano-1-((1R,2S)-2-methoxycyclohexyl)-1H-pyrazol-4- yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; I-53-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4R)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide; I-53-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide; I-64-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4R)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-64-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-64-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4S)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-64-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4R)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-67-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1S,2S)-2-me thoxycyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-67-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1R,2R)-2-me thoxycyclopentyl)- 1H-pyrazol-4-yl)phenyl)amino)nicotinamide; I-67-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1S,2R)-2-me thoxycyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-67-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1R,2S)-2-me thoxycyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide; I-68-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4R)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicoti namide; I-68-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicoti namide; I-68-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4S)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicoti namide; I-68-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4R)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicoti namide; I-69-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4R)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyrida zine-3-carboxamide; I-69-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyrida zine-3-carboxamide; I-69-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4S)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyrida zine-3-carboxamide; I-69-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4R)-4-(m ethoxy- d3)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyrida zine-3-carboxamide; I-76-a: 6-(cyclopropanecarboxamido)-4-((3-(1-((3S,4R)-4-fluorotetrah ydrofuran-3-yl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)nicotinamide; I-76-b: 6-(cyclopropanecarboxamido)-4-((3-(1-((3R,4S)-4-fluorotetrah ydrofuran-3-yl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)nicotinamide; I-76-c: 6-(cyclopropanecarboxamido)-4-((3-(1-((3S,4S)-4-fluorotetrah ydrofuran-3-yl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)nicotinamide; I-76-d: 6-(cyclopropanecarboxamido)-4-((3-(1-((3R,4R)-4-fluorotetrah ydrofuran-3-yl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)nicotinamide; I-77-a: 6-(cyclopropanecarboxamido)-4-((3-(1-((1R,2R)-2-fluorocyclop entyl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)nicotinamide; I-77-b: 6-(cyclopropanecarboxamido)-4-((3-(1-((1S,2S)-2-fluorocyclop entyl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)nicotinamide; I-77-c: 6-(cyclopropanecarboxamido)-4-((3-(1-((1S,2R)-2-fluorocyclop entyl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)nicotinamide; I-77-d: 6-(cyclopropanecarboxamido)-4-((3-(1-((1R,2S)-2-fluorocyclop entyl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)nicotinamide; I-80-a: 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1-((3S,4R)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide; I-80-b: 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1-((3R,4S)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide; I-80-c: 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1-((3S,4S)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide; I-80-d: 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1-((3R,4R)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide; I-85-a: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd ro-2H-pyran-3-yl)-1H- pyrazol-3-yl)phenyl)amino)nicotinamide; I-85-b: (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd ro-2H-pyran-3-yl)-1H- pyrazol-3-yl)phenyl)amino)nicotinamide; I-89-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4R)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-89-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-89-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4S)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-89-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4R)-4-me thoxytetrahydrofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-90-a: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1R,2R)-2-me thoxycyclopentyl)- 1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-90-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1S,2S)-2-me thoxycyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; I-90-c: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1S,2R)-2-me thoxycyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide; and I-90-d: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1R,2S)-2-me thoxycyclopentyl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide. [00236] In some embodiments, provided herein is a compound of Table 5 or Table 6: Table 5 [00237] Compounds in Table 5 are named: I-37: 4-((3-(3-cyano-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyraz ol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; and I-79: N-(4-((3-(1-(2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2-methoxy phenyl)amino)-5- methoxypyridin-2-yl)cyclopropanecarboxamide. Table 6

[00238] Compounds in Table 6 are named: I-37-a: (S)-4-((3-(3-cyano-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-p yrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; I-37-b: (R)-4-((3-(3-cyano-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-p yrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; I-79-a: N-(4-((3-(1-((1S,2S)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)- 5-methoxypyridin-2-yl)cyclopropanecarboxamide; I-79-b: N-(4-((3-(1-((1R,2R)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)- 5-methoxypyridin-2-yl)cyclopropanecarboxamide; I-79-c: N-(4-((3-(1-((1S,2R)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)- 5-methoxypyridin-2-yl)cyclopropanecarboxamide; and I-79-d: N-(4-((3-(1-((1R,2S)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2 -methoxyphenyl)amino)- 5-methoxypyridin-2-yl)cyclopropanecarboxamide. Additional Forms of Compounds [00239] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [00240] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. [00241] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” and “physiologically acceptable excipient” refer to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009. [00242] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as one aspect of delayed and sustained release behaviours. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted. [00243] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid. In some embodiments, the compound described herein (i.e., free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2- oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. [00244] In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt. In some embodiments, a compound described herein is prepared as a hydrochloride salt. [00245] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base. In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt. In some embodiments, the compounds provided herein are prepared as a sodium salt. [00246] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00247] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl. In one aspect, isotopically labeled compounds described herein, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. [00248] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. [00249] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis. Definitions [00250] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [00251] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as "C ₁ -C ₄ " indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. [00252] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e., a C1- C ₁₀ alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6 alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. [00253] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and –CH2CH=CH2. [00254] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH ₃ -C≡CCH ₂ CH ₃ , - CH ₂ C≡CH. [00255] An “alkoxy” group refers to an -O(alkyl) group, where alkyl is as defined herein. ^[00256] The term “alkylamine” refers to a group consisting of an alkyl group (e.g., a C1-12 alkyl) and an amine (e.g., -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , and the like), or a radical thereof. Examples of alkylamines include -CH ₂ NH ₂ , -CH ₂ NHCH ₂ , -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ NH ₂ , - CH2NHCH2CH3, -NHCH2CH3, and the like. The term “aminoalkyl” is used interchangeably with alkylamine, wherein both terms are meant to include both alkyl radicals and nitrogen radicals. Alkyl amides are not encompassed in the term alkylamine as used herein. [00257] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. Carbocycles, as used herein, may refer to aromatic or non- aromatic, saturated or unsaturated, monocyclic or polycyclic rings containing only carbon ring atoms. Unless otherwise specified, it should be understood that carbocycles may be substituted or unsubstituted, as defined herein. The term carbocycle generally encompasses both cycloalkyl and aryl. For illustrative purposes only, examples of carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexene, benzene, naphthalene, decalin, and the like. In some embodiments, carbocycle is a C ₃ to C ₁₈ cycloalkyl (including monocyclic, bicylic, tricyclic, etc.) or a C6 to C18 aryl (including monocyclic, bicylic, tricyclic, etc.). [00258] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Alternatively, aryl means an aromatic carbocycle, and is not limited in terms of the number of rings. An aryl ring may be monocyclic, bicyclic, tricyclic, etc. In a polycyclic carbocycle, both rings must be aromatic for the group to be considered aryl. As used herein, aromatic is as defined in Huckel’s rule (4n+2 e-). In one aspect, aryl is phenyl or a naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is C ₆ -C ₁₃ aryl. Depending on the structure, an aryl group may be a monoradical or a diradical (i.e., an arylene group). In some embodiments, aryl is phenyl or phenylene. In some embodiments, aryl is phenyl or naphthyl. [00259] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 12 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3- C6cycloalkyl. In some embodiments, cycloalkyl is a bicyclic spirocyclic C7-12 cycloalkyl. In some embodiments, cycloalkyl is a monocyclic C _3-6 cycloalkyl ring. Unless otherwise specified, a cycloalkyl group may be optionally substituted. [00260] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo. When used as a prefix, halo does not denote any number of instances. For example, haloalkyl includes methyl derivatives -CH2F, -CHF2, and -CF3. [00261] The term “haloalkyl” refers to an alkyl group wherein at least one, and possibly more, hydrogen atoms have been replaced with a halogen. For example, haloalkyl includes methyl derivatives -CH2F, -CHF2, and -CF3. Haloalkyl is non-limiting in terms of number of halogens and carbons. Generally, haloalkyl refers to C ₁ -C ₁₂ haloalkyl. [00262] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is a C1-C6fluoroalkyl. Examples of fluoroalkyl include methyl derivatives -CH2F, -CHF2, and -CF3; ethyl derivatives, -CH2CH2F, - CH ₂ CF ₃ , and -CF ₂ CF ₃ ; and the like. [00263] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl. Heteroalkyl may include nitriles, amides, esters, ethers, amines, thioethers, thioesters, carbamates, carbonates, polyethers, polyamines, and the like. [00264] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic. [00265] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C ₁ -C ₉ heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9 heteroaryl. [00266] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2- C ₁₀ heterocycloalkyl. In another aspect, a heterocycloalkyl is a C ₂ -C ₆ heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. [00267] Examples of heterocycles include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. [00268] Some embodiments of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H- indazolyl, benzofuranyl, benzothiofuranyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl. [00269] Some embodiments of 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included are fused, brdiged, and spiro compounds containing, for example, the above heterocycles. [00270] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups. [00271] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [00272] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH ₂ , -NH(alkyl), -N(alkyl) ₂ , -OH, -O(alkyl), -CO ₂ H, -CO ₂ alkyl, - C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -OCH3, -CO2H, - CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, - S(=O) ₂ NH(C ₁ -C ₄ alkyl), -S(=O) ₂ N(C ₁ -C ₄ alkyl) ₂ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -S(C1-C4 alkyl), -S(=O)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl). In some embodiments, optional substituents are independently selected from halogen, -CN, -NH ₂ , -OH, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ , and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). [00273] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. [00274] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. [00275] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist. [00276] The term “inhibitor” as used herein, generally refers to a molecule that interacts with a target either directly or indirectly (preferably directly), to reduce the capacity of the target to perform a function. Typically, the function is associated with the target’s role in the pathogenesis of a disease. As used herein, a kinase inhibitor is a compound that reduces the catalytic activity of a kinase, for example, by interacting directly with the kinase. Inhibitors may be competitive, uncompetitive, or non-competitive with the substrate. Inhibitors may be orthosteric or allosteric. In some embodiments, an inhibitor binds an ATP binding site. In some embodiments, an inhibitor binds a pseudokinase domain (JH2) of a JAK (e.g., JAK2). [00277] The terms “administer,” “administering”, “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. [00278] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time. [00279] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study. The terms “therapeutically effective amount” or “effective amount” also refer to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician. [00280] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. [00281] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. Pharmaceutical compositions [00282] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [00283] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be performed by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. [00284] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. [00285] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses. [00286] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [00287] Pharmaceutical compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [00288] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00289] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00290] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. [00291] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00292] In some embodiments, the pharmaceutical composition provided herein is formulated for oral administration. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00293] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00294] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00295] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. [00296] The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. [00297] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions. In some embodiments, the pharmaceutical composition comprises between about 10 and about 500 mg (e.g., about 30 to about 300 mg) of a compound disclosed herein. Methods of Dosing and Treatment Regimens [00298] In one embodiment, the compounds of Formula (I) are used in the preparation of medicaments for the treatment of diseases or conditions that would benefit from or by the reduction or inhibition of JAK2 activity. In addition, a method for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound of Formula (0), (00), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), (IV), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof, in therapeutically effective amounts to said mammal. [00299] In certain embodiments, provided herein is a method for treating or preventing a disease in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (0), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (0), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [00300] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-C), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-D), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-E), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-F), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H), or a pharmaceutically acceptable salt thereof. [00301] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof. [00302] In certain embodiments, provided herein is a method for treating or preventing a disease in a subject, the method comprising administering to the subject an effective amount of a compound of Formula (00), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (00), or a pharmaceutically acceptable salt thereof, is a compound of Formula (V), or a pharmaceutically acceptable salt thereof. [00303] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of Formula (V-A), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of Formula (V-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of Formula (V-C), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of Formula (V-D). [00304] In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V) or Formula (VI), or a pharmaceutically acceptable salt thereof, is a compound of Formula (VII), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V) or Formula (VI), or a pharmaceutically acceptable salt thereof, is a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof. [00305] In some embodiments, the compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, is a compound of Formula (VIII-A), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, is a compound of Formula (VIII-B). [00306] In some embodiments, the disease is a disease associated with JAK-mediated signaling pathways. In some embodiments, the disease is a disease associated with JAK2-mediated signaling. In some embodiments, the disease is associated with hyperactivity of JAK2 signaling. In some embodiments, the disease is characterized by a mutation to a JAK2 gene or protein, which results in pathologically high kinase activity (e.g., constitutive activity, or cytokine- independent signaling). In some embodiments, the disease is characterized by a V617F mutation to a JAK. In some embodiments, the disease is characterized by a mutation to JAK2. Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and myelofibrosis as well as other myeloproliferative disorders. JAK2 mutations have also been associated with various leukemias and lymphomas. [00307] In one embodiment, provided herein is a method for treating cancer, comprising administering an effective amount of a compound of Formula (0), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (0), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (0), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), (IV), or a pharmaceutically acceptable salt thereof. [00308] In some embodiments, provided herein is a method for treating a hematological malignancy comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (0), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the hematological malignancy is a leukemia or a lymphoma. [00309] In some embodiments, provided herein is a method for treating a myeloproliferative neoplasm comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (0), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or primary myelofibrosis. In some embodiments, the myeloproliferative neoplasm is polycythemia vera. In some embodiments, the myeloproliferative neoplasm is essential thrombocytopenia. In some embodiments, the myeloproliferative neoplasm is primary myelofibrosis. [00310] In one embodiment, provided herein is a method for treating cancer, comprising administering an effective amount of a compound of Formula (00), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (00), or a pharmaceutically acceptable salt thereof, is a compound of Formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (00), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. [00311] In some embodiments, provided herein is a method for treating a hematological malignancy comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (00), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the hematological malignancy is a leukemia or a lymphoma. [00312] In some embodiments, provided herein is a method for treating a myeloproliferative neoplasm comprising administering an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (00), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or primary myelofibrosis. In some embodiments, the myeloproliferative neoplasm is polycythemia vera. In some embodiments, the myeloproliferative neoplasm is essential thrombocytopenia. In some embodiments, the myeloproliferative neoplasm is primary myelofibrosis. [00313] In some embodiments, the disease is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, myelodysplastic syndromes (MDS), polycythemia vera (PV), essential thrombocythemia (ET), malignant solid tumor, primary myelofibrosis (MF), mixed phenotype acute leukemia, multiple myeloma, mantle cell lymphoma (MCL), peripheral T-cell lymphoma, post-polycythemic myelofibrosis phase, myelofibrosis, myelofibrosis transformation in essential thrombocythemia, myeloid neoplasm, chronic myelomonocytic leukemia (CLL), waldenstrom macroglobulinemia, secondary acute myeloid leukemia, therapy-related acute myeloid leukemia, lymphoplasmacytic lymphoma, diffuse large b-cell lymphoma (DLBCL), chronic myeloid leukemia (CML), lymphoproliferative disorder, non-Hodgkin lymphoma (NHL), B-cell lymphoblastic lymphoma, chronic lymphocytic leukemia (CLL), double-hit lymphoma (DHL), lymphoblastic lymphoma, mixed phenotype acute leukemia, plasma cell leukemia, primary cutaneous T-cell non-Hodgkin lymphoma, marginal zone lymphoma (MZL), T-cell acute lymphoblastic leukemia, follicular lymphoma (FL), and T-cell lymphoblastic lymphoma. [00314] In some embodiments, the disease is selected from the group consisting of: chronic eosinophilic leukemia, secondary acute myeloid leukemia, myeloproliferative neoplasm, glioblastoma, malignant solid tumor, acute myeloid leukemia, primary myelofibrosis, leukemia, essential thrombocythemia, myelofibrosis transformation in essential thrombocythemia, polycythemia vera, post-polycythemic myelofibrosis phase, myelofibrosis, b-cell acute lymphoblastic leukemia, hematopoietic and lymphoid malignancy, acute megakaryoblastic leukemia, malignant bone marrow neoplasm, t-cell lymphoblastic lymphoma, melanoma, basal cell carcinoma, lymphoproliferative disorder, t-cell acute lymphoblastic leukemia, breast carcinoma, myelodysplastic/myeloproliferative neoplasm, and myeloid leukemia. [00315] In some embodiments, the disease is a cancer of the breast, skin, prostate, cervix, uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and/or lymphatic system. [00316] In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including, but not limited to, chronic rnyelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin’s disease and non- Hodgkin’s disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom’s macroglobulinernia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, aligodendrogliorna, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mutinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget’s disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) pituitary cancer, including, but limited to, Cushing’s disease, prol actin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, but not limited to, pappillary, nodular, and diffuse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonserninoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcorna; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer); (40) Wilms’ tumor; (41) bladder cancer, including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America). [00317] In some embodiments, the leukemia is selected from the group consisting of chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), chronic myelomonocytic leukemia (CMML), and acute monocytic leukemia (AMoL), or any combination thereof. In some embodiments, the leukemia is chronic lymphocytic leukemia (CLL). In some embodiments, the leukemia is acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the leukemia is chronic myelogenous leukemia (CML). In some embodiments, the leukemia is acute myelogenous leukemia (AML). In some embodiments, the leukemia is chronic myelomonocytic leukemia (CMML). In some embodiments, the leukemia is acute monocytic leukemia (AMoL). In some embodiments, the leukemia is a relapsed or refractory leukemia. In some embodiments, the leukemia is resistant to treatment with front-line cancer therapy. [00318] In some embodiments, the lymphoma is selected from the group consisting of Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, B-cell lymphoma, and NK/T-cell lymphoma, or any combination thereof. In some embodiments, the lymphoma is Burkitt’s lymphoma. In some embodiments, the lymphoma is Hodgkin’s lymphoma. In some embodiments, the lymphoma is a non-Hodgkin’s lymphoma (NHL). In some embodiments, the lymphoma is a B-cell lymphoma. In some embodiments, the lymphoma is a NK/T-cell lymphoma. In some embodiments, the lymphoma is a relapsed or refractory lymphoma. In some embodiments, the lymphoma is resistant to treatment with front-line cancer therapy. [00319] In another embodiment, a compound or composition disclosed herein may be used to treat a myeloproliferative disorder. In one embodiment, the myeloproliferative disorder is polycythemia vera, essential thrombocythemia, or chronic idiopathic myelofibrosis. In another embodiment, the myeloproliferative disorder is myeloid metaplasia with myelofibrosis, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic eosinophilic leukemia, hypereosinophilic syndrome, systematic mast cell disease, atypical CML or juvenile myelomonocytic leukemia. In another embodiment, the myeloproliferative disorder is multiple myeloma or a myelodysplastic syndrome. In another embodiment, the myeloproliferative disorder is multiple myeloma. In another embodiment, the myeloproliferative disorder is a myelodysplastic syndrome. In another embodiment, the myeloproliferative disorder is relapsed or refractory. In another embodiment, the myeloproliferative disorder is resistant to treatment with front-line cancer therapy. [00320] In still another embodiment, a compound or composition disclosed herein may be used to treat an inflammatory disease, disorder, or condition in a subject in need thereof. For example, in some embodiments, provided herein is a method of treating an inflammatory disease, disorder, or condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of any one or more of Formulae (0), (00), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), (IV), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound (e.g., disclosed herein) for use in a method of treating an inflammatory disease, disorder or condition. In other embodiments, provided herein is a compound for use in the manufacture of a medicament for treating an inflammatory disease, disorder, or condition. [00321] In some embodiments, the inflammatory disease, disorder, or condition is an autoimmune or autoinflammatory disease, disorder, or condition. In some embodiments, the autoimmune or autoinflammatory disease, disorder, or condition is or comprises allergies, asthma, rheumatoid arthritis (RA), psoriatic arthritis, psoriasis, systemic lupus erythematosus (SLE), spondyloarthritis, myelofibrosis, juvenile idiopathic arthritis, ankylosing spondylitis, Sjögren’s syndrome, inflammatory bowel disease, or alopecia areata. In some embodiments, the autoimmune or autoinflammatory disease, disorder, or condition is rheumatoid arthritis (RA). In some embodiments, the autoimmune or autoinflammatory disease, disorder, or condition is systemic lupus erythematosus (SLE). In some embodiments, the autoimmune or autoinflammatory disease, disorder, or condition is myelofibrosis. In some embodiments, the autoimmune or autoinflammatory disease, disorder, or condition is inflammatory bowel disease (e.g., IBS, IBS-D). In some embodiments, the autoimmune or autoinflammatory disease, disorder, or condition is psoriasis. [00322] In some embodiments, the inflammatory disease, disorder, or condition is an inflammatory disease, disorder, or condition associated with illness (e.g., viral infection, bacterial infection, fungal infection). In some embodiments, the inflammatory disease, disorder, or condition is associated with a viral infection. In some embodiments, the inflammatory disease, disorder, or condition is associated with a coronavirus infection. In some embodiments, the inflammatory disease, disorder, or condition is an inflammatory disease, disorder, or condition affecting the lungs and/or lower respiratory tract. In some embodiments, the inflammatory disease, disorder, or condition is or comprises an acute respiratory syndrome (e.g., severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), acute respiratory distress syndrome (ARDS), pneumonia (e.g., COVID pneumonia), hyperinflammation, cytokine storm syndrome (including those associated with COVID-19), and the like). In some embodiments, the inflammatory disease, disorder, or condition is associated with viral inflammation of the lungs. In some embodiments, the inflammatory disease, disorder, or condition is COVID pneumonia, Long COVID, Post-COVID respiratory illness, COPD, or the like. In some embodiments, the inflammatory diseases, disorder, or condition associated with a viral infection is or comprises SARS, MERS, ARDS, hyperinflammation, and/or cytokine storm syndrome. In some embodiments, the inflammatory diseases, disorder, or condition associated with a viral infection is associated with SARS-CoV-2 infection, or a variant or sub- variant thereof (e.g., delta, omicron, etc.). [00323] In some embodiments, the inflammatory disease, disorder, or condition is an inflammatory disease, disorder, or condition affecting the skin. In some embodiments, the inflammatory disease, disorder, or condition is a dermatoligical condition. In some embodiments, the inflammatory disease, disorder, or condition is or comprises a dermatitis and/or an eczema. In some embodiments, the inflammatory disease, disorder, or condition is atopic dermatitis, contact dermatitis, dyshidrotic eczema, neurodermatitis, nummular eczema, seborrheic dermatitis, and/or stasis dermatitis. In some embodiments, the inflammatory disease, disorder, or condition is atopic dermatitis. [00324] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (0), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00325] In some embodiments, provided herein is a compound of Formula (V), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (00), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00326] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a disease. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (0), (I), (I-A), (I-B), (I-C), (I-D), (I- E), (I-F), (I-G), (I-H), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00327] In some embodiments, provided herein is a compound of Formula (V), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a disease. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (00), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00328] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treating a disease. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (0), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00329] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt thereof, for use in the treating a disease. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (00), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00330] In some embodiments, provided herein is a method for manufacturing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (0), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is for use in treating a disease. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00331] In some embodiments, provided herein is a method for manufacturing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (V), or a pharmaceutically acceptable salt thereof, is a compound of any one or more of Formulae (00), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is for use in treating a disease. In some embodiments, the disease is a hematological malignancy (e.g., a leukemia or lymphoma). In some embodiments, the disease is a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or primary myelofibrosis). [00332] In some embodiments, provided herein is a method of treating a JAK2-associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof. [00333] Compounds disclosed herein are administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a contemplated compound disclosed herein is administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration includes subcutaneous injections, intravenous, or intramuscular injections or infusion techniques. [00334] Also contemplated herein are combination therapies, for example, co-administering a disclosed compound and an additional active agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected). Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. [00335] Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents are administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection. [00336] Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment is conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks. [00337] The components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that are administered either simultaneously or sequentially. [00338] In some embodiments, for contemplated treatment of pain, a disclosed compound is co- administered with another therapeutic for pain such as an opioid, a cannabinoid receptor (CB-1 or CB-2) modulator, a COX-2 inhibitor, acetaminophen, and/or a non-steroidal anti- inflammatory agent. Additional therapeutics e.g., for the treatment of pain that are co- administered include morphine, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol. [00339] In some embodiments, for contemplated treatment of pain, a disclosed compound is co- administration include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib, parecoxib, rimonabant, and/or etoricoxib. [00340] Additional combination therapies include, but are not limited, combinations of a compound disclosed herein (e.g., of any one or more of Formulae (0), (00), (I), (I-A), (I-B), (I- C), (I-D), (I-E), (I-F), (I-G), (I-H), (II), (III), (IV), (V), (V-A), (V-B), (V-C), (V-D), (VI), (VII), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable salt thereof) and a Bcl-2 inhibitor (e.g., venetoclax), an HDAC inhibitors (e.g., vorinostat), a BET inhibitor (e.g., mivebresib), a proteasome inhibitor (e.g., bortezomib), a LSD1 inhibitor (e.g., IMG-7289), or a CXCR2 inhibitor, or any combination thereof. [00341] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound disclosed herein in combination with a Bcl-2 inhibitor, a HDAC inhibitor, a BET inhibitor, or a proteasome inhibitor, or any combination thereof. In some embodiments, the additional active agent is a Bcl-2 inhibitor. In some embodiments, the Bcl-2 inhibitor is venetoclax. In some embodiments, the additional active agent is an HDAC inhibitor. In some embodiments, the HDAC inhibitor is vorinostat. In some embodiments, the additional active agent is a BET inhibitor. In some embodiments, the BET inhibitor is mivebresib. In some embodiments, the additional active agent is a proteasome inhibitor. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the disease, disorder, or condition is a T-cell lymphoma (e.g., a cutaneous T-cell lymphoma). In some embodiments, the additional active agent is a LSD1 inhibitor. In some embodiments, the LSD1 inhibitor is IMG-7289. In some embodiments, the disease, disorder, or condition is a myeloproliferative neoplasms. In some embodiments, the additional active agent is a CXCR2 inhibitor. EXAMPLES [00342] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. Synthesis Examples [00343] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. Compounds are generally prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6 ^th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared. [00344] Example 0-1: Preparation of 2,2-difluorocyclopropane-1-carboxamide (Int-1). [00345] To a solution of 2,2-difluorocyclopropane-1-carboxylic acid (1.0 g, 8.19 mmol, 1.0 equiv) in DCM (15 mL) was added oxalyl chloride (5.2 g, 40.98 mmol, 5 equiv) dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. It was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (10 mL) and cooled to 0 °C. To the solution was added aqueous ammonia solution (5 mL) dropwise and stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.0% methanol in DCM) to afford Int-1 (0.3 g, 30.24%). MS(ES): m/z 122.12 [M+H] ⁺ . [00346] The intermediates disclosed in the following table were prepared in the same manner as Int-1. [00347] Example 0-2: Preparation of 2,2-difluorocyclopropane-1-carboxamide (Int-5). [00348] To a solution of 2-bromothiazole (40 g, 243.9 mmol, 1.0 equiv) in diethyl ether (400 mL) was added a solution of n-butyllithium in hexane (2.5 M, 175.6 mL, 439.0 mmol, 1.8 equiv) dropwise at -78 °C. The reaction mixture was stirred for 30 min and was added dropwise tributyltin chloride (95.2 g, 292.6 mmol, 1.2 equiv). The reaction mixture was allowed to warm at room temperature and stirred for 5 h. It was poured into ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 22% ethyl acetate in hexane) to afford Int-5 (24.0 g, 26%). MS(ES): m/z 375.1 [M+H] ⁺ . [00349] Example 1-1: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-2-((4-(morpholine-4-carbonyl)phenyl)ami no)pyrimidine-5-carboxamide and (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-2- ((4-(morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxa mide, (Compound I-1-a) and (Compound I-1-b).

[00350] Synthesis of compound (±)-1.1. To a solution of cyclobutanone (5 g, 71.34 mmol, 1.0 equiv) in chloroform (100 mL) at 0 °C was added a solution of bromine (11.35 g, 71.34 mmol, 1.0 equiv) in chloroform (60 mL) dropwise. After the addition it was allowed to warm to rt and stirred for 16 h. The reaction mixture was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was used in the next step without purification (5 g, 47%). [00351] Synthesis of compound (±)-1.2. A mixture of (±)-1.1 (5 g, 34.02 mmol, 2.0 equiv), potassium carbonate (9.3 g, 67.56 mmol, 4.0 equiv) and 4-bromo-1H-pyrazole (2.5 g, 17.01 mmol, 1.0 equiv) in acetonitrile (50 mL) was stirred at rt for 72 h. It was transferred into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 16% ethyl acetate in hexane) to afford (±)-1.2 (0.68 g, 19%). [00352] Synthesis of compound (±)-1.3. To a solution of (±)-1.2 (0.68 g, 3.16 mmol, 1.0 equiv) and ethylene glycol (0.196 g, 3.16 mmol, 1.0 equiv) in benzene (10 mL) was added boron trifluoride diethyl etherate (0.222 g, 1.6 mmol, 0.5 equiv). The reaction mixture was stirred at 100 °C for 16 h. It was cooled to room temperature and transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-1.3 (0.23 g, 28%). [00353] Synthesis of compound (±)-1.4. A mixture of (±)-1.3 (0.23 g, 0.88 mmol, 1.0 equiv)), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line (0.243 g, 0.97 mmol, 1.1 equiv), potassium phosphate (0.565 g, 2.66 mmol, 3.0 equiv), dioxane (10 mL) and water (2 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (0.065 g, 0.08 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 °C for 1.5 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane) to afford (±)-1.4 (0.16 g, 60%). MS(ES): m/z 302.41 [M+H] ⁺ . [00354] Compound 1.4-a and 1.4-b. The racemate was subjected to chiral SFC separation (column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phases: (A) CO2 (B) 0.1% diethyl amine in propane-2-ol:acetronitrile (1:1); flow rate: 80 mL/min) to afford first eluting fraction (1.4-a, MS(ES): m/z 302.41 [M+H] ⁺ ) and second eluting fraction (1.4-b, MS(ES): m/z 302.41 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00355] Synthesis of compound 1.5-a and 1.5-b. A solution of 1.4-a (0.035 g, 0.18 mmol, 1.0 equiv), 2,4-dichloropyrimidine-5-carboxamide (0.055 g, 0.18 mmol, 1.0 equiv) and N, N- diisopropylethylamine (0.071 g, 5.5 mmol, 3.0 equiv) in n-butanol (4 mL) was stirred at 100 °C for 1 h. The reaction mixture was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3% methanol in DCM) to afford 1.5-a (0.055 g, 66%). MS(ES): m/z 457.8 [M+H] ⁺ . Compound 1.5-b was prepared from 1.4-b in the same manner. MS(ES): m/z 457.8 [M+H] ⁺ . [00356] Synthesis of Compound I-1-a and Compound I-1-b. A mixture of 1.5-a (0.055 g, 0.12 mmol, 1.0 equiv), (4-aminophenyl)(morpholino)methanone (0.030 g, 0.14 mmol, 1.2 equiv) and cesium carbonate (0.117 g, 0.36 mmol, 3.0 equiv) in 1,4-dioxane (4 mL) was degassed by bubbling through a stream of argon for 10 min.2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.015 g, 0.002 mmol, 0.2 equiv) and palladium acetate (0.003 g, 0.001 mmol, 0.1 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 140 °C in a microwave reactor for 3 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford Compound I-1-a (0.019 g, 25%). MS(ES): m/z 627.31 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.94 (s, 1H), 9.92 (s, 1H), 8.76 (s, 1H), 8.42 (bs, 1H) 8.27 (s, 1H), 8.08 (bs, 1H), 7.96 (s, 1H), 7.80 (d, J = 8 Hz, 2H), 7.47 (bs, 1H), 7.37-7.35 (d, J = 8 Hz, 3H), 7.13-7.09 (t, J = 8 Hz, 1H), 4.95-4.91 (t, J = 8 Hz, 1H), 3.90-3.70 (m, 4H), 3.70-3.60 (m, 6H), 3.60-3.40 (m, 4H), 3.00-2.90 (m, 1H), 2.45-2.30 (m,1H), 2.30-2.10 (m, 3H). [00357] Compound I-1-b was prepared from 1.5-b in the same manner. MS(ES): m/z 627.31 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.94 (s, 1H), 9.92 (s, 1H), 8.76 (s, 1H), 8.42 (bs, 1H) 8.27 (s, 1H), 8.08 (bs, 1H), 7.96 (s, 1H), 7.80 (d, J = 8 Hz, 2H), 7.47 (bs, 1H), 7.37-7.35 (d, J = 8 Hz, 3H), 7.13-7.09 (t, J = 8 Hz, 1H), 4.95-4.91 (t, J = 8 Hz, 1H), 3.90-3.70 (m, 4H), 3.70- 3.60 (m, 6H), 3.60-3.40 (m, 4H), 3.00-2.90 (m, 1H), 2.45-2.30 (m,1H), 2.30-2.10 (m, 3H). [00358] Example 1-2: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-3-yl )-2- methoxyphenyl)amino)-2-((4-(morpholine-4-carbonyl)phenyl)ami no)pyrimidine-5-carboxamide and (S)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-3-yl )-2-methoxyphenyl)amino)-2- ((4-(morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxa mide, (Compound I-2-a) and (Compound I-2-b).

[00359] Synthesis of compound (±)-2.1. Compound (±)-2.1 was prepared from (±)-1.1 and 3- bromo-1H-pyrazole, following the procedure described in the synthesis of (±)-1.2. The product was purified by flash column chromatography on silica gel (Combiflash®, 16% ethyl acetate in hexane). [00360] Synthesis of compound (±)-2.2. Compound (±)-2.2 was prepared from (±)-2.1 following the procedure described in the synthesis of (±)-1.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). [00361] Synthesis of compound (±)-2.3. Compound (±)-2.3 was prepared from (±)-2.2 following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 302.41 [M+H] ⁺ . [00362] Compound 2.3-a and 2.3-b. The racemate was subjected to chiral HPLC separation (Column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol:acetonitrile (70: 30); flow rate: 20 mL/min) to afford first eluting fraction (2.3-a, MS(ES): m/z 302.41 [M+H] ⁺ ) and second eluting fraction (2.3-b, MS(ES): m/z 302.41 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00363] Synthesis of compound 2.4-a and 2.4-b. Compound compound 2.4-a and 2.4-b were prepared from 2.3-a and 2.3-b respectively, following the procedure described in the synthesis of 1.5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3% methanol in DCM). MS(ES): m/z 457.8 [M+H] ⁺ . [00364] Synthesis of Compound I-2-a and Compound I-2-b. Compound I-2-a was prepared from 2.4-a, following the procedure described in the synthesis of Compound I-1-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 627.31 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.95 (s, 1H), 9.92 (s, 1H), 8.76 (s, 1H), 8.52 (bs, 1H) 8.08 (bs, 1H), 7.93 (s, 1H), 7.80 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 1H), 7.48 (bs, 1H), 7.36 (d, J = 8 Hz, 2H), 7.14 (t, J = 8 Hz, 1H), 6.79 (s, 1H), 4.95 (t, J = 8 Hz, 1H), 3.86-3.75 (m, 3H), 3.64-3.40 (m, 11H), 3.00-2.90 (m, 1H), 2.31-2.16 (m, 4H). [00365] Compound I-2-b was prepared from 2.4-b in the same manner. MS(ES): m/z 627.31 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.95 (s, 1H), 9.92 (s, 1H), 8.76 (s, 1H), 8.52 (bs, 1H) 8.08 (bs, 1H), 7.93 (s, 1H), 7.80 (d, J = 8 Hz, 2H), 7.53 (d, J = 8 Hz, 1H), 7.48 (bs, 1H), 7.36 (d, J = 8 Hz, 2H), 7.14 (t, J = 8 Hz, 1H), 6.79 (s, 1H), 4.95 (t, J = 8 Hz, 1H), 3.86-3.75 (m, 4H), 3.64-3.40 (m, 11H), 3.00-2.90 (m, 1H), 2.31-2.16 (m, 3H). [00366] Example 1-3: (R)-2-(2,2-difluorocyclopropane-1-carboxamido)-4-((2-methoxy -3-(1- methyl-1H-pyrazol-3-yl)phenyl)amino)pyrimidine-5-carboxamide and (S)-2-(2,2- difluorocyclopropane-1-carboxamido)-4-((2-methoxy-3-(1-methy l-1H-pyrazol-3- yl)phenyl)amino)pyrimidine-5-carboxamide, (Compound I-3-a) and (Compound I-3-b). [00367] Synthesis of compound 3.1. A mixture of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.62 mmol, 1.0 equiv), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.51 g, 12.93 mmol, 1.5 equiv) and potassium phosphate (3.65 g, 17.24 mmol, 2.0 equiv) in dioxane (40 mL) and water (8 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (0.126 g, 0.17 mmol, 0.05 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 120 ^o C for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 3.1 (0.7 g, 37%). MS(ES): m/z 220.21 [M+H] ⁺ . [00368] Synthesis of compound 3.2 and compound 3.3. To a solution of 3.1 (0.7 g, 3.19 mmol, 1.0 equiv) in DMF (15 ml) was added potassium carbonate (1.3 g, 9.5 mmol, 3 equiv) followed by methyl iodide (0.676 g, 4.8 mmol, 1.5 equiv). The reaction mixture was stirred at rt for 3 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtred, and concentrated under reduced pressure. The residue was purified by HPLC to afford 3.2 (0.07 g, 9.4%, MS(ES): m/z 234.25 [M+H] ⁺ ) and 3.3 (0.22 g, 30%, MS(ES): m/z 234.25 [M+H] ⁺ ). [00369] Synthesis of compound 3.4. A mixture of 10% palladium on carbon (0.1 g) and 3.3 (0.2 g, 0.85 mmol, 1.0 equiv) in methanol was stirred under hydrogen (1 atm) for 2 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 3.4 (0.127 g, 73%). MS(ES): m/z 204.4 [M+H] ⁺ . [00370] Synthesis of compound 3.5. Compound 3.5 was prepared from 3.4, following the procedure described in the synthesis of 1.5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford 3.5. MS(ES): m/z 359.75 [M+H] ⁺ . [00371] Synthesis of compound (±)-I-3. A mixture of 3.5 (0.17 g, 0.47 mmol, 1.0 equiv), Int- 1 (0.287 g, 2.37 mmol, 5 equiv) and cesium carbonate (0.462 g, 1.42 mmol, 3.0 equiv) in N,N- dimethylacetamide (6 mL) was degassed by bubbling through a stream of argon for 10 min. Xantphos (0.055 g, 0.09 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.043 g, 0.05 mmol, 0.1 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 140 °C in a microwave reactor for 1 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford (±)-I-3 (0.048 g, 23%). MS(ES): m/z 444.23 [M+H] ⁺ . [00372] Isolation of Compound I-3-a and Compound I-3-b. The racemate was subjected to chiral HPLC separation (Column: CHIRALPAK IH (250 x 20 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol:acetonitrile (70: 30); flow rate: 20 mL/min) to afford first eluting fraction (Compound I-3-a) and second eluting fraction (Compound I-3-b). *The absolute configuration of the chiral center is not determined. ^[00373] Compound I-3-a: MS(ES): m/z 444.23 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 12.11 (s, 1H), 11.13 (s, 1H), 9.10-9.08 (d, J = 8 Hz, 1H), 8.84 (s, 1H), 8.24 (bs, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.52-7.50 (d, J = 8 Hz, 1H), 7.14-7.10 (t, J = 8 Hz, 1H), 6.73 (s, 1H), 3.92 (s, 3H), 3.64 (s, 3H), 3.19-3.16 (m, 1H), 2.11-1.93 (m, 2H). ^[00374] Compound I-3-b: MS(ES): m/z 444.33 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 12.11 (s, 1H), 11.15 (s, 1H), 9.10-9.08 (d, J = 8 Hz, 1H), 8.84 (s, 1H), 8.25 (bs, 1H), 7.78 (s, 1H), 7.69 (bs, 1H), 7.52-7.50 (d, J = 8 Hz, 1H), 7.14-7.10 (t, J = 8 Hz, 1H), 6.73 (s, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 3.22-3.14 (m, 1H), 2.12-1.99 (m, 2H). [00375] Example 1-4: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and (S)-4-((3-(1-(5,8- dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl) amino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-4-a) and (Compound I-4-b). [00376] Synthesis of compound (±)-4.1. To a solution of (±)-1.4 (0.160 g, 0.83 mmol, 1.0 equiv) and 4,6-dichloronicotinamide (0.280 g, 0.92 mmol, 1.1 equiv) in THF (10 mL) at 0 °C was added a solution of sodium bis(trimethylsilyl)amide solution in THF (1 M, 5.8 mL, 5.8 mmol, 7.0 equiv) dropwise. The reaction mixture was stirred at rt for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.9% methanol in DCM) to afford (±)-4.1 (0.190 g, 50%). MS(ES): m/z 457.1 [M+H] ⁺ . [00377] Synthesis of compound (±)-I-4. A mixture of (±)-4.1 (0.190 g, 0.41 mmol, 1.0 equiv), cyclopropanecarboxamide (0.177 g, 2.08 mmol, 5 equiv) and cesium carbonate (0.406 g, 1.2 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) was degassed by bubbling through a stream of argon for 10 min.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.072 g, 0.12 mmol, 0.3 equiv) and tris(dibenzylideneacetone)dipalladium.chloroform adduct (0.065 g, 0.060 mmol, 0.15 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 110 °C for 3 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford (±)-I-4 (0.070 g, 33%). MS(ES): m/z 505.3 [M+H] ⁺ . [00378] Isolation of Compound I-4-a and Compound I-4-b. The racemate was subjected to chiral SFC separation (Column: CHIRALPAK IC (250 x 21 mm, 5 μm); mobile phases: (A) CO2 (B) 0.1% diethylamine in propane-2-ol:acetronitrile (1:1); flow rate: 80 mL/min) to afford first eluting fraction (Compound I-4-a) and second eluting fraction (Compound I-4-b). *The absolute configuration of the chiral center is not determined. [00379] Compound I-4-a: MS(ES): m/z 505.3 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 10.76 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.50 (bs, 1H), 7.41 (d, J = 8 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), 7.16 (t, J = 8 Hz, 1H), 4.92 (m, 1H), 3.80 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 1 H), 2.40-2.18 (m, 3H), 2.00-1.97 (m, 1H), 0.78- 0.76 (m, 4H). [00380] Compound I-4-b: MS(ES): m/z 505.3 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 10.76 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.50 (bs, 1H), 7.41 (d, J = 8 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), 7.16 (t, J = 8 Hz, 1H), 4.92 (m, 1H), 3.80 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 1 H), 2.40-2.18 (m, 3H), 2.00-1.97 (m, 1H), 0.78- 0.76 (m, 4H). [00381] Example 1-5: (S)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and (R)-4-((3-(1-(1,4- dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl) amino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-5-a) and (Compound I-5-b).

[00382] Synthesis of compound (±)-5.1. To a solution of cyclopentanone (10 g, 118.88 mmol, 1.0 equiv) in DCM (100 mL) was added N-bromosuccinimide (25.42 g, 142.85 mmol, 1.2 equiv) in small portions at 0 °C. The reaction mixture was stirred at rt for 16 h. It was transferred into ice-cold saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used in the next step without purification (11 g, 57%). [00383] Synthesis of compound (±)-5.2. Compound (±)-5.2 was prepared from (±)-5.1 and 4- bromo-1H-pyrazole, following the procedure described in the synthesis of (±)-1.2. The product was purified by flash column chromatography on silica gel (Combiflash®, 26% ethyl acetate in hexane). [00384] Synthesis of compound (±)-5.3. Compound (±)-5.3 was prepared from (±)-5.2 following the procedure described in the synthesis of (±)-1.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). [00385] Synthesis of compound (±)-5.4. Compound (±)-5.4 was prepared from (±)-5.3 following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 316.37 [M+H] ⁺ . [00386] Compound 5.4-a and 5.4-b. The racemate was subjected to chiral SFC separation (column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phases: (A) CO2 (B) 0.1% diethyl amine in propane-2-ol: acetonitrile (1: 1); flow rate: 80 mL/min) to afford first eluting fraction (5.4-a, MS(ES): m/z 316.37 [M+H] ⁺ ) and second eluting fraction (5.4-b, MS(ES): m/z 316.37 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00387] Synthesis of compound 5.5-a and 5.5-b. Compound 5.5-a was prepared from 5.4-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 470.93 [M+H] ⁺ . Compound 5.5-b was prepared from 5.4-b in the same manner. MS(ES): m/z 470.93 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00388] Synthesis of Compound I-5-a and Compound I-5-b. A mixture of 5.5-a (0.150 g, 0.319 mmol, 1.0 equiv), cyclopropanecarboxamide (0.135 g, 1.15 mmol, 5 equiv) and cesium carbonate (0.312 g, 0.957 mmol, 3.0 equiv) in 1, 4-dioxane (5 mL) was degassed by bubbling through a stream of argon for 10 min.4, 5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.055 g, 0.095 mmol, 0.3 equiv) and tris(dibenzylideneacetone)dipalladium chloroform adduct (0.049 g, 0.047 mmol, 0.15 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 130 °C for 3 h. The reaction mixture was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.6% methanol in DCM) to afford Compound I-5-a (0.022 g, 13%). MS(ES): m/z 519.57 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.75 (s, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 8.15 (bs, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.50 (bs, 1H), 7.40-7.38 (d, J = 8 Hz, 1H), 7.29-7.27 (d, J = 8 Hz, 1H), 7.18-7.16 (t, J = 8 Hz, 1H), 4.62-4.60 (t, J = 8 Hz, 1H), 3.82 (m, 4H), 3.57 (s, 3H), 2.33-2.20 (m, 2H), 2.00-1.80 (m, 4H), 1.70 (m, 1H), 0.78-0.77 (m, 4H). [00389] Compound I-5-b was prepared from 5.5-b in the same manner. MS(ES): m/z 519.57 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.75 (s, 1H), 8.60 (s, 1H), 8.19 (s, 1H), 8.15 (bs, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.50 (bs, 1H), 7.40-7.38 (d, J = 8 Hz, 1H), 7.29- 7.27 (d, J = 8 Hz, 1H), 7.18-7.16 (t, J = 8 Hz, 1H), 4.62-4.60 (t, J = 8 Hz, 1H), 3.82 (m, 4H), 3.57 (s, 3H), 2.33-2.20 (m, 2H), 2.00-1.80 (m, 4H), 1.70 (m, 1H), 0.78-0.77 (m, 4H). [00390] Example 1-6: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-((S)-2,2-difluorocyclopropane-1-carbo xamido)nicotinamide; 4-((3-(1- ((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-metho xyphenyl)amino)-6-((R)-2,2- difluorocyclopropane-1-carboxamido)nicotinamide; 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1- yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-((R)-2,2-diflu orocyclopropane-1- carboxamido)nicotinamide; and 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )- 2-methoxyphenyl)amino)-6-((S)-2,2-difluorocyclopropane-1-car boxamido)nicotinamide, (Compound I-6-a), (Compound I-6-b), (Compound I-6-c), and (Compound I-6-d). [00391] Synthesis of compound 6.1-a. Compound 6.1-a was prepared from 1.4-a and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 457.2 [M+H] ⁺ . [00392] Synthesis of compound 6.2-a. Compound 6.2-a was prepared from 6.1-a and Int-1, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 541.36 [M+H] ⁺ . [00393] Isolation of Compound I-6-a and Compound I-6-b. Isomers of 6.2-a were separated by chiral HPLC (column: CHIRALPAK IH (250 x 20 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: methanol (1: 1); flow rate: 20 mL/min) to afford first eluting fraction (Compound I-6-a) and second eluting fraction (Compound I-6-b). *The absolute configuration of the chiral center is not determined. [00394] Compound I-6-a: MS(ES): m/z 541.36 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 10.93 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.18 (bs, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.55 (bs, 1H), 7.44-7.42 (d, J = 8 Hz, 1H), 7.31-7.29 (d, J = 8 Hz, 1H), 7.20-7.16 (t, J = 8 Hz, 1H), 4.95-4.90 (m, 1H), 3.79 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 2H), 2.40-2.18 (m, 3H), 2.00- 1.90 (m, 2H). [00395] Compound I-6-b: MS(ES): m/z 541.4 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 10.93 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.18 (bs, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.55 (bs, 1H), 7.43 (d, J = 8 Hz, 2H), 7.30 (d, J = 8 Hz, 1H), 7.19 (t, J = 8 Hz, 1H), 4.95-4.90 (m, 1H), 3.79 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 2H), 2.40-2.18 (m, 3H), 2.00-1.90 (m, 2H). [00396] Synthesis of compound 6.1-b. Compound 6.1-b was prepared from 1.4-b and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 457.2 [M+H] ⁺ . [00397] Synthesis of compound 6.2-b. Compound 6.2-b was prepared from 6.1-b and Int-1, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 541.36 [M+H] ⁺ . [00398] Isolation of Compound I-6-c and Compound I-6-d. Isomers of 6.2-b were separated by chiral HPLC (Column: CHIRALPAK IH (250 x 20 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: methanol (1: 1); flow rate: 20 mL/min) to afford first eluting fraction (I-6-c) and second eluting fraction (I-6-d). *The absolute configuration of the chiral center is not determined. [00399] Compound I-6-c: MS(ES): m/z 541.36 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 10.93 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.18 (bs, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.55 (bs, 1H), 7.44-7.42 (d, J = 8 Hz, 1H), 7.31-7.29 (d, J = 8 Hz, 1H), 7.20-7.16 (t, J = 8 Hz, 1H), 4.95-4.90 (m, 1H), 3.79 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 2H), 2.40-2.18 (m, 3H), 2.00- 1.90 (m, 2H). ^[00400] Compound I-6-d: MS(ES): m/z 541.4 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 10.93 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 8.18 (bs, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.55 (bs, 1H), 7.43 (d, J = 8 Hz, 2H), 7.30 (d, J = 8 Hz, 1H), 7.19 (t, J = 8 Hz, 1H), 4.95-4.90 (m, 1H), 3.79 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 2H), 2.40-2.18 (m, 3H), 2.00-1.90 (m, 2H). [00401] Example 1-7: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-((1r,3R)-3-methylcyclobutane-1-carbox amido)nicotinamide and 4-((3- (1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-me thoxyphenyl)amino)-6-((1r,3S)-3- methylcyclobutane-1-carboxamido)nicotinamide, (Compound I-7-a) and (Compound I-7-b). [00402] Synthesis of Compound I-7-a and Compound I-7-b. Compound I-7-a was prepared from 6.1-a and Int-2, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 533.41 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 10.22 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.12 (bs, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.47 (bs, 1H), 7.41 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.19 (t, J = 8 Hz, 1H), 4.98-4.89 (m, 1H), 3.79-3.76 (m, 4H), 3.56 (s, 3H), 3.00-2.90 (m, 1H), 2.39-2.16 (m, 7H), 1.71-1.63 (m, 2H), 1.07 (d, J = 6 Hz, 3H). [00403] Compound I-7-b was prepared from 6.1-b in the same manner. MS(ES): m/z 533.41 [M+H] ⁺ . ): δ 10.90 (s, 1H), 10.22 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.12 (bs, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.47 (bs, 1H), 7.41 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.19 (t, J = 8 Hz, 1H), 4.98-4.89 (m, 1H), 3.79-3.76 (m, 4H), 3.56 (s, 3H), 3.00-2.90 (m, 1H), 2.39-2.16 (m, 7H), 1.71-1.63 (m, 2H), 1.07 (d, J = 6 Hz, 3H). [00404] Example 1-8: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide and (S)-4-((3- (1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-methox yphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide carboxamide, (Compound I-8-a) and (Compound I-8-b). [00405] Synthesis of compound 8.1. To a suspension of 4,6-dioxo-1,4,5,6- tetrahydropyridazine-3-carboxylic acid (3.0 g, 19.22 mmol, 1.0 equiv) in triethylamine (1.94 g, 19.22 mmol, 1.0 equiv) was added phosphorus oxychloride (38.25 g, 250.00 mmol, 13.0 equiv). The reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to rt and slowed added into a cold aquous ammonia solution and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford 8.1 (0.67 g, 19%). MS(ES): m/z 193.7 [M+H] ⁺ . [00406] Synthesis of compound 8.2-a and 8.2-b. Compound 8.2-a was prepared from 8.1 and 1.4-a, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.9% methanol in DCM). MS(ES): m/z 457.9 [M+H] ⁺ . Compound 8.2-b was prepared from 8.1 and 1.4-b in the same manner. MS(ES): m/z 457.9 [M+H] ⁺ . [00407] Synthesis of Compound I-8-a and Compound I-8-b. Compound I-8-a was prepared from 8.2-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 506.38 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 11.00 (s, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.50-7.48 (d, J = 8 Hz, 1H), 7.31-7.29 (d, J = 8 Hz, 1H), 7.23-7.21 (d, J = 8 Hz, 1H), 4.95-4.93 (m, 1H), 3.81-3.80 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 1H), 2.41-2.15 (m, 3H), 2.10-2.00 (m, 1H), 0.82-0.78 (m, 4H). [00408] Compound I-8-b was prepared from 8.2-b in the same manner. MS(ES): m/z 506.40 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 11.00 (s, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.50-7.48 (d, J = 8 Hz, 1H), 7.31-7.29 (d, J = 8 Hz, 1H), 7.23-7.21 (d, J = 8 Hz, 1H), 4.95-4.93 (m, 1H), 3.81-3.80 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 1H), 2.41-2.15 (m, 3H), 2.10-2.00 (m, 1H), 0.82-0.78 (m, 4H). [00409] Example 1-9: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-((S)-2,2-dimethylcyclopropane-1-carbo xamido)nicotinamide and 4- ((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)-6-((S)- 2,2-dimethylcyclopropane-1-carboxamido)nicotinamide, (Compound I-9-a) and (Compound I- 9-b). [00410] Synthesis of Compound I-9-a and Compound I-9-b. Compound I-9-a was prepared from 6.1-a and (S)-2,2-dimethylcyclopropane-1-carboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (3.2% methanol in DCM). MS(ES): m/z 533.2 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.93 (s, 1H), 10.58 (s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 7.38 (d, J = 7.2 Hz 1H), 7.29 (d, J = 7.2 Hz 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.94- 4.92 (bs, 1H), 3.78 (m, 4H), 3.56 (s, 3H), 2.96 (m, 1H), 2.28-2.16 (m, 3H), 1.85 (m, 1H), 1.10 (s, 3H), 1.07 (s, 3H), 0.93 (m, 1H), 0.75 (m, 1H). [00411] Compound I-9-b was prepared from 6.1-b as above. MS(ES): m/z 533.2 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.93 (s, 1H), 10.58 (s, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 7.38 (d, J = 7.2 Hz 1H), 7.29 (d, J = 7.2 Hz 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.94-4.92 (bs, 1H), 3.78 (m, 4H), 3.56 (s, 3H), 2.96 (m, 1H), 2.28-2.16 (m, 3H), 1.85 (m, 1H), 1.10 (s, 3H), 1.07 (s, 3H), 0.93 (m, 1H), 0.75 (m, 1H). [00412] Example 1-10: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide and (S)-4-((3- (1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-methox yphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide, (Compound I-10-a) and (Compound I- 10-b). [00413] Synthesis of compound 10.1-a and 10.1-b. Compound 10.1-a was prepared from 5.4- a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.1% methanol in DCM). MS(ES): m/z 471.93 [M+H] ⁺ . Compound 10.1-b was prepared from 5.4-b in the same manner. MS(ES): m/z 471.93 [M+H] ⁺ . [00414] Synthesis of Compound I-10-a and Compound I-10-b. Compound I-10-a was prepared from 10.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.3% methanol in DCM). MS(ES): m/z 520.56 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.28 (s, 1H), 10.96 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 4.59 (t, J = 8.0 Hz, 1H), 3.79 (m, 4H), 3.54 (s, 3H), 2.40-2.20 (m, 3H), 2.10-2.00 (m, 1H), 2.00-1.80 (m, 3H), 0.79 (m, 4H). [00415] Compound I-10-b was prepared from 10.1-b in the same manner. MS(ES): m/z 520.56 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.28 (s, 1H), 10.96 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 4.59 (t, J = 8.0 Hz, 1H), 3.79 (m, 4H), 3.54 (s, 3H), 2.40-2.20 (m, 3H), 2.10-2.00 (m, 1H), 2.00-1.80 (m, 3H), 0.79 (m, 4H). [00416] Example 1-11: 4-((3-(1-((R)-1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-((S)-2,2-dimethylcyclopropane-1-carbo xamido)nicotinamide and 4- ((3-(1-((S)-1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)-6-((S)- 2,2-dimethylcyclopropane-1-carboxamido)nicotinamide, (Compound I-11-a) and (Compound I-11-b). [00417] Synthesis of Compound I-11-a and Compound I-11-b. Compound I-11-a was prepared from 5.5-a and (S)-2,2-dimethylcyclopropane-1-carboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM). MS(ES): m/z 547.63 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 10.54 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.45 (s, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.15 (m, 1H), 4.57 (m, 1H), 3.77 (m, 4H), 3.55 (s, 3H), 2.30 (m, 3H), 1.84 (m, 4H), 1.10 (s, 3H), 1.07 (s, 3H), 0.93 (bs, 1H), 0.75 (bs, 1H). [00418] Compound I-11-b was prepared from 5.5-b in the same manner. MS(ES): m/z 547.63 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 10.54 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.45 (s, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.15 (m, 1H), 4.57 (m, 1H), 3.77 (m, 4H), 3.55 (s, 3H), 2.30 (m, 3H), 1.84 (m, 4H), 1.10 (s, 3H), 1.07 (s, 3H), 0.93 (bs, 1H), 0.75 (bs, 1H). [00419] Example 1-12: 4-((3-(1-((1R,4S)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and 4-((3-(1-((1S,4R)-5- oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)am ino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-12-a) and (Compound I-12-b). [00420] Synthesis of compound (±)-cis-12.1. To a stirred solution of (±)-1.2 (3 g, 13.95 mmol, 1 equiv) in THF (80 mL) at 0 °C was added a solution of allylmagnesium bromide (1 M in THF, 48.8 mL, 48.8 mmol, 3.5 equiv). The reaction mixture was stirred at room temperature for 16 h. It was slowly quenched by a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 8% ethyl acetate in hexane) to afford (±)-cis-12.1 (0.6 g, 17%). MS (ES): m/z 257.13 [M+H] ⁺ . [00421] Synthesis of compound (±)-cis-12.2. To a solution of (±)-cis-12.1 (0.6 g, 2.3 mmol, 1 equiv) in DMF (15 mL) at 0 °C was added sodium hydride (0.336 g, 7 mmol, 3 equiv) and stirred at room temperature of 15 min. To the mixture was added allyl bromide (1.13 g, 9.33 mmol, 4 equiv) and stirred for 15 min. It was transferred into cold water slowly, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-cis-12.2 (0.38 g, 55%). MS (ES): m/z 297.20 [M+H] ⁺ . [00422] Synthesis of compound (±)-cis-12.3. To a stirred solution of (±)-cis-12.2 (0.38 g, 1.28 mmol, 1 equiv) in DCM (20 mL) was added 2 ^nd gen. Grubbs catalyst (0.195 g, 0.23 mmol, 0.18 equiv). The reaction mixture was stirred at room temperature under argon for 16 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-cis-12.3 (0.26 g, 76%). MS (ES): m/z 269.14 [M+H] ⁺ . [00423] Synthesis of compound (±)-cis-12.4. Compound (±)-cis-12.4 was prepared from (±)- cis-12.3, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS (ES): m/z 311.39 [M+H] ⁺ . [00424] Synthesis of compound (±)-cis-12.5. A mixture of (±)-cis-12.4 (0.23 g, 0.738 mmol, 1.0 equiv) and 10% palladium on charcoal (200 mg) in methanol (10 mL) was stirred under hydrogen (1 atm) for 1 h. The reaction mixture was diluted with 10% methanol in DCM and filter through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was used in the next step without purification. MS (ES): m/z 313.40 [M+H] ⁺ . [00425] Compound cis-12.5-a and cis-12.5-b. The racemate was subjected to chiral SFC separation (Column: CHIRALPAK IB-N (250 x 4.6 mm, 5 μm); mobile phases: (A) CO2 (B) 0.1% DEA in propane-2-ol: acetonitrile (1:1); flow rate: 20 mL/min) to afford first eluting fraction (cis-12.5-a) and second eluting fraction (cis-12.5-b). MS(ES): m/z: 313.40 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00426] Synthesis of compound cis-12.6-a and cis-12.6-b. Compound cis-12.6-a was prepared from cis-12.5-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS (ES): m/z 467.95 [M+H] ⁺ . Compound cis- 12.6-b was prepared from cis-12.5-b in the same manner. MS (ES): m/z 467.95 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00427] Synthesis of Compound I-12-a and Compound I-12-b. Compound I-12-a was prepared from cis-12.6-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS (ES): m/z 516.60 [M+H] ⁺ ; ¹ H NMR (DMSO- d6, 400 MHz): 10.90 (s, 1H), 10.75 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.15 (bs, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.50 (bs, 1H), 7.41 (d, J = 7.6 Hz, 1H), 77.28 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 4.76 (d, J = 7.6 Hz, 1H), 3.57 (s, 3H), 3.00-2.90 (m, 1H), 2.17-2.13 (m, 1H), 1.98- 1.95 (m, 1H), 1.80-1.71(m, 2H), 1.70-1.40 (m, 4H), 11.322-1.22 (m, 4H), 0.76-0.75 (m, 4H). [00428] Compound I-12-b was prepared from cis-12.6-b in the same manner. MS (ES): m/z 516.60 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 10.90 (s, 1H), 10.75 (s, 1H), 8.60 (s, 1H), 8.27 (s, 1H), 8.15 (bs, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.50 (bs, 1H), 7.41 (d, J = 7.6 Hz, 1H), 77.28 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 4.76 (d, J = 7.6 Hz, 1H), 3.57 (s, 3H), 3.00- 2.90 (m, 1H), 2.17-2.13 (m, 1H), 1.98-1.95 (m, 1H), 1.80-1.71(m, 2H), 1.70-1.40 (m, 4H), 11.322-1.22 (m, 4H), 0.76-0.75 (m, 4H). [00429] Example 1-13: 4-((3-(1-((R)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-((S)-spiro[2.3]hexane-1-carboxamido)n icotinamide; 4-((3-(1-((R)-5,8- dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl) amino)-6-((R)-spiro[2.3]hexane- 1-carboxamido)nicotinamide; 4-((3-(1-((S)-5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-((R)-spiro[2.3]hexane-1-carboxamido)n icotinamide; and 4-((3-(1-((S)- 5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphe nyl)amino)-6-((S)- spiro[2.3]hexane-1-carboxamido)nicotinamide; (Compound I-13-a), (Compound I-13-b), (Compound I-13-c), and (Compound I-13-d). [00430] Synthesis of compound 13.1-a and 13.1-b. Compound 13.1-a was prepared from 6.1- a and Int-4, following the procedure described in the synthesis of I-5-a. The product purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 545.6 [M+H] ⁺ . Compound 13.1-b was prepared from 6.1-b in the same manner. MS(ES): m/z 545.42 [M+H] ⁺ . [00431] Isolation of Compound I-13-a and Compound I-13-b. Compound 13.1-a was subjected to chiral HPLC separation (Column: CHIRALPAK IH (250 x 20 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: acetonitrile (70: 30); flow rate: 20 mL/min) to afford first eluting fraction (Compound I-13-a) and second eluting fraction (Compound I-13-b). ^[00432] Compound I-13-a: MS(ES): m/z 545.6 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 10.59 (s, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 8.13 (bs, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.47 (bs, 1H), 7.39 (d, J = 8 Hz, 1H), 7.28 (d, J = 8 Hz,1H), 7.15 (t, J = 8 Hz, 1H), 4.93 (m, 1H), 3.85-3.70 (m, 4H), 3.56 (s, 3H), 3.00-2.90 (m, 1H), 2.40-2.10 (m, 4H), 2.10-1.90 (m, 6H), 1.06-1.02 (m, 1H), 0.95 (m,1H). [00433] Compound I-13-b: MS(ES): m/z 545.6 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 10.59 (s, 1H), 8.59 (s, 1H), 8.25 (s, 1H), 8.13 (bs, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.47 (bs, 1H), 7.39 (d, J = 8 Hz, 1H), 7.28 (d, J = 8 Hz,1H), 7.15 (t, J = 8 Hz, 1H), 4.93 (m, 1H), 3.85-3.70 (m, 4H), 3.56 (s, 3H), 3.00-2.90 (m, 1H), 2.40-2.10 (m, 4H), 2.10-1.90 (m, 6H), 1.06-1.02 (m, 1H), 0.95 (m,1H). [00434] Isolation of Compound I-13-c and Compound I-13-d. Compound 13.1-b was subjected to chiral HPLC separation (Column: CHIRALPAK IH (250 x 20 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: acetonitrile (70: 30); flow rate: 20 mL/min) to afford first eluting fraction (Compound I-13c) and second eluting fraction (Compound I-13d). *The absolute configuration of the chiral center is not determined. [00435] Compound I-13-c: MS(ES): m/z 545.42 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 10.60 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 8.14 (bs, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.48 (bs, 1H), 7.40 (d, J = 8 Hz, 1H), 7.29 (d, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 4.94-4.92 (m, 1H), 3.80 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 1H), 2.33-2.10 (m, 4H), 2.10-1.90 (m, 6H), 1.04 (m, 1H), 0.95 (m, 1H). ^[00436] Compound I-13-d: MS(ES): m/z 545.42 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 10.60 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 8.14 (bs, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.48 (bs, 1H), 7.40 (d, J = 8 Hz, 1H), 7.29 (d, J = 8 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 4.94-4.92 (m, 1H), 3.80 (m, 4H), 3.57 (s, 3H), 3.00-2.90 (m, 1H), 2.33-2.10 (m, 4H), 2.10-1.90 (m, 6H), 1.04 (m, 1H), 0.95 (m, 1H). [00437] Example 1-14: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-imidazol-4-y l)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and (S)-4-((3-(1-(5,8- dioxaspiro[3.4]octan-1-yl)-1H-imidazol-4-yl)-2-methoxyphenyl )amino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-14-a) and (Compound I-14-b). [00438] Synthesis of compound (±)-14.1. A mixture of 4-bromo-1H-imidazole (15.0 g, 102.04 mmol, 1.0 equiv), cesium carbonate (99.79 g, 306.04 mmol, 3.0 equiv) and (±)-1.1 (30.40 g, 204 mmol, 2.0 equiv) in acetonitrile (150 mL) was stirred at 90 ºC for 16 h. The reaction mixture was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford (±)-14.1 (2.78 g, 13%). [00439] Synthesis of compound (±)-14.2. Compound (±)-14.2 was prepared from (±)-14.1 following the procedure described in the synthesis of (±)-1.3. The product was purified by flash column chromatography on silica gel (Combiflash®, 17% ethyl acetate in hexane). [00440] Synthesis of compound (±)-14.3. Compound (±)-14.3 was prepared from (±)-14.2 following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 302.35 [M+H] ⁺ . [00441] Compound 14.3-a and 14.3-b. The racemate was subjected to chiral HPLC separation (Column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: acetonitrile (70:30); flow rate: 20 mL/min) to afford first eluting fraction (14.3-a, MS(ES): m/z 302.35 [M+H] ⁺ ) and second eluting fraction (14.3-b, MS(ES): m/z 302.35 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00442] Synthesis of compound 14.4-a and 14.4-b. Compound 14.4-a was prepared from 14.3-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.9% methanol in DCM). MS(ES): m/z 456.90 [M+H] ⁺ . Compound 14.4-b was prepared from 14.3-b in the same manner. MS(ES): m/z 456.90 [M+H] ⁺ . [00443] Synthesis of Compound I-14-a and Compound I-14-b. Compound I-14-a was prepared from 14.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM). MS(ES): m/z 505.55 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.74 (s, 1H), 8.61 (s, 1H), 8.15 (bs, 2H), 8.02 (s, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.49 (bs,1H), 7.29 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 4.92 (m, 1H), 3.90-3.70 (m, 4H), 3.65 (s, 3H), 3.16 (m, 1H), 2.23 (m, 4H), 2.0 (m, 1H), 0.77 (m, 4H). [00444] Compound I-14-b was prepared from 14.4-b in the same manner. MS(ES): m/z 505.55 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.74 (s, 1H), 8.61 (s, 1H), 8.15 (bs, 2H), 8.02 (s, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.49 (bs,1H), 7.29 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 4.92 (m, 1H), 3.90-3.70 (m, 4H), 3.65 (s, 3H), 3.16 (m, 1H), 2.23 (m, 4H), 2.0 (m, 1H), 0.77 (m, 4H). [00445] Example 1-15: 4-((3-(1-((1R,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and 4-((3-(1-((1S,4R)-5- oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)am ino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-15-a) and (Compound I-15-b).

[00446] Synthesis of compound (±)-trans-15.1. To a solution of (±)-1.2 (15 g, 69.75 mmol, 1.0 equiv) and magnesium bromide ethyl etherate (5.4 g, 20.93 mmol, 0.3 equiv) in DCM (150 mL) at 0 °C was added a solution of vinyl magnesium bromide (1 M in THF, 244.0 mL, 244 mmol, 3.5 equiv) dropwise. The reaction mixture was stirred at rt for 16 h. It was poured into a saturated aqueous ammonium chloride solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (22% ethyl acetate in hexane) to afford (±)-trans-15.1 (2.6 g, 15%). [00447] Synthesis of compound (±)-trans-15.2. To a suspension of sodium hydride (60 wt% in mineral oil, 1.03 g, 25.92 mmol, 3.0 equiv) in DMF (25 mL) at 0 °C was added (±)-trans-15.1 (2.1 g, 8.64 mmol, 1.0 equiv) and stirred for 30 min. To the mixture was added allyl bromide (4.18 g, 34.56 mmol, 4 equiv) dropwise at 0 °C. The reaction mixture was allowed to warm at rt and stir for 1 h. It was transferred into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-trans- 15.2 (1.4 g, 57%). [00448] Synthesis of compound (±)-trans-15.3. To a solution of (±)-trans-15.2 (1.4 g, 4.94 mmol, 1.0 equiv) in DCM (25 mL) was added 2nd gen. Grubbs catalyst (0.836 g, 0.98 mmol, 0.2 equiv). The reaction mixture was stirred under argon at rt for 16 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 8% ethyl acetate in hexane) to afford (±)-trans-15.3 (0.7 g, 56%). [00449] Synthesis of compound (±)-trans-15.4. Compound (±)-trans-15.4 was prepared from (±)-trans-15.3, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 298.3 [M+H] ⁺ . [00450] Synthesis of compound (±)-trans-15.5. A mixture of 10% palladium on carbon (0.2 g) and (±)-trans-15.4 (0.5 g, 1.68 mmol, 1.0 equiv) in methanol was stirred under hydrogen atmosphere (1 atm) for 2 h. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford (±)-trans-15.5 (0.400 g, 79%). MS(ES): m/z 300.2[M+H] ⁺ . [00451] Compound trans-15.5-a and trans-15.5-b. The racemate was subjected to chiral HPLC separation (column: CHIRALPAK AD-H (250 x 30 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: methanol (1:1); flow rate: 25 mL/min) to afford first eluting fraction (trans-15.5-a, MS(ES): m/z 300.2 [M+H] ⁺ ) and second eluting fraction (trans-15.5-b, MS(ES): m/z 300.1 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00452] Synthesis of compound trans-15.6-a and trans-15.6-b. Compound trans-15.6-a was prepared from trans-15.5-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 455.5 [M+H] ⁺ . Compound trans-15.6-b was prepared from trans-15.5-b in the same manner. MS(ES): m/z 455.5 [M+H] ⁺ . [00453] Synthesis of Compound I-15-a and Compound I-15-b. Compound I-15-a was prepared from trans-15.6-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 503.3 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 10.75 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.16 (bs, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.50 (s, 1H), 7.41 (d, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 4.82- 4.79 (m, 1H), 3.71-3.68 (m, 2H), 3.55 (s, 3H), 2.37-2.32 (m, 2H), 2.00-1.92 (m, 4H), 1.80-1.67 (m, 3H), 0.79-0.77 (m, 4H). [00454] Compound I-15-b was prepared from trans-15.6-b in the same manner. MS(ES): m/z 503.3 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.75 (s, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 8.16 (bs, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.40 (d, J = 8 Hz, 1H), 7.29 (d, J = 8 Hz, 1H), 7.17 (t, J = 8 Hz, 1H), 4.82-4.79 (m, 1H), 3.71-3.68 (m, 2H), 3.54 (s, 3H), 2.34-2.31 (m, 2H), 2.14-1.92 (m, 4H), 1.80-1.67 (m, 3H), 0.79-0.77 (m, 4H). [00455] Example 1-16: 4-((3-(1-((5R,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and 4-((3-(1-((5S,6S)-1- oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)am ino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-16-a) and (Compound I-16-b). [00456] Synthesis of compound (±)-16.1. A solution of n-BuLi in THF (1.6 M, 91.3 mL, 228.27 mmol, 0.8 equiv) was added dropwise to a solution of 2,3-dihydrofuran (20.0 g, 285.34 mmol, 1.0 equiv) in anhydrous THF under argon at 0 °C in 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. It was cooled to -78 °C and was added cyclobutanone (14.0 g, 199.74 mmol, 0.7 equiv) dropwise in 5 min. The reaction mixture was allowed warm to room temperature and stirred for additional 2 h. It was transferred into ice-cold saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-16.1 (20 g, 50.0%). MS(ES): m/z 141.2 [M+H] ⁺ . It was used in the next step without purification. [00457] Synthesis of compound (±)-16.2. A mixture of compound (±)-16.1 (20 g, 142.85 mmol, 1.0 equiv) and DOWEX-50WX (2.0 g) in DCM was stirred for 24 h. It was filtered through a pad of Celite® and rinsed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane to afford (±)-16.2 (10.0 g, 50.0%). MS(ES):m/z 133.2 [M+H] ^+. [00458] Synthesis of compound (±)-16.3. A solution of tert-butyl hydrazine carboxylate (10.6 g, 75.75 mmol, 1.0 equiv) and compound (±)-16.2 (10.0 g, 75.75 mmol, 1.0 equiv) in ethanol (100 mL) was heated to reflux overnight. It was cooled to rt and concentrated under reduced pressure to afford (±)-16.3 (20.0 g, 88%). MS(ES):m/z 255.3 [M+H] ⁺ . [00459] Synthesis of compound (±)-trans-16.4 and (±)-cis-16.4. To a solution of (±)-16.3 (20.0 g, 78.63 mmol, 1.0 equiv) in acetic acid (125 mL) was added sodium cynoborohydride (4.95 g, 78.63 mmol, 1.0 equiv) in small portions. The reaction mixture was stirred at room temperature for 3 h. It was poured into water and adjust pH to 7 by adding 1 N sodium hydroxide. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford (±)-trans-16.4 (6.0 g, 30%), MS(ES): m/z: 257.3 [M+H] ⁺ and (±)-cis-16.4 (8.0 g, 40%). MS(ES): m/z: 257.3 [M+H] ⁺ . [00460] Synthesis of compound (±)-cis-16.5. To solution of (±)-cis-16.4 (0.8 g, 3.12 mmol, 1.0 equiv) in DCM (8.0 mL) was added hydrochloric acid in dioxane (4 M, 8.0 mL) at 0 °C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether to afford (±)-cis-16.5 (0.800 g, 100%). MS(ES): m/z: 157.3 [M+H] ⁺ . [00461] Synthesis of compound (±)-cis-16.6. A mixture of (±)-cis-16.5 (0.8 g, 5.12 mmol, 1.0 equiv), 1,1,3,3-tetramethoxypropane (1.68 g, 10.24 mmol, 2.0 equiv) and aqueous hydrochloric acid (12 M, 1.36 mL, 16.38 mmol, 3.2 equiv) in a seal tube was stirred at 100 °C for 1 h. The reaction mixture transferred into ice-water and extracted with methyl tert-butyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-cis-16.6 (1.04 g, 98%). MS(ES): m/z: 193.26 [M+H] ⁺ . [00462] Synthesis of compound (±)-cis-16.7. To a solution of (±)-cis-16.6 (1.04 g, 5.409 mmol, 1.0 equiv) in acetic acid was added N-bromosuccinimide (0.962 g, 5.409 mmol, 1.0 equiv) in small portions and stirred at room temperature for 1 h. The reaction mixture was poured into saturated NaHCO3 and extracted with methyl tert-butyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-cis-16.7. MS(ES): m/z: 272.2 [M+H] ⁺ . [00463] Synthesis of compound (±)-cis-16.8. Compound (±)-cis-16.8 was prepared from (±)- cis-16.7, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 45% ethyl acetate in hexane). MS(ES): m/z 314.5 [M+H] ⁺ . [00464] Compound cis-16.8-a and cis-16.8-b. The racemate was subjected to chiral HPLC separation (Column: CHIRALPAK IB-N (250 x 4.6 mm, 5 μm); mobile phases: 0.1% DEA in propane-2-ol: acetonitrile (1:1); flow rate: 20 mL/min) to afford first eluting fraction (cis-16.8-a, MS(ES): m/z 313.40 [M+H] ⁺ ) and second eluting fraction (cis-16.8-b, MS(ES): m/z 313.40 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00465] Synthesis of compound cis-16.9-a and cis-16.9-b. Compound cis-16.9-a was prepared from cis-16.8-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS (ES): m/z 467.95 [M+H] ⁺ . Compound cis- 16.9-b was prepared from cis-16.8-b in the same manner. MS (ES): m/z 467.95 [M+H] ⁺ . [00466] Synthesis of Compound I-16-a and Compound I-16-b. Compound I-16-a was prepared from cis-16.9-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS (ES): m/z 516.60 [M+H] ⁺ ; ¹ H NMR (DMSO- d6, 400 MHz): 10.89 (s, 1H), 10.76 (s, 1H), 8.59 (s, 1H), 8.17 (s, 2H), 8.03 (s, 1H), 7.90 (s,1H), 7.51 (s,1H), 7.39 (d, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz 1H), 7.14 (d, J = Hz 1H), 4.51 (s, 1H), 3.60-3.50 (m, 5H), 3.25-3.15 (m, 1H), 2.30-2.10 (m, 2H), 2.05-1.90 (m, 2H), 1.90-1.75 (m, 4H), 1.75-1.60 (m, 2H), 0.76-0.75 (m, 4H). [00467] Compound I-16-b was prepared from cis-16.9-b in the same manner. MS (ES): m/z 516.60 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 10.89 (s, 1H), 10.76 (s, 1H), 8.59 (s, 1H), 8.17 (s, 2H), 8.03 (s, 1H), 7.90 (s,1H), 7.51 (s,1H), 7.39 (d, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz 1H), 7.14 (d, J = Hz 1H), 4.51 (s, 1H), 3.60-3.50 (m, 5H), 3.25-3.15 (m, 1H), 2.30-2.10 (m, 2H), 2.05-1.90 (m, 2H), 1.90-1.75 (m, 4H), 1.75-1.60 (m, 2H), 0.76-0.75 (m, 4H). [00468] Example 1-17: 4-((3-(1-((5S,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and 4-((3-(1-((5R,6S)-1- oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)am ino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-16-c) and (Compound I-16-d). [00469] Synthesis of Compound I-16-c and Compound I-16-d. Compound I-16-c and Compound I-16-d were prepared from (±)-trans-16.4, following the same procedures in the synthesis of Compound I-16-a and Compound I-16-b. [00470] Compound I-16-c: MS (ES): m/z 516.60 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 10.89 (s, 1H), 10.76 (s, 1H), 8.59 (s, 1H), 8.22 (s, 21H), 8.15 (s, 1H), 8.03 (s,1H), 7.96 (s, 1H), 7.50 (s, 1H), 7.38 (d, J = 8 Hz, 1H), 7.28 (d, J = 8 Hz, 1H), 7.15 (t, J = 8 Hz, 1H), 4.59 (t, J = 7.6 Hz, 1H), 3.75-3.65 (m, 2H), 3.56 (s, 3H), 2.30-2.20 (m, 2H), 2.00-1.70 (m, 7H), 1.6-1.5 (m, 2H), 0.78 (m, 4H). ^[00471] Compound I-16-d: MS (ES): m/z 516.60 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 10.89 (s, 1H), 10.76 (s, 1H), 8.59 (s, 1H), 8.22 (s, 21H), 8.15 (s, 1H), 8.03 (s,1H), 7.96 (s, 1H), 7.50 (s, 1H), 7.38 (d, J = 8 Hz, 1H), 7.28 (d, J = 8 Hz, 1H), 7.15 (t, J = 8 Hz, 1H), 4.59 (t, J = 7.6 Hz, 1H), 3.75-3.65 (m, 2H), 3.56 (s, 3H), 2.30-2.20 (m, 2H), 2.00-1.70 (m, 7H), 1.6-1.5 (m, 2H), 0.78 (m, 4H). [00472] Example 1-18: 4-((3-(1-((5S,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide; 4-((3-(1- ((5R,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-metho xyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; 4-((3-(1-((5R,6R)-1-oxaspiro[4.4]nonan-6- yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanec arboxamido)pyridazine-3-carboxamide; and 4-((3-(1-((5S,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide; (Compound I-18-a), (Compound I-18-b), (Compound I-18-c), and (Compound I-18-d). [00473] Synthesis of compound trans-18.1-a, trans-18.1-b, cis-18.1-a and cis-18.1-b. Compound trans-18.1-a was prepared from trans-16.8-a and 4,6-dichloropyridazine-3- carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS (ES): m/z 467.95 [M+H] ⁺ . Compound trans-18.1-b, cis-18.1-a and cis-18.1-b was prepared from trans-16.8-a, cis-16.8-a and cis-16.8-b respectively in the same manner. [00474] Synthesis of Compounds I-18-a, I-18-b, I-18-c, and I-18-d. Compound I-18-a was prepared from trans-18.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.9% methanol in DCM). MS (ES): m/z 517.59 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.32 (s, 1H), 10.99 (s, 1H), 8.55 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.89 (s,1H), 7.46 (d, J = 8 Hz, 2H), 7.29 (d, J = 8 Hz, 1H), 7.19 (m, 1H), 4.59 (t, J = 7.6 Hz, 1H), 3.80-3.65 (m, 2H), 3.56 (s, 3H), 2.25 (m, 2H), 2.08 (m, 1H), 1.90-1.80 (m, 2H), 1.80-1.70 (m, 3H), 1.60-1.45 (m, 1H), 1.45-1.35 (m, 1H), 1.35-1.30 (m, 1H), 0.82 (bs, 4H). [00475] Compound I-18-b was prepared from trans-18.1-b in the same manner. MS (ES): m/z 517.59 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.32 (s, 1H), 10.99 (s, 1H), 8.55 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.89 (s,1H), 7.46 (d, J = 8 Hz, 2H), 7.29 (d, J = 8 Hz, 1H), 7.19 (m, 1H), 4.59 (t, J = 7.6 Hz, 1H), 3.80-3.65 (m, 2H), 3.56 (s, 3H), 2.25 (m, 2H), 2.08 (m, 1H), 1.90-1.80 (m, 2H), 1.80-1.70 (m, 3H), 1.60-1.45 (m, 1H), 1.45-1.35 (m, 1H), 1.35-1.30 (m, 1H), 0.82 (bs, 4H). [00476] Compound I-18-c was prepared from cis-18.1-a in the same manner. MS (ES): m/z 517.59 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.34 (s, 1H), 11.01 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.92 (bs, 1H), 7.49 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 4.54 (m, 1H), 3.65-3.55 (m, 5H), 3.30-3.20 (m, 1H), 2.40-1.95 (m, 2H), 1.95-1.75 (m, 4H), 1.75-1.65 (m, 2H), 1.40-1.20 (m, 2H), 0.84 (bs, 4H). [00477] Compound I-18-d was prepared from cis-18.1-b in the same manner. MS (ES): m/z 517.59 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.34 (s, 1H), 11.01 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.92 (bs, 1H), 7.49 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 4.54 (m, 1H), 3.65-3.55 (m, 5H), 3.30-3.20 (m, 1H), 2.40-1.95 (m, 2H), 1.95-1.75 (m, 4H), 1.75-1.65 (m, 2H), 1.40-1.20 (m, 2H), 0.84 (bs, 4H). [00478] Example 1-19: 4-((3-(1-((1R,4R)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and 4-((3-(1-((1S,4S)-5- oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)am ino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-19-a) and (Compound I-19-b).

[00479] Synthesis of compound (±)-trans-19.1. To a solution of (±)-trans-15.1 (6 g, 24.68 mmol, 1 equiv) in DMF (180 mL) was added sodium hydride (3.4 g, 74 mmol, 3 equiv) at 0 °C and stirred at room temperature of 15 min. To the mixture was added 1,4-dibromobutane (26.64 g, 123.40 mmol, 5 equiv) and stirred for 15 min. The reaction mixture poured into ice-water slowly, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-trans-19.1 (1.67 g, 18%). MS (ES): m/z 378.11 [M+H] ⁺ . [00480] Synthesis of compound (±)-trans-19.2. To a stirred solution of (±)-trans-19.1 (1.67 g, 4.42 mmol, 1 equiv) in THF (20 mL) was added potassium tert-butoxide solution (1M in THF, 13.2 mL, 13.2 mmol, 3 equiv) dropwise at 0 °C. The reaction mixture stirred at room temperature for 30 min. It was poured into water, stirred and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue purified by combi-flash using 8% ethyl acetate in hexane) to afford (±)-trans-19.2 (0.7 g, 53%). MS (ES): m/z 297.20 [M+H] ⁺ . [00481] Synthesis of compound (±)-trans-19.3. To a stirred solution of (±)-trans-19.2 (0.7 g, 2.36 mmol, 1 equiv) in DCM (20 mL) was added 2 ^nd gen. Grubbs catalyst (0.359 g, 0.424 mmol, 0.18 equiv). The reaction mixture was stirred at room temperature of 16 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-trans-19.3 (0.45 g, 71%). MS (ES): m/z 269.14 [M+H] ⁺ . [00482] Synthesis of compound (±)-trans-19.4. Compound (±)-trans-19.4 was prepared from (±)-trans-19.3, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane).56% yield. MS (ES): m/z 311.39 [M+H] ⁺ . [00483] Synthesis of compound (±)-trans-19.5. A mixture of (±)-trans-19.4 (0.3 g, 0.96 mmol, 1.0 equiv) and palladium on carbon (10 wt%, 200 mg) in methanol (10 mL) was stirred under hydrogen (1 atm) for 1 h. The reaction mixture diluted by 10% methanol in DCM and filter through a pad of Celite® under nitrogen atmosphere. The filtrate was concentrated under reduced pressure to afford (±)-trans-19.5 (0.25 g, 83%). MS (ES): m/z 313.40 [M+H] ⁺ . [00484] Compound trans-19.5-a and trans-19.5-b. The racemate was subjected to chiral HPLC separation (Column: CHIRALPAK IB-N (250 x 4.6 mm, 5 μm); mobile phases: 0.1% DEA in propane-2-ol: acetonitrile (1:1); flow rate: 20 mL/min) to afford first eluting fraction (trans-19.5-a MS(ES): m/z: 313.40 [M+H] ⁺ .) and second eluting fraction (trans-19.5-b MS(ES): m/z: 313.40 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00485] Synthesis of compound trans-19.6-a and trans-19.6-b. Compound trans-19.6-a was prepared from trans-19.5-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS (ES): m/z 467.95 [M+H] ⁺ . Compound trans- 19.6-b was prepared from trans-19.5-b in the same manner. MS (ES): m/z 467.95 [M+H] ⁺ . [00486] Synthesis of Compound I-19-a and Compound I-19-b. Compound I-19-a was prepared from trans-19.6-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS (ES): m/z 517.50 [M+H] ⁺ ; ¹ H NMR (DMSO- d6, 400 MHz): 10.91 (s, 1H), 10.76 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 8.16 (bs, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.50 (bs, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.18 (m, 1H), 4.78 (m, 1H), 3.74 (m, 1H), 3.58 (s, 3H), 3.39 (m, 1H), 2.25 (m, 1H), 2.05-1.90 (m, 2H), 1.70-1.60 (m, 1H), 1.53 (m, 1H), 1.45-1.20 (m, 6H), 0.80 (bs, 4H). [00487] Compound I-19-b was prepared from trans-19.6-b in the same manner. MS (ES): m/z 517.50 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): ¹ H NMR (DMSO-d6, 400 MHz): 10.91 (s, 1H), 10.76 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 8.16 (bs, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.50 (bs, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.18 (m, 1H), 4.78 (m, 1H), 3.74 (m, 1H), 3.58 (s, 3H), 3.39 (m, 1H), 2.25 (m, 1H), 2.05-1.90 (m, 2H), 1.70-1.60 (m, 1H), 1.53 (m, 1H), 1.45-1.20 (m, 6H), 0.80 (bs, 4H). [00488] Example 1-20: 4-((3-(1-((1R,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide and 4-((3-(1- ((1S,4R)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-metho xyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide, (Compound I-20-a) and (Compound I- 20-b). [00489] Synthesis of compound trans-20.1-a and trans-20.1-b. Compound trans-20.1-a was prepared from trans-15.5-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product residue was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 455.5 [M+H] ⁺ . Compound trans-20.1-b was prepared from trans-15.5-b in the same manner. MS(ES): m/z 455.5 [M+H] ⁺ . [00490] Synthesis of Compound I-20-a and Compound I-20-b. Compound I-20-a was prepared from trans-19.6-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 504.2 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 11.00 (s, 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.49 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.20 (t, J = 8 Hz, 1H), 4.83 (t, J = 8 Hz, 1H), 3.70 (t, J = 4 Hz, 2H), 3.58 (s, 3H), 2.37 (m, 1H), 2.13 (m, 2H), 1.95 (m, 1H), 1.80-1.67 (m, 3H), 1.30-1.25 (m, 2H), 0.85-0.83 (m, 4H). [00491] Compound I-20-b was prepared from trans-19.6-b in the same manner. MS(ES): m/z 504.2 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 11.00 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.50 (d, J = 8 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 7.22 (t, J = 8 Hz, 1H), 4.83 (t, J = 8 Hz, 1H), 3.70 (t, J = 4 Hz, 2H), 3.58 (s, 3H), 2.36 (m, 1H), 2.14 (m, 2H), 1.94 (m, 1H), 1.80-1.57 (m, 3H), 1.30-1.25 (m, 2H), 0.85-0.83 (m, 4H). [00492] Example 1-21: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(1-fluorocyclopropane-1-carboxamido)n icotinamide and (S)-4-((3-(1- (5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-methoxyph enyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide, (Compound I-21-a) and (Compound I-21- b). [00493] Synthesis of Compound I-21-a and Compound I-21-b. Compound I-21-a was prepared from 6.1-a and Int-3, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM). MS(ES): m/z 523.34 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.94 (s, 1H), 10.08 (s, 1H), 8.66 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.98 (s, 2H), 7.59 (s, 1H), 7.45 (m, 1H), 7.32 (d, J = 4 Hz, 1H), 7.20 (t, J = 8 Hz, 1H), 4.95 (m, 1H), 3.84-3.79 (m, 4H), 3.62 (s, 3H), 3.00 (m, 1H), 2.42-2.20 (m, 3H), 1.47-1.25 (m, 4H). [00494] Compound I-21-b was prepared from 6.1-b in the same manner. MS(ES): m/z 523.34 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.94 (s, 1H), 10.08 (s, 1H), 8.66 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.98 (s, 2H), 7.59 (s, 1H), 7.45 (m, 1H), 7.32 (d, J = 4 Hz, 1H), 7.20 (t, J = 8 Hz, 1H), 4.95 (m, 1H), 3.84-3.79 (m, 4H), 3.62 (s, 3H), 3.00 (m, 1H), 2.42-2.20 (m, 3H), 1.47- 1.25 (m, 4H). [00495] Example 1-22: 4-((3-(1-((5S,6R)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(1-fluorocyclopropane-1-carboxamido)p yridazine-3-carboxamide and 4-((3-(1-((5R,6S)-1-oxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide, (Compound I-22-a) and (Compound I-22-b).

[00496] Synthesis of compound trans-22.1-a. Compound trans-22.1-a was prepared from trans-16.8-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane) to afford 2.0 (0.080 g, 45%). MS (ES): m/z 468.94 [M+H] ⁺ . Compound trans-22.1-b was prepared from trans-16.8-b in the same manner. MS (ES): m/z 468.94 [M+H] ⁺ . [00497] Synthesis of Compound I-22-a and Compound I-22-b. Compound I-22-a was prepared from 6.1-a and Int-3, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 535.58 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.03 (s, 1H), 10.82 (s, 1H), 8.62 (s, 1H), 8.25 (bs, 1H) 8.05 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.50 (d, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 4.60 (t, J = 8 Hz, 1H), 3.74 (m, 2H), 3.62 (s, 3H), 2.35-2.27 (m, 2H), 1.91-1.86 (m, 2H), 1.82-1.73 (m, 3H), 1.60-1.20 (m, 7H). Compound I-22-b was prepared from 6.1-b in the same manner. MS(ES): m/z 535.58 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.03 (s, 1H), 10.82 (s, 1H), 8.62 (s, 1H), 8.25 (bs, 1H) 8.05 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.50 (d, J = 8 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 4.60 (t, J = 8 Hz, 1H), 3.74 (m, 2H), 3.62 (s, 3H), 2.35-2.27 (m, 2H), 1.91-1.86 (m, 2H), 1.82-1.73 (m, 3H), 1.60-1.20 (m, 7H). [00498] Example 1-23: 4-((3-(1-((1R,4S)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(1-fluorocyclopropane-1-carboxamido)p yridazine-3-carboxamide and 4-((3-(1-((1S,4R)-5-oxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2-methoxyphenyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)pyridazine-3-carboxamide, (Compound I-23-a) and (Compound I-23-b) [00499] Synthesis of Compound I-23-a and Compound I-23-b. Compound I-23-a was prepared from trans-20.1-a and Int-3, following the procedure described in the synthesis of I-5- a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 521.55 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.02 (s, 1H), 10.84 (s, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.21 (d, J = 15.6 Hz, 1H), 4.81 (t, J = 10 Hz, 1H), 3.68 (m, 2H), 3.58 (s, 3H), 2.40-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.85 (m, 2H), 1.80-1.60 (m, 3H), 1.50-1.40 (m, 2H), 1.40-1.30 (m, 2H). [00500] Compound I-23-b was prepared from trans-20.1-b in the same manner. MS(ES): m/z 521.55 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.02 (s, 1H), 10.84 (s, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8 Hz, 1H), 7.21 (d, J = 15.6 Hz, 1H), 4.81 (t, J = 10 Hz, 1H), 3.68 (m, 2H), 3.58 (s, 3H), 2.40-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.85 (m, 2H), 1.80-1.60 (m, 3H), 1.50-1.40 (m, 2H), 1.40-1.30 (m, 2H). [00501] Example 1-24: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(1-fluorocyclopropane-1-carboxamido)n icotinamide and (S)-4-((3-(1- (1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-methoxyph enyl)amino)-6-(1- fluorocyclopropane-1-carboxamido)nicotinamide, (Compound I-24-a) and (Compound I-24- b). [00502] Synthesis of Compound I-24-a and Compound I-24-b. Compound I-24-a was prepared from 5.5-a and Int-3, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 537.56 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 10.08 (s, 1H), 8.64 (s, 1H), 8.23 (bs, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.58 (bs, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.60 (t, J = 8.0 Hz, 1H), 3.81 (m, 4H), 3.57 (s, 3H), 2.23 (m, 2H), 1.99 (m, 3H), 1.84 (m, 1H), 1.43-1.25 (m, 4H). [00503] Compound I-24-b was prepared from 5.5-b in the same manner. MS(ES): m/z 537.56 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 10.08 (s, 1H), 8.64 (s, 1H), 8.23 (bs, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.58 (bs, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.60 (t, J = 8.0 Hz, 1H), 3.81 (m, 4H), 3.57 (s, 3H), 2.23 (m, 2H), 1.99 (m, 3H), 1.84 (m, 1H), 1.43-1.25 (m, 4H). [00504] Example 1-26: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- (trifluoromethoxy)phenyl)amino)-6-(cyclopropanecarboxamido)n icotinamide and (S)-4-((3-(1- (5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-(trifluor omethoxy)phenyl)amino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-26-a) and (Compound I-26-b). [00505] Synthesis of compound 26.1. To a solution of diisopropylamine (1.46, 14.52 mmol, 1.0 equiv) in THF (30 mL) was added n-butyllithium (2.5 M in hexane, 5.8 mL,14.52 mmol,1.0 equiv) at -78 ^o C. The reaction mixture was stirred at 0 ^o C for 30 min. To the solution was added 1-bromo-2-(trifluoromethoxy)benzene (3.5 g, 14.52 mmol, 1.0 equiv) dropwise at -100 ^o C and stirred for 2 h. CO2 gas was purged into reaction mixture for 30 min. It was transferred into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM) to afford 26.1 (2.0 g, 48%). [00506] Synthesis of compound 26.2. To a solution of 26.1 (0.800 g, 2.807 mmol, 1.0 equiv) in tert-butanol (8 mL) and toluene (8 mL) was added N, N-diisopropylethylamine (0.435 g, 3.36 mmol, 1.2 equiv) and diphenyl phosphoryl azide (0.926 g, 3.36 mmol, 1.2 equiv). The reaction mixture was stirred at 120 °C for 16 h. It was cooled to rt, transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 26.2 (0.500 g, 50%). [00507] Synthesis of compound 26.3 To a solution of 26.2 (0.500 g, 1.40 mmol, 1.0 equiv) in DCM (5 mL) was added 4 M hydrochloric acid in dioxane (5 mL) dropwise at room temperature. The reaction mixture was stirred for 16 h. It was transferred into saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 26.3 (0.300 g, 87%). [00508] Synthesis of compound 26.4. A mixture of 26.3 (0.200 g, 0.78 mmol, 1.0 equiv, bispinacolato diboron (0.297 g, 1.17 mmol, 1.5 equiv) and potassium acetate (0.230 g, 0.23 mmol, 3.0 equiv) in 1,4-dioxane (4 mL) was degassed by bubbling through a stream of argon for 10 min.1,1-Bis(diphenylphosphino)ferrocene dichloropalladium DCM complex (0.063 g, 0.078 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 110 °C for 16 h. It was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% ethyl acetate in hexane) to afford 26.4 (0.120 g, 5%). MS(ES): m/z 304 [M+H] ⁺ . [00509] Synthesis of compound 26.5. Compound 26.5 was prepared from 26.4 and (±)-1.3, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane) to afford 26.5 (0.600 g, 64%). MS(ES): m/z 356.0 [M+H] ⁺ . [00510] Compound 26.5-a and 26.5-b. The racemate was subjected to chiral SFC separation (Column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phases: (A) CO ₂ (B) 0.1% diethylamine in propane-2-ol: acetronitrile (1: 1); flow rate: 80 mL/min) to afford first eluting fraction (26.5-a, MS(ES): m/z 356 [M+H] ⁺ ) and second eluting fraction (26.5-b, MS(ES): m/z 356 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00511] Synthesis of compound 26.6-a and 26.6-b. Compound 26.6-a was prepared from 26.5-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 510 [M+H] ⁺ . Compound 26.6-b was prepared from 26.5- b in the same manner. MS(ES): m/z 510 [M+H] ⁺ . [00512] Synthesis of Compound I-26-a and Compound I-26-b. Compound I-26-a was prepared from 26.6-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 559.3 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.07 (s, 1H), 10.81 (s, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 8.19 (bs, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.57 (bs, 1H), 7.48-7.44 (m, 3H), 4.95 (d, J = 8 Hz, 1H), 3.80-3.70 (m, 4H), 2.93 (m, 1H), 2.40-2.10 (m, 4H), 2.01 (m, 1H), 0.78 (m, 4H). [00513] Compound I-26-b was prepared from 26.6-b in the same manner. MS(ES): m/z 559.3 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.07 (s, 1H), 10.81 (s, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 8.19 (bs, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.57 (bs, 1H), 7.48-7.44 (m, 3H), 4.95 (d, J = 8 Hz, 1H), 3.80-3.70 (m, 4H), 2.93 (m, 1H), 2.40-2.10 (m, 4H), 2.01 (m, 1H), 0.78 (m, 4H). [00514] Example 1-27: 4-((3-(1-((1S,4S)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide and 4-((3-(1- ((1R,4R)-5-oxaspiro[3.5]nonan-1-yl)-1H-pyrazol-4-yl)-2-metho xyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide, (Compound I-27-a) and (Compound I- 27-b). [00515] Synthesis of compound 27.1-a and 27.1-b. Compound 27.1-a was prepared from 19.6-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS (ES): m/z 468.94 [M+H] ⁺ . Compound 27.1-b was prepared from 19.6-b in the same manner. MS (ES): m/z 468.94 [M+H] ⁺ . [00516] Synthesis of Compound I-27-a and Compound I-27-b. Compound I-27-a was prepared from 27.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS (ES): m/z 517.59 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.35 (s, 1H), 11.01 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.92 (bs, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 8 Hz, 1H), 4.79 (t, J = 9.6 Hz, 1H), 3.76 (m, 1H), 3.58 (s, 3H), 3.51 (m, 1H), 2.25 (m, 1H), 2.10 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.60-1.20 (m, 7H), 0.84 (m, 4H). [00517] Compound I-27-b was prepared from 27.1-b in the same manner. MS (ES): m/z 517.59 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.35 (s, 1H), 11.01 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.92 (bs, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 8 Hz, 1H), 4.79 (t, J = 9.6 Hz, 1H), 3.76 (m, 1H), 3.58 (s, 3H), 3.51 (m, 1H), 2.25 (m, 1H), 2.10 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.60-1.20 (m, 7H), 0.84 (m, 4H). [00518] Example 1-28: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- cyanophenyl)amino)-6-(cyclopropanecarboxamido) and (S)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan- 6-yl)-1H-pyrazol-4-yl)-2-cyanophenyl)amino)-6-(cyclopropanec arboxamido)nicotinamide, nicotinamide (Compound I-28-a) and (Compound I-28-b).

[00519] Synthesis of compound 28.1. To a solution of 2-bromo-6-fluorobenzonitrile (5 g, 25 mmol, 1.0 equiv) in DMSO (40 mL) was pressurized with ammonia gas (10 atm) in an autoclave. The reaction mixture was stirred at 120 °C for 2 h. It was cooled to room temperature and poured onto ice-water. Precipitates were collected by filtration, rinsed with water, and dried under reduced pressure to afford 28.1 (4.4 g, 89%). MS(ES): m/z 198.26 [M+1] ⁺ . [00520] Synthesis of compound 28.2. A mixture of 28.1 (4.4 g, 22.3 mmol, 1.0 equiv), bis(pinacolato)diboron (6.8 g, 26.8 mmol, 1.2 equiv), tricyclohexylphosphine (0.625 g, 2.23 mmol, 0.1 equiv), tris(dibenzylideneacetone)dipalladium (0) (0.613 g, 0.67 mmol, 0.03 equiv) and potassium acetate (3.28 g, 33.5 mmol, 1.5 equiv) in 1,4-dioxane (50 mL) was degassed by bubbling through a stream of argon for 15 min. The reaction mixture was stirred at 120 °C for 3 h. It was cooled to rt, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 23 % ethyl acetate in hexane) to afford 28.2 (3.1 g, 57%). MS(ES): m/z 245.67 [M+H] ⁺ . [00521] Synthesis of compound (±)-28.3. Compound (±)-28.3 was prepared from 28.2 and (±)-5.3, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 311.37 [M+H] ⁺ . [00522] Compound 28.3-a and 28.3-b. The racemate was subjected to chiral HPLC separation (Column: CHIRALPAK IC (250 x 4.6 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: acetonitrile (1:1); flow rate: 20 mL/min) to afford first eluting fraction (28.3-a, MS(ES): m/z 311.37 [M+H] ⁺ ) and second eluting fraction (28.3-b, MS(ES): m/z 311.37 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00523] Synthesis of compound 28.4-a and 28.4-b. Compound 28.4-a was prepared from 28.3-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 465.90 [M+H] ⁺ . Compound 28.4-b was prepared from 28.3-b in the same manner. MS(ES): m/z 465.90 [M+H] ⁺ . [00524] Synthesis of I-28-a and I-28-b. Compound I-28-a was prepared from 28.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM). MS(ES): m/z 514.55 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 10.88 (s, 1H), 8.69 (s, 1H), 8.34 (bs, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.70 (m, 1H), 7.64 (bs, 1H), 7.48 (s, 1H), 7.47 (s, 1H), 4.65 (m, 1H), 3.82 (m, 4H), 2.27 (m, 1H), 2.00- 1.80 (m, 3H), 1.80-1.70 (m, 1H), 0.78 (bs, 4H). [00525] Compound I-28-b was prepared from 28.4-b in the same manner. MS(ES): m/z 514.55 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 10.88 (s, 1H), 8.69 (s, 1H), 8.34 (bs, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.70 (m, 1H), 7.64 (bs, 1H), 7.48 (s, 1H), 7.47 (s, 1H), 4.65 (m, 1H), 3.82 (m, 4H), 2.27 (m, 1H), 2.00-1.80 (m, 3H), 1.80-1.70 (m, 1H), 0.78 (bs, 4H). [00526] Example 1-29: (R)-4-((3-(1-(1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl )-2- cyanophenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-c arboxamide and (S)-4-((3-(1- (1,4-dioxaspiro[4.4]nonan-6-yl)-1H-pyrazol-4-yl)-2-cyanophen yl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide, (Compound I-29-a) and (Compound I- 29-b). [00527] Synthesis of compound 29.1-a and 29.1-b. Compound 29.1-a was prepared from 28.3-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 467.02 [M+H] ⁺ . Compound 29.1-b was prepared from 28.3-b in the same manner. MS(ES): m/z 467.02 [M+H] ⁺ . [00528] Synthesis of Compound I-29-a and Compound I-29-b. Compound I-29-a was prepared from 29.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 515.28 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.43 (s, 1H), 11.27 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.75 (t, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 4.65 (t, J = 8.4 Hz, 1H), 3.90-3.70 (m, 4H), 2.35-2.20 (m, 2H), 2.09 (m, 1H), 2.00-1.80 (m, 3H), 1.73 (m, 1H), 0.90-0.75 (m, 4H). [00529] Compound I-29-b was prepared from 29.1-b in the same manner. MS(ES): m/z 515.28 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 11.43 (s, 1H), 11.27 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.75 (t, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 4.65 (t, J = 8.4 Hz, 1H), 3.90-3.70 (m, 4H), 2.35-2.20 (m, 2H), 2.09 (m, 1H), 2.00-1.80 (m, 3H), 1.73 (m, 1H), 0.90-0.75 (m, 4H). [00530] Example 1-30: (R)-4-((3-(1-(5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl )-2- cyanophenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3-c arboxamide and (S)-4-((3-(1- (5,8-dioxaspiro[3.4]octan-1-yl)-1H-pyrazol-4-yl)-2-cyanophen yl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide, (Compound I-30-a) and (Compound I- 30-b).

[00531] Synthesis of compound (±)-30.1. Compound (±)-30.1 was prepared from 28.2 and (±)-1.3, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 296.33[M+H] ⁺ . [00532] Compound 30.1-a and 30.1-b. The racemate was subjected to chiral SFC separation (Column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phases: (A) CO2 (B) 0.1% diethyl amine in propane-2-ol: acetonitrile (70: 30); flow rate: 80 mL/min) to afford first eluting fraction (30.1-a, MS(ES): m/z 296.33 [M+H] ⁺ ), and second eluting fraction (30.1-b, MS(ES): m/z 296.33 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. *The absolute configuration of the chiral center is not determined. [00533] Synthesis of compound 30.2-a and 30.2-b. Compound 30.2-a was prepared from 30.1-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS (ES): m/z 451.87 [M+H] ⁺ . Compound 30.2-b was prepared from 30.1-b in the same manner. MS (ES): m/z 451.87 [M+H] ⁺ . [00534] Synthesis of Compound I-30-a and Compound I-30-b. A mixture of 30.2-a (0.090 g, 0.199 mmol, 1.0 equiv), cyclopropanecarboxamide (0.084 g, 0.995 mmol, 5.0 equiv) and cesium carbonate (0.194 g, 0.598 mmol, 3.0 equiv) in DMA (4 mL) was degassed by bubbling through a stream of argon for 10 min.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.034 g, 0.0598 mmol, 0.3 equiv) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.003 g, 0.029 mmol, 0.15 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 140 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford Compound I-30-a (0.012 g, 12%). MS (ES): m/z 500.52 [M+H] ⁺ ; ¹ H NMR (DMSO- d6, 400 MHz): 11.44 (s, 1H), 11.28 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.76 (t, J = 8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 4.97 (t, J = 6.8 Hz, 1H), 3.90-3.75 (m, 4H), 3.09 (m, 1H), 2.40-2.15 (m, 3H), 2.10 (m, 1H), 0.85 (m, 4H). [00535] Compound I-30-b was prepared from 30.2-b in the same manner. MS (ES): m/z 500.52 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.44 (s, 1H), 11.28 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.76 (t, J = 8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 4.97 (t, J = 6.8 Hz, 1H), 3.90-3.75 (m, 4H), 3.09 (m, 1H), 2.40-2.15 (m, 3H), 2.10 (m, 1H), 0.85 (m, 4H). [00536] Example 1-33: (R)-4-((3-(2-(1,4-dioxaspiro[4.4]nonan-6-yl)thiazol-5-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and (S)-4-((3-(2-(1,4- dioxaspiro[4.4]nonan-6-yl)thiazol-5-yl)-2-methoxyphenyl)amin o)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-33-a) and (Compound I-33-b). [00537] Synthesis of compound 33.2. To a solution of cyclopent-2-en-1-one (5.0 g, 60.9 mmol, 1.0 equiv) in acetonitrile (30 mL) was added pyridine-N-oxide (8.7 g, 91.4 mmol, 1.5 equiv) followed by N-bromosuccinimide (10.8, 60.9 mmol, 1.0 equiv) slowly at 0 °C. The reaction mixture was stirred at room temperature for 16 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.1% ethyl acetate in hexane) to afford 33.2 (6.1 g, 61%). MS(ES): m/z 162 [M+H] ⁺ . [00538] Synthesis of compound 33.3: A solution of 33.2 (7.0 g, 43.4 mmol, 1.0 equiv) and Int-5 (16.26 g, 43.4 mmol, 1.0 equiv) in dioxane (35 mL) was degassed by bubbling through a stream of argon for 20 min. Bis(triphenylphosphine)palladium(II) dichloride (1.52 g, 2.1 mmol, 0.05 equiv) and copper(I) iodide(0.83 g, 4.3 mmol, 0.1 equiv) were added and reaction degassed for another 10 min. The reaction mixture was stirred at 100 °C for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford 33.3 (3.5 g, 49%). MS(ES): m/z 166.2 [M+H] ⁺ . [00539] Synthesis of compound 33.4. To a solution of 33.3 (2 g, 12.1 mmol, 1.0 equiv) in benzene (100 mL) was added ethylene glycol (3.0 g, 48.4 mmol, 4 equiv) and p-toluene sulfonic acid (0.012 g, 1.21 mmol, 0.1 equiv). The reaction mixture was heated to reflux with a Dean- Stark apparatus to remove water for 7 h. It was cooled to room temperature, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford 33.4 (0.78 g, 31 %). MS(ES): m/z 210.2 [M+H] ⁺ . [00540] Synthesis of compound (±)-33.5. A mixture of palladium hydroxide on carbon (10 wt%, 0.45 g) and 33.4 (0.9 g, 4.0 mmol, 1.0 equiv) in methanol was stirred under hydrogen (20 atm) for 3 day. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford (±)-33.5 (0.31 g, 34%). MS(ES): m/z 212.2[M+H] ⁺ . [00541] Synthesis of compound (±)-33.6. To a solution of (±)-33.5 (0.62 g, 2.9 mmol, 1.0 equiv) in acetonitrile (15 mL) was added N-bromosuccinimide (0.62 mL, 3.5 mmol, 1.2 equiv) at room temperature and stirred for 2 h. The reaction mixture was added into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15 to 20 % ethyl acetate in hexane) to afford (±)-33.6 (0.52 g, 61%). MS(ES): m/z 291.2 [M+H] ⁺ . [00542] Synthesis of compound (±)-33.7. Compound (±)-33.7 was prepared from (±)-33.6 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 15 to 20 % ethyl acetate in hexane). MS(ES): m/z 333.4 [M+H] ⁺ . [00543] Synthesis of compound 33.7-a and 33.7-b. The racemate was subjected to chiral HPLC separation (Column: CHIRALPAK IC (250 x 4.6 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol: acetonitrile (1:1); flow rate: 20 mL/min) to afford first eluting fraction (33.7-a, MS(ES): m/z 333.4 [M+H] ⁺ ), and second eluting fraction (33.7-b, MS(ES): m/z 333.4 [M+H] ⁺ ). *The absolute configuration of the chiral center is not determined. [00544] Synthesis of compound 33.8-a and 33.8-b. Compound 33.8-a was prepared from 33.7-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 488.02 [M+H] ⁺ . Compound 33.8-b was prepared from 33.7-b in the same manner. MS(ES): m/z 488.02 [M+H] ⁺ . [00545] Synthesis of Compound I-33-a and Compound I-33-b. Compound I-33-a was prepared from 33.8-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2 to 3% methanol in DCM). MS(ES): m/z 536.4 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.94 (s, 1H), 10.80 (s, 1H), 9.07 (s, 1H), 8.60 (s, 1H), 8.16 (bs, 1H), 8.13 (s, 1H), 7.51 (m, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.04 (m, 2H), 6.83 (m, 1H), 4.0-3.96 (m, 1H), 3.83-3.74 (m, 2H), 3.60-3.53 (m, 2H), 3.40 (s, 3H), 2.13 (m, 1H), 2.00 (m, 1H), 1.82 (m, 2H), 1.66 (m, 2H), 1.56 (m, 1H), 0.80 (m, 4H). [00546] Compound I-33-b was prepared from 33.8-b in the same manner. MS(ES): m/z 536.4 [M+H] ⁺ . ¹ H NMR (DMSO-d6, 400 MHz): δ 10.94 (s, 1H), 10.80 (s, 1H), 9.07 (s, 1H), 8.60 (s, 1H), 8.16 (bs, 1H), 8.13 (s, 1H), 7.51 (m, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.04 (m, 2H), 6.83 (m, 1H), 4.0-3.96 (m, 1H), 3.83-3.74 (m, 2H), 3.60-3.53 (m, 2H), 3.40 (s, 3H), 2.13 (m, 1H), 2.00 (m, 1H), 1.82 (m, 2H), 1.66 (m, 2H), 1.56 (m, 1H), 0.80 (m, 4H). [00547] Example 1-34: (R)-4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-3-yl)-2 - methoxyphenyl)amino)-2-((4-(morpholine-4-carbonyl)phenyl)ami no)pyrimidine-5-carboxamide and (S)-4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-3-yl)-2 -methoxyphenyl)amino)-2-((4- (morpholine-4-carbonyl)phenyl)amino)pyrimidine-5-carboxamide , (Compound I-34-a) and (Compound I-34-b). [00548] Synthesis of compound (±)-34.1. To a solution of 2-oxaspiro[3.3]heptan-5-ol (0.5 g, 4.38 mmol, 1.0 equiv) in DCM (15 mL) at to 0 °C was added triethylamine (1.32 g, 13.15 mmol, 3.0 equiv) followed by methansulfonyl chloride (0.75 g, 6.57 mmol, 1.5 equiv). The mixture was stirred at rt for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-34.1 (0.5 g, 59%). It was used in the next step without purification. [00549] Synthesis of compound 34.2. A mixture of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.62 mmol, 1.0 equiv), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.51 g, 12.93 mmol, 1.5 equiv) and potassium phosphate (3.65 g, 17.24 mmol, 2.0 equiv) in dioxane (40 mL) and water (8 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (0.126 g, 0.17 mmol, 0.05 equiv) was added, and degassed for another 5 min. The reaction mixture was stirred at 120 ^o C for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 34.2 (0.7 g, 37%). MS(ES): m/z 220.21 [M+H] ⁺ . [00550] Synthesis of compound (±)-34.3. A mixture of 34.2 (0.5 g, 2.28 mmol, 1.0 equiv), cesium carbonate (2.2 g, 6.8 mmol, 3.0 equiv) and (±)-34.1 (0.57 g, 2.97 mmol, 1.3 equiv) in DMF (15 mL) was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane) to afford (±)-34.3 (0.4 g, 56%). MS(ES): m/z 316.35 [M+H] ⁺ . [00551] Synthesis of compound (±)-34.4. A mixture of 10% palladium on carbon (0.2 g) and (±)-34.3 (0.4 g, 1.27 mmol, 1.0 equiv) in methanol was stirred at rt under hydrogen atmosphere (1 atm) for 2 h. It was filtered through Celite®. The filtrate was concentrated under reduced pressure to afford (±)-34.4 (0.180 g, 50%). MS(ES): m/z 286.6 [M+H] ⁺ . [00552] 34.4-a and 34.4-b. The racemate was separated by chiral HPLC: (column: CHIRALPAK IB-N (250 x 21 mm, 5 μm); mobile phases: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in propane-2-ol : methanol (50: 50); flow rate: 20 mL/min) to afford first eluting fraction (34.4-a) and second eluting fraction (34.4-b). MS(ES): m/z 286.6 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00553] Synthesis of compound 34.5-a and 34.5-b. Compound 34.5-a was prepared from 34.4-a and 2,4-dichloropyrimidine-5-carboxamide, following the procedure described in the synthesis of 1.5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 441.9 [M+H] ⁺ . Compound 34.5-b was prepared from 34.4-b in the same manner. MS(ES): m/z 441.9 [M+H] ⁺ . [00554] Synthesis of I-34-a and I-34-b. A mixture of 34.5-a (0.032 g, 0.07 mmol, 1.0 equiv), (4-aminophenyl)(morpholino)methanone (0.018 g, 0.08 mmol, 1.2 equiv) and cesium carbonate (0.071 g, 0.21 mmol, 3.0 equiv) in 1,4-dioxane (4 mL) was degassed by bubbling through a stream of argon for 10 min.2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.009 g, 0.014 mmol, 0.2 equiv) and palladium acetate (0.002 g, 0.007 mmol, 0.1 equiv) were added and degassed for another 5 min. The reaction mixture was stirred in a microwave reactor at 140 ^o C for 3 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford I-34-a (0.012 g, 27%). MS(ES): m/z 611.41 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400M Hz): δ 11.97 (s, 1H), 9.93 (s, 1H), 8.78 (s, 1H), 8.54 (bs, 1H), 8.09 (s, 2H), 7.83 (d, J = 8 Hz, 2H), 7.58 (d, J = 7.2 Hz 1H), 7.48 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.19 (t, J = 8 Hz, 1H), 6.83 (s, 1H), 4.95 (t, J = 4 Hz, 1H), 4.69 (d, J = 8 Hz, 1H), 4.53 (d, J = 4 Hz, 1H), 4.45 (d, J = 4 Hz, 1H), 4.13 (d, J = 4 Hz, 1H), 3.67 (s, 3H), 3.63-3.53 (m, 8H), 2.34-2.22 (m, 2H), 2.13 (m, 2H). I-34-b was prepared from 34.5-b in the same manner. MS(ES): m/z 611.41 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400M Hz): δ 11.97 (s, 1H), 9.94 (s, 1H), 8.78 (s, 1H), 8.53 (bs, 1H), 8.09 (bs, 2H), 7.83 (d, J = 8 Hz, 2H), 7.58 (d, J = 7.2 Hz 1H), 7.48 (s, 1H), 7.38 (d, J = 4 Hz, 2H), 7.19 (t, J = 8 Hz, 1H), 6.82 (s, 1H), 4.95 (t, J = 4 Hz, 1H), 4.69 (d, J = 8 Hz, 1H), 4.53 (d, J = 8 Hz, 1H), 4.45 (d, J = 4 Hz, 1H), 4.13 (d, J = 8 Hz, 1H), 3.67 (s, 3H), 3.62-3.52 (m, 8H), 2.34-2.21 (m, 2H), 2.12 (m, 2H). [00555] Example 1-35: (R)-4-((3-(1-(2-oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-4-yl)-2 - methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide and (S)-4-((3-(1-(2- oxaspiro[3.3]heptan-5-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)a mino)-6- (cyclopropanecarboxamido)nicotinamide, (Compound I-35-a) and (Compound I-35-b). [00556] Synthesis of compound 35.1-a and 35.1-b. Compound 35.1-a was prepared from 34.4-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 441.2 [M+H] ⁺ . Compound 35.1-b was prepared from 34.4-b in the same manner. [00557] Synthesis of compound I-35-a and I-35-b. Compound I-35-a was prepared from 35.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5- a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 489.04 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400M Hz): δ 10.95 (s, 1H), 10.78 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 8.18 (bs, 1H), 8.08 (s, 1H), 7.95-7.12 (m, 5H), 4.96 (s, 1H), 4.70 (s, 1H), 4.54 (bs, 2H), 4.12 (s, 1H), 3.62 (s, 3H), 2.28-2.02 (m, 5H), 0.81 (m, 4H). Compound I-35-b was prepared from 35.1-b in the same manner. MS(ES): m/z 489.04 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400M Hz): δ 10.95 (s, 1H), 10.78 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 8.18 (bs, 1H), 8.08 (s, 1H), 7.95-7.12 (m, 5H), 4.96 (s, 1H), 4.70 (s, 1H), 4.54 (bs, 2H), 4.12 (s, 1H), 3.62 (s, 3H), 2.28-2.02 (m, 5H), 0.81 (m, 4H). [00558] Example I-36-a and I-36-b: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- (tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyri dazine-3-carboxamide and (S)- 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-3-yl)-1H-pyrazol-4- yl)phenyl)amino)pyridazine-3-carboxamide [00559] Synthesis of compound 36.1. A mixture of 4-bromo-1H-pyrazole (2.0 g, 13.61 mmol, 1.0 equiv), 5-bromo-3,4-dihydro-2H-pyran (8.93 g, 54.79 mmol, 4.0 equiv) and potassium carbonate (3.78 g, 27.39 mmol, 2.0 equiv) in 1,4-dioxane (15 mL) was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere, N, N-dimethylethylenediamine (0.241 g, 2.739 mmol, 0.2 equiv) followed by copper iodide (0.261 g, 1.369 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 120 ^o C for 16 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 36.2 (1.2 g, 39%). MS(ES): m/z 229.08 [M+H] ⁺ . [00560] Synthesis of compound 36.2. A mixture of 36.1 (1.2 g, 5.24 mmol, 1.0 equiv), 2- methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anili ne (1.96 g, 7.86 mmol, 1.5 equiv) and potassium phosphate (3.35 g, 15.789 mmol, 3.0 equiv) in dioxane (10 mL) and water (2 mL) was degassed by bubbling through a stream of argon for 10 min. Under argon atmosphere, [1,1'- Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (0.387 g, 0.526 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100 ^o C for 16 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 31% ethyl acetate in hexane) to afford 36.2 (0.8 g, 56%). MS(ES): m/z 272.3 [M+H] ⁺ . [00561] Synthesis of compound 36.3-a and 36.3-b. A mixture of 10% palladium on carbon (0.3 g) and 36.2 (0.8 g, 2.95 mmol, 1.0 equiv) in methanol was stirred at rt under hydrogen atmosphere (1 atm) for 2 h. It was filtered through a pad of Celite®. The organic layer was concentrated under reduced pressure to afford (±)-36.3 (0.500 g, Yield: 62.04%). MS(ES): m/z 274.4 [M+H] ⁺ . The racemate was separated using chiral HPLC (column: CHIRALPAK IG (250 * 20 mm, 5 um; mobile phase: 0.1% diethylamine in methanol; flow rate: 15 mL/min) to afford first eluting fraction (36.3-a) (0.190 g, Yield: 38%), MS(ES): m/z 274.4 [M+H] ⁺ , and second eluting fraction (36.3-b) (0.190 g, Yield: 38%). MS(ES): m/z 274.4 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00562] Synthesis of compound 36.4-a and 36.4-b. Compound 36.4-a was prepared from 36.3-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.3% methanol in DCM) to afford 36.4-a. MS(ES): m/z 429.6 [M+H] ⁺ . Compound 36.4-b was prepared from 36.3-b in the same manner. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.3% methanol in DCM). MS(ES): m/z 429.6 [M+H] ⁺ . [00563] Synthesis of I-36-a and I-36-b. Compound I-36-a was prepared from 36.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 478.28 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.29 (s, 1H), 10.98 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.47-7.45 (d, J = 8 Hz, 1H), 7.30-7.19 (m, 3H), 4.36 (bs, 1H), 4.02-4.00 (m, 1H), 3.83-3.80 (m, 1H), 3.68 ((m, 1H),-3.63 (s, 3H), 3.47 (m, 1H), 2.16-2.09 (m, 3H), 1.74-1.68 (m, 2H), 0.81 (m, 4H). Compound I-32-b was prepared from 36.4-b in the same manner. MS(ES): m/z 478.28 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.29 (s, 1H), 11.97 (s, 1H), 8.52 (s, 1H), 8.29 (bs, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.91(s, 1H), 7.47-7.45 (m, 1H), 7.30-7.28 (m, 1H), 7.21-7.19 (m, 1H), 4.36 (bs, 1H), 4.02-4.00 (m, 1H), 3.83-3.81 (m, 1H), 3.68 ((m, 1H)), 3.53 (s, 3H), 3.47 (m, 1H), 2.16- 2.09 (m, 3H), 1.74-1.68 (m, 2H), 0.82 (m, 4H). [00564] Example I-37-a and I-37-b: (S)-4-((3-(3-cyano-1-((tetrahydro-2H-pyran-2-yl)methyl)- 1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarbo xamido)pyridazine-3- carboxamide and (R)-4-((3-(3-cyano-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-p yrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00565] Synthesis of compound (±)-37.1. To a solution of (tetrahydro-2H-pyran-2-yl)methanol (0.5 g, 4.31 mmol, 1.0 equiv) and triethylamine (0.9 mL, 6.46 mmol, 1.5 equiv) in DCM (6 mL) was added methanesulfonyl chloride (0.42 mL, 5.60 mmol, 1.3 equiv) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was used in the next step without further purification. MS(ES): m/z 195.25 [M+H] ⁺ . [00566] Synthesis of compound (±)-37.2 and (±)-37.3. To a solution of (±)-37.1 (1.36 g, 7.01 mmol, 1.2 equiv) and 4-bromo-1H-pyrazole-3-carbonitrile (1 g, 5.84 mmol, 1.0 equiv) in acetonitrile (20 mL) was added potassium carbonate (2.42 g, 17.54 mmol, 3 equiv). The reaction mixture was stirred at 90 °C for 12 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10-15% ethyl acetate in hexane) to afford (±)-37.2 (0.29 g, Yield: 18%), (±)-37.3 (0.98 g, Yield: 62.39%). MS(ES): m/z 271.13 [M+H] ⁺ . [00567] Synthesis of compound (±)-37.4. Compound (±)-37.4 was prepared from (±)-37.3 following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 23% ethyl acetate in hexane). MS(ES): m/z 313.3 [M+H] ⁺ . [00568] Compound 37.4-a and 37.4-b. The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO ₂ (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (37.4- a), MS(ES): m/z 313.3 [M+H] ⁺ , and second eluting fraction (37.4-b). MS(ES): m/z 313.3 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00569] Synthesis of compound 37.5-a and 37.5-b. Compound 37.5-a was prepared from 37.4-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 468.9 [M+H] ⁺ . Compound 37.5-b was prepared from 37.4-b in the same manner, MS(ES): m/z 468.9 [M+H] ⁺ . [00570] Synthesis of I-37-a and I-37-b. Compound I-37-a was prepared from 37.5-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 517.5 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.36 (s,1H), 11.06 (s, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.52 (m, 1H), 7.4 (m, 1H), 7.36 (m, 1H), 4.33 (m, 2H), 3.89 (m, 1H), 3.74 (m, 1H), 3.51 (s, 3H), 2.10 (m, 1H), 1.79 (m, 1H), 1.64 (m, 1H), 1.47-1.30 (m, 2H), 1.25-1.22 (m, 2H), 0.86 (m, 4H). Compound I-37-b was prepared from 37.5-b in the same manner. MS(ES): m/z 517.5 [M+H] ⁺ ; ¹ H NMR (DMSO- d6, 400 MHz): δ 11.36 (s,1H), 11.06 (s, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.52 (m, 1H), 7.4 (m, 1H), 7.36 (m, 1H), 4.33 (m, 2H), 3.89 (m, 1H), 3.74 (m, 1H), 3.51 (s, 3H), 2.10 (m, 1H), 1.79 (m, 1H), 1.64 (m, 1H), 1.47-1.30 (m, 2H), 1.25-1.22 (m, 2H), 0.86 (m, 4H). [00571] Example I-38-a and I-38-b: 4-((3-(3-cyano-1-((1S,2S)-2-methoxycyclohexyl)-1H- pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxam ido)pyridazine-3- carboxamide and 4-((3-(3-cyano-1-((1R,2R)-2-methoxycyclohexyl)-1H-pyrazol-4- yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00572] Synthesis of compound (±)-trans-38.1. A mixture of 4-bromo-1H-pyrazole-3- carbonitrile (1 g, 5.81 mmol, 1.0 equiv), 7-oxabicyclo[4.1.0]heptane (0.855 g, 8.72 mmol, 1.5 equiv) and cesium carbonate (5.66 g, 17.44 mmol, 3.0 equiv) in DMF (20 mL) was stirred at 100 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford (±)-trans-38.1 (0.7 g, Yield: 45%). MS(ES): m/z 271.1 [M+H] ⁺ . [00573] Synthesis of compound (±)-trans-38.2. To a solution of (±)-trans-38.1 (0.7 g, 2.59 mmol, 1.0 equiv) in DMF (20 mL) at 0 °C and added sodium hydride (0.208 g, 5.20 mmol, 2.0 equiv). The reaction mixture was stirred at 0 °C for 30 min. Methyl iodide (0.547 g, 3.88 mmol, 1.5 equiv) was added and stirred at room temperature for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-trans-38.2 (0.6 g, Yield: 81%). MS(ES): m/z 285.3 [M+H] ⁺ . [00574] Synthesis of compound trans-38.3-a and trans-38.3-b. Compound (±)-trans-38.3 was prepared from (±)-trans-38.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.3% methanol in DCM). MS(ES): m/z 327.4 [M+H] ⁺ . The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO2 (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50) flow rate: 80 mL/min) to afford first eluting fraction (trans-38.3-a), MS(ES): m/z 327.4 [M+H] ⁺ , and afford second eluting fraction (trans-38.3-b). MS(ES): m/z 327.4 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00575] Synthesis of compound trans-38.4-a and trans-38.4-b. Compound trans-38.4-a was prepared from trans-38.3-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 482.7 [M+H] ⁺ . Compound trans-38.4-a was prepared from trans-38.3-b following the same manner. MS(ES): m/z 482.7 [M+H] ⁺ . [00576] Synthesis of I-38-a and I-38-b. Compound I-38-a was prepared from trans-38.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.9% methanol in DCM). MS(ES): m/z 531.5 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s, 1H), 11.02 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.46 (s, 1H), 7.34-7.30 (m, 2H), 4.23 (bs, 1H), 3.48(s, 3H), 3.30 (m, 1H) 3.1 (m, 2H), 2.29 (m, 1H), 2.05-1.73 (m, 4H), 1.32-1.19 (m, 4H), 0.80 (m, 4H). Compound I-38-b was prepared from trans-38.4-b in the same manner. MS(ES): m/z 531.5 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s, 1H), 11.02 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.46 (s, 1H), 7.34-7.30 (m, 2H), 4.23(bs, 1H), 3.48 (s, 3H), 3.30 (m, 1H), 3.10 (m, 2H), 2.29 (m, 1H), 2.05-1.73 (m, 4H), 1.32- 1.19 (m, 4H), 0.80 (m, 4H). [00577] Example I-39: 4-((3-(3-cyano-1-cyclohexyl-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00578] Synthesis of compound 39.1 and 39.2. A mixture of 4-bromo-1H-pyrazole-3- carbonitrile (0.5 g, 2.90 mmol, 1.0 equiv), bromocyclohexane (0.710 g, 4.3 mmol, 1.5 equiv) and potassium carbonate (1.20 g, 8.7 mmol, 3.0 equiv) in acetonitrile (7 mL) was stirred at 90 ^o C for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 39.1 (0.120 g, Yield: 16%) and 39.2 (0.2 g, Yield: 27.04%). MS(ES): m/z 255.4 [M+1] ⁺ . [00579] Synthesis of compound 39.3. Compound 39.3 was prepared from 39.2 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 297.3 [M+H] ⁺ . [00580] Synthesis of compound 39.4. Compound 39.4 was prepared from 39.3 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 33% ethyl acetate in hexane). MS (ES): m/z 452.3[M+H] ⁺ . [00581] Synthesis of compound I-39. Compound I-32-a was prepared from 32.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS (ES): m/z 501.4 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400 MHz): 11.34 (s, 1H), 11.04 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.17 (s,1H), 7.90 (s, 1H), 7.49-7.47 (d, J = 8 Hz, 1H), 7.39-7.37 (d, J = 8 Hz, 1H), 7.32-7.30 (d, J = 8 Hz, 1H), 7.07-7.06 (d, J = 4 Hz, 1H), 6.82- 6.80 (d, J = 8 Hz, 1H), 4.36 (s, 1H), 3.99-3.96 (d, J = 12 Hz, 1H), 3.48 (s, 3H), 2.08 (m,1H), 1.81 (m, 2H), 1.68-1.65 (d, J = 12 Hz, 1H), 1.54 (s, 2H), 1.42-1.39 ( d, J = 12 Hz, 2H), 1.22 (s, 2H), 0.83-0.82 (m, 4H). Example I-40: (S)-4-((3-(5-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) -2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide

[00582] Synthesis of compound 40.1. To a solution of (R)-tetrahydrofuran-3-ol (1 g, 11.35 mmol, 1.0 equiv) in DCM (30 mL) at 0 °C was added triethylamine (3.44 g, 34.09 mmol, 3.0 equiv) followed by methanesulfonyl chloride (1.94 g, 17.04 mmol, 1.5 equiv) and stirred at rt for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used in the next step without further purification (1 g, Yield: 53%). [00583] Synthesis of compound 40.2 and 40.3. A mixture of 4-bromo-1H-pyrazole-3- carbonitrile (0.75 g, 4.36 mmol, 1.0 equiv), potassium carbonate (1.81 g, 13.15 mmol, 3.0 equiv) and 40.1 (1.0 g, 6.54 mmol, 1.5 equiv) in acetonitrile (10 mL) was stirred at 90 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 40.2 and 40.3. MS(ES): m/z 243.2 [M+H] ⁺ . [00584] Synthesis of compound 40.4. Compound 40.4 was prepared from 40.2 following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.2% methanol in DCM). MS(ES): m/z 285.3 [M+H] ⁺ . [00585] Synthesis of compound 40.5. Compound 40.5 was prepared from 40.4 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.6% methanol in DCM). MS(ES): m/z 440.7 [M+H] ⁺ . [00586] Synthesis of I-40. Compound I-40 was prepared from 40.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.0% methanol in DCM). MS(ES): m/z 489.4 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.34 (s, 1H), 11.04 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.52-7.51 (d, J = 4 Hz, 1H), 7.34-7.30 (t, J = 8 Hz, 1H), 7.07-7.06 (d, J = 4 Hz, 1H), 5.34 (m, 1H), 4.10-4.09 (d, J = 4 Hz, 2H), 4.03-3.99 (t, J = 8 Hz, 2H), 3.50 (s, 3H), 2.08 (s, 1H), 1.54-1.49 (t, J = 12 Hz, 2H), 0.83-0.82 (d, J = 4 Hz, 4H). Example I-41: (R)-4-((3-(5-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) -2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00587] Synthesis of compound 41.1. To a solution of (S)-tetrahydrofuran-3-ol (1 g, 11.35 mmol, 1.0 equiv) in DCM (30 mL) and triethylamine (3.44 g, 34.09 mmol, 3.0 equiv) at 0 °C was added methansulfonyl chloride (1.94 g, 17.04 mmol, 1.5 equiv) and stirred at rt for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was used in the next step without further purification (1.00 g, Yield: 53%). [00588] Synthesis of compound 41.2 and 41.3. A mixture of 4-bromo-1H-pyrazole-3- carbonitrile (0.75 g, 4.36 mmol, 1.0 equiv), potassium carbonate (1.81 g, 13.15 mmol, 3.0 equiv) and 41.1 (1.0 g, 6.54 mmol, 1.5 equiv) in acetonitrile (10 mL) was stirred at 90 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford 41.2 (0.3 g, Yield: 28%) and 41.3 (0.45 g, Yield: 42%). MS(ES): m/z 243.2 [M+H] ⁺ . [00589] Synthesis of compound 41.4. Compound 41.4 was prepared from 41.2 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.2% methanol in DCM). MS(ES): m/z 285.3 [M+H] ⁺ . [00590] Synthesis of compound 41.5. Compound 41.5 was prepared from 41.4 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.6% methanol in DCM). MS(ES): m/z 440.8 [M+H] ⁺ . [00591] Synthesis of I-41. Compound I-41 was prepared from 41.5 following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.0% methanol in DCM). MS(ES): m/z 489.4 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.34 (s, 1H), 11.04 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.52-7.51 (d, J = 4 Hz, 1H), 7.34-7.30 (t, J = 8 Hz, 1H), 7.07-7.06 (d, J = 4 Hz, 1H), 5.34 (m, 1H), 4.13-4.01 (m, 4H), 3.50 (s, 3H), 2.08 (s, 1H), 1.54-1.51 (m, 2H), 0.83-0.82 (m, 4H). [00592] Example I-42: 4-((3-(5-cyano-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) -2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide

[00593] Synthesis of compound 42.1. To a solution of tetrahydro-2H-pyran-4-ol (1.0 g, 9.80 mmol, 1.0 equiv) and triethylamine (3.43 mL, 24.50 mmol, 2.5 equiv) in DCM (15 mL) was added methanesulfonyl chloride (1.34 g, 11.76 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 42.1 (1.0 g, Yield: 59%). MS(ES): m/z 181.22 [M+H] ⁺ . [00594] Synthesis of compound 42.2 and 42.3. A mixture of 42.1 (1.0 g, 5.55 mmol, 1.0 equiv), potassium carbonate (2.29 g, 13.37 mmol, 3.0 equiv) and 4-bromo-1H-pyrazole-3-carbonitrile (0.954 g, 5.55 mmol, 1.0 equiv) in acetonitrile (20 ml) was stirred at 90 ^o C for 4 h. It was transferred into ice- water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 42.2 (0.6 g, Yield: 42%). MS(ES): m/z 257.10 [M+H] ⁺ and 42.3 (0.3 g, Yield: 21%). MS(ES): m/z 257.10 [M+H] ⁺ . [00595] Synthesis of compound 42.4. Compound 42.4 was prepared from 42.3 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane). MS(ES): m/z 299.3 [M+H] ⁺ . [00596] Synthesis of compound 42.5. Compound 42.5 was prepared from 42.4 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 82% ethyl acetate in hexane). MS(ES): m/z 454.9 [M+H] ⁺ . [00597] Synthesis of I-42. Compound I-42 was prepared from 42.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.4% methanol in DCM). MS(ES): m/z 503.5 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.34 (s, 1H), 11.04 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.90 (s,1H), 7.50 (d, J = 8 Hz 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.33-7.29 (m, 1H), 4.66-4.62 (m, 1H), 4.00-3.97 (m, 4H), 3.37 (s, 3H), 2.08-1.98 (m,5H), 0.84-0.82 (m, 4H). [00598] Example I-43: 4-((3-(5-cyano-1-cyclohexyl-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00599] Synthesis of compound 43.1. Compound 43.1 was prepared from 39.1 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 297.3 [M+H] ⁺ . [00600] Synthesis of compound 43.2. Compound 43.2 was prepared from 43.1 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 33% ethyl acetate in hexane). MS (ES): m/z 452.7[M+H] ⁺ . [00601] Synthesis of compound I-43. Compound I-43 was prepared from 43.2 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS (ES): m/z 501.3 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400 MHz): 11.34 (s, 1H), 11.04 (s, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 8.03 (s,1H), 7.90 (s, 1H), 7.52-7.50 (d, J = 8 Hz, 1H), 7.38-7.32 (m, 1H), 7.08-7.306 (d, J = 8 Hz, 1H), 4.45 (bs, 1H), 3.49 (s, 3H), 2.07-2.05 (d, J = 8 Hz, 3H), 1.88-1.85 (d, J = 12 Hz, 4H), 1.70-168 (d, J = 8 Hz, 1H), 1.55 (bs, 1H), 1.49-1.46 (d, J = 12 Hz, 1H), 1.23 (bs, 1H), 0.82(m, 4H). [00602] Example I-44: 4-((3-(3-cyano-1-cyclohexyl-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide [00603] Synthesis of compound 44.1. Compound 44.1 was prepared from 39.3 and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 33% ethyl acetate in hexane). MS (ES): m/z 451[M+H] ⁺ . [00604] Synthesis of compound I-44. Compound I-44 was prepared from 44.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS (ES): m/z 500 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400 MHz): 10.97 (s, 1H), 10.78 (s, 1H), 8.62(s, 1H), 8.39(s, 1H), 8.08 (s,1H), 7.48-7.47 (t, J = 4 Hz, 1H), 7.31-7.28 (d, J = 8 Hz, 1H), 7.07-7.05 (d, J = 8 Hz, 1H), 6.84 (s, 2H), 4.00-3.97 (m, 1H), 3.50 (s, 3H), 2.08 (m, 3H), 1.82-1.78 (m, 3H), 1.67 (bs, 1H), 1.56 (bs, 2H), 1.44-1.42 (m, 1H), 1.25 (s,1H), 0.86 (m, 4H). [00605] Example I-45: 4-((3-(4-cyano-1-cyclohexyl-1H-pyrazol-3-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide

[00606] Synthesis of compound 45.1 and 45.2. To a solution of 3-iodo-1H-pyrazole-4- carbonitrile (1.5 g, 6.85 mmol, 1.0 equiv), bromocyclohexane (1.67 g, 10.27 mmol, 1.5 equiv) and potassium carbonate (2.8 g, 20.55 mmol, 3.0 equiv) in acetonitrile (22.5 mL) was stirred at 80 ^o C for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 45.1 (0.25 g, Yield: 12.12%) and 45.2 (0.5 g, Yield: 24%). MS(ES): m/z 302 [M+H] ⁺ . [00607] Synthesis of compound 45.3. Compound 45.3 was prepared from 45.2 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 297.3 [M+H] ⁺ . [00608] Synthesis of compound 45.4. Compound 45.4 was prepared from 45.3 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS (ES): m/z 452[M+H] ⁺ . [00609] Synthesis of compound I-45. Compound I-45 was prepared from 45.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, (3%) methanol in DCM). MS (ES): m/z 501.5 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): 11.33 (s, 1H), 11.04 (s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.55 (s, 1H), 7.28 (s, 1H), 7.06-7.05 (d, J = 4 Hz, 1H), 6.81-6.80 (d, J = 4 Hz, 1H), 4.17 (bs, 1H), 3.52 (s, 3H), 2.07 (m, 3H), 1.82 (m,3H), 1.72 (m, 4H), 1.54 (m, 1H), 0.84 (m, 4H). [00610] Example I-46: 4-((3-(1-cyclohexyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)- 6- (cyclopropanecarboxamido)pyridazine-3-carboxamide [00611] Synthesis of compound 46.1. To a solution of cyclohexanol (1.0 g, 9.98 mmol, 1.0 equiv) in DCM (15 mL) and triethylamine (2.8 mL, 19.96 mmol, 2.0 equiv) at 0 °C was added. methanesulfonyl chloride (0.93 mL, 12.00 mmol, 1.2 equiv) was added dropwise and reaction mixture was stirred at room temperature for 30 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 46.1 (0.91 g, Yield: 51%). MS(ES): m/z 179.2 [M+H] ⁺ . [00612] Synthesis of compound 46.2. To a solution of 4-bromo-1H-pyrazole (0.910 g, 5.105 mmol, 1.5 equiv) in DMF (20 mL) at 0 °C was added sodium hydride in portions (0.500 g, 10.20 mmol, 3.0 equiv).46.1 (0.500 g, 3.401 mmol, 1.0 equiv) was added and reaction mixture at 85 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 46.2 (0.35 g, Yield: 30%). MS(ES): m/z 230.2 [M+1] ⁺ . [00613] Synthesis of compound 46.3. Compound 46.3 was prepared from 46.2 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 38% ethyl acetate in hexane). MS(ES): m/z 272.3 [M+H] ⁺ . [00614] Synthesis of compound 46.4. Compound 46.4 was prepared from 46.3 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane). MS(ES): m/z 427.9 [M+H] ⁺ . [00615] Synthesis of I-46. Compound I-46 was prepared from 46.4 following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.7% methanol in DCM). MS(ES): m/z 476.5 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400 MHz): δ 11.29 (s, 1H), 11.97 (s, 1H), 8.53 (s, 1H), 8.20, (s, 1H), 8.13 (s, 1H) 7.91-7.87 (s, 2H), 7.46-7.44 (d, J = 8 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), 7.20-7.18 (m, 1H), 4.185 (bs, 1H), 3.574 (s, 3H), 2.065 (bs, 3H), 1.840-1.657 (m, 5H), 1.426-1.396 (m, 2H), 1.240 (m, 1H), 0.813 (m, 4H). [00616] Example I-47: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd rofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide [00617] Synthesis of compound 47.1. A mixture of 4-bromo-1H-pyrazole (1.8 g, 12.25 mmol, 1.0 equiv), potassium carbonate (5.06 g, 36.73 mmol, 3.0 equiv) and 41.1 (3.0 g, 18.37 mmol, 1.5 equiv) in acetonitrile (30 mL) was stirred at 90 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 47.1 (0.5 g, Yield: 19%). MS(ES): m/z 218.10 [M+H] ⁺ . [00618] Synthesis of compound 47.2. Compound 47.2 was prepared from 47.1 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.3% methanol in DCM). MS(ES): m/z 260.5 [M+H] ⁺ . [00619] Synthesis of compound 47.3. Compound 47.3 was prepared from 47.2 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 415.9 [M+H] ⁺ . [00620] Synthesis of I-47. Compound I-47 was prepared from 47.3 following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 464.3 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.97 (s, 1H), 8.53 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.47-7.45 (d, J = 8 Hz, 1H), 7.30-7.28 (d, J = 8 Hz, 1H), 7.21-7.17 (t, J = 8 Hz, 1H), 5.09 (s, 1H), 4.03-3.81 (m, 4H), 3.57 (s, 3H), 2.41-2.32 (m, 2H), 2.08 (m, 1H), 0.80 (m, 4H). [00621] Example I-48 (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd rofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide [00622] Synthesis of compound 48.1. Compound 48.1 was prepared following the procedure described in the synthesis of 47.1. It was used in the next step without further purification. [00623] Synthesis of compound 48.2. Compound 48.2 was prepared from 48.1 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.3% methanol in DCM). MS(ES): m/z 260.5 [M+H] ⁺ . [00624] Synthesis of compound 48.3. Compound 48.3 was prepared from 48.2 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 415.9 [M+H] ⁺ . [00625] Synthesis of I-48. Compound I-48 was prepared from 48.3 following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 464.3 [M+H] ⁺ ; H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.97 (s, 1H), 8.53 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.47-7.45 (d, J = 8 Hz, 1H), 7.30-7.28 (d, J = 8 Hz, 1H), 7.21-7.17 (t, J = 8 Hz, 1H), 5.09 (s, 1H), 4.03-3.81 (m, 4H), 3.57 (s, 3H), 2.41-2.32 (m, 2H), 2.08 (m, 1H), 0.80 (m, 4H). [00626] Example I-49: 4-((3-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)- 6- (cyclopropanecarboxamido)nicotinamide [00627] Synthesis of compound 49.1. To a solution of 4-bromo-1H-pyrazole (3 g, 20.41 mmol, 1.0 equiv) in DMF (30 mL) at 0 °C was added sodium hydride (2.04 g, 51.02 mmol, 2.5 equiv) in portions and stirred at 0 °C for 30 min. To the mixture was added bromocyclobutane (2.76 g, 20.41 mmol, 1.0 equiv) and stirred at rt for 16 h. It was transferred into crushed ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 49.1 (1.80 g, Yield: 44%). MS(ES): m/z 202.1 [M+1] ⁺ . [00628] Synthesis of compound 49.2. Compound 49.2 was prepared from 49.1 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, using 43% ethyl acetate in hexane). MS(ES): m/z 244.4 [M+H] ⁺ . [00629] Synthesis of compound 49.3. Compound 49.3 was prepared from 49.2 and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 398.7 [M+H] ⁺ . [00630] Synthesis of I-49. Compound I49 was prepared from 49.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, using 3.0% methanol in DCM). MS(ES): m/z 447.36 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.74 (s, 1H), 8.58 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.49 (s, 1H), 7.38-7.36 (d, J = 8 Hz, 1H), 7.27-7.25 (d, J = 8 Hz, 1H), 7.16-7.12 (t, J = 8 Hz, 1H), 4.91- 4.86 (t, J = 8 Hz, 1H), 3.56 (s, 3H), 1.99-1.96 (t, J = 8 Hz, 1H), 1.80-1.79 (d, J = 4 Hz, 2H), 0.77-0.75 (d, J = 8 Hz, 4H). [00631] Example I-50: 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-pyrazol- 4-yl)-2- methoxyphenyl)amino)nicotinamide [00632] Synthesis of compound 50.1. To a solution of 4-bromo-1H-pyrazole (3 g, 20.41 mmol, 1.0 equiv) in 1,2 dichloroethane (30 mL) was added cyclopropylboronic acid (2.63 g, 30.62 mmol, 1.5 equiv), 2,2’bipyridine (3.52 g, 22.60 mmol, 1.1 equiv), copper acetate (4.09 g, 22.60 mmol, 1.1 equiv) and sodium carbonate (4.74 g, 45.20 mmol, 2.2 equiv). The reaction mixture was stirred at 85 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 13% ethyl acetate in hexane) to afford 50.1 (1.0 g, Yield: 26%). MS(ES): m/z 188.1 [M+1] ⁺ . [00633] Synthesis of compound 50.2. Compound 50.2 was prepared from 50.1 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 230.3 [M+H] ⁺ . [00634] Synthesis of compound 50.3. Compound 50.3 was prepared from 50.2 and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 384.7 [M+H] ⁺ . [00635] Synthesis of I-50. Compound I-50 was prepared from 50.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 433.31 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.87 (s, 1H), 10.74 (s, 1H), 8.59 (s, 1H), 8.21 (s, 2H), 8.02 (s, 1H), 7.89 (s, 1H), 7.48 (s, 1H), 7.37-7.35 (d, J = 8 Hz, 1H), 7.27-7.25 (d, J = 8 Hz, 1H), 7.15-7.14 (t, J = 4 Hz, 1H), 3.78 (s, 1H), 3.56 (s, 3H), 1.97 (bs, 1H), 1.09 (bs, 2H), 0.77-0.75 (m, 4H). [00636] Example I-51: 4-((3-(1-cyclobutyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)- 6- (cyclopropanecarboxamido)pyridazine-3-carboxamide [00637] Synthesis of compound 51.1. Compound 51.1 was prepared from 49.2 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 399.7 [M+H] ⁺ . [00638] Synthesis of I-51. Compound I-51 was prepared from 51.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM. MS(ES): m/z 448.43 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.97 (s, 1H), 8.53 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.47-7.45 (d, J = 8 Hz, 1H), 7.29-7.27(d, J = 8 Hz, 1H), 7.20-7.18 (d, J = 8 Hz, 1H),7.16 (m, 1H), 4.89 (m, 1H) ,3.57 (s, 3H), 2.43-2.39 (t, J = 8 Hz, 2H), 2.09-2.07 (d, J = 8 Hz, 1H), 1.80-1.77 (t, J = 4 Hz, 2H), 1.47 (s, 1H), 1.19-1.15 (m, 2H), 0.85-0.81 (t, J = 12 Hz, 4H). [00639] Example I-52: 6-(cyclopropanecarboxamido)-4-((3-(1-cyclopropyl-1H-pyrazol- 4-yl)-2- methoxyphenyl)amino)pyridazine-3-carboxamide [00640] Synthesis of compound 52.1. Compound 52.1 was prepared from 50.2 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.3% methanol in DCM). MS(ES): m/z 385.7 [M+H] ⁺ . [00641] Synthesis of I-52. Compound I-52 was prepared from 52.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM). MS(ES): m/z 434.41 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.97 (s, 1H), 8.53 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.90-7.88 (d, J = 8 Hz, 1H)7.87 (s, 1H), 7.45-7.44 (d, J = 4 Hz, 1H), 7.29-7.27 (d, J = 8 Hz, 1H), 7.20-7.16 (t, J = 8 Hz, 1H), 3.79- 3.78 (d, J = 4 Hz, 1H), 3.57 (s, 3H), 2.07 (s, 1H), 2.00-1.98 (d, J = 8 Hz, 1H), 1.23 (bs, 6H), 1.09-1.05 (d, J = 16 Hz, 2H), 0.99-0.97 (t, J = 8 Hz, 2H), 0.85-0.81 (m, 4H). [00642] Example I-53-a and I-53-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- ((3S,4R)-4-methoxytetrahydrofuran-3-yl)-1H-pyrazol-3-yl)phen yl)amino)pyridazine-3- carboxamide and 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4- methoxytetrahydrofuran-3-yl)-1H-pyrazol-3-yl)phenyl)amino)py ridazine-3-carboxamide

[00643] Synthesis of compound (±)-trans-53.1. To a solution of 3-iodo-1H-pyrazole (3.5 g, 18.04 mmol, 1.0 equiv) in THF at-78 ^o C was added lithium diisopropylamide (9.9 mL,19.8 mmol, 1.1 equiv) dropwise. The reaction mixture was stirred at-40 ^o C for 1 h. A solution of 3,6- dioxabicyclo[3.1.0]hexane (1.24 g, 14.43 mmol, 0.8 equiv) in THF was added dropwise. The reaction mixture was stirred at room temperature for 1 h then at 80 ^o C for 24 h. It was cooled to room temperature and transferred into ice-water and product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 28% ethyl acetate in hexane) to afford (±)-trans- 53.1 (2.1 g, 42%). MS(ES): m/z 281.1 [M+H] ⁺ . [00644] Synthesis of compound (±)-trans-53.2 To a solution of (±)-trans-53.1 (2.1 g, 7.5 mmol, 1.0 equiv) in DMF (25 mL) was added sodium hydride (1.08 g, 22.53 mmol, 2.5 equiv) in portions at 0 °C and stirred for 30 min. To the mixture was added methyl iodide (3.19 g, 22.5 mmol, 3.0 equiv) and stirred at room temperature for 1 h. It was transferred into cold water, stirred, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford (±)-trans-53.2 (1.5 g, Yield: 68%). %). MS (ES): m/z 295.1 [M+H] ⁺ . [00645] Synthesis of compound trans-53.3-a and trans-53.3-b. Compound (±)-trans-53.3 was prepared from (±)-trans-53.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 290.3 [M+H] ⁺ . The racemate was separated by HPLC (column: CHIRALPAK IB- N (250 * 21 mm, 5 um); mobile phase: (A) 0.1% diethylamine in n-hexane (B) 0.1% diethylamine in propane 2-ol: acetonitrile (70 : 30); flow rate: 20 mL/min) to afford first eluting fraction (trans-53.3-a) and second eluting fraction (trans-53.3-b). MS(ES): m/z 290.3 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00646] Synthesis of compound trans-53.4-a and trans-53.4-b. Compound trans-53.4-a was prepared from trans-53.3-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 445.8 [M+H] ⁺ . Compound trans-53.4-b was prepared from trans-53.3-b in the same manner. MS(ES): m/z 445.8 [M+H] ⁺ . [00647] Synthesis of compound I-53-a and I-53-b. Compound I-53-a was prepared from trans- 53.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5- a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 494.52 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.98 (s, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.70-7.68 (d, J = 8 Hz, 1H), 7.41-7.39 (d, J = 8 Hz, 1H), 7.25-7.21 (t, J = 16 Hz, 1H), 6.76 (s, 1H), 5.00 (s, 1H), 4.10 (m, 4H), 3.81-3.78 (d, J = 12 Hz, 1H), 3.60 (s, 3H), 3.34 (s, 3H), 1.23 (bs, 1H), 0.81 (m, 4H). Compound I-53-b was prepared from trans-53.4-b in the same manner. MS(ES): m/z 494.52 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.32 (s, 1H), 10.99 (s, 1H), 8.55 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.70-7.68 (d, J = 8 Hz, 1H), 7.41-7.39 (d, J = 8 Hz, 1H), 7.25- 7.21 (t, J = 16 Hz, 1H), 6.76 (s, 1H), 5.00 (s, 1H), 4.09 (m, 4H), 3.80 (m, 1H), 3.59 (s, 3H), 3.34 (s, 3H), 1.23 (s, 1H), 0.82 (m, 4H). [00648] Example I-54: 4-((3-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide H [00649] Synthesis of compound 54.1. To a solution of bicyclo[1.1.1]pentan-1-ylhydrazine (0.5 g, 2.29 mmol, 1.0 equiv) in ethanol (15 mL) was added 1,1,3,3-tetramethoxypropane (0.479 g, 2.29 mmol, 1.0 equiv) and hydrochloric acid (0.341 g, 9.35 mmol, 3.2 equiv). The reaction mixture was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 54.1 (0.6 g, Yield: 88%). MS(ES): m/z 135.12 [M+1] ⁺ . [00650] Synthesis of compound 54.2. To a solution of 54.1 (0.6 g, 4.47 mmol, 1.0 equiv) in acetic acid (12 mL) at 10 °C was added N-bromosuccinimide (0.871 g, 4.92 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 2 h. It was transferred into ice cold water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 54.2 (0.6 g, Yield: 63%). MS(ES): m/z 214.08 [M+1] ⁺ . [00651] Synthesis of compound 54.3. Compound 54.3 was prepared from 54.2 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 256.3 [M+H] ⁺ . [00652] Synthesis of compound 54.4. Compound 54.4 was prepared from 54.3 and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 410.8 [M+H] ⁺ . [00653] Synthesis of I-54. Compound I-54 was prepared from 54.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, using 3.1% methanol in DCM). MS(ES): m/z 459.36 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.73 (s, 1H), 8.59 (s, 1H), 8.17-8.14 (d, J = 16 Hz, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.49 (s, 1H), 7.40-7.38 (d, J = 8 Hz, 1H), 7.29-7.27 (d, J = 8 Hz, 1H), 7.16-7.14 (d, J = 8 Hz, 1H), 3.56 (s, 3H), 2.32-2.27 (s, 6H), 1.99-1.96 (t, 1H), 1.09 (s, 2H), 0.77-0.76 (d, J = 4 Hz, 4H). [00654] Example I-55: 4-((3-(1-(bicyclo[1.1.1]pentan-1-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00655] Synthesis of compound 55.1. Compound 55.1 was prepared from 54.3 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 411.2 [M+H] ⁺ . [00656] Synthesis of I-55. Compound I-55 was prepared from 55.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, using 3.1% methanol in DCM). MS(ES): m/z 460.3 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.97 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.48-7.46 (d, J = 8 Hz, 1H), 7.30-7.28 (d, J = 8 Hz, 1H), 7.192 (t, J = 8 Hz, 1H), 3.57 (s, 3H), 2.63 (s, 1H), 2.27 (s, 6H), 2.07 (m, 1H), 1.22 (s, 1H), 0.81 (m, 4H). [00657] Example I-56: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-phenyl-1H-pyr azol-3- yl)phenyl)amino)pyridazine-3-carboxamide [00658] Synthesis of compound 56.1. To a solution of 3-bromo-1H-pyrazole (0.5 g, 3.42 mmol, 1.0 equiv), iodobenzene (0.83 g, 4.10 mmol, 1.2 equiv), potassium carbonate (1.18 g, 8.56 mmol, 2.5 equiv), cyclohexane-1,2-diamine (0.097 g, 0.856 mmol, 0.25 equiv) and copper(I) iodide (0.65 g, 0.342 mmol, 0.1 equiv) in 1, 4-dioxane (30 mL) was stirred at 100 ^o C for 3 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane) to afford 56.1 (0.31 g, Yield: 83%). MS (ES): m/z 224.07 [M+H] ⁺ . [00659] Synthesis of compound 56.2. Compound 56.2 was prepared from 56.1 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS(ES): m/z 266.3 [M+H] ⁺ . [00660] Synthesis of compound 56.3.. Compound 56.3 was prepared from 56.2 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 421.8 [M+H] ⁺ . [00661] Synthesis of I-56. Compound I-56 was prepared from 56.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3 % methanol in DCM). MS(ES): m/z 470.5 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s,1H), 11.04 (s, 1H), 8.94 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.95-7.90 (m, 3H), 7.61-7.53 (m, 3H), 7.39-7.34 (m, 2H), 7.29-7.25 (m, 1H), 3.65 (s, 3H), 2.10-2.09 (bs, 1H), 0.83 (m, 4H). [00662] Example I-57: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-phenyl-1H-pyr azol-4- yl)phenyl)amino)pyridazine-3-carboxamide

[00663] Synthesis of compound 57.1. A mixture of 4-bromo-1H-pyrazole (0.5 g, 3.42 mmol, 1.0 equiv), iodobenzene (0.83 g, 4.10 mmol, 1.2 equiv), potassium carbonate (1.18 g, 8.56 mmol, 2.5 equiv), 1.1 (0.097 g, 0.856 mmol, 0.25 equiv) and copper(I)iodide (0.65 g, 0.342 mmol, 0.1 equiv) in 1, 4-dioxane was stirred at 100 ^o C for 3 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane) to afford 57.1 (0.31 g, Yield: 83%). MS (ES): m/z 224.07 [M+H] ⁺ . [00664] Synthesis of compound 57.2. Compound 56.2 was prepared from 56.1 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane). MS(ES): m/z 266.3 [M+H] ⁺ . [00665] Synthesis of compound 57.3. Compound 57.3 was prepared from 57.2 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 421.8 [M+H] ⁺ . [00666] Synthesis of I-57. Compound I-57 was prepared from 57.3 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3 % methanol in DCM). MS(ES): m/z 470.5 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 11.04 (s, 1H), 8.94 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.95-7.90 (m, 3H), 7.61- 7.53 (m, 3H), 7.39-7.34 (m, 2H), 7.29-7.25 (m, 1H), 3.65 (s, 3H), 2.10-2.09 (bs, 1H), 0.83 (m, 4H). [00667] Example I-58: 6-(cyclopropanecarboxamido)-4-((3-(5-ethyl-1-(tetrahydro-2H- pyran-4- yl)-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)pyridazine-3-carb oxamide [00668] Synthesis of compound 58.1. To a mixture of 5-ethyl-1H-pyrazol-3-amine (4.5 g, 40.54 mmol, 1.0 equiv) in water at 40 ^o C was added oxone (18.66 g, 60.81.8 mmol, 1.5 equiv) in small portions and stirred for 18 h. I t was transferred into a saturated solution of NaHCO3 and extracted with diethyl ether (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum, the residue was directly purified by column chromatography on silica gel (15% ethyl acetate in hexane) to afford 58.1 (1.1 g, Yield: 19%). MS(ES): m/z 142.1 [M+H] ⁺ . [00669] Synthesis of compound 58.3. A mixture of 58.1 (1.1 g, 3.23 mmol, 1.0 equiv), cesium carbonate (6.33 g, 19.50 mmol, 2.5 equiv) and 4-bromotetrahydro-2H-pyran (1.54 g, 9.36 mmol, 1.2 equiv) in DMF (15 mL) was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, using 15% ethyl acetate in hexane) to afford 58.3 (0.7 g, Yield: 63%). MS(ES): m/z 226.25 [M+H] ⁺ . [00670] Synthesis of compound 58.4. A mixture of 58.3 (0.7 g, 3.11 mmol, 1.0 equiv) and palladium on carbon (10%, 0.07 g) in methanol was stirred under hydrogen pressure (~20 psi) at rt for 3 h. It was filtered over a pad of Celite® and the filtrate was concentrated under reduced pressure to afford 58.4 (0.45 g, Yield: 76%). MS(ES): m/z 196.7 [M+H] ⁺ . [00671] Synthesis of compound 58.5. To a solution of 58.4 (0.35 g, 1.79 mmol, 1.0 equiv) in HCl (37%) and water was added NaNO2 (0.161 g, 2.33 mmol, 1.3 equiv) at 0 ^o C. It was stirred for 30 min and was added potassium iodide (0.38 g, 2.33 mmol, 1.3 equiv). The mixture was stirred for 1 h. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 solution followed by brine. It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 58.4 (0.3 g, Yield: 56%). MS(ES): m/z 307.15 [M+H] ⁺ . [00672] Synthesis of compound 58.6. Compound 58.6 was prepared from 58.5 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 31% ethyl acetate in hexane). MS(ES): m/z 302.39 [M+H] ⁺ . [00673] Synthesis of compound 58.7. Compound 58.7 was prepared from 58.6 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.3% methanol in DCM). MS(ES): m/z= 457.7 [M+H] ⁺ . [00674] Synthesis of I-58. Compound I-58 was prepared from 58.7 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 506.58 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.29 (s, 1H), 10.96 (s, 1H), 8.52 (s, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.70-7.68 (d, J = 8 Hz, 1H), 7.36- 7.35 (d, J = 8 Hz, 1H), 7.22-7.20 (t, J = 8 Hz, 1H), 6.51 (s, 1H), 4.40-4.37 (m, 1H), 3.99-3.97 (m, 2H), 3.64 (s, 3H), 3.53-3.50 (t, J = 12 Hz, 3H), 2.75-2.71 (m, 2H), 2.17-2.07 (m, 2H), 1.83- 1.80 (m, 1H), 1.26-1.22 (m, 4H), 0.82-0.80 (m, 4H). [00675] Example I-59: 4-((3-(1-((1R,3r,5S)-8-oxabicyclo[3.2.1]octan-3-yl)-1H-pyraz ol-3-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide

[00676] Synthesis of compound 59.1. To a solution of 8-oxabicyclo[3.2.1]octan-3-one (4.0 g, 31.6 mmol, 1.0 equiv) in THF (200 mL) at-78°C was added a solution of L-selectride (1 M in THF, 100 mL, 63.39 mmol, 2.0 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. It was transferred into a hydrochloric acid solution (5 N) and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 59.1 (2.45 g, Yield: 60%). MS(ES): m/z 128.17 [M+H] ⁺ . [00677] Synthesis of compound 59.2. To a solution of 59.1 (1.0 g, 7.80 mmol, 1.0 equiv) and triethylamine (2.17 mL, 15.60 mmol, 2.0 equiv) in DCM (20 mL) at 0 °C was added methanesulfonyl chloride (0.729 mL, 9.36 mmol, 1.2 equiv) dropwise. The reaction mixture was stirred at room temperature for 30 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 59.2 (1.0 g, Yield: 62.14%). MS(ES): m/z 206.26 [M+H] ⁺ . [00678] Synthesis of compound 59.4. To a solution of 59.3 (1.0 g, 5.101 mmol, 1.5 equiv) and 3-bromo-1H-pyrazole (0.500 g, 3.401 mmol, 1.0 equiv) in DMF (20 mL) at 0 °C was added sodium hydride in portions (0.500 g, 10.20 mmol, 3.0 equiv). The reaction mixture was stirred at 85 ^o C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 24% ethyl acetate in hexane) to afford 59.4 (0.580 g, Yield: 47%). MS(ES): m/z 257.13 [M+2] ⁺ . [00679] Synthesis of compound 59.5 Compound 59.5 was prepared from 59.4 and 2-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 41% ethyl acetate in hexane). MS(ES): m/z 299.37 [M+H] ⁺ . [00680] Synthesis of compound 59.6. Compound 59.6 was prepared from 59.5 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 42% ethyl acetate in hexane). MS(ES): m/z 454.92 [M+H] ⁺ . [00681] Synthesis of I-59. Compound I-59 was prepared from 59.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.7% methanol in DCM). MS(ES): m/z 503.56 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.98 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H) 7.86 (s, 2H), 7.71-7.69 (d, J = 8 Hz, 1H), 7.38-7.36 (d, J = 8 Hz, 1H), 7.23-7.21 (t, J = 8 Hz, 1H), 6.70 (s, 1H), 4.69 (s, 1H), 4.45 (s, 2H), 3.59 (s, 3H), 2.12-2.07 (m, 1H), 1.94-1.89 (m, 4H), 1.23-1.18 (m, 4H), 0.85-0.81 (m, 4H). [00682] Example I-: 4-((3-(1-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4- yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide

[00683] Synthesis of compound 60.1. To a solution of bicyclo[3.1.0]hexan-3-ol (0.8 g, 8.15 mmol, 1.0 equiv) and triethylamine (2.47 g, 24.48 mmol, 3.0 equiv) in DCM (15 mL) at 0 °C and added methansulfonyl chloride (1.39 g, 12.24 mmol, 1.5 equiv) and stirred at rt for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 60.1 (0.850 g, Yield: 59%). [00684] Synthesis of compound 60.2. A mixture of 4-bromo-1H-pyrazole (0.47 g, 3.23 mmol, 1.0 equiv), cesium carbonate (3.15 g, 9.69 mmol, 3.0 equiv) and 60.1 (0.85 g, 4.85 mmol, 1.5 equiv) in DMF (15 mL) was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 23% ethyl acetate in hexane) to afford 60.2 (0.7 g, Yield: 95%). MS(ES): m/z 228.3 [M+H] ⁺ . [00685] Synthesis of compound 60.3. Compound 60.3 was prepared from 60.2 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.5% methanol in DCM). MS(ES): m/z 270.35 [M+H] ⁺ . [00686] Synthesis of compound 60.4. Compound 60.4 was prepared from 60.3 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 425.9 [M+H] ⁺ . [00687] Synthesis of I-60. Compound I-60 was prepared from 60.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4% methanol in DCM). MS(ES): m/z 474.8 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.96 (s, 1H), 8.54 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.45-7.42 (m, 1H), 7.28-7.26 (t, J = 4 Hz, 1H), 7.19-7.15 (t, J = 8 Hz, 1H), 4.52-4.48 (m, 1H), 3.57 (s, 3H), 2.45- 2.06 (m, 4H), 1.40-1.39 (m, 2H), 0.82-0.80 (m, 4H), 0.43-0.41 (m, 1H), 0.36-0.32 (m, 1H). [00688] Example I-61-a and I-61-b: (R)-4-((3-(1-(1,4-dioxaspiro[4.5]decan-6-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyrida zine-3-carboxamide and (S)- 4-((3-(1-(1,4-dioxaspiro[4.5]decan-6-yl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide [00689] Synthesis of compound (±)-61.1. To a solution of di-tert-butyl (E)-diazene-1,2- dicarboxylate (20.0 g, 86.95 mmol, 1.0 equiv) and cyclohexanone (12.8 mL) in acetonitrile (800 mL) at 0 ^o C was added L-proline (1.0 g, 8.69 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 24 h. It was transferred into water, stirred, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-61.1 (13.5 g, 61%). MS(ES): m/z 256.09 [M+H] ⁺ . [00690] Synthesis of compound (±)-61.2. To a solution of (±)-61.1 (13.5 g, 52.94 mmol, 1.0 equiv) in ethanol (270 mL) was added 6 N HCl (270 mL) at room temperature. The reaction mixture was stirred at for 4 h and was added malonodialdehyde tetramethylacetal (10 mL). The reaction mixture was heated to reflux for 3 h. It was cooled to rt, transferred into water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)- 61.2 (1.2 g, Yield: 14%). MS (ES): m/z 165.05 [M+H] ⁺ . [00691] Synthesis of compound (±)-61.3. To a solution of (±)-61.2 (1.2 g, 7.31 mmol, 1.0 equiv) and ethylene glycol (0.680 g, 10.97 mmol, 1.5 equiv) in benzene (10 mL) was added boron trifluoride etherate (0.515 g, 3.65 mmol, 0.5 equiv). The reaction mixture was heated to reflux for 16 h. It was cooled to room temperature, transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (12 mL) and added N-bromo succnamide (1.56 g, 8.78 mmol, 1.5 equiv) in portions. The reaction mixture was stirred at room temperature for 1 h. It was transferred into water, stirred, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford (±)-61.3 (1.0 g, Yield: 48%). MS (ES): m/z 288.16 [M+H] ⁺ . [00692] Synthesis of compound (±)-61.4. Compound (±)-61.4 was prepared from (±)-61.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 3% methanol in DCM). MS(ES): m/z 330.40 [M+H] ⁺ . [00693] Compound 61.4-a and 61.4-b. The racemate was separated by HPLC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); (A) 0.1% diethylamine in N-hexane (B) 0.1% diethylamine in propane 2-ol: acetonitrile (70:30); flow rate: 20 mL/min) to afford first eluting fraction (61.4-a) and second eluting fraction (61.4-a). MS(ES): m/z 330.40 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00694] Synthesis of compound 61.5-a and 61.5-b. Compound 61.5-a was prepared from 61.4-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES): m/z 485.95 [M+H] ⁺ . Compound 61.5-b was prepared from 61.4-b in the same manner. MS(ES): m/z 485.95 [M+H] ⁺ . [00695] Synthesis of compound I-61-a and I-61-b. Compound I-61-a was prepared from 61.5-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 534.55 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.29 (s, 1H), 10.95 (s, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.87 (s, 1H), 7.47-7.45 (d, J = 7.6 Hz, 1H), 7.28-7.26 (d, J = 7.2 Hz, 1H), 7.20-7.18 (t, J = 8 Hz, 1H), 4.35 (m, 1H), 3.70 (m, 2H), 3.50 (s, 3H), 2.88-2.87 (m, 1H), 2.17 (m, 1H), 2.07 (m, 1H), 1.98-1.94 (m, 1H), 1.79-1.76 (m, 2H), 1.56 (m, 3H), 1.28 (s, 2H), 0.82 (m, 4H). Compound I-61-b was prepared from 61.5-b in the same manner. MS(ES): m/z 534.55 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.95 (s, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.47-7.45 (d, J = 8.0 Hz, 1H), 7.28-7.26 (d, J = 8.0 Hz, 1H), 7.20-7.18 (m, 1H), 4.37 (m, 1H), 3.70 (m, 2H), 3.50 (s, 3H), 2.88-2.87 (m, 1H), 2.17 (m, 1H), 2.07 (m, 1H), 1.98-1.94 (m, 1H), 1.79-1.76 (m, 2H), 1.56 (m, 3H), 1.28 (s, 2H), 0.82 (m, 4H). [00696] Example I-62: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(1- (methoxymethyl)cyclopentyl)-1H-pyrazol-4-yl)phenyl)amino)pyr idazine-3-carboxamide [00697] Synthesis of compound 62.1. To a solution of cyclopentanecarboxylic acid (5 g, 43.85 mmol, 1.0 equiv) in 1,2-dichloroethane (70 mL) was added bromine (7.01 g, 43.85 mmol) and chlorosulfonic acid (5.08 g, 43.85 mmol). The mixture was stirred at 85 °C for 2 h. Most solvent was removed under reduced pressure. The residue was dissolved in methanol (70 mL) and the mixture was heated to reflux for 12 h. It was cooled to rt and most solvent was removed under reduced pressure. The residue was dissolved in DCM (100 mL), washed with water (50 mL*3) and brine (80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford 62.1 (4.6 g, 51% yield). MS (ES): m/z 208.07 [M+H] ⁺ . [00698] Synthesis of compound 62.2. A mixture of 62.1 (4.6 g, 22.22 mmol, 1.0 equiv), 4- bromo-1H-pyrazole (3.26 g, 22.22 mmol, 1.0 equiv) and potassium carbonate (7.66 g, 55.55 mmol, 2.5 equiv) in DMF (20 mL) was stirred at room temperature for 12 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 62.2 (2.4 g, Yield: 77%). MS (ES): m/z 274.13 [M+H] ⁺ . [00699] Synthesis of compound 62.3 To a solution of 62.2 (2.4 g, 8.79 mmol, 1.0 equiv) in THF (21 mL), was added lithium aluminum hydride (0.66 g, 17.58 mmol, 2.0 equiv) in portions at 0 ^o C. The reaction mixture was stirred at room temperature for 6 h. It was quenched with cold saturated anhydrous sodium sulfate solution, filtered over a pad of Celite® and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 62.3 (0.80 g, Yield: 38%). MS (ES): m/z 246.09 [M+H] ⁺ . [00700] Synthesis of compound 62.4. To a solution of 62.3 (0.8 g, 3.26 mmol, 1.0 equiv) in DMF (8 mL), was added NaH (60% in mineral oil, 0.195 g, 4.89 mmol, 1.5 equiv) in portions at 0 ^o C. The reaction mixture was stirred at room temperature for 30 min. To the mixture was added methyl iodide (0.69 g, 4.89 mmol, 1.5 equiv) and stirred at rt for 4 h. It was quenched with cold water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 62.4. MS (ES): m/z 260.10 [M+H] ⁺ . [00701] Synthesis of compound 62.5. Compound 62.5 was prepared from 62.4 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 23% ethyl acetate in hexane). MS(ES): m/z 302.39 [M+H] ⁺ . [00702] Synthesis of compound 62.6. Compound 62.6 was prepared from 62.5 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 457.9 [M+H] ⁺ . [00703] Synthesis of I-62. Compound I-62 was prepared from 62.6 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 506.48 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.29 (s,1H), 11.97 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 8.13 (s,1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.48-7.46 (d, J = 7.6 Hz, 1H), 7.28-7.26 (d, J = 8 Hz, 1H), 7.20-7.16 (d, J = 8.4 Hz, 1H), 3.59-3.55 (m, 6H), 3.16 (s, 3H), 2.09-2.06 (m, 1H), 1.98-1.95 (m, 2H), 1.68-1.66 (m, 4H), 0.85-0.75 (m, 4H). [00704] Example I-63: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(1- (methoxymethyl)cyclobutyl)-1H-pyrazol-4-yl)phenyl)amino)pyri dazine-3-carboxamide [00705] Synthesis of compound 63.1. A mixture of ethyl 1-bromocyclobutane-1-carboxylate (2.0 g, 66 mmol, 9.0 equiv), potassium carbonate (2.29 g, 134.96 mmol, 3.0 equiv) and 4- bromo-1H-pyrazole (1.42 g, 9.66 mmol, 1.0 equiv) in DMF (20 mL) was stirred at room temperature for 10 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 63.1 (0.3 g, Yield: 11%). MS(ES): m/z 274.13 [M+H] ⁺ . [00706] Synthesis of compound 63.2. To a solution of 63.1 (0.3 g, 1.10 mmol, 1.0 equiv) in THF (6 mL) was added lithium aluminum hydride (1 M solution in THF, 2.19 mL, 2.19 mmol, 2.0 equiv) dropwise at 0 ^o C. The reaction mixture was stirred at 0 ^o C for 1 h. It was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 63.2 (0.170 g, 67%). MS(ES): m/z 232.09 [M+H] ⁺ . [00707] Synthesis of compound 63.3. To a solution of 63.2 (0.170 g, 0.735 mmol, 1.0 equiv) in DMF (6 mL) was added sodium hydride (60% in mineral oil, 0.070 g, 1.46 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and was added methyl iodide (0.156 g,1.09 mmol, 1.5 equiv). It was stirred at room temperature for 1 h, transferred into ice water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (38% ethyl acetate in hexane) to afford 63.2 (0.085 g, Yield: 47%). MS(ES): m/z: 246.12 [M+H] ⁺ . [00708] Synthesis of compound 63.4. Compound 63.4 was prepared from 63.3 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane). MS(ES): m/z 288.36 [M+H] ^+. [00709] Synthesis of compound 63.5. Compound 63.5 was prepared from 63.4 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane). MS(ES): m/z 443.90 [M+H] ⁺ . [00710] Synthesis of I-63. Compound I-63 was prepared from 63.5 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 492.55 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s, 1H), 8.53 (s, 1H), 8.13 (s, 2H), 7.96 (s, 1H), 7.87(s, 1H), 7.48 (d, J = 8 Hz,1H), 7.28 (d, J = 8 Hz, 2H), 7.47 (q, J = 8 Hz, 1H), 3.74 (s, 2H), 3.56 (s, 3H), 3.22 (s, 3H), 2.32-2.28 (m, 3H), 1.97- 1.87 (m, 2H), 1.53-1.33 (m, 2H), 0.86-0.81 (m, 4H). [00711] Example I-64-a and I-64-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- ((3S,4R)-4-methoxytetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phen yl)amino)nicotinamide and 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-meth oxytetrahydrofuran-3-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide

[00712] Synthesis of compound (±)-trans-64.1. A mixture of 4-bromo-1H-pyrazole (1.00 g, 6.84 mmol, 1.0 equiv), 3,6-dioxabicyclo[3.1.0]hexane (0.885 g, 10.87 mmol, 1.5 equiv) and cesium carbonate (6.67 g, 20.54 mmol, 3.0 equiv) in DMF (20 mL) was stirred at 100 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford (±)-trans-64.1 (0.7 g, Yield: 44%). MS(ES): m/z 234.05 [M+H] ⁺ . [00713] Synthesis of compound (±)-trans-64.2. To a solution of (±)-trans-64.1 (0.7 g, 2.59 mmol, 1.0 equiv) in DMF (20 mL) at 0 °C was added sodium hydride (60% in mineral oil, 0.208 g, 5.20 mmol, 2.0 equiv). The reaction mixture was stirred at 0 °C for 30 min. Methyl iodide (0.547 g, 3.88 mmol, 1.5 equiv) was added and reaction mixture was stirred at room temperature for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford (±)-trans-64.2 (0.6 g, Yield: 86%). MS(ES): m/z 248.09 [M+H] ⁺ . [00714] Synthesis of compound (±)-trans-64.3. Compound (±)-trans-64.3 was prepared from (±)-trans-64.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.3% methanol in DCM. MS(ES): m/z 290.34 [M+H] ⁺ . [00715] Compound trans-64.3-a and trans-64.b. The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO2 (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (trans-64.3-a), MS(ES): m/z 290.34 [M+H] ⁺ , and second eluting fraction (trans-64.3-b) MS(ES): m/z 290.34 [M+H] ⁺ . [00716] Synthesis of compound trans-64.4-a and trans-64.4-b. Compound trans-64.4-a was prepared from trans-64.3-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 444.82 [M+H] ⁺ . Compound trans-64.4-b was prepared from trans-64.3-b in the same manner. MS(ES): m/z 444.82 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00717] Synthesis of I-64-a and I-64-b. Compound I-64-a was prepared from trans-64.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 493.3 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.73 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 8.02-8.00 (m, 2H), 7.47 (s, 1H), 7.40- 7.38 (d, J = 4 Hz, 1H), 7.29-7.27 (d, J = 8 Hz, 1H), 7.17-7.14 (t, J = 4 Hz, 1H), 5.01 (s, 1H), 4.21-4.15 (m, 2H), 4.09-3.99 (m, 2H), 3.79-3.77 (m, 1H), 3.57 (s, 3H), 3.32 (s, 3H), 1.99-1.96 (m, 1H), 0.77-0.75 (m, 4H). Compound I-64-b was prepared from trans-64.4-b in the same manner. MS(ES): m/z 493.3 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.74 (s, 1H), 8.59 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 8.02-8.00 (m, 2H), 7.48 (s, 1H), 7.40-7.38 (d, J = 8 Hz, 1H), 7.29-7.27 (d, J = 8 Hz, 1H), 7.17-7.14 (t, J = 8 Hz, 1H), 5.01 (s, 1H), 4.21-4.15 (m, 2H), 4.09-3.99 (s, 2H), 3.79-3.77 (d, J = 8 Hz, 1H), 3.57 (s, 3H), 3.32 (s, 3H), 1.99-1.96 (t, J = 8 Hz, 1H), 0.77-0.75 (m, 4H). Example I-65: 6-(cyclopropanecarboxamido)-4-((3-(1-((1r,3r)-3-fluorocyclob utyl)-1H-pyrazol- 4-yl)-2-methoxyphenyl)amino)nicotinamide

[00718] Synthesis of compound trans-65.1. To a solution of 3-(benzyloxy)cyclobutan-1-one (25 g, 142.05 mmol, 1.0 equiv) in methanol (250 mL) was added sodium borohydride (16.19 g, 426.13 mmol, 2.0 equiv) in portions at 0 ^o C. The reaction mixture was stirred at room temperature for 3 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford trans-65.1 (21 g, Yield: 83%). MS (ES): m/z 179.3 [M+H] ⁺ . [00719] Synthesis of compound trans-65.2. To a solution of trans-65.1 (21 g, 117.91 mmol, 1.0 equiv) in DCM (210 mL) was added diethylaminosulfur trifluoride (37.98 g, 235.95 mmol, 3.0 equiv) in portions at 0 ^o C. The reaction mixture was stirred at room temperature for 16 h. It was transferred into ice-water, stirred, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3% ethyl acetate in hexane) to afford trans-65.2 (5.3 g, Yield: 25%). MS (ES): m/z 181.22 [M+H] ⁺ . [00720] Synthesis of compound trans-65.3. A mixture of trans-65.2 (5.3 g, 117.91 mmol, 1.0 equiv) and palladium on charcoal (10%, 140 mg) in methanol (10 mL) was stirred under hydrogen (1 atm) at room temperature. The mixture was filtered, and the filtrate concentrated to afford trans-65.3 (2.3 g, Yield: 25%). MS (ES): m/z 91.10 [M+H] ⁺ . [00721] Synthesis of compound cis-65.4. To a solution of trans-65.3 (2.3 g, 25.55 mmol, 1.0 equiv) and 4-nitrobenzoic acid (4.69 g, 28.11 mmol, 1.1 equiv) in THF (23 mL) was added triphenylphonine (8.70 g, 33.22 mmol, 2.0 equiv) at 10 °C. To the mixture was added diisopropyl azodicarboxylate (6.71 g, 33.22 mmol, 2.0 equiv) and stirred at rt for 6 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20% ethyl acetate in hexane) to afford cis-65.4 (2.2 g, Yield: 32%). MS(ES): m/z 240.20 [M+H] ⁺ . [00722] Synthesis of compound cis-65.5. A solution of cis-65.4 (2.2 g, 117.91 mmol, 1.0 equiv) in methanol (10 mL) was added potassium carbonate (2.5 g, 18.41 mmol, 2.0 equiv) and stirred at rt for 12 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford cis-65.5 (0.79 g, Yield: 96%). [00723] Synthesis of compound cis-65.6. A solution of cis-65.5 (0.79 g, 8.77 mmol, 1.0 equiv) and pyridine (2.08 g, 26.33 mmol, 3.0 equiv) in DCM (10 mL) at 0 °C was added p- toluenesulfonic anhydride (3.4 g, 10.53 mmol, 1.2 equiv) and stirred for 2 h. It was transferred into ice-water and extracted with DCM acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford cis-65.6 (0.49 g, Yield: 23%). [00724] Synthesis of compound trans-65.7. A mixture of cis-65.6 (0.81 g, 3.33 mmol, 1.0 equiv), 4-bromo-1H-pyrazole (0.49 g, 3.33 mmol, 1.1 equiv) and cesium carbonate (2.7 g, 8.33 mmol, 2.5 equiv) in DMF (10 mL) was stirred at 80 °C for 2 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford trans-65.7 (0.45 g). It was used in the next step without purification. MS(ES): m/z 220.06 [M+H] ⁺ . [00725] Synthesis of compound trans-65.8. Compound trans-65.8 was prepared from trans- 65.7 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 23% ethyl acetate in hexane). MS(ES): m/z 262.30 [M+H] ⁺ . [00726] Synthesis of compound trans-65.9. Compound trans-65.9 was prepared from trans- 65.8 and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 416.8 [M+H] ⁺ . [00727] Synthesis of I-65. Compound I-65 was prepared from trans-65.9 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 465.50 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s,1H), 10.76 (s, 1H), 8.59 (s, 1H), 8.28 (s, 1H), 8.13 (s,1H), 8.02-8.00 (d, J = 6.4 Hz, 1H), 7.48 (bs, 1H), 7.38-7.36 (d, J = 7.2 Hz, 2H), 7.28-7.26 (d, J = 7.6 Hz, 1H), 7.17-7.13 (t, J = 8.4 Hz, 1H), 5.52-5.34 (m, 1H), 5.17 (bs, 1H), 3.57 (s, 3H), 2.83-2.74 (m, 4H), 1.91-2.03 (m, 1H), 0.77- 0.76 (d, J = 5.6 Hz, 4H). [00728] Example I-66: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahyd rofuran- 3-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide [00729] Synthesis of compound 66.1. Compound 66.1 was prepared from 47.2 and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.6% methanol in DCM). MS(ES): m/z 414.9 [M+H] ⁺ . [00730] Synthesis of I-66. Compound I-66 was prepared from 66.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM). MS(ES): m/z 463.43 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.72 (s, 1H), 8.59 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.46 (s, 1H), 7.39-7.37 (d, J = 8 Hz, 1H), 7.30-7.26 (t, J = 4 Hz, 1H), 7.17-7.13 (t, J = 4 Hz, 1H), 5.08- 5.06 (m, 1H), 4.03-3.81 (m, 4H), 3.57 (s, 3H), 2.41-2.32 (m, 2H), 1.98-1.96 (m, 1H), 0.77-0.75 (m, 4H). [00731] Example I-67-a and I-67-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- ((1S,2S)-2-methoxycyclopentyl)-1H-pyrazol-4-yl)phenyl)amino) nicotinamide and 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1R,2R)-2-meth oxycyclopentyl)-1H-pyrazol- 4-yl)phenyl)amino)nicotinamide [00732] Synthesis of compound (±)-trans-67.1. A mixture of 4-bromo-1H-pyrazole (20 g, 136.98 mmol, 1.0 equiv), 6-oxabicyclo[3.1.0]hexane (13.8 g, 164.38 mmol, 1.2 equiv) and cesium carbonate (89 g, 273.97 mmol, 2.0 equiv) in DMF (160 mL) was stirred at 90 ^o C for 3 h. It was poured over water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane) to afford (±)-trans-67.1 (11 g, 35%). MS(ES): m/z 233.09 [M+2] ⁺ . [00733] Synthesis of compound (±)-trans-67.2. To a solution of (±)-trans-67.1 (5 g, 21.64 mmol, 1.0 equiv) in DMF (6 mL) at 0 ^o C was added sodium hydride (60% in mineral oil, 1.29 g, 32.46 mmol, 1.0 equiv) in portions followed by the addition of methyl iodide (3.99 g, 28.13 mmol, 1.3 equiv). The reaction stirred at room temperature for 6 h. It was poured over water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-trans-67.2 (3.8 g, 57%). MS(ES): m/z 247.12 [M+2] ⁺ . [00734] Synthesis of compound (±)-trans-67.3. Compound (±)-trans-67.3 was prepared from (±)-trans-67.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1% methanol in DCM). MS(ES): m/z 288.3 [M+H] ⁺ . [00735] Compound trans-67.3-a and trans-67.3-b. The racemate was separated by HPLC (column: CHIRALPAK IC (250*4.6) mm, 5 um); mobile phase: (A) 0.1% diethylamine in n- hexane (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 20 mL/min) to afford first eluting fraction (trans-67.3-a), MS(ES): m/z 288.36 [M+H] ⁺ and second eluting fraction (trans-67.3-a), MS(ES): m/z 288.36 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00736] Synthesis of compound trans-67.4-a and trans-67.4-b. Compound trans-67.4-a was prepared from trans-67.3-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, was purified by flash column chromatography on silica gel (Combiflash®, 82% ethyl acetate in hexane). MS(ES): m/z 442.92 [M+H] ⁺ . Compound trans-67.4-b was prepared from trans-67.3-b in the same manner. MS(ES): m/z 442.92 [M+H] ⁺ . [00737] Synthesis of I-67-a and I-67-b. Compound I-67-a was prepared from trans-67.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.4% methanol in DCM). MS(ES): m/z 491.56 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.87 (s, 1H), 10.73 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.95 (s,1H), 7.48 (m, 1H), 7.39-7.37 (d, J = 7.6 Hz 1H), 7.28-7.26 (d, J = 8 Hz, 1H), 7.16-7.12 (m, 1H), 4.63-4.62(m, 1H), 4.02-3.99 (m, 1H), 3.57 (s, 3H), 3.19 (s, 3H), 2.17-2.16 (m, 1H), 2.04-1.99 (m, 2H), 1.83-1.64 (m, 2H), 1.29-1.23 (m, 2H), 0.77-0.76 (m, 4H). Compound I-67-b was prepared from trans-67.4-b in the same manner. MS(ES): m/z 491.56 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.73 (s, 1H), 8.59 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.95 (s,1H), 7.48 (m, 1H), 7.39-7.37 (d, J = 7.6 Hz 1H), 7.28-7.26 (d, J = 8 Hz, 1H), 7.16-7.12 (m, 1H), 4.63-4.62(m, 1H), 4.02-3.99 (m, 1H), 3.57 (s, 3H), 3.19 (s, 3H), 2.17-2.16 (m, 1H), 2.04-1.99 (m, 2H), 1.83-1.64 (m, 2H), 1.29- 1.23 (m, 2H), 0.77-0.76 (m, 4H). [00738] Example I-68-a and I-68-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- ((3S,4R)-4-(methoxy-d ₃ )tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)ni cotinamide and 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-(m ethoxy-d ₃ )tetrahydrofuran-3- yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide [00739] Synthesis of compound (±)-trans-68.1. To a solution of (±)-trans-64.1 (1.5 g, 6.493 mmol, 2.0 equiv) in DMF (20 mL) was added sodium hydride (0.61 g, 15.45 mmol, 1.2 equiv) at 0 °C for 30 min. To the mixture was added iodomethane-d3 (1.96 g, 13.51 mmol, 1.05 equiv) dropwise at 0 °C and stirred for 30 min. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane) to afford (±)-trans-68.1 (1.4 g, 87%). MS(ES): m/z 251.11 [M+H] ⁺ . [00740] Synthesis of compound (±)-trans-68.2. Compound (±)-trans-68.2 was prepared from (±)-trans-68.1 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane). MS(ES): m/z 293.34 [M+H] ⁺ . [00741] Compound trans-68.2-a and trans-68.2-b. The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO2 (B) 0.1% diethylamine in propane-2-ol: acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (trans-68.2-a), MS(ES): m/z 293.34 [M+H] ⁺ and second eluting fraction (trans-68.2-b). MS(ES): m/z 293.34 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00742] Synthesis of compound trans-68.3-a and trans-68.3-b. Compound trans-68.3-a was prepared from trans-68.2-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane). MS(ES): m/z 447.91 [M+H] ⁺ . Compound trans- 68.3-b was prepared from trans-68.2-b in the same manner. MS(ES): m/z 447.91 [M+H] ⁺ . [00743] Synthesis of I-68-a and I-68-b. Compound I-68-a was prepared from trans-68.3-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 496.37 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s,1H), 10.74 (s, 1H), 8.60 (s, 1H), 8.31 (s, 1H), 8.15 (bs,1H), 8.03-8.01(d, J = 8.0 Hz, 2H), 7.49 (s,1H), 7.41-7.39 (d, J = 8.0 Hz, 1H), 7.29-7.30 (d, J = 4.0 Hz, 1H), 7.19-7.15 (m, 1H), 5.02 (s, 1H), 4.22-4.17 (m, 2H), 4.10 (s, 2H), 3.81-3.78 (m, 1H), 3.58 (s, 3H), 2.00-1.98 (m, 1H), 0.79- 0.77 (m, 4H). Compound I-68-b was prepared from trans-68.3-b in the same manner. MS(ES): m/z 496.42 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.87 (s,1H), 10.71 (s, 1H), 8.57 (s, 1H), 8.28 (s, 1H), 8.12 (bs,1H), 8.00-7.98 (d, J = 8.0 Hz, 2H), 7.46 (bs,1H), 7.38-7.36 (d, J = 8.0 Hz, 1H), 7.27-7.25 (d, J = 8.0 Hz, 1H), 7.15-7.12 (m, 1H), 4.99 (s, 1H), 4.19-4.13 (m, 2H), 3.98 (s, 3H), 3.77-3.75 (m, 1H), 3.55 (s, 3H), 1.97-1.94 (m, 1H), 0.75-0.74 (m, 4H). [00744] Example I-69-a and I-69-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- ((3S,4R)-4-(methoxy-d ₃ )tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)py ridazine-3- carboxamide and 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-(m ethoxy- d ₃ )tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)py ridazine-3-carboxamide

[00745] Synthesis of compound trans-69.1-a and trans-69.1-b. Compound trans-69.1-a was prepared from trans-68.2-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane). MS(ES): m/z 448.91 [M+H] ⁺ . Compound trans-69.1-b was prepared from trans-68.2-b in the same manner. MS(ES): m/z 448.91 [M+H] ⁺ . [00746] Synthesis of compound I-69-a and I-69-b Compound I-69-a was prepared from trans- 69.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5- a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 497.55 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s,1H), 10.98 (s, 1H), 8.5860 (s, 1H), 8.31 (s, 1H), 8.15 (bs,1H), 8.03-8.01(d, J = 8.0 Hz, 2H), 7.49 (bs,1H), 7.41-7.39 (d, J = 8.0 Hz, 1H), 7.29-7.30 (d, J = 8.0 Hz, 1H), 7.19-7.15 (m, 1H), 5.02 (m, 1H), 4.22-4.17 (m, 2H), 4.10 (s, 2H), 3.81-3.78 (m, 1H), 3.58 (s, 3H), 2.00-1.98 (m, 1H), 0.79-0.77 (m, 4H). Compound I-69-b was prepared from trans-69.1-b in the same manner. MS(ES): m/z 497.55 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s,1H), 10.98 (s, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.13 (s,1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.41-7.39 (dd, J = 8.0 Hz, 1H), 7.29-7.30 (dd, J = 4.0 Hz, 1H), 7.19-7.15 (m, 1H), 5.02 (s, 1H), 4.22-4.17 (m, 2H), 4.10 (m, 2H), 3.81-3.78 (m, 1H), 3.57 (s, 3H), 2.08-2.06 (1H), 0.83-0.81 (d, 4H). [00747] Example I-70-a and I-70-b: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- (spiro[2.4]heptan-4-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridaz ine-3-carboxamide and (S)-6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2.4]hept an-4-yl)-1H-pyrazol-4- yl)phenyl)amino)pyridazine-3-carboxamide

[00748] Synthesis of compound (±)-70.1. A mixture of ethyl 2-oxocyclopentane-1-carboxylate (50 g, 244.8 mmol, 1.0 equiv), 1,2-dibromoethane (38.3 g, 563.04 mmol, 2.3 equiv) and potassium carbonate (1.392 g, 6.57 mmol, 3.0 equiv) in acetone (500 mL) was stirred at 80 ^o C temperature for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (30% ethyl acetate in hexane) to afford (±)-70.1 (50 g, Yield: 100%). MS(ES): m/z 264.13 [M+H] ⁺ . [00749] Synthesis of compound (±)-70.2. To a mixture of (±)-70.1 (50 g, 117.48 mmol, 1.0 equiv) in water (500 mL) was dropwise added hydrobromic acid (120 mL) at 0 ^o C and stirred at room temperature for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (40% ethyl acetate in hexane) to afford (±)-70.2 (23 g, Yield: 63%). MS(ES): m/z 192.07 [M+H] ⁺ . [00750] Synthesis of compound (±)-70.3. To a solution of (±)-70.2 (23 g, 86.35 mmol, 1.0 equiv) in ethanol (230 mL) was added potassium hydroxide (32.81 g, 172.7 mmol, 2.0 equiv) in portions. The reaction mixture was stirred at 80 ^o C for 5 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford (±)- 70.3 (9.8 g, Yield: 74%). MS(ES): m/z 111.16 [M+H] ⁺ . [00751] Synthesis of compound (±)-70.4. To a solution of (±)-70.3 (5.7 g, 51.8 mmol, 1.0 equiv) and tert-butyl hydrazinecarboxylate (7.52 g, 56.9 mmol, 1.1 equiv) in methanol (50 mL) was heated to reflux for 12 h. It was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexane) to afford (±)-70.4 (3.9 g, Yield: 34%). MS(ES): m/z 22.03 [M+H] ⁺ . [00752] Synthesis of compound (±)-70.5. To a solution of (±)-70.4 (3.9 g, 17.4 mmol, 1.0 equiv) in acetic acid (30 mL) and water (10 mL) was added sodium cyanoborohydride (1.1 g, 17.4 mmol, 1.0 equiv) in portions at rt. The reaction mixture was stirred for 1 h. It was transferred into ice-water, stirred, neutralized with 1 N sodium hydroxide solution, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-70.5 (3.8 g, Yield: 97%). MS(ES): m/z 227.32 [M+H] ⁺ . [00753] Synthesis of compound (±)-70.6. To a solution of (±)-70.5 (3.8 g, 16.8 mmol, 1.0 equiv) in ethanol (20 mL) was added 6 N hydrochloric acid (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h and was added 1,1,3,3-tetramethoxypropane (2.75 g, 16.8 mmol, 1.0 equiv). It was heated to reflux for 2 h, cooled to rt, transferred into ice-water and neutralized using aqueous sodium bicarbonate. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-70.6 (1.7 g, Yield: 62%). MS(ES): m/z 163.24 [M+H] ⁺ . It was used in the next step without further purification. [00754] Synthesis of compound (±)-70.7. To a solution of (±)-70.6 (1.7 g, 3.65 mmol, 1.0 equiv) in acetic acid (5 mL) was added N-bromosuccinimide (0.581 g, 3.65 mmol, 1 equiv) at 0 °C. The reaction mixture was allowed to warm at room temperature and stirred for 2 h. It was transferred into ice-water and neutralized using aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)- 70.7 (1.3 g, Yield: 51%). MS(ES): m/z 242.13 [M+H] ⁺ . [00755] Synthesis of compound (±)-70.8. Compound (±)-70.8 was prepared from (±)-70.7 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 284.38 [M+H] ⁺ . [00756] Compound 70.8-a and 70.8-b. The racemate was separated by HPLC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) 0.1% diethylamine in n-hexane (B) 0.1% diethylamine in propane-2-ol : acetonitrile (70 : 30); flow rate: 20 mL/min) to afford first eluting fraction (70.8-a), MS(ES): m/z 284.38 [M+H] ⁺ , and second eluting fraction (70.8- b). MS(ES): m/z 284.38 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00757] Synthesis of compound 70.9-a and 70.9-b. Compound 70.9-a was prepared from 70.8-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 439.92 [M+H] ⁺ . Compound 70.9-b was prepared from 70.8-b in the same manner. MS(ES): m/z 439.92 [M+H] ⁺ . [00758] Synthesis of I-70-a and I-70-b. Compound I-70-a was prepared from 70.9-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2 % methanol in DCM). MS(ES): m/z 488.38 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.97 (s, 1H), 8.53 (s, 1H), 8.15 (m, 2H), 7.92 (s 1H), 7.87 (s, 1H), 7.44 (m, 1H), 7.27-7.18 (m, 1H), 6.74 (bs, 1H), 4.37 (s, 1H), 3.55 (s, 3H), 2.29 (m, 1H), 2.06-1.81 (m, 4H), 1.49 (m, 2H), 0.81 (m, 4H), 0.62-0.41 (m, 4H). Compound I-70-b was prepared from 70.9-b in the same manner. MS(ES): m/z 488.62 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 10.98 (s, 1H), 8.54 (s, 1H), 8.15 (s, 2H), 7.92 (s 1H), 7.88 (s, 1H), 7.51 (m, 1H), 7.26-7.18 (m, 1H), 6.74 (m, 1H), 4.37 (s, 1H), 3.55 (s, 3H), 2.07-1.81 (m, 4H), 1.49 (m, 2H), 0.81 (s, 4H), 0.62-0.41 (m, 4H) 0.16 (m, 1H). [00759] Example I-71: 4-((3-(1-((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)-1H-pyrazol-4- yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide

[00760] Synthesis of compound 71.1. To a solution of bicyclo[3.1.0]hexan-3-one (2.0 g, 20.81 mmol, 1.0 equiv) in methanol (30 mL) was added tert-butyl hydrazinecarboxylate (2.75 g, 20.81 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 4 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 71.1 (2.4 g, 55%). MS(ES): m/z 211.28 [M+H] ⁺ . [00761] Synthesis of compound 71.2. To a solution of 71.1 (2.4 g, 11.41 mmol, 1.0 equiv) in acetic acid (15 mL) and water (10 mL) at 0 °C was added sodium cyanoborohydride (0.845 g, 22.25 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 71.2 (1.5 g, 62%). MS(ES): m/z 213.29 [M+H] ⁺ . [00762] Synthesis of compound 71.3. To a solution of 71.2 (1.5 g, 7.07 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added HCl in dioxane (4 M, 10 mL). The reaction mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure to afford 71.3 (0.9 g, Yield: 86%). MS(ES): m/z 113.18 [M+1] ⁺ . [00763] Synthesis of compound 71.4. To a solution of 71.3 (0.9 g, 6.06 mmol, 1.0 equiv) in ethanol (15 mL) was added 1,1,3,3-tetramethoxypropane (0.994 g, 6.06 mmol, 1.0 equiv) and hydrochloric acid (0.729 g, 19.45 mmol, 3.2 equiv). The reaction mixture was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 71.4 (0.9 g, Yield: 100%). MS(ES): m/z 148.2 [M+1] ⁺ . [00764] Synthesis of compound 71.5. To a solution of 71.4 (0.9 g, 6.07 mmol, 1.0 equiv) in acetic acid (13 mL) at 0 °C was added bromine (0.97 g, 6.11 mmol, 1.0 equiv) dropwise. The reaction mixture was stirred at room temperature for 2 h. It was transferred into ice-water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 71.5 (0.57 g, Yield: 41%). MS(ES): m/z 228.11 [M+2] ⁺ . [00765] Synthesis of compound 71.6. Compound 71.6 was prepared from 71.5 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 270.35 [M+H] ⁺ . [00766] Synthesis of compound 71.7. Compound 71.7 was prepared from 71.6 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.6% methanol in DCM). MS(ES): m/z 425.89 [M+H] ⁺ . [00767] Synthesis of I-71. Compound I-71 was prepared from 71.7 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.1% methanol in DCM). MS(ES): m/z 474.33 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s, 1H), 10.97(s, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.90-7.88 (d, J = 11.2 Hz, 2H), 7.45- 7.46 (d, J = 1.6 Hz, 1H), 7.43-7.44 (d, J = 1.2 Hz, 1H), 7.19-7.16 (t, J = 8 Hz, 1H), 4.98-4.93 (m, 1H), 3.55 (s, 3H), 2.21-2.03 (m, 5H), 1.36-1.34 (m, 2H), 0.73-0.85 (m, 4H), 0.55-0.59 (m, 1H), 0.32-0.39 (m, 1H). [00768] Example I-72-a and I-72-b: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- (spiro[2.4]heptan-4-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotin amide and (S)-6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2.4]hept an-4-yl)-1H-pyrazol-4- yl)phenyl)amino)nicotinamide

[00769] Synthesis of compound 72.1-a and 72.1-b. Compound 72.1-a was prepared from 70.8-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 438.93 [M+H] ⁺ . Compound 72.1-b was prepared from 72.1-b in the same manner. MS(ES): m/z 438.93 [M+H] ⁺ . [00770] Synthesis of I-72-a and I-72-b. Compound I-72-a was prepared from 72.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2 % methanol in DCM). MS(ES): m/z 487.48 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.74 (s, 1H), 8.58 (s, 1H), 8.14 (s, 2H), 8.02 (s, 1H), 7.91 (s 1H), 7.38 (bs, 1H), 7.36 (s, 1H), 7.27 (s, 1H), 7.16-7.12 (m, 1H), 4.39-4.36 (m, 1H), 3.54 (s, 3H), 2.68 (s, 1H), 2.49-2.29 (m, 2H), 2.03-1.99 (m, 2H), 1.81-1.79 (m, 1H), 1.51-1.49 (m, 1H), 1.23-1.19 (m, 2H), 0.75 (m, 3H), 0.71-0.67 (m, 1H), 0.46 (m, 1H), 0.15 (m, 1H). Compound I-72-b was prepared from 72.1- b in the same manner. MS(ES): m/z 487.53 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s, 1H), 10.74 (s, 1H), 8.58 (s, 1H), 8.14 (s, 2H), 8.02 (s, 1H), 7.91 (s 1H), 7.38 (bs, 1H), 7.36- 7.59 (s, 1H), 7.27 (s, 1H), 7.16-7.12 (t, 1H), 4.39-4.36 (m, 1H), 3.54 (s, 3H), 2.68 (s, 1H), 2.49- 2.29 (m, 2H), 2.03-1.99 (m, 3H), 1.81-1.79 (m, 2H), 1.51-1.49 (m, 2H), 1.23-1.19 (m, 2H), 0.77 (s, 3H), 0.75 (m, 1H), 0.68 (m, 1H), 0.16 (m, 1H). [00771] Example I-73-a and I-73-b: (S)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- (spiro[2.4]heptan-5-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotin amide and (R)-6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(spiro[2.4]hept an-5-yl)-1H-pyrazol-4- yl)phenyl)amino)nicotinamide

[00772] Synthesis of compound (±)-73.1. To a solution of spiro[2.4]heptan-5-ol (0.750 g, 6.686 mmol, 1.0 equiv) and triethylamine (1.01 g, 10.0294 mmol, 1.5 equiv) in DCM (10 mL) at 0 ^o C was added methanesulfonyl chloride and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-73.1 (0.750 g, Yield: 100%). [00773] Synthesis of compound (±)-73.2. A mixture of (±)-73.1 (0.750 g, 5.102 mmol, 1.0 equiv), 4-bromo-1H-pyrazole (1.06 g, 5.612 mmol, 1.1 equiv) and cesium carbonate (4.145 g, 12.755 mmol, 2.5 equiv) in DMF (10 mL) was stirred at 80 ^o C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford (±)-73.2 (0.580 g, Yield: 47.14%). [00774] Synthesis of compound (±)-73.3. Compound (±)-73.3 was prepared from (±)-73.2 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 284.38 [M+H] ⁺ . [00775] Compound 73.3-a and 73.3-b. The racemate was separated by HPLC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) 0.1% diethylamine in n-hexane (B) 0.1% diethylamine in propane-2-ol:Acetonitrile(70:30); flow rate: 20 mL/min) to afford 1.6 (fraction-1) (0.190 g, Yield: 35.19%), MS(ES): m/z 283.38[M+H] ⁺ and 1.7(fraction-2). (0.195 g, Yield: 36.11%). MS(ES): m/z 284.38 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00776] Synthesis of compound 73.4-a and 73.4-b. Compound 73.4-a was prepared from 73.3-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS(ES): m/z 438.93 [M+H] ⁺ . Compound 73.4-b was prepared from 73.3-b in the same manner. MS(ES): m/z 438.93 [M+H] ⁺ . [00777] Synthesis of I-73-a and I-73-b. Compound I-73-a was prepared from 73.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM). MS(ES): m/z 487.58[M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.87 (s, 1H), 10.74 (s, 1H), 8.58 (s, 1H), 8.23 (s, 1H), 8.14 (s,1H), 8.02(s 1H), 7.93 (s, 1H), 7.48 (bs, 1H), 7.39-7.38 (d, J = 8 Hz, 1H), 7.27-7.25 (d, J = 8 Hz, 1H), 7.16-7.12 (t, J = 7.6 Hz, 1H), 4.91-4.88 (t, J = 7.2 Hz, 1H), 3.58 (s, 3H), 2.34-2.12 (m, 1H), 2.11 (s, 1H), 2.05-1.95 (m, 1H), 1.85-1.76 (m, 1H), 1.57-1.63 (m, 1H), 1.22 (s, 2H), 0.77-0.75 (d, 4H), 0.59-0.50 (m, 4H). Compound I-73-b was prepared from 73.4-b in the same manner. MS(ES): m/z 487.54 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.87 (s, 1H), 10.74 (s, 1H), 8.58 (s, 1H), 8.23 (s, 1H), 8.14 (s,1H), 8.02 (s 1H), 7.93 (s, 1H), 7.48 (bs, 1H), 7.39-7.38 (d, J = 8 Hz, 1H), 7.27-7.25 (d, J = 8 Hz, 1H), 7.16-7.12 (t, J = 4.6 Hz, 1H), 4.91-4.88 (t, J = 7.2 Hz, 1H), 3.58 (s, 3H), 2.34-2.12 (m, 1H), 2.11-2.08 (s, 1H), 2.05-1.95 (m, 1H), 1.85-1.76 (m, 1H), 1.57-1.63 (m, 1H), 1.22 (s, 2H), 0.77-0.75 (d, 4H), 0.59-0.496 (m, 4H). [00778] Example I-74-a and I-74-b: (R)-4-((3-(1-(4-oxaspiro[2.5]octan-7-yl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine -3-carboxamide and (S)-4- ((3-(1-(4-oxaspiro[2.5]octan-7-yl)-1H-pyrazol-4-yl)-2-methox yphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide

[00779] Synthesis of compound 74.1. To a solution of 3,3-diethoxypropanoic acid (28.84 g, 178.06 mmol, 1.0 equiv) in THF (280 mL) was added a solution of N, N′-carbonyldiimidazole (77.88 g, 480.76 mmol, 1.5 equiv) in THF (280 mL) dropwise at room temperature. The mixture was stirred at room temperature for 2 h. The solution was transferred into the mixture of monomethyl monopotassium malonate (50 g, 320.51 mmol, 1.8 equiv) and magnesium chloride (39.66 g, 417.54 mmol, 1.3 equiv) in THF (320 mL). The resulting mixture was stirred at room temperature for 16 h. It was acidified with sodium hydrogen sulfate solution (2 M in water, 420 mL) and extracted with ethyl acetate. The combined organic phases were washed with sat. sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 74.1 (32 g, Yield: 46%). It was used in the next step without further purification. MS(ES): m/z 219.10 [M+H] ⁺ . [00780] Synthesis of compound (±)-74.2. To a solution of 74.1 (32 g, 146.78 mmol, 1.0 equiv) in methanol (30 mL) at 0 °C was added sodium borohydride (6.69 g, 176.14 mmol, 1.3 equiv) in portions. The reaction mixture was stirred at 0 °C to rt for 2 h. Most methanol was removed under reduced pressure and the residue was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-74.2 (22.5 g, Yield: 69%). MS(ES): m/z 221.27 [M+H] ⁺ . [00781] Synthesis of compound (±)-74.3. To a solution of (±)-74.2 (25.5 g, 34.05 mmol, 1.0 equiv) and imidazole (10.24 g, 150.68 mmol, 1.3 equiv) in DMF (30 mL) at 0 °C was added tert-butyldimethylsilyl chloride (19.12 g, 127.50 mmol, 1.1 equiv). The reaction mixture was stirred at rt for 6 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-74.3 (20 g, Yield: 39%). MS(ES): m/z 335.53 [M+H] ⁺ . [00782] Synthesis of compound (±)-74.4. To a solution of (±)-74.3 (20 g, 59.88 mmol, 1.0 equiv) in diethyl ether (160 mL) was added titanium tetraisopropoxide (4.2 g, 14.97 mmol, 0.25 equiv) at rt and stirred for 10 min. To the reaction mixture was added ethylmagnesium bromide (1 M in THF, 180.3 mL, 179.64 mmol, 3.0 equiv) dropwise. The resulting solution was stirred for 4 h at room temperature. It was diluted with diethyl ether and quenched by the addition of a saturated aqueous solution of ammonium chloride. The insoluble solids were removed by filtration and the filtrate was extracted with diethyl ether. The organic layer combine was dried over anhydrous magnesium sulfate. It was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-74.4 (10 g, Yield: 51%). MS(ES): m/z 333.53 [M+H] ⁺ . [00783] Synthesis of compound (±)-74.5. To a solution of (±)-74.4 (9.0 g, 27.10 mmol 1.0 equiv) in methanol (120 mL) was added p-toluenesulfonic acid monohydrate (8.85 g, 51.50 mmol, 1.9 equiv) at rt stirred for 16 h. The reaction was poured over a saturated aqueous solution of sodium bicarbonate and extracted with DCM. The combine organic layers were washed with brine, dried over anhydrous anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20% ethyl acetate in hexane) to afford (±)-74.5 (2.8 g, Yield: 67%). MS(ES): m/z 159.20 [M+H] ⁺ . [00784] Synthesis of compound (±)-74.6. To a solution of (±)-74.5 (2.8 g, 17.72 mmol, 1.0 equiv) in DCM (20 mL) was added bis(trimethylsilyl)trifluoroacetamide (3.5 mL, 13.22 mmol, 0.75 equiv) at rt. The reaction mixture was stirred for 2 h. It was cooled to -10 ^o C and was added triethylsilane (12.6 mL, 76.20 mmol, 4.3 equiv), followed by boron trifluoride diethyl ether complex (3.40 mL, 26.9 mmol, 1.5 equiv) dropwise. The mixture was then allowed to warm to 0 °C slowly and stirred for 30 min. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated. The crude further purified by flash column chromatography on silica gel (Combiflash®, 12% ethyl acetate in hexane) to afford (±)-74.6 (1.0 g, Yield: 19%). MS(ES): m/z 129.01 [M+H] ⁺ . [00785] Synthesis of compound (±)-74.7. To a solution of (±)-74.6 (1.0 g, 34.05 mmol, 1.0 equiv) in DCM (30 mL) was added triethylamine (1.9 g, 19.53 mmol, 2.5 equiv) and methansulfonyl chloride (1.15 g, 10.15 mmol, 1.3 equiv) at 0 °C and stirred at rt for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-74.7 (1.1 g, Yield: 69%). MS(ES): m/z 207.27 [M+H] ⁺ . [00786] Synthesis of compound (±)-74.8. To a solution of 4-bromo-1H-pyrazole (1.1 g, 5.33 mmol, 1.0 equiv) in DMF (30 mL) was added sodium hydride (60% in mineral oil, 0.27 g, 6.94 mmol, 1.3 equiv) in portions at 0 °C and stirred for 30 min. To the mixture was added (±)-74.8 (0.86 g, 5.87 mmol, 1.1 equiv) at rt and stirred at 110 °C for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 19% ethyl acetate in hexane) to afford (±)-74.8 (0.31 g, Yield: 24%). MS(ES): m/z 258.13 [M+2] ⁺ . [00787] Synthesis of compound (±)-74.9. Compound (±)-74.9 was prepared from (±)-74.8 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 1.3% methanol in DCM). MS(ES): m/z 300.37 [M+H] ⁺ . [00788] Synthesis of compound 74.9-a and 74.9-b. The racemate was separated by HPLC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) 0.1% diethylamine in n- hexane (B) 0.1% diethylamine in propane-2-ol : acetonitrile (70 : 30); flow rate: 20 mL/min) to afford first eluting fraction (74.9-a), MS(ES): m/z 283.13 [M+H] ⁺ , and first eluting fraction (74.9-b). MS(ES): m/z 283.13 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00789] Synthesis of compound 74.10-a and 74.10-b. Compound 74.10-a was prepared from 74.9-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.4% methanol in DCM). MS(ES): m/z 455.9 [M+H] ⁺ . Compound 74.10-b was prepared from 74.9-b in the same manner. MS(ES): m/z 455.9 [M+H] ⁺ . [00790] Synthesis of I-74-a and I-74-b. Compound I-74-a was prepared from 74.10-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 504.56 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s, 1H), 10.98 (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.46-7.45 (d, J = 8 Hz, 1H), 7.29-7.27 (d, J = 8 Hz, 1H), 7.20-7.18 (t, 1H), 4.58 (bs, 1H), 3.91-3.88 (m, 1H), 3.57 (s, 4H), 2.09-2.06 (m, 3H), 1.61 (m, 1H), 1.23 (m, 4H), 0.85-0.75 (m, 6H), 0.62-0.53 (m, 3H). Compound I-74-b was prepared from 74.10-b in the same manner. MS(ES): m/z 504.56 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s, 1H), 10.98 (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.46-7.45 (d, J = 8 Hz, 1H), 7.29-7.27 (d, J = 8 Hz, 1H), 7.20-7.16 (t, 1H), 4.57-4.55 (m, 1H), 3.92-3.88 (m, 1H), 3.57 (s, 3H), 2.09-2.06 (m, 3H), 1.61 (m, 1H), 1.23 (m, 4H), 0.85-0.75 (m, 6H), 0.62-0.51 (m, 3H). [00791] Example I-75-a and I-75-b: ((R)-4-((3-(1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-4- yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyrida zine-3-carboxamide and (s)- 4-((3-(1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-4-yl)-2-met hoxyphenyl)amino)-6- (cyclopropanecarboxamido)pyridazine-3-carboxamide

[00792] Synthesis of compound (±)-75.1. To a solution of 3-hydroxydihydrofuran-2(3H)-one (100 g, 980 mmol, 1.0 equiv) and imidazole (133.3 g, 1960 mmol, 2.0 equiv) in DCM (40 mL) at 0 °C was added TBDPS-Cl (296 g, 1070 mmol, 1.1 equiv) in portions. The reaction mixture was stirred at rt for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% ethyl acetate in hexane) to afford (±)-75.1 (160 g, Yield: 48%). MS(ES): m/z 341.5 [M+H] ⁺ . [00793] Synthesis of compound (±)-75.2. To a solution of (±)-75.1 (160 g, 469.89 mmol, 1.0 equiv) in THF (120 mL) and diethyl ether (120 mL) at 15 °C was added titanium isopropoxide (66.04 g, 232.5 mmol, 0.5 equiv) followed by the addition of ethyl magnesium bromide (3.0 M in diethyl ether, 470.58 mL, 1411.76 mmol, 3.0 equiv). It was stirred for 1 h at 15 °C and then temperature for 1 h. It was poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 20% ethyl acetate in hexane) to afford (±)-75.2 (75 g, Yield: 43 %). MS(ES): m/z 371.5 [M+H] ⁺ . [00794] Synthesis of compound (±)-75.3. To a solution of (±)-75.2 (75 g, 202.7 mmol, 1.0 equiv) in pyridine (320 mL) was added p-toluenesulfonyl chloride (77.02 g, 405.4 mmol, 2.0 equiv) in portions at 0 °C. The reaction mixture was stirred at room temperature for 2 h and it was heated to reflux for 2 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% ethyl acetate in hexane) to afford (±)- 75.3 (40 g, Yield: 56%). MS(ES): m/z 353.5 [M+H] ⁺ . [00795] Synthesis of compound (±)-75.4. To a solution of (±)-75.1 (40 g, 70.91 mmol, 1.0 equiv) in THF (400 mL) was added tetra-n-butyl ammonium fluoride (1 M in THF, 227.2 mL, 227.27 mmol, 2.0 equiv) at 0 °C and stir for 30 min. The reaction mixture was allowed to warm to rt and stirred for 16 h. It was poured over crushed ice, stirred, neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 50% ethyl acetate in hexane) to afford (±)-75.4 (7.2 g, Yield: 56%). MS(ES): m/z 115.14 [M+H] ⁺ . [00796] Synthesis of compound (±)-75.5. To a solution of (±)-75.4 (7.2 g, 42.93 mmol, 1.0 equiv) in DCM (50 mL) was added pyridinium chlorochromate (40.7 g, 189.3 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After completion of reaction, diethyl ether was added, and the precipitates were removed by filtration. The filtrate was concentrated under reduced pressure to afford (±)-75.5 (5.4 g, Yield: 76%). It was used in the next step without further purification. MS(ES): m/z 113.13 [M+H] ⁺ . [00797] Synthesis of compound (±)-75.6. To a solution of (±)-75.5 (5.4 g, 48.21 mmol, 1.0 equiv) in ethanol (54 mL) was added tert-butyl hydrazinecarboxylate (6.99 g, 53.03 mmol, 1.1 equiv). The reaction mixture was heated to reflux for 12 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 17% ethyl acetate in hexane) to afford (±)-75.6 (1.9 g, Yield: 17%). MS(ES): m/z 227.28 [M+H] ⁺ . [00798] Synthesis of compound (±)-75.7. To a solution of (±)-75.6 (1.9 g, 8.40 mmol, 1.0 equiv) in acetic acid (10 mL) was added sodium cyanoborohydride (0.52 g, 8.40 mmol, 1.0 equiv) in portions. The reaction mixture was stirred at room temperature for 1 h. It was poured into ice- water, stirred, neutralized with 1 N sodium hydroxide solution, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-75.7 (1.4 g, Yield: 74%). MS(ES): m/z 229.28 [M+H] ⁺ . [00799] Synthesis of compound (±)-75.8. To a solution of (±)-75.7 (1.4 g, 6.14 mmol, 1.0 equiv) in ethanol (15 mL) was added 1,1,3,3-tetramethoxypropane (1.0 g, 6.14 mmol, 1.0 equiv) and hydrochloric acid (0.341 g, 9.35 mmol, 3.2 equiv). The reaction mixture was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-75.8 (1.42 g, Yield: 88%). MS(ES): m/z 165.21 [M+1] ⁺ . [00800] Synthesis of compound (±)-75.9. To a solution of (±)-75.8 (1.42 g, 8.65 mmol, 1.0 equiv) in acetic acid (12 mL) was cooled to 10 °C and added bromine (1.37 g, 8.66 mmol, 1.0 equiv) dropwise. The reaction mixture was stirred at room temperature for 2 h. It was transferred into ice cold water, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-75.9. MS(ES): m/z 244.10 [M+2] ⁺ . [00801] Synthesis of compound (±)-75.10. Compound (±)-75.10 was prepared from (±)-75.9 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 286.50 [M+H] ⁺ . [00802] Synthesis of compound 75.10-a and 75.10-b. The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO2 (B) 0.1% diethylamine in propane-2-ol : acetronitrile (50 : 50); flow rate: 80 mL/min) to afford first eluting fraction (75.10-a), MS(ES): m/z 286.35 [M+H] ⁺ and second eluting fraction (75.10-b). MS(ES): m/z 286.35 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00803] Synthesis of compound 75.11-a and 75.11-b. Compound 75.11-a was prepared from 75.10-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane). MS(ES): m/z 441.89 [M+H] ⁺ . Compound 75.11-b was prepared from 75.10-b in the same manner. MS(ES): m/z 441.89 [M+H] ⁺ . [00804] Synthesis of I-75-a and I-75-b. Compound I-75-a was prepared from 75.11-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 490.51 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.31 (s, 1H), 10.99 (s, 1H), 8.54 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.88 (s,1H), 7.48-7.46 (d, J = 7.6 Hz, 1H), 7.31-7.29 (d, J = 7.6 Hz, 1H), 7.22-7.18 (d, J = 8.0 Hz, 1H), 4.82-4.80 (m, 1H), 4.19-4.13 (m, 2H), 3.93-3.90 (m, 2H), 3.56 (s, 3H), 2.33 (1H), 1.24-1.18 (m, 4H), 0.84-0.76 (m, 4H). Compound I-75-b was prepared from 75.11-b in the same manner. MS(ES): m/z 490.54 [M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 11.31 (s, 1H), 10.98 (s, 1H), 8.54 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.88 (s,1H), 7.48-7.46 (d, J = 7.6 Hz, 1H), 7.31-7.29 (d, J = 7.6 Hz, 1H), 7.22-7.18 (d, J = 8.0 Hz, 1H), 4.82-4.80 (dd, J = 2.8 Hz, 1H), 4.19-4.13 (m, 2H), 3.93-3.90 (m, 2H), 3.56 (s, 3H), 2.33 (m, 1H), 1.23 (s, 4H), 0.84-0.76 (m, 4H). [00805] Example I-76-a and I-76-b: 6-(cyclopropanecarboxamido)-4-((3-(1-((3S,4R)-4- fluorotetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl )amino)nicotinamide and 6- (cyclopropanecarboxamido)-4-((3-(1-((3R,4S)-4-fluorotetrahyd rofuran-3-yl)-1H-pyrazol-4-yl)- 2-methoxyphenyl)amino)nicotinamide

[00806] Synthesis of compound (±)-cis-76.1. To a solution of (±)-trans-64.1 (2.89 g, 17.31 mmol, 1.0 equiv) in THF (40 mL) was added diethyl azodicarboxylate (4.51 g, 25.97 mmol, 1.5 equiv) and triphenylphosphine (6.80 g, 25.95 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 5 min and was added 4-nitrobenzoic acid (4.0 g, 17.31 mmol, 1.0 equiv). The mixture was stirred at room temperature for 12 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-cis-76.1 (4.3 g, Yield: 65%). MS(ES): m/z 383.17 [M+H] ⁺ . [00807] Synthesis of compound (±)-cis-76.2. To a solution of (±)-cis-76.1 (4.3 g, 11.25 mmol, 1.0 equiv) in methanol (40 mL) was added potassium carbonate (4.6 g, 33.09 mmol, 3.0 equiv) and stirred at room temperature for 8 h. It was filtered through a pad of Celite®. The filtrated was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford (±)-cis-76.2 (1.5 g, Yield: 57%). MS(ES): m/z 234.07 [M+H] ⁺ . [00808] Synthesis of compound (±)-trans-76.3. To a solution of (±)-cis-76.2 (1.5 g, 6.43 mmol, 1.0 equiv) in THF (10 mL) was added diethylaminosulfur trifluoride (1.55 g, 9.65 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at rt for 48 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% ethyl acetate in hexane) to afford (±)-trans-76.3 (0.45 g, Yield: 31%). MS(ES): m/z 236.06 [M+H] ⁺ . [00809] Synthesis of compound (±)-trans-76.4. Compound (±)-trans-76.4 was prepared from (±)-trans-76.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 278.30 [M+H] ⁺ . [00810] Compound trans-76.4-a and trans-76.4-b. The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO2 (B) 0.1% diethylamine in propane-2-ol : acetronitrile (50 : 50); flow rate: 80 mL/min) to afford first eluting fraction (trans-76.4-a), MS(ES): m/z 278.30 [M+H] ⁺ and second eluting fraction (trans- 76.4-b). MS(ES): m/z 278.30 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00811] Synthesis of compound trans-76.5-a and trans-76.5-b. Compound trans-76.5-a was prepared from trans-76.4-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane). MS(ES): m/z 432.85 [M+H] ⁺ . Compound trans- 76.5-b was prepared from trans-76.4-b in the same manner. MS(ES): m/z 432.85 [M+H] ⁺ . [00812] Synthesis of I-76-a and I-76-b. Compound I-76-a was prepared from trans-76.5-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 481.50 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.75 (s, 1H), 8.59 (s, 1H), 8.35 (s,1H), 8.13 (bs,1H), 8.03 (s, 1H), 8.02 (s, 1H) 7.50-7.14 (m, 4H), 5.75-5.48 (m, 1H), 4.99-4.93 (m, 1H), 4.39-4.42 (m, 1H), 4.23-4.28 (m, 1H), 4.12-4.05 (m, 1H), 3.67 (s, 3H), 1.91-1.99 (m, 1H), 1.23-1.28 (m, 1H), 067-0.82 (m, 4H). Compound I-76- b was prepared from trans-76.5-b in the same manner. MS(ES): m/z 481.35 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (m,1H), 10.75 (s, 1H), 8.59 (m, 1H), 8.35 (s,1H), 8.14 (bs,1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.50-7.14 (m, 5H), 5.42-5.29 (m, 1H), 4.99-4.93 (m, 1H), 4.39-4.42 (m, 1H), 4.23-4.28 (m, 1H), 4.12-4.05 (m, 1H), 3.67 (s, 3H), 1.91-1.99 (m, 1H), 1.23-1.28 (m, 1H), 067-0.82 (m, 4H). [00813] Example I-77-a and I-77-b: 6-(cyclopropanecarboxamido)-4-((3-(1-((1R,2R)-2- fluorocyclopentyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)ni cotinamide and 6- (cyclopropanecarboxamido)-4-((3-(1-((1S,2S)-2-fluorocyclopen tyl)-1H-pyrazol-4-yl)-2- methoxyphenyl)amino)nicotinamide [00814] Synthesis of compound (±)-cis-77.1. To a solution of (±)-trans-67.1 (10 g, 43.29 mmol, 1.0 equiv) and 4-nitrobenzoic acid (7.2 g, 43.29 mmol, 1.0 equiv) in THF (100 mL) was added diethyl azodicarboxylate (15.06 g, 86.58 mmol, 2.0 equiv) at 0 °C followed by addition of triphenylphosphine (22.68 g, 86.58 mmol, 2.0 equiv) in portions. The reaction mixture was stirred at room temperature for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5% ethyl acetate in hexane) to afford (±)- cis-77.1. (6.9 g, Yield: 42 %). MS(ES): m/z 381.20 [M+H] ⁺ . [00815] Synthesis of compound (±)-cis-77.2. To a solution of (±)-cis-77.1 (6.9 g, 18.15 mmol, 1.0 equiv) in methanol (70 mL) was added potassium carbonate (7.51 g, 54.47 mmol, 3.0 equiv) and stirred at room temperature for 12 h. It was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 20% ethyl acetate in hexane) to afford (±)-cis-77.2 (3.4 g, Yield: 83%). MS(ES): m/z 232.5 [M+H] ⁺ . [00816] Synthesis of compound (±)-trans-77.3. To a solution of (±)-cis-77.2 (3.4 g, 14.78 mmol, 1.0 equiv) in THF (30 mL) was added diethylaminosulfur trifluoride (3.57 g, 22.17 mmol, 1.5 equiv) in portions at 0 °C. The reaction mixture was stirred at room temperature for 12 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (±)-trans-77.3 (2.8 g). MS(ES): m/z 234.08 [M+H] ⁺ . [00817] Synthesis of compound (±)-trans-77.4. Compound (±)-trans-77.4 was prepared from (±)-trans-77.3 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 276.33 [M+H] ⁺ . [00818] Synthesis of compound trans-77.4-a and trans-77.4-b. The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO2 (B) 0.1% diethylamine in propane-2-ol : acetronitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (trans-77.4-a), MS(ES): m/z 276.35 [M+H] ⁺ and afford second eluting fraction (trans-77.4-b). MS(ES): m/z 276.35 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00819] Synthesis of compound trans-77.5-a and trans-77.5-b. Compound trans-77.5-a was prepared from trans-77.4-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane). MS(ES): m/z 430.9 [M+H] ⁺ . Compound trans- 77.5-b was prepared from trans-77.4-b in the same manner. MS(ES): m/z 430.9 [M+H] ⁺ . [00820] Synthesis of I-77-a and I-77-b. Compound I-77-a was prepared from trans-77.5-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM). MS(ES): m/z 479.51 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.74 (s, 1H), 8.60 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 8.03 (m, 1H), 8.00 (s, 1H), 7.04 (m, 1H), 7.40-7.38 (d, J = 8.0 Hz, 1H), 7.30-7.28 (d, J = 8.0 Hz, 1H), 7.16-7.14 (t, 1H), 5.35-5.34 (m, 1H), 5.21 (m, 1H), 4.95-4.90 (m, 2H), 3.59 (s, 3H), 2.09-1.85 (m, 6H), 0.78-0.77 (d, 4H). Compound I-77-b was prepared from trans-77.5-b in the same manner. MS(ES): m/z 479.51 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.90 (s, 1H), 10.75 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 8.03 (m, 1H), 8.00 (s, 1H), 7.49 (m, 1H), 7.40-7.39 (d, J = 8.0 Hz, 1H), 7.30- 7.28 (d, J = 8.0 Hz, 1H), 7.17-7.15 (t, 1H), 5.36-5.21 (m, 2H), 4.94-4.89 (m, 1H), 3.59 (s, 3H), 2.09-1.85 (m, 6H), 0.78-0.77 (m, 4H). [00821] Example I-78-a and I-78-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- ((2R,3R)-3-methoxyspiro[4.4]nonan-2-yl)-1H-pyrazol-4-yl)phen yl)amino)nicotinamide and 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((2S,3S)-3-meth oxyspiro[4.4]nonan-2-yl)-1H- pyrazol-4-yl)phenyl)amino)nicotinamide [00822] Synthesis of compound 78.1. To a solution of cyclopentanone (50 g, 595.23 mmol, 1.0 equiv) in toluene (500 mL) was added pyrocatechol (39.2 g, 357.14 mmol, 0.6 equiv) and p- TsOH (3 g). The mixture was heated to reflux with a Dean-Stark trap for 18 h. It was cooled to rt and concentrated under reduced pressure. The residue was added ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 78.1 (21 g, Yield: 20%), MS(ES): m/z 177.22 [M+H] ⁺ . [00823] Synthesis of compound 78.2. To a solution of 78.2 (21 g, 117.97 mmol, 1 equiv) and anhydrous nitromethane (29.11 g, 477.27 mmol, 4.0 equiv) in anhydrous DCM (25 mL) at -75 °C was added TiCl4 (44.6 g, 235.95 mmol, 2 equiv) and allyltrimethylsilane (40.8 g, 357.95 mmol, 3 equiv) in anhydrous DCM (10 mL). The solution mixture was stirred at-75 °C for 4 h, and it was allowed to warm to -45 °C stirring for 48 h. It was poured over a saturated aqueous solution of NH4Cl and extracted with DCM. The extract was washed until neutrality and filtrated on a pad of Celite®. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane) to afford 78.2 (9.8 g, Yield: 56 %). MS(ES): m/z 151.23 [M+H] ⁺ . [00824] Synthesis of compound 78.3. To a solution of 78.2 (9.8 g, 65.33 mmol, 1.0 equiv) in anhydrous DCM (25 mL) was added first generation Grubbs catalyst (1.07 g, 1.306 mmol, 0.02 equiv). The solution was stirred for 72 h at room temperature. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% ethyl acetate in hexane) to afford 78.3 (3.9 g, Yield: 77%), MS(ES): m/z 123.21 [M+H] ⁺ . [00825] Synthesis of compound 78.4. To a solution of 78.3 (3.9 g, 31.96 mmol, 1.0 equiv) in anhydrous DCM (25 mL) at 0 °C and added mCPBA (8.2 g, 47.95 mmol, 1.5 equiv) in portions. The mixture was stirred at room temperature for 6 h. It was quenched by a saturated aqueous solution of Na2S2O3 (30 mL) and NaHCO3 (15 mL). The mixture was filtered through a pad of Celite®. The filtrate was washed with brine. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 78.4 (1.4 g, Yield: 32%), MS(ES): m/z 139.21 [M+H] ⁺ . [00826] Synthesis of compound (±)-trans-78.5. A mixture of 78.4 (1.4 g, 10.14 mmol, 1.0 equiv), 4-bromo-1H-pyrazole (1.64 g, 11.15 mmol, 1.1 equiv) and cesium carbonate (6.59 g, 20.28 mmol, 2.0 equiv) in DMF (25 mL) was stirred at 120 °C for 2 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford (±)-trans-78.5 (0.68 g, Yield: 24 %), MS(ES): m/z 286.19 [M+H] ⁺ . [00827] Synthesis of compound (±)-trans-78.6. To a solution of (±)-trans-78.5 (0.68 g, 2.38 mmol, 1.0 equiv) in DMF (10 mL) at 0 °C was added NaH (60% in mineral oil, 0.14 g, 3.57 mmol, 1.5 equiv) in portions. The reaction mixture was stirred for 30 min and added MeI (0.5 g, 3.57 mmol, 1.5 equiv). It was stirred at rt for 2 h, transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10 % ethyl acetate in hexane) to afford (±)-trans-78.6 (0.32 g, Yield: 24 %), MS(ES): m/z 300.21 [M+H] ⁺ . [00828] Synthesis of compound (±)-trans-78.7. Compound (±)-trans-78.7 was prepared from (±)-trans-78.6 and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ani line, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 23% ethyl acetate in hexane). MS(ES): m/z 342.46 [M+H] ⁺ . [00829] Compound trans-78.7-a and trans-78.7-b. The racemate was separated by SFC (column: CHIRALPAK IB-N (250 * 21 mm, 5 um); mobile phase: (A) liquid CO2 (B) 0.1% diethylamine in propane-2-ol : acetonitrile (50: 50); flow rate: 80 mL/min) to afford first eluting fraction (trans-78.7-a), MS(ES): m/z 342.46 [M+H] ⁺ and second eluting fraction (trans-78.7-b). MS(ES): m/z 342.46 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00830] Synthesis of compound trans-78.8-a and trans-78.8-b. Compound trans-78.8-a was prepared from trans-78.7-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM). MS(ES): m/z 497.12 [M+H] ⁺ . Compound trans-78.8-b was prepared from trans-78.7-b in the same manner. MS(ES): m/z 497.12 [M+H] ⁺ . [00831] Synthesis of I-78-a and I-78-b. Compound I-78-a was prepared from trans-78.8-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM). MS(ES): m/z 545.65 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.88 (s,1H), 10.74 (s, 1H), 8.59 (s, 1H), 8.28 (s, 1H), 8.13 (s,1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.48-7.15 (m, 4H), 4.69 (s, 1H), 4.12 (s, 1H), 3.57 (s, 3H), 3.13 (s, 3H), 2.05 (m, 3H), 1.60 (m, 10H), 0.774 (m, 4H). Compound I-78-b was prepared from trans-78.8-b in the same manner. MS(ES): m/z 545.65 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s,1H), 10.75 (s, 1H), 8.59 (s, 1H), 8.29 (s, 1H), 8.15 (s,1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.48-7.15 (m, 4H), 4.69 (s, 1H), 4.12 (s, 1H), 3.57 (s, 3H), 3.11 (s, 3H), 2.05 (m, 3H), 1.60 (s, 10H), 0.78 (m, 4H). [00832] Example I-79: N-(4-((3-(1-((1S,2S)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2 - methoxyphenyl)amino)-5-methoxypyridin-2-yl)cyclopropanecarbo xamide and N-(4-((3-(1- ((1S,2S)-2-fluorocyclopentyl)-1H-pyrazol-4-yl)-2-methoxyphen yl)amino)-5-methoxypyridin-2- yl)cyclopropanecarboxamide [00833] Synthesis of compound 79.1. A solution of 6-chloro-4-iodopyridin-3-ol (1.0 g, 0039 mmol, 1.0 equiv), in DMF (7 mL) at 0 ^o C was added sodium hydride (0.313 g, 0078 mmol, 2 equiv) in portions. The reaction mixture was stirred at 0 ^o C for 0.5 h. Methyl Iodide (0.292 mL, 0047 mmol, 1.2 equiv) was added dropwise into reaction mixture at 0 ^o C and was stirred for 3 h. It was poured over ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column using 27% ethyl acetate in hexane) to afford 79.1 (0.710 g, 63%). MS(ES): m/z 270.47 [M+H] ⁺ . [00834] Synthesis of compound trans-79.1-a and trans-79.1-b. To a solution of trans-76.4-a (0.160 g, 0.598 mmol, 1.0 equiv) in 1,4-dioxane (2 mL) was added 79.1 (0.181 g, 0.658 mmol, 1.1 equiv) and cesium carbonate (0.641 g, 1.97 mmol, 3.0 equiv). The reaction mixture was degassed by bubbling through a stream of argon for 15 min.4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (0.076 g, 0.136 mmol, 0.25 equiv) and palladium(II) acetate. (0.018 g, 0.082 mmol, 0.1 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 80 ^o C for 2 h. It was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 20 % ethyl acetate in hexane) to afford trans-79.1-a (0.089 g, Yield: 44%). MS(ES): m/z 417.88[M+H] ⁺ . Compound trans-79.1- b was prepared from trans-76.4-b and 79.1 in the same manner. MS(ES): m/z 417.88[M+H] ⁺ . [00835] Synthesis of I-79-a and I-79-b. Compound I-79-a was prepared from trans-79.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 19to 21% ethyl acetate in hexane). MS(ES): m/z 466.18 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.58 (s, 1H), 9.52 (s, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.71-7.69 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.28- 7.26 (t, J = 6.8 Hz, 1H), 7.17-7.15 (d, J = 7.6 Hz, 1H), 5.33-5.20 (m, 1H), 4.95-4.90 (m, 1H), 3.98 (s, 3H), 3.56 (s, 3H), 2.32-2.27 (m, 2H), 2.20-2.11 (m, 2H), 1.87-1.78 (m, 2H), 1.56-1.51 (m, 1H), 0.94-0.90 (m, 4H). Compound I-79-b was prepared from trans-79.1-b in the same manner. MS(ES): m/z 466.14 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.58 (s, 1H), 9.54 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.71-7.70 (d, J = 6.4 Hz, 1H), 7.64 (s, 1H), 7.28-7.26 (t, J = 7.2 Hz, 1H), 7.25-7.17 (m, 1H), 5.34-5.20 (m, 1H), 4.96-4.90 (m, 1H), 3.98 (s, 3H), 3.56 (s, 3H), 2.32-2.27 (m, 2H), 2.20-2.11 (m, 2H), 1.87-1.78 (m, 2H), 1.56-1.51 (m, 1H), 0.94-0.90 (m, 4H). [00836] Example I-80-a and I-80-b 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1- ((3S,4R)-4-methoxytetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyri din-2-yl)amino)nicotinamide and 6-(cyclopropanecarboxamido)-4-((3-methoxy-4-(1-((3R,4S)-4-me thoxytetrahydrofuran-3-yl)- 1H-pyrazol-4-yl)pyridin-2-yl)amino)nicotinamide

[00837] Synthesis of compound 80.1. Compound 80.1 was prepared from 4,6- dichloronicotinonitrile and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane). MS(ES): m/z 222.64 [M+H] ⁺ . [00838] Synthesis of compound 80.2. To a solution of 4-bromopyridin-3-ol (10 g, 57.47 mmol, 1.0 equiv) in concentrated sulfuric acid (60 mL) was added 70% nitric acid (5.42 g, 86.20 mmol, 1.5 equiv) at 0 ^o C. The reaction mixture was stirred at room temperature for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1.5% methanol in DCM) to afford 80.2 (3.1 g, 25%). MS(ES): m/z 219.99 [M+H] ⁺ . [00839] Synthesis of compound 80.3. To a mixture of 80.2 (3.1 g, 14.16 mmol, 1.0 equiv) and potassium carbonate (5.86 g, 42.48 mmol, 3.0 equiv) in DMF (60 mL) was added methyl iodide (3.01 g, 21.24 mmol, 1.5 equiv) dropwise at 0 ^o C. The reaction mixture was stirred at room temperature for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (12% ethyl acetate in hexane) to afford 80.3 (1.6 g, 49%). MS(ES): m/z 234.02[M+H] ⁺ . [00840] Synthesis of compound (±)-trans-80.4. A mixture of (±)-trans-67.2 (6.2 g, 25.30 mmol, 1.0 equiv), bis(pinacolato)diboron (9.61 g, 37.95 mmol, 1.5 equiv) and potassium acetate (7.44 g, 75.91 mmol, 3.0 equiv) in 1,4-dioxane (60 mL) was degassed by bubbling through a stream of argon for 20 min. (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.206 g, 0.253 mmol, 0.01 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 ^o C for 2 h. It was filtered through a pad of Celite ® and rinsed with ethyl acetate. The filtrate was washed with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The residue was triturated with hexane to obtain (±)-trans-80.4 (6.01 g, Yield: 81%). MS(ES): m/z 293.19 [M+H] ⁺ . [00841] Synthesis of compound (±)-trans-80.5. A mixture of (±)-trans-80.4 (1.6 g, 6.87 mmol, 1.0 equiv), 80.3 (3.03 g, 10.30 mmol, 1.5 equiv) and tripotassium phosphate (4.37 g, 20.61 mmol, 3.0 equiv) in dioxane (30 mL) and water (8 mL) was degassed by bubbling through a stream of argon for 15 min. [1,1'-Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (1.12 g, 1.37 mmol, 0.2 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100 ^o C for 2 h. It was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (35% ethyl acetate in hexane) to afford (±)-trans-80.5 (0.440 g, 20%). MS(ES): m/z 321.30 [M+H] ⁺ . [00842] Synthesis of compound (±)-trans-80.6. A mixtuer of (±)-trans-80.5 (0.440 g, 1.37 mmol, 1.0 equiv) and palladium on charcoal) (10% wt, 0.220 g) in methanol (15 mL) was stirred under hydrogen (1 atm) for 3 h. It was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford (±)-trans-80.6 (0.25 g, 63%). MS(ES): m/z 291.32[M+H] ⁺ . [00843] Synthesis of compound trans-80.6-a and trans-80.6-b. The racemate (0.25 g) was separated by HPLC (column: CHIRALPAK IC (250 * 4.6 mm, 5 um); mobile phase: (A) 0.1% diethylamine in n-hexane (B) 0.1% diethylamine in propane-2-ol : acetonitrile (50 : 50); flow rate: 20 mL/min) to afford first eluting fraction (trans-80.6-a), MS(ES): m/z 291.32 [M+H] ⁺ and second eluting fraction (trans-80.6-b). MS(ES): m/z 291.32 [M+H] ⁺ . [00844] Synthesis of compound trans-80.7-a and trans-80.7-b. A mixture of trans-80.6-a (0.100 g, 0.344 mmol, 1.0 equiv), 80.1 (0.091 g, 0.413 mmol, 1.2 equiv) and cesium carbonate (0.335 g, 1.03 mmol, 3.0 equiv) in dioxane (7 mL) was degassed by bubbling through a stream of argon gas for 15 min.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.039g ,0.0681 mmol ,0.2 equiv) and tris(dibenzylideneacetone)dipalladium chloroform complex (0.035g ,1.0.034 mmol ,0.1 equiv) were added and the mixture was stirred at 110 ^o C for 15 min. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.1% methanol in DCM) to afford trans-80.7-a (0.077 g, Yield: 47%). MS(ES): m/z 476.51 [M+H] ⁺ . Compound trans-80.7-b was prepared from trans-80.6-b and 80.1 in the same manner. MS(ES): m/z 476.51 [M+H] ⁺ . [00845] Synthesis of I-80-a and I-80-b. To a solution of trans-80.7-a (0.077 g, 0.162 mmol, 1.0 equiv) in methanol (22 mL) was added dimethyl sulfoxide (1.8 mL), potassium carbonate (0.250g) and hydrogen peroxide (0.2 mL) at room temperature. The reaction mixture was stirred at for 1 h. It was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.9% methanol in DCM) to afford I-80-a (0.038 g, Yield: 48%), MS(ES): m/z 494.30 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 12.17 (s, 1H), 10.73 (s, 1H), 9.57 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 8.00-7.99 (d, J = 4 Hz, 1H), 7.58 (s, 1H), 7.25-7.24 (d, J = 4 Hz, 1H), 5.05 (s, 1H), 4.23-4.16 (m, 2H), 4.10- 4.00 (m, 2H), 3.80-3.78 (d, J = 8 Hz, 1H), 3.71 (s, 3H), 3.37 (s, 3H), 2.08-2.03 (m, 1H), 0.84- 0.80 (m, 4H). Compound I-80-b was prepared from trans-80.7-b in the same manner. MS(ES): m/z 494.30 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 12.17 (s, 1H), 10.73 (s, 1H), 9.57 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 8.00-7.99 (d, J = 4 Hz, 1H), 7.58 (s, 1H), 7.25-7.24 (d, J = 4 Hz, 1H), 5.05 (s, 1H), 4.23-4.16 (m, 2H), 4.10-4.00 (m, 2H), 3.80-3.78 (d, J = 8 Hz, 1H), 3.71 (s, 3H), 3.37 (s, 3H), 2.08-2.03 (m, 1H), 0.84-0.80 (m, 4H). [00846] Example I-81: 4-((3-(3-cyano-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) -2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00847] Synthesis of compound 81.1. Compound 81.1 was prepared from 42.2 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane). MS(ES): m/z 299.35 [M+H] ⁺ . [00848] Synthesis of compound 81.2. Compound 81.2 was prepared from 81.1 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane). MS(ES) : m/z 454.89 [M+H] ⁺ . [00849] Synthesis of I-81. Compound I-81 was prepared from 81.2 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM). MS(ES): m/z 503.41 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.02 (s, 1H), 9.95 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.60-7.58 (d, J = 8 Hz 1H), 7.45-7.43 (d, J = 8 Hz 1H), 7.29-7.23 (m, 1H), 6.06 (s, 1H), 4.48 (m, 1H), 4.18-4.15 (m, 1H), 3.62-3.347 (m, 2H), 3.55 (s, 3H), 2.19 - 2.14 (m, 2H), 1.45-1.39 (m,2H), 1.30-1.28 (m, 2H), 0.83-0.81 (m, 4H). [00850] Example I-84: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H- pyran-4-yl)-1H-pyrazol-3-yl)phenyl)amino)nicotinamide [00851] Synthesis of compound 84.1. A mixture of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.62 mmol, 1.0 equiv), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.51 g, 12.93 mmol, 1.5 equiv) and potassium phosphate (3.65 g, 17.24 mmol, 2.0 equiv) in dioxane (40 mL) and water (8 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.126 g, 0.17 mmol, 0.05 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 120 ^o C for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 84.1 (0.7 g, 37%). MS(ES): m/z 220.21 [M+H] ⁺ . [00852] Synthesis of compound 84.2. A mixture of 84.1 (1 g, 4.56 mmol, 1.0 equiv), 4-bromo- 3,6-dihydro-2H-pyran (2.23 g, 13.69 mmol, 3 equiv) and potassium carbonate (1.89 g, 13.69 mmol, 2.0 equiv) in 1,4-dioxane (15 mL) was degassed by bubbling through a stream of argon for 10 min. N, N-dimethylethylenediamine (0.120 g, 1.36 mmol, 0.3 equiv) and copper iodide (0.174 g, 0.9 mmol, 0.2 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 120 ^o C for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford 1.2 (0.450 g, 33%). MS(ES): m/z 302.41 [M+H] ⁺ . [00853] Synthesis of compound 84.3. A mixture of palladium on carbon (10%, 0.2 g) and 84.2 (0.45 g, 1.49 mmol, 1.0 equiv) in methanol (5 mL) was stirred at rt under hydrogen ( 1 atm) for 2 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford 84.3 (0.237 g, Yield: 58%). MS(ES): m/z 274.4 [M+H] ⁺ . [00854] Synthesis of compound 84.4. Compound 84.4 was prepared from 84.3 and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 428.8 [M+H] ⁺ . [00855] Synthesis of I-84. Compound I-84 was prepared from 84.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 477.37 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 10.76 (s, 1H), 8.61 (s, 1H), 8.16 (bs, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.65-7.63 (d, J = 6.8 Hz, 1H), 7.49 (bs, 1H), 7.39-7.37 (d, J = 7.2 Hz, 1H), 7.21-7.17 (m, 1H), 6.75-6.74 (d, J = 2 Hz, 1H), 4.48 (m, 1H), 4.01-3.98 (d, J = 10.8 Hz, 2H), 3.60 (s, 3H), 3.50-3.42 (m, 2H), 2.03-2.00 (m, 5H), 0.79-0.78 (d, J = 4 Hz, 4H). [00856] Example I-85-a and I-85-b: (R)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- (tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)phenyl)amino)nico tinamide and (S)-6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2H- pyran-3-yl)-1H-pyrazol-3- yl)phenyl)amino)nicotinamide [00857] Synthesis of compound 85.1. A mixture of 84.1 (2.1 g, 9.58 mmol, 1.0 equiv), 5-bromo- 3,4-dihydro-2H-pyran (4.69 g, 28.74 mmol, 3 equiv) and potassium carbonate (3.96 g, 28.74 mmol, 2.0 equiv) in 1,4-dioxane (15 mL) was degassed by bubbling through a stream of argon for 10 min. N, N-Dimethylethylenediamine (0.253 g, 2.87 mmol, 0.3 equiv) and copper iodide (0.366 g, 1.91 mmol, 0.2 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 120 ^o C for 16 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford 85.1 (0.400 g, 14%). MS(ES): m/z 302.41 [M+H] ⁺ . [00858] Synthesis of compound (±)-85.2. A mixture of palladium on carbon (10%, 0.2 g) and 85.1 (0.40 g, 1.49 mmol, 1.0 equiv) in methanol (5 mL) was stirred at room temperature under hydrogen atmosphere for 2 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduced pressure to afford (±)-85.2 (0.300 g, Yield: 83%). MS(ES): m/z 274.4 [M+H] ⁺ . [00859] Compound 85.2-a and 85.2-b. The racemate (0.300 g) was separated by HPLC (column: CHIRALPAK IH (250 * 21 mm, 5 um); mobile phases: (A) 0.1% diethylamine in n- hexane (B) 0.1% diethylamine in propane-2-ol : acetonitrile (70 : 30); flow rate: 20 mL/min) to afford first eluting fraction (85.2-a, 0.11 g, Yield: 37%, MS(ES): m/z 274.4 [M+H] ⁺ ) and second eluting fraction (85.2-b, 0.11 g, Yield: 37%). MS(ES): m/z 274.4 [M+H] ⁺ . *The absolute configuration of the chiral center is not determined. [00860] Synthesis of compound 85.3-a and 85.3-b. Compound 85.3-a was prepared from 85.2-a and 4,6-dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 428.8 [M+H] ⁺ . Compound 85.3-b was prepared from 85.2-b in the same manner. MS(ES): m/z 428.8 [M+H] ⁺ . [00861] Synthesis of I-85-a and I-85-b. Compound I-85-a was prepared from 85.3-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 477.37 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 10.77 (s, 1H), 8.61 (s, 1H), 8.16 (bs, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.64-7.63 (d, J = 7.2 Hz, 1H), 7.50 (bs, 1H), 7.39-7.37 (d, J = 7.2 Hz, 1H), 7.21-7.17 (m, 1H), 6.75 (bs, 1H), 4.37 (m, 1H), 4.06-4.04 (d, J = 9.6 Hz, 1H), 3.85-3.82 (d, J = 10.4 Hz, 1H), 3.70-3.65 (m, 2H), 3.604 (s, 3H), 2.34-2.31 (m, 2H), 2.00 (m, 1H), 1.76-1.70 (m, 2H), 0.79 (m, 4H). Compound I-85-b was prepared from 85.3-b in the same manner. MS(ES): m/z 477.37 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.91 (s, 1H), 10.77 (s, 1H), 8.61 (s, 1H), 8.16 (bs, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.64-7.63 (d, J = 4 Hz, 1H), 7.50 (bs, 1H), 7.39-7.38 (d, J = 4 Hz, 1H), 7.21-7.18 (T, J = 8 Hz, 1H), 6.75-6.74 (d, J = 4 Hz, 1H), 4.37 (m, 1H), 4.06-4.04 (d, J = 8 Hz, 1H), 3.85-3.82 (d, J = 12 Hz, 1H), 3.70-3.65 (m, 2H), 3.60 (s, 3H), 2.34-2.31 (m, 2H), 2.00 (m, 1H), 1.76-1.70 (m, 2H), 0.79-0.78 (d, J = 4 Hz, 4H). δ 10.91 (s, 1H), 10.76 (s, 1H), 8.61 (s, 1H), 8.16 (bs, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.64-7.63 (d, J = 7.2 Hz, 1H), 7.50 (bs, 1H), 7.39-7.38 (d, J = 7.2 Hz, 1H), 7.21-7.18 (m, 1H), 6.75 (bs, 1H), 4.37 (m, 1H), 4.06-4.04 (d, J = 9.6 Hz, 1H), 3.85-3.82 (d, J = 10.4 Hz, 1H), 3.70-3.65 (m, 2H), 3.604 (s, 3H), 2.34-2.31 (m, 2H), 2.00 (m, 1H), 1.76-1.70 (m, 2H), 0.79 (m, 4H). [00862] Example I-86: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H- pyran-4-yl)-1H-pyrazol-4-yl)phenyl)amino)nicotinamide

[00863] Synthesis of compound 86.1. To a solution of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.62 mmol, 1.0 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole-1-carboxylate (2.51 g, 12.93 mmol, 1.5 equiv) and potassium phosphate (3.65 g, 17.24 mmol, 2.0 equiv) in 1, 4-dioxane (40 mL) and water (8 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.126 g, 0.17 mmol, 0.05 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 120 ^o C for 6 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 86.1 (0.5 g, 26%). MS(ES): m/z 220.21 [M+H] ⁺ . [00864] Synthesis of compound 86.2. A mixture of 86.1 (0.5 g, 2.28 mmol, 1.0 equiv), 4-bromo- 3,6-dihydro-2H-pyran (1.12 g, 6.84 mmol, 3 equiv) and potassium carbonate (0.63 g, 4.56 mmol, 2.0 equiv) in 1,4-dioxane (15 mL) was degassed by bubbling through a stream of argon for 10 min. N,N-dimethylethylenediamine (0.60 g, 0.068 mmol, 0.3 equiv) and copper iodide (0.087 g, 0.45 mmol, 0.2 equiv) were added, and degassed for 5 min. The reaction mixture was stirred at 120 ^o C for 6 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 18% ethyl acetate in hexane) to afford 86.2 (0.350 g, 51%). MS(ES): m/z 302.41 [M+H] ⁺ . [00865] Synthesis of compound 86.3. A mixture of palladium on carbon (10%, 0.175 g) and 86.2 (0.35 g, 1.16 mmol, 1.0 equiv) in methanol (5 mL) was stirred at room temperature under hydrogen (1 atm) for 2 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was reduced under vacuum pressure to afford 86.3 (0.20 g, Yield: 63%). MS(ES): m/z 274.4 [M+H] ⁺ . [00866] Synthesis of compound 86.4. Compound 86.4 was prepared from 86.3 and 4,6- dichloronicotinamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.1% methanol in DCM). MS(ES): m/z 428.8 [M+H] ⁺ . [00867] Synthesis of I-86. Compound I-86 was prepared from 86.4 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 477.37 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 10.89 (s, 1H), 10.76 (s, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.50 (s, 1H), 7.39-7.38 (d, J = 7.6 Hz, 1H), 7.28-7.26 (d, J = 7.6 Hz, 1H), 7.17-7.13 (t, J = 8 Hz, 1H), 4.47 (m, 1H), 3.99-3.96 (m, 2H), 3.57 (s, 3H), 3.48-3.45 (m, 2H), 2.00 (m, 5H), 0.78-0.76 (m, 4H). Example I-87: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H-pyran-4-yl)- 1H-pyrazol-3-yl)phenyl)amino)pyridazine-3-carboxamide [00868] Synthesis of compound 87.1. Compound 87.1 was prepared from 84.3-a and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.9% methanol in DCM). MS(ES): m/z 429.9 [M+H] ⁺ . [00869] Synthesis of I-87. Compound I-87 was prepared from 87.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM). MS(ES): m/z 478.37 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.32 (s, 1H), 10.99 (s, 1H), 8.55 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.48-7.46 (d, J = 7.2 Hz, 1H), 7.30-7.28 (d, J = 7.2 Hz, 1H), 7.21-7.19 (m, 1H), 4.47 (m, 1H), 3.99-3.96 (m, 2H), 3.58 (s, 3H), 3.48-3.45 (m, 2H), 2.08-2.01 (m, 5H), 0.81 (bs, 4H). [00870] Example I-88: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(tetrahydro-2 H- pyran-4-yl)-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carbox amide [00871] Synthesis of compound 88.1. Compound 88.1 was prepared from 86.3 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by combi flash chromatography using 55% ethyl acetate in hexane). MS(ES) : m/z 429.88 [M+H] ⁺ . [00872] Synthesis of I-88. Compound I-88 was prepared from 88.1 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3.7% methanol in DCM). MS(ES) : m/z 478.52 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 11.00 (s, 1H), 8.56 (s, 1H), 8.28 (s, 1H) 8.15 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.49-7.47 (d, J = 6.4 Hz, 1H), 7.31-7.10 (m, 2H), 4.48 (m, 1H), 4.00-3.98 (m, 2H), 3.59 (s, 3H), 3.50-3.35 (m, 2H), 2.09-2.02 (m, 2H), 1.64-1.57 (m, 2H), 1.35 (m, 1H), 0.891 (m, 4H). Example I-89-a and I-89-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3S,4R)-4- methoxytetrahydrofuran-3-yl)-1H-pyrazol-4-yl)phenyl)amino)py ridazine-3-carboxamide and 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((3R,4S)-4-meth oxytetrahydrofuran-3-yl)-1H- pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide [00873] Synthesis of compound trans-89.1-a and trans-89.1-b. Compound trans-89.1-a was prepared from trans-64.3-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by Combi flash using 35% ethyl acetate in hexane). MS(ES): m/z 445.88 [M+H] ⁺ . Compound trans-89.1-b was prepared from trans-64.3-b in the same manner. MS(ES): m/z 445.88 [M+H] ⁺ . [00874] Synthesis of I-89-a and I-89-b. Compound I-89-a was prepared from trans-89.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3 % methanol in DCM). MS(ES): m/z 470.5 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.34 (s,1H), 11.00 (s, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.50- 7.48 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.23-7.19 (t, J = 8 Hz, 1H), 5.03 (m, 1H), 4.22-4.17 (m, 2H), 4.10-4.01 (m, 2H), 3.81-3.79 (m, 1H), 3.59 (s, 3H), 1.34 (m, 1H), 0.82 (m, 4H). Compound I-89-b was prepared from trans-89.1-b in the same manner. MS(ES): m/z 470.5 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.23 (s,1H), 10.89 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.39-7.37 (d, J = 7.2 Hz, 1H), 7.21-7.19 (d, J = 7.2 Hz, 1H), 7.12-7.10 (m, 1H), 4.93 (m, 1H), 4.11-4.06 (m, 2H), 3.98-3.90 (m, 2H), 3.70-3.68 (m, 1H), 3.48 (s, 3H), 1.98 (m, 1H), 0.71(m, 4H). [00875] Example I-90-a and I-90-b: 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- ((1R,2R)-2-methoxycyclopentyl)-1H-pyrazol-4-yl)phenyl)amino) pyridazine-3-carboxamide and 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-((1S,2S)-2-me thoxycyclopentyl)-1H-pyrazol- 4-yl)phenyl)amino)pyridazine-3-carboxamide [00876] Synthesis of compound trans-90.1-a and trans-90.1-b. Compound trans-90.1-a was prepared from trans-67.3-a and 4,6-dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)-4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane). MS(ES): m/z 443.9 [M+H] ⁺ . Compound trans-90.1-b was prepared from trans-67.3-b in the same manner. MS(ES): m/z 443.9 [M+H] ⁺ . [00877] Synthesis of I-90-a and I-90-b. Compound I-90-a was prepared from trans-90.1-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 3 % methanol in DCM). MS(ES): m/z 492.37 [M+H] ⁺ ; ¹ H NMR (DMSO-d ⁶ , 400 MHz): δ 11.32 (s,1H), 10.99 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.48- 7.46 (d, J = 6.4 Hz, 1H), 7.28-7.19 (m, 2H), 4.64 (m, 1H), 4.00 (m, 1H), 3.58 (s, 3H), 3.19 (s, 3H), 2.17 (m, 1H), 2.07-2.02 (m, 3H), 1.81 (m, 2H), 1.65 (m, 1H), 0.82 (m, 4H). Compound I- 90-b was prepared from trans-90.1-b in the same manner. MS(ES): m/z 492.35 [M+H] ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ 11.32 (s,1H), 10.99 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.48-7.46 (d, J = 6.8 Hz, 1H), 7.30-7.28 (d, J = 7.2 Hz, 1H), 7.21-7.19 (m, 1H), 4.64-4.63 (m, 1H), 4.01 (m, 1H), 3.58 (s, 3H), 3.19 (s, 3H), 2.17 (m, 1H), 2.07-2.02 (m, 3H), 1.81-1.65 (m, 3H), 0.81 (m, 4H). [00878] Example I-91: ((R)-4-((3-(3-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl )-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00879] Synthesis of compound 91.1. Compound 91.1 was prepared from 41.3 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 38% ethyl acetate in hexane). MS(ES): m/z :285.32 [M+H] ⁺ . [00880] Synthesis of compound 91.2. Compound 91.2 was prepared from 91.1 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM). MS(ES): m/z 440.86 [M+H] ⁺ . [00881] Synthesis of I-91. Compound I-32-a was prepared from 32.4-a and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM). MS(ES) m/z 489.43 [M+H] ⁺ , ¹ H NMR (DMSO-d6, 400 MHz): δ 11.34 (s, 1H), 11.04 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H) 7.50-7.49 (d, J = 7.6 Hz, 1H), 7.38-7.32 (m, 2H), 5.24-5.23 (m, 1H), 4.02-3.99 (m, 4H), 3.85-3.81 (m, 2H), 3.50 (s, 3H), 2.42-2.36 (m, 2H), 2.10-2.07 (m, 2H), 0.84-0.82 (m, 4H). [00882] Example I-92: (S)-4-((3-(3-cyano-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) -2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)pyridazine-3 -carboxamide [00883] Synthesis of compound 92.1. Compound 92.1 was prepared from 40.3 and 2-methoxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, following the procedure described in the synthesis of (±)-1.4. The product was purified by flash column chromatography on silica gel (Combiflash®, 38% ethyl acetate in hexane). MS(ES): m/z :285.32 [M+H] ⁺ . [00884] Synthesis of compound 92.2. Compound 92.2 was prepared from 92.1 and 4,6- dichloropyridazine-3-carboxamide, following the procedure described in the synthesis of (±)- 4.1. The product was purified by Combi flash using 2.8% methanol in DCM). MS(ES): m/z 440.86 [M+H] ⁺ . [00885] Synthesis of I-92. Compound I-92 was prepared from 92.2 and cyclopropanecarboxamide, following the procedure described in the synthesis of I-5-a. The product was purified by Combi flash using 2.5% methanol in DCM). MS(ES) m/z 489.26 [M+H] ⁺ ; 1H NMR (DMSO-d6, 400 MHz): δ 11.33 (s, 1H), 11.04 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H) 7.51-7.49 (d, J = 7.6 Hz, 1H), 7.38-7.32 (m, 2H), 5.24 (m, 1H), 4.02-3.99 (m, 4H), 3.85-3.81 (m, 2H), 3.50 (s, 3H), 2.42-2.36 (m, 2H), 2.10-2.07 (m, 2H), 0.84- .082 (m, 4H). Biology Examples [00886] Example 2-1: JAK2 (JH2) Binding Assay [00887] Binding constants (Kds) and target selectivity were assessed using a high-throughput system for screening compounds against human kinases. KINOMEscan™ (DiscoverX), is a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized, active-site directed ligand. The assay is performed by combining three components: DNA-tagged kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand is measured via quantitative PCR of the DNA tag. [00888] Kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM (DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. [00889] Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements were distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plate. Each had a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 µM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Binding constants (Kds) were calculated with a standard dose- response curve using the Hill equation (1): where the Hill slope is set to -1. Curves are fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm. [00890] Results of the JAK2 JH2 Domain Binding Assay are presented in Table 7. Compounds denoted as “A” had a Kd lower than 10 nM; compounds denoted as “B” had a Kd from 10 nM to 50 nM; compounds denoted as “C” had a K _d from 50 nM to 1 μM; and compounds denoted as “D” had a K _d greater than 1 μM but no more than 5 μM. TABLE 7. Results of JAK2-JH2 Binding Assay

[00891] Compounds in Table 7 have the structures shown in Tables 2-6. Ref-1 is 6- (cyclopropanecarbonylamino)-4-[2-methoxy-3-(1-methyl-1,2,4-t riazol-3-yl)anilino]-N- (trideuteriomethyl)pyridazine-3-carboxamide, CAS No.1609392-27-9. [00892] Example 2-2: Kinetic Solubility Assay [00893] Preparation of Stock Solutions [00894] Stock solutions of test compounds are prepared in DMSO at the concentration of 10 mM, and the stock solution of control compound is prepared in DMSO at the concentration of 30 mM. Diclofenac is used as positive control in the assay. [00895] Procedures for Solubility Determination [00896] 30 µL stock solution of each compound is placed in order into the respective 96-well rack, followed by adding 970 µL of PBS at pH 4.0 and pH 7.4 into each vial of the cap-less solubility sample plate. This study is performed in duplicate. One stir stick is added to each vial and then vials are sealed using a molded PTDE/SIL 96-Well Plate Cover. The solubility sample plate is transferred to the plate shaker and incubated at RT for 2 hours with shaking at 1100 rpm. After 2 hours incubation, stir sticks are removed using a big magnet and all samples from the solubility sample plate are transferred into the filter plate. Samples are vacuum-filtered. The filtered samples are diluted with methanol, which may vary according to the solubility value and the LC/MS signal response. [00897] Standard(s) (STD(s)) [00898] 10 mM DMSO compound stock solutions are diluted with DMSO to 300 µM and then diluted with methanol to obtain 0.3 µM STDs. [00899] Sample Analysis [00900] Samples are analyzed by LC-MS/MS. [00901] The solution filtered is analyzed and quantified against a standard of known concentration in DMSO using LC coupled with Mass spectral peak identification and quantitation. The solubility values of the test compounds are calculated according to the following equation (2): where INJ VOL is the injection volume, and DF is the dilution factor. [00902] Example 2-3: Caco2 Permeability Assay: [00903] Preparation of Caco-2 Cells [00904] 50 μL and 25 mL of cell culture medium are added to each well of the Transwell insert and reservoir, respectively. And then the HTS transwell plates are incubated at 37 °C, 5% CO2 for 1 hour before cell seeding. [00905] Caco-2 cell cells are diluted to 6.86х10 ⁵ cells/mL with culture medium and 50 μL of cell suspension are dispensed into the filter well of the 96-well HTS Transwell plate. Cells are cultivated for 14-18 days in a cell culture incubator at 37 °C, 5% CO2, 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating. [00906] Preparation of Working Solutions [00907] Stock solutions of positive controls are prepared in DMSO at the concentration of 10 mM. Digoxin and propranolol are used as control compounds in this assay. [00908] Assessment of Cell Monolayer Integrity Medium is removed from the reservoir and each Transwell insert and replaced with prewarmed fresh cuture medium. Then, transepithelial electrical resistance (TEER) across the monolayer is measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA). The TEER value should be greater than 230 ohm•cm ² , for a well-qualified Caco-2 monolayer. The TEER value is calucated according to the following equation (3): (3) TEER value (ohm•cm ² ) = TEER measurement (ohms) x Area of membrane (cm ² ) [00909] Assay Procedures [00910] The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 μM working solutions. The stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then are diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 μM working solutions. The final concentration of DMSO in the incubation system is 0.5%. [00911] To determine the rate of drug transport in the apical to basolateral direction, 75 μL of 5 μM working solutions of test compounds are added to the Transwell insert (apical compartment) and the wells in the receiver plate (basolateral compartment) are filled with 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). To determine the rate of drug transport in the basolateral to apical direction, 235 μL of 5 μM working solutions of test compounds are added to the receiver plate wells (basolateral compartment) and then the Transwell inserts (apical compartment) are filled with 75 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). Time 0 samples are prepared by transferring 50 μL of 5 μM working solution to wells of the 96-deepwell plate, followed by the addition of 200 μL cold methanol containing appropriate internal standards (IS). The plates are incuabted at 37 °C for 2 hours. [00912] At the end of the incubation, 50 μL samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap) are transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold acetonitrile or methanol containing appropriate internal standards (IS). Samples are vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 µL of the supernatant is mixed with an appropriate volume of ultra-pure water before LC-MS/MS analysis. [00913] To determine the Lucifer Yellow leakage after 2 hour transport period, stock solution of Lucifer yellow is prepared in ultra-pure water and is diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 μM.100 μL of the Lucifer yellow solution is added to each Transwell insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates are incubated at 37 °C for 30 minutes.80 μL samples are removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal is measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission. [00914] Example 2-4: Plasma Protein Binding Assay [00915] Preparation of Working Solutions [00916] The working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 μM, and then the working solutions are spiked into plasma. The final concentration of compound is 1 μM. The final concentration of DMSO is 0.5%. Ketoconazole is used as positive control. [00917] Preparation of Dialysis Membranes [00918] Dialysis membranes are soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. [00919] Procedure for Equilibrium Dialysis [00920] The dialysis setup is assembled according to the manufacturer’s instruction. Each cell is mixed with 150 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay is performed in duplicate. The dialysis plate is sealed and incubated in an incubator at 37°C with 5% CO ₂ at 100 rpm for 6 hours. At the end of incubation, 50 μL of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate. [00921] Procedure for Sample Analysis [00922] 50 μL of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample.400 μL of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 μM ketoplofen) is added to precipitate protein and release compounds. Samples are vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50 µL of the supernatant is diluted by 150 µL acetonitrile containing internal standards : ultra-pure H ₂ O = 1:1, and the mixture is used for LC-MS/MS analysis. [00923] Example 2-5: Hepatocyte Stability Assays [00924] 10 mM stock solutions of test compound and positive control are prepared in DMSO. Thawing medium and supplement incubation medium (serum-free) are placed in a 37°C water bath for at least 15 minutes prior to use. [00925] Preparation of Working Solutions [00926] Stock solutions are diluted to 100 μM by combining 198 μL of 50% acetonitrile/50% water and 2 μL of 10 mM stock solution. Verapamil is used as positive control in the assay. [00927] Preparation of Hepatocytes [00928] Vials of cryopreserved hepatocytes are removed from storage, ensuring that vials remain at cryogenic temperatures. The pressure is removed by loosening and re-tightening the cap. The vials are thawed in a 37°C water bath with gently shaking. Vials remain in water bath until all ice crystals have dissolved and are no longer visible. Vials are sprayed with 70% ethanol before being transferred to a biosafety cabinet. Then, the contents are poured into a 50 mL thawing medium conical tube. Vials are centrifuged at 100 g for 10 minutes at room temperature. Thawing medium is aspirated and hepatocytes are re-suspended with serum-free incubation medium to yield ~1.5 × 10 ⁶ cells/mL. [00929] Cell viability and density are counted using a trypan blue exclusion, and then cells are diluted with serum-free incubation medium to a working cell density of 0.5×10 ⁶ viable cells/ml. A portion of the hepatocytes at 0.5×10 ⁶ viable cells/mL is boiled for 5 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed. Aliquots of 198 μL hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes. [00930] Procedure for Hepatocyte Stability Analysis [00931] Aliquots of 2 μL of the 100 μM test compound and 2 μL positive control are added into respective wells of the non-coated 96-well plate to start the reaction. The final concentration of test compound is 1 μM. This assay is performed in duplicate. The plate is incubated in the incubator for the designed time points.25 μL of contents are transferred and mixed with 6 volumes (150 μL) of cold acetonitrile with IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 200 nM diclofenac) to terminate the reaction at time points of 0, 15, 30, 60, 90 and 120 minutes. Samples are centrifuged for 25 minutes at 3,220 g and aliquots of 150 μL of the supernatants are used for LC-MS/MS analysis. [00932] Example 2-6: General Cytotoxicity Assay in HEK293 cells [00933] HEK293T cells are harvested from flask into cell culture medium, and then the cells are counted. The cells are diluted with culture medium to the desired density, and 40 μL of cell suspension is added into each well of a 384-well cell culture plate. The plates are covered with a lid and spun at room temperature at 1,000 RPM for 1 minute and then transferred into 37 °C 5% CO2 incubator overnight. Test compounds are dissolved at 10 mM DMSO stock solution.45 μL of stock solution is then transferred to a 384 PP-plate. A 3-fold, 10-point dilution is performed via transferring 15 μL compound into 30 μL DMSO by using TECAN (EVO200) liquid handler. The plates are spun at room temperature at 1,000 RPM for 1 minute and shaken on a plate shaker for 2 minutes. 40 nL of diluted compound is transferred from compound source plate into the cell plate by using liquid handler Echo550. After compound treatment for 48 hours, CTG detection is performed for compound treatment plates: the plates are removed from incubators and equilibrated at room temperature for 15 minutes.30 μL of CellTiter-Glo reagent is added into each well to be detected. The plates are then placed at room temperature for 30 min followed by reading on EnVision. Inhibition activity is calculated with the following formula: %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC), wherein HC is reading obtained from cells treated with 0.1% DMSO only and LC is reading from cells treated with 10 μL staurosporine. IC50 values are calculated using XLFit. Composition Examples [00934] Example 3-1: Parenteral Pharmaceutical Composition. To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, and the like), 100 mg of a water-soluble salt of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection [00935] Example 3-2: Oral Pharmaceutical Composition. To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration. [00936] Example 3-3: Topical Gel Pharmaceutical Composition. To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is mixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration. [00937] Example 3-4: Ophthalmic Solution. To prepare a pharmaceutical opthalmic solution composition, 100 mg of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is mixed with 0.9 g of NaCl in 100 mL of purified water and filterd using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration. * * * [00938] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.