Jak2 inhibitors and their use as pharmaceuticals

Abstract

The disclosure is directed to compounds of Formula I. Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

Description

JAK2 INHIBITORS AND THEIR USE AS PHARMACEUTICALSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 649,083, filed May 17, 2024, the entirety of which is incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure is directed to JAK2 inhibitors and methods of their use.BACKGROUND OF THE INVENTION

[0003] The Janus kinase (JAK) family of kinases (JAK1, JAK2, JAK3, and TYK2) are a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals. JAKs are in the cell selectively associated with the cytoplasmic domains of various cytokine receptors. Receptor-associated JAKs are activated in a ligand-dependent manner. Upon binding of the ligand and subsequent activation, JAKs can phosphorylate another JAK protein on the paired receptor and the intracellular tail of the receptors to which the JAKs are bound. These phosphorylated peptides serve as docking sites for a family of transcription factors, the signal transducers and activators of transcription (STAT). Upon binding of the STATs to the activated receptor-JAK complex, the STATs are phosphorylated, dimerize, and then are translocated to the nucleus where the binding of DNA and regulate gene expression occurs. Alterations in JAK2 signaling can occur through point mutations / deletions / insertions or chromosomal translocations. These JAK2 alterations drive diseases that are primarily characterized by abnormal proliferation of terminally differentiated myeloid cells. Examples of disease with JAK2 alterations are essential thrombocytosis or essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), primary myelofibrosis (PMF), and secondary myelofibrosis (SMF). Clinical features of these diseases include progressive anemia, splenomegaly, and constitutional symptoms (cough, fatigue, puritus, and bone pain).

[0004] Existing compounds that inhibit JAK2 (e.g. ruxoltinib and fedratinib) have been developed for these myeloproliferative indications and have proven beneficial to patients in terms of spleen volume reduction and symptomatic improvement. However, a significant limitation in the clinical effectiveness of existing JAK2 inhibitors has been the inability to achieve clinically effective doses while avoiding toxicity in patients with myeloid proliferative disease, due to their strong inhibition of wildtype JAK2. Treatment of patients with the approved JAK2 inhibitors can result in anemia and thrombocytopenia and these toxicities are consistentwith the known function of wildtype JAK2 in regulation of erythrocytes and platelets. Thus, there exists a need for JAK2 compounds that inhibit mutant JAK2 activity while sparing cytokine-mediated activity of wildtype JAK2, in order to increase the therapeutic window and allow for more complete inhibition of the mutant protein.

[0005] Additional small molecule JAK2 selective inhibitors are needed.SUMMARY OF THE INVENTION

[0006] The disclosure is directed to compounds of Formula I:or a pharmaceutically acceptable salt or solvate thereof, whereinS(O)(=NRb)Rb, -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -C(O)R20, -OC1-C6alkyl, C1-C6alkyl, C1- C6haloalkyl, -C3-C8cycloalkyl, - C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3-C10hetero-cycloalkenyl; wherein said -OC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C3-C10cycloalkenyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; wherein R20is C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6- C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl, or C3-C10heterocycloalkenyl, wherein said - C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, or C3-C10heterocycloalkenyl, are optionally substituted by 1-6 Rfgroups;RA1, RA2, RA3, RA4and RA5are each independently H, D, halo, -CN, C1-C6alkyl, -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, - NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); ritMAANWCyBisB1is CRB1;B2is CRB2or N;B3is CRB3or N;B4is CRB4or N;RB1, RB2, RB3, and RB4are each independently H, D, halo, C1-C6alkyl, C1-C6haloalkyl, - O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, C3-C10heterocycloalkenyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, - S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), - B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3- C10 cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C 10 heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; or RB2and RB3, may, together with the carbon atoms to which they are attached, form a ring structure; or RB3and RB4, may, together with the carbon atoms to which they are attached, form a ring structure; each Rfis independently H, D, oxo, halogen, -O C1-C8alkyl, C1-C8alkyl, haloalkyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, - C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C8alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd;each Rais independently H, D, -C(O)Rb, -C(O)ORC, -C(O)NRcRd, -C(=NRb)NRbRc, - C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORC)2, -P(O)RcRb, -P(O)ORcORb, -S(O)Rb, -S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiR\ -C1-C1oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each Rb, is independently H, D, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each Rcor Rdis independently H, D, -C1-C10 alkyl, -C2-C6alkenyl, -C2-C6alkynyl, -OC1- C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or Rcand Rd, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group; and Cycis a substituted bicyclyl.

[0007] Stereoisomers of the compounds of Formula I, and the pharmaceutical salts and stereoisomers thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula I are described, as well as pharmaceutical compositions including the compounds of Formula I.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0008] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. C6rtain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0009] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-C6alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6alkyl. “Co alkyl” refers to a covalent bond.

[0010] It is further intended that the compounds of the invention are stable. As used herein “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.

[0011] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.

[0012] The term “alkyl,” when used alone or as part of a substituent group, refers to a straighter branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 6 carbons atoms (“C1-C6”), in the group. Examples of alkyl groups include methyl (Me, C1alkyl), ethyl (Et, C2alkyl), n-propyl (C3alkyl), isopropyl (C3alkyl), butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (C3alkyl), isopentyl (C3alkyl), tertpentyl (C3alkyl), hexyl (C6alkyl), isohexyl (C6alkyl), and the like. Alkyl groups may be optionally substituted. Unless otherwise specified, in those embodiments wherein the alkyl group is substituted, the alkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), - OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the alkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; or the alkyl group is optionally substituted by 1-6 Rfgroups.

[0013] The term “halo” or halogen refers to chloro, fluoro, bromo, or iodo.

[0014] The term “cycloalkyl” when used alone or as part of a substituent group refers to cyclic- containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C3-C10”), preferably from 3 to 6 carbon atoms (“C3.C6”). Cycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkyl group, the cyclic groups can share one common atom (i.e., spirocyclic). In other embodiments having at least one multicyclic cycloalkyl group, the cyclic groups share two common atoms (e.g., fused or bridged). Examples of cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopropylmethyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1 -methylcyclopropyl (C4), 2-m ethylcyclopentyl (C4), adamantanyl (C10), spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, and the like. Cycloalkyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the cycloalkyl group is substituted, the cycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkyl, and C1-C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the cycloalkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; or the cycloalkyl group is optionally substituted by 1-6 Rfgroups.

[0015] The term “cycloalkenyl” when used alone or as part of a substituent group refers to monocyclic or multi cyclic, partially saturated ring structure having from 3 to 10 carbon atoms (“C3-C10”), preferably from 3 to 6 carbon atoms (“Cs-C6”). Cycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic cycloalkenyl group, the cyclic groups can share one common atom (z.e., spirocyclic). In other embodiments having at least one multicyclic cycloalkenyl group, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 cycloalkenyl refers to a cycloalkenyl group having between three and six carbon atoms. The cycloalkenyl group may be attached at any carbon atom of the partially saturated ring such that the result is a stable structure. Cycloalkenyl groups include groups in which the partially saturated ring is fused to an aryl group. Examples of cycloalkenyl groups include, for example, cyclopropenyl (C3), cyclobutenyl (C4), cyclopropenylmethyl (C4), cyclopentenyl (C5), cyclohexenyl (C6), 1 -methylcyclopropenyl (C4), 2-m ethylcyclopentenyl (C4), adamantenyl (C10), spiro[3.3]heptenyl, bicyclo[3.3.0]octenyl, indanyl, and the like.Cycloalkenyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the cycloalkenyl group is substituted, the cycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1- C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1- C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and - S(O)2N(C1-C6alkyl)2. In other embodiments, the cycloalkenyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; or the cycloalkenyl group is optionally substituted by 1-6 Rfgroups.

[0016] The term “heterocycloalkyl” when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. Heterocycloalkyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic heterocycloalkyl group, the cyclic groups can share one common atom (z.e., spirocyclic). In other embodiments having at least one multicyclic heterocycloalkyl group, the cyclic groups share two common atoms (e.g.,fused or bridged). The term -C3-C6 heterocycloalkyl refers to a heterocycloalkyl group having between three and six carbon ring atoms. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the group such that the result is a stable structure. Examples of heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl, oxepanyl, dioxepanyl, azocanyl diazocanyl, oxocanyl, dioxocanyl, azaspiro[2.2]pentanyl, oxaazaspiro[3.3]heptanyl, p oxaspiro[3.3]heptanyl, dioxaspiro[3.3]heptanyl, 3-azabicyclo[3.1.0]hexanyl, , and the like. Heteroycloalkyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heterocycloalkyl group is substituted, the heterocycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy, - C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, - S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the heterocycloalkyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, - SRa, -NRaRd, or NRcRd; or the heterocycloalkyl group is optionally substituted by 1-6 Rfgroups.

[0017] The term “heterocycloalkenyl” when used alone or as part of a substituent group refers to any three to twelve membered monocyclic or multicyclic, partially saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. Heterocycloalkenyl groups of the disclosure include monocyclic groups, as well as multicyclic groups such as bicyclic and tricyclic groups. In those embodiments having at least one multicyclic heterocycloalky enyl group, the cyclic groups can share one common atom (z.e., spirocyclic). In other embodiments having at least one multicyclic heterocycloalkenyl group, the cyclic groups share two common atoms (e.g., fused or bridged). The term -C3-C6 heterocycloalkenyl refers to a heterocycloalkenyl group having between three and six carbon atoms. The heterocycloalkenyl group may be attached at any heteroatom or carbon atom of ring system such that the result is a stable structure. Heterocycloalkenyl groups include groups in which the partially saturated ring is fused to an aryl group, such as, for example isoindoline,, or for example a dihydroisoquinolinone such as 3,4-dihydroisoquinolin-l(2H)-one,which the partially saturated ring is fused to a heteroaryl group, such as, for example, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,, wherein represents a point of attachment. Heteroycloalkenyl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heterocycloalkenyl group is substituted, the heterocycloalkenyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), - OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the heterocycloalkenyl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; or the heterocycloalkenyl group is optionally substituted by 1-6 Rfgroups.

[0018] The term “heterocyclic group,” when used alone or as part of a substituent group, refers to a heterocycloalkyl group or a heterocycloalkenyl group.

[0019] The term “heteroaryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to five heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like. Heteroaryl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the heteroaryl group is substituted, the heteroaryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1- C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), - OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the heteroaryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; or the heteroaryl group is optionally substituted by 1-6 Rfgroups.

[0020] The term “aryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic carbon ring structure. Aryl rings can include a total of 5, 6, 7, 8, 9, or 10 ringatoms. Examples of aryl groups include but are not limited to, phenyl, napthyl, and the like. Aryl groups of the disclosure are optionally substituted. Unless otherwise specified, in those embodiments wherein the aryl group is substituted, the aryl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1- C6haloalkyl, and C1-C6haloalkoxy, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1- C6alkyl), -OC(O)N(C1-C6alkyl)2, -S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the aryl group is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; or the aryl group is optionally substituted by 1-6 Rfgroups.

[0021] The term “bicyclyl” refers to a bicyclic ring system, i.e., a moiety that has two joined rings. Bicyclyl groups include fused rings (i.e., the two rings share two adjacent atoms), spirocyclic rings (i.e., the two rings share one common atom) and bridged rings (i.e., the two rings share three or more common atoms). In the bicyclyl groups of the disclosure, the rings that comprise the bicyclyl group may be cycloalkyl, heterocycloalkyl, cycloakenyl, heterocycloalkenyl, aryl, heteroaryl, or any combination thereof. In some embodiments the bicyclyl group is substituted. In some embodiments, the bicyclyl group is substituted by one of more of the groups described herein.

[0022] When a range of carbon atoms is used herein, for example, C1-C6, all ranges, as well as individual numbers of carbon atoms are encompassed, for example, “C1-3” includes C1-3, C1-2, C2. 3, C1, C2, and C3. The term “C1-ealk” refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, -CH2-, -CH(CHs)-, -CH(CH3)-CH2-, and -C(CH3)2-. The term “-Coalk-” refers to a bond.

[0023] The term “Co-C6alk” when used alone or as part of a substituent group refers to an aliphatic linker having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. The term “-C1alk-”, for example, refers to a -CH2-. The term “-Coalk-” refers to a bond.

[0024] Unless otherwise specified, in those embodiments wherein the -C1-C6alkyl, -C1-C10 alkyl, -C1-C8alkoxide, -C2-C6alkenyl, -C2-C1oalkenyl, -C2-C6alkynyl, -C2-C1oalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are substituted, they can be optionally substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy, - C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, -OC(O)NH(C1-C6alkyl), -OC(O)N(C1-C6alkyl)2, - S(O)2NH(C1-C6alkyl), and -S(O)2N(C1-C6alkyl)2. In other embodiments, the -C1-C6alkyl, -C1- C10 alkyl, -C1-C8alkoxide, -C2-C6alkenyl, -C2-C 10 alkenyl, -C2-C6alkynyl, -C2-C1oalkynyl, aryl,heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, - NRaRd, or NRcRd; or the -C1-C6alkyl, -C1-C10 alkyl, -C1-C8alkoxide, -C2-C6alkenyl, -C2- C1oalkenyl, -C2-C6alkynyl, -C2-C1oalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are optionally substituted by 1-6 Rfgroups.

[0025] As used herein, “alkoxy” refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

[0026] As used herein, “hydroxylalkyl” refers to an alkyl group substituted by OH.

[0027] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0028] Compounds of the invention may also include tautomeric forms. All tautomeric forms are encompassed.

[0029] In some embodiments, the compounds of the present invention may exist as rotational isomers. In some embodiments, the compounds of the present invention exist as mixtures of rotational isomers in any proportion. In other embodiments, the compounds of the present invention exist as particular rotational isomers, substantially free of other rotational isomers.

[0030] Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0031] In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at leastabout 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0032] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ’s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 1 (1977) p. 1-19, each of which is incorporated herein by reference in its entirety.

[0033] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0034] A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0035] A “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.

[0036] “Subject” includes humans. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0037] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

[0038] “Compounds of the present disclosure,” and equivalent expressions, are meant to embrace compounds of Formula I as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula I as well as the pharmaceutically acceptable salts, where the context so permits.

[0039] As used herein, the term “isotopic variant” refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance. For example, an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non -radioactive isotopes such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be2H / D, any carbon may be13C, or any nitrogen may be15N, and that the presence and placement of such atoms may be determined within the skill of the art.

[0040] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers,” for example, diastereomers, enantiomers, and atropisomers. The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (A')- stereoisomers at each asymmetric center, or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures, racemic or otherwise, thereof. Where one chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are encompassed by that structure. Where more than one chiral center exists in astructure, but no specific stereochemistry is shown for the centers, all enantiomers and diastereomers, individually or as a mixture, are encompassed by that structure. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0041] The disclosure is directed to compounds of Formula I:or a pharmaceutically acceptable salt or solvate thereof, whereinA2is CRA2or N;A3is CRA3or N;A4is O, S or NRA4;A5is CRA5or N;R1is H, OH, NH2, -NRcRd, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, - S(O)(=NRb)Rb, -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -C(O)R20, -OC1-C6alkyl, C1-C6alkyl, C1- C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or Cs-C1o hetero-cycloalkenyl; wherein said -OC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C3-C10cycloalkenyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; wherein R20is C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6- C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl, or C3-C10heterocycloalkenyl, wherein said - C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, or C3-C10heterocycloalkenyl, are optionally substituted by 1-6 Rfgroups;RA1, RA2, RA3, RA4and RA5are each independently H, D, halo, -CN, C1-C6alkyl, -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(0)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb);B1is CRB1;B2is CRB2or N;B3is CRB3or N;B4is CRB4or N;RB1, RB2, RB3, and RB4are each independently H, D, halo, C1-C6alkyl, C1-C6haloalkyl, - O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, C3-C10heterocycloalkenyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, - S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), - B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3- C10 cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C 10 heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; or RB2and RB3, may, together with the carbon atoms to which they are attached, form a ring structure; or RB3and RB4, may, together with the carbon atoms to which they are attached, form a ring structure; each Rfis independently H, D, oxo, halogen, -OC1-C8alkyl, C1-C8alkyl, haloalkyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, - C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C8alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; each Rais independently H, D, -C(O)Rb, -C(O)ORC, -C(O)NRcRd, -C(=NRb)NRbRc, - C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORc)2, -P(O)RcRb, -P(O)ORcORb, -S(O)Rb, -S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiR\ -C1-C1oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;each Rb, is independently H, D, -C1-C6alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each Rcor Rdis independently H, D, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1- C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or Rcand Rd, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group; and Cycis a substituted bicyclyl.

[0042] In some embodiments, CyAin Formulaother

[0043] In some embodiments, A1in CyAin Formula (I) is CRA1or N. In some embodiments, A1in CyAin Formula (I) is CRA1. In other embodiments, A1in CyAin Formula (I) is N.

[0044] In some embodiments, A2in CyAin Formula (I) is CRA2or N. In some embodiments, A2in CyAin Formula (I) is CRA2. In other embodiments, A2in CyAin Formula (I) is N.

[0045] In some embodiments, A3in CyAin Formula (I) is CRA3or N. In some embodiments, A3in CyAin Formula (I) is CRA3. In other embodiments, A3in CyAin Formula (I) is N.

[0046] In some embodiments, A4in CyAin Formula (I) is O, S or NRA4. In some embodiments, A4in CyAin Formula (I) is NRA4. In other embodiments, A4in CyAin Formula (I) is O. In other embodiments, A4in CyAin Formula (I) is S.

[0047] In some embodiments, A5in CyAin Formula (I) is CRA5or N. In some embodiments, A5in CyAin Formula (I) is CRA5. In other embodiments, A5in CyAin Formula (I) is N.

[0048] In some embodiments, R1in CyAin Formula (I) is H, OH, NH2, -NRcRd, -C(O)ORb, - C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, - C(O)R20, -OC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl or Cs-C1o hetero-cycloalkenyl; wherein said -OC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C3-C10cycloalkenyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0049] In some embodiments, R1in CyAin Formula (I) is H. In some embodiments, R1in CyAin Formula (I) is OH. In some embodiments, R1in CyAin Formula (I) is NH2. In some embodiments, R1in CyAin Formula (I) is -NRcRd. In some embodiments, R1in CyAin Formula (I) is -C(O)ORb. In some embodiments, R1in CyAin Formula (I) is -C(O)NRcRd. In some embodiments, R1in CyAin Formula (I) is -S(O)Rb. In some embodiments, R1in CyAin Formula (I) is -S(O)2NRcRd. In some embodiments, R1in CyAin Formula (I) is -S(O)(=NRb)Rb. In some embodiments, R1in CyAin Formula (I) is -S(O)2Rb. In some embodiments, R1in CyAin Formula (I) is -C(O)NRbORb. In other embodiments, R1in CyAin Formula (I) is -S(O)2ORb. In other embodiments, R1in CyAin Formula (I) is -C(O)R20. In other embodiments, R1in CyAin Formula (I) is -OC1-C6alkyl. In other embodiments, R1in CyAin Formula (I) is C1-C6alkyl. In other embodiments, R1in CyAin Formula (I) is C1-C6haloalkyl. In other embodiments, R1in CyAin Formula (I) is -C3-C8cycloalkyl. In other embodiments, R1in CyAin Formula (I) is -C3- C10 cycloalkenyl. In other embodiments, R1in CyAin Formula (I) is C6-C1o aryl. In yet other embodiments, R1in CyAin Formula (I) is C3-C10heteroaryl. In yet other embodiments, R1in CyAin Formula (I) is C3-C10heterocycloalkyl. In yet other embodiments, R1in CyAin Formula (I) is C3-C10hetero-cycloalkenyl. In yet other embodiments, the -OC1-C6alkyl, C1-C6alkyl, C1- C6haloalkyl, C3-C8cycloalkyl, -C3-C10cycloalkenyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0050] In some embodiments, R20in CyAin Formula (I) is C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, or C3- C10 heterocycloalkenyl, wherein said -C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, or C3-C10heterocycloalkenyl, are optionally substituted by 1-6 Rfgroups.

[0051] In some embodiments, R20in CyAin Formula (I) is C1-C6alkyl. In some embodiments, R20in CyAin Formula (I) is C1-C6haloalkyl. In some embodiments, R20in CyAin Formula (I) is -C3-C8cycloalkyl. In other embodiments, R20in CyAin Formula (I) is -C3-C10cycloalkenyl. In other embodiments, R20in CyAin Formula (I) is C6-C1o aryl. In other embodiments, R20in CyAin Formula (I) is C3-C10heteroaryl. In yet other embodiments, R20in CyAin Formula (I) is C3- C10 heterocycloalkyl. In yet other embodiments, R20in CyAin Formula (I) is C3-C10heterocycloalkenyl. In yet other embodiments, the C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3- C10 cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C 10 heterocycloalkyl, or C3-C10heterocycloalkenyl, are optionally substituted by 1-6 Rfgroups.

[0052] In some embodiments, R20in CyAin Formula (I) is C1-C6alkyl, C1-C6haloalkyl, or C3- Cs cycloalkyl, wherein said - C1-C6alkyl, C1-C6haloalkyl, or C3-C8cycloalkyl, is optionally substituted by 1-6 Rfgroups. In some embodiments, R20in CyAin Formula (I) is C1-C6alkyl optionally substituted by 1-6 Rfgroups. In other embodiments, R20in CyAin Formula (I) is C1- C6haloalkyl optionally substituted by 1-6 Rfgroups. In other embodiments, R20in CyAin Formula (I) is C3-C8cycloalkyl optionally substituted by 1-6 Rfgroups.

[0053] In some embodiments, R20in CyAin Formula (I) is a C3-C8cycloalkyl group. In some embodiments, R20in CyAin Formula (I) is a cyclopropyl group. In other embodiments, R20in CyAin Formula (I) is a cyclobutyl group.

[0054] In some embodiments, R1in CyAin Formula (I) isCyAin Formula (I) isIn some embodiments, R1in CyAin Formula (I) isIn some embodiments, R1in CyAin Formula (I) isIn someembodiments, R1in CyAin Formula (I) isIn other embodiments, R1in CyAinO oFormula (I) isIn other embodiments, R1in CyAin Formula (I) is. In other embodiments, R1in CyAin Formula (I) is. In other embodiments, R1in CyAinO OFormula (I) isIn other embodiments, R1in CyAin Formula (I) is. In other embodiments, R1in CyAin Formula (I) is. In yet other embodiments, R1inOCyAin Formula (I) is. In yet other embodiments, R1in CyAin Formula (I) isOO. In yet other embodiments, R1in CyAin Formula (I) is. In yet other embodiments, R1in CyAin Formula (I) is. In yet other embodiments, R1in CyAin. , y embodiments, R1in CyAin Formula (I)In other embodiments, R1in CyAinFormula

[0056] In some embodiments, R1in CyAin Formula (I) is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, or optionally substitutedpyrazolyl. In some embodiments, R1in CyAin Formula (I) is optionally substituted pyridinyl. In other embodiments, R1in CyAin Formula (I) is optionally substituted pyrimidinyl. In other embodiments, R1in CyAin Formula (I) is optionally substituted pyridazinyl. In other embodiments, R1in CyAin Formula (I) is optionally substituted pyrazolyl.

[0057] In some embodiments, R1in CyAin Formula (I) isIn some embodiments, R1in CyAin Formula (I) is. In some embodiments, R1in CyAin Formula (I) isIn other embodiments, R1in CyAin Formula (I) isIn other embodiments, R1in CyAin Formula (other embodiments,R1in CyAin Formula (yet other embodiments, R1in CyAin Formula (I) isIn yet other embodiments, R1in CyAin Formula (I) isIn yet other embodiments, R1in CyAin Formula (

[0058] In some embodiments, RA1in CyAin Formula (I) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, - NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0059] In some embodiments, RA1in CyAin Formula (I) is H. In some embodiments, RA1in CyAin Formula (I) is D. In some embodiments, RA1in CyAin Formula (I) is halo. In someembodiments, RA1in CyAin Formula (I) is C1-C6alkyl. In some embodiments, RA1in CyAin Formula (I) is -OC1-C6alkyl. In some embodiments, RA1in CyAin Formula (I) is C1-C6haloalkyl. In some embodiments, RA1in CyAin Formula (I) is C3-C8cycloalkyl. In some embodiments, RA1in CyAin Formula (I) is -C2-C6 alkenyl. In other embodiments, RA1in CyAin Formula (I) is -C2-C6 alkynyl. In other embodiments, RA1in CyAin Formula (I) is -ORa. In other embodiments, RA1in CyAin Formula (I) is -SRa. In other embodiments, RA1in CyAin Formula (I) is -NRcRd. In other embodiments, RA1in CyAin Formula (I) is -NRaRc. In other embodiments, RA1in CyAin Formula (I) is -C(O)Rb. In other embodiments, RA1in CyAin Formula (I) is -C(O)ORb. In other embodiments, RA1in CyAin Formula (I) is -C(O)NRcRd. In other embodiments, RA1in CyAin Formula (I) is -S(O)Rb. In other embodiments, RA1in CyAin Formula (I) is -S(O)2NRcRd. In other embodiments, RA1in CyAin Formula (I) is - S(O)(=NRb)Rb. In yet other embodiments, RA1in CyAin Formula (I) is -SFs. In yet other embodiments, RA1in CyAin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RA1in CyAin Formula (I) is -P(O)RbRb. In yet other embodiments, RA1in CyAin Formula (I) is - P(O)(ORb)(ORb). In yet other embodiments, RA1in CyAin Formula (I) is -B(ORc)(ORd). In yet other embodiments, RA1in CyAin Formula (I) is -S(O)2Rb. In yet other embodiments, RA1in CyAin Formula (I) is -C(O)NRbORb. In yet other embodiments, RA1in CyAin Formula (I) is S(O)2ORb. In yet other embodiments, RA1in CyAin Formula (I) is -OS(O)2ORb. In yet other embodiments, RA1in CyAin Formula (I) is -OPO(ORb)(ORb).

[0060] In some embodiments, RA2in CyAin Formula (I) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, - NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0061] In some embodiments, RA2in CyAin Formula (I) is H. In some embodiments, RA2in CyAin Formula (I) is D. In some embodiments, RA2in CyAin Formula (I) is halo. In some embodiments, RA2in CyAin Formula (I) is C1-C6alkyl. In some embodiments, RA2in CyAin Formula (I) is -OC1-C6alkyl. In some embodiments, RA2in CyAin Formula (I) is C1-C6haloalkyl. In some embodiments, RA2in CyAin Formula (I) is C3-C8cycloalkyl. In some embodiments, RA2in CyAin Formula (I) is -C2-C6 alkenyl. In other embodiments, RA2in CyAin Formula (I) is -C2-C6 alkynyl. In other embodiments, RA2in CyAin Formula (I) is -ORa. In other embodiments, RA1in CyAin Formula (I) is -SRa. In other embodiments, RA2in CyAin Formula (I) is -NRcRd. In other embodiments, RA2in CyAin Formula (I) is -NRaRc. In otherembodiments, RA2in CyAin Formula (I) is -C(O)Rb. In other embodiments, RA2in CyAin Formula (I) is -C(O)ORb. In other embodiments, RA2in CyAin Formula (I) is -C(O)NRcRd. In other embodiments, RA2in CyAin Formula (I) is -S(O)Rb. In other embodiments, RA2in CyAin Formula (I) is -S(O)2NRcRd. In other embodiments, RA2in CyAin Formula (I) is - S(O)(=NRb)Rb. In yet other embodiments, RA2in CyAin Formula (I) is -SFs. In yet other embodiments, RA2in CyAin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RA2in CyAin Formula (I) is -P(O)RbRb. In yet other embodiments, RA2in CyAin Formula (I) is - P(O)(ORb)(ORb). In yet other embodiments, RA2in CyAin Formula (I) is -B(ORc)(ORd). In yet other embodiments, RA2in CyAin Formula (I) is -S(O)2Rb. In yet other embodiments, RA2in CyAin Formula (I) is -C(O)NRbORb. In yet other embodiments, RA2in CyAin Formula (I) is S(O)2ORb. In yet other embodiments, RA2in CyAin Formula (I) is -OS(O)2ORb. In yet other embodiments, RA2in CyAin Formula (I) is -OPO(ORb)(ORb).

[0062] In some embodiments, RA3in CyAin Formula (I) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, - NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0063] In some embodiments, RA3in CyAin Formula (I) is H. In some embodiments, RA3in CyAin Formula (I) is D. In some embodiments, RA3in CyAin Formula (I) is halo. In some embodiments, RA3in CyAin Formula (I) is C1-C6alkyl. In some embodiments, RA3in CyAin Formula (I) is -OC1-C6alkyl. In some embodiments, RA3in CyAin Formula (I) is C1-C6haloalkyl. In some embodiments, RA3in CyAin Formula (I) is C3-C8cycloalkyl. In some embodiments, RA3in CyAin Formula (I) is -C2-C6 alkenyl. In other embodiments, RA3in CyAin Formula (I) is -C2-C6 alkynyl. In other embodiments, RA3in CyAin Formula (I) is -ORa. In other embodiments, RA3in CyAin Formula (I) is -SRa. In other embodiments, RA3in CyAin Formula (I) is -NRcRd. In other embodiments, RA3in CyAin Formula (I) is -NRaRc. In other embodiments, RA3in CyAin Formula (I) is -C(O)Rb. In other embodiments, RA3in CyAin Formula (I) is -C(O)ORb. In other embodiments, RA3in CyAin Formula (I) is -C(O)NRcRd. In other embodiments, RA3in CyAin Formula (I) is -S(O)Rb. In other embodiments, RA3in CyAin Formula (I) is -S(O)2NRcRd. In other embodiments, RA3in CyAin Formula (I) is - S(O)(=NRb)Rb. In yet other embodiments, RA3in CyAin Formula (I) is -SFs. In yet other embodiments, RA3in CyAin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RA3in CyAin Formula (I) is -P(O)RbRb. In yet other embodiments, RA3in CyAin Formula (I) is -P(O)(ORb)(ORb). In yet other embodiments, RA3in CyAin Formula (I) is -B(ORc)(ORd). In yet other embodiments, RA3in CyAin Formula (I) is -S(O)2Rb. In yet other embodiments, RA3in CyAin Formula (I) is -C(O)NRbORb. In yet other embodiments, RA3in CyAin Formula (I) is S(O)2ORb. In yet other embodiments, RA3in CyAin Formula (I) is -OS(O)2ORb. In yet other embodiments, RA3in CyAin Formula (I) is -OPO(ORb)(ORb).

[0064] In some embodiments, at least one of RA1, RA2, or RA3in CyAin Formula (I) is H. In some embodiments, each of RA1, RA2, or RA3in CyAin Formula (I) is H. In other embodiments, at least one of RA1, RA2, or RA4in CyAin Formula (I) is H. In other embodiments, each of RA1, RA2, or RA4in CyAin Formula (I) is H. In yet other embodiments, at least one of RA1, RA2, RA3or RA5in CyAin Formula (I) is H. In yet other embodiments, each of RA1, RA2, RA3or RA5in CyAin Formula (I) is H.

[0065] In some embodiments, RA4in CyAin Formula (I) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, - NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0066] In some embodiments, RA4in CyAin Formula (I) is H. In some embodiments, RA4in CyAin Formula (I) is D. In some embodiments, RA4in CyAin Formula (I) is halo. In some embodiments, RA4in CyAin Formula (I) is C1-C6alkyl. In some embodiments, RA4in CyAin Formula (I) is -OC1-C6alkyl. In some embodiments, RA4in CyAin Formula (I) is C1-C6haloalkyl. In some embodiments, RA4in CyAin Formula (I) is C3-C8cycloalkyl. In some embodiments, RA4in CyAin Formula (I) is -C2-C6 alkenyl. In other embodiments, RA4in CyAin Formula (I) is -C2-C6 alkynyl. In other embodiments, RA4in CyAin Formula (I) is -ORa. In other embodiments, RA4in CyAin Formula (I) is -SRa. In other embodiments, RA4in CyAin Formula (I) is -NRcRd. In other embodiments, RA4in CyAin Formula (I) is -NRaRc. In other embodiments, RA4in CyAin Formula (I) is -C(O)Rb. In other embodiments, RA4in CyAin Formula (I) is -C(O)ORb. In other embodiments, RA4in CyAin Formula (I) is -C(O)NRcRd. In other embodiments, RA4in CyAin Formula (I) is -S(O)Rb. In other embodiments, RA4in CyAin Formula (I) is -S(O)2NRcRd. In other embodiments, RA4in CyAin Formula (I) is - S(O)(=NRb)Rb. In yet other embodiments, RA4in CyAin Formula (I) is -SFs. In yet other embodiments, RA4in CyAin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RA4in CyAin Formula (I) is -P(O)RbRb. In yet other embodiments, RA4in CyAin Formula (I) is - P(O)(ORb)(ORb). In yet other embodiments, RA4in CyAin Formula (I) is -B(ORc)(ORd). In yetother embodiments, RA4in CyAin Formula (I) is -S(O)2Rb. In yet other embodiments, RA4in CyAin Formula (I) is -C(O)NRbORb. In yet other embodiments, RA4in CyAin Formula (I) is S(O)2ORb. In yet other embodiments, RA4in CyAin Formula (I) is -OS(O)2ORb. In yet other embodiments, RA4in CyAin Formula (I) is -OPO(ORb)(ORb).

[0067] In some embodiments, RA5in CyAin Formula (I) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, - NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0068] In some embodiments, RA5in CyAin Formula (I) is H. In some embodiments, RA5in CyAin Formula (I) is D. In some embodiments, RA5in CyAin Formula (I) is halo. In some embodiments, RA5in CyAin Formula (I) is C1-C6alkyl. In some embodiments, RA5in CyAin Formula (I) is -OC1-C6alkyl. In some embodiments, RA5in CyAin Formula (I) is C1-C6haloalkyl. In some embodiments, RA5in CyAin Formula (I) is C3-C8cycloalkyl. In some embodiments, RA5in CyAin Formula (I) is -C2-C6 alkenyl. In other embodiments, RA5in CyAin Formula (I) is -C2-C6 alkynyl. In other embodiments, RA5in CyAin Formula (I) is -ORa. In other embodiments, RA5in CyAin Formula (I) is -SRa. In other embodiments, RA5in CyAin Formula (I) is -NRcRd. In other embodiments, RA5in CyAin Formula (I) is -NRaRc. In other embodiments, RA5in CyAin Formula (I) is -C(O)Rb. In other embodiments, RA5in CyAin Formula (I) is -C(O)ORb. In other embodiments, RA5in CyAin Formula (I) is -C(O)NRcRd. In other embodiments, RA5in CyAin Formula (I) is -S(O)Rb. In other embodiments, RA5in CyAin Formula (I) is -S(O)2NRcRd. In other embodiments, RA5in CyAin Formula (I) is - S(O)(=NRb)Rb. In yet other embodiments, RA5in CyAin Formula (I) is -SFs. In yet other embodiments, RA5in CyAin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RA5in CyAin Formula (I) is -P(O)RbRb. In yet other embodiments, RA5in CyAin Formula (I) is - P(O)(ORb)(ORb). In yet other embodiments, RA5in CyAin Formula (I) is -B(ORc)(ORd). In yet other embodiments, RA5in CyAin Formula (I) is -S(O)2Rb. In yet other embodiments, RA5in CyAin Formula (I) is -C(O)NRbORb. In yet other embodiments, RA5in CyAin Formula (I) is S(O)2ORb. In yet other embodiments, RA5in CyAin Formula (I) is -OS(O)2ORb. In yet other embodiments, RA5in CyAin Formula (I) is -OPO(ORb)(ORb).

[0069] In some embodiments, CyBin Formula (

[0070] In some embodiments, B1in CyBin Formula (I) is CRB1.

[0071] In some embodiments, B2in CyBin Formula (I) is CRB2or N. In some embodiments, B2in CyBin Formula (I) is CRB2. In other embodiments, B2in CyBin Formula (I) is N.

[0072] In some embodiments, B3in CyBin Formula (I) is CRB3or N. In some embodiments, B3in CyBin Formula (I) is CRB3. In other embodiments, B3in CyBin Formula (I) is N.

[0073] In some embodiments, B4in CyBin Formula (I) is CRB4or N. In some embodiments, B4in CyBin Formula (I) is CRB4. In other embodiments, B4in CyBin Formula (I) is N.

[0074] In some embodiments, RB1in CyBin Formula (I) is H, D, halo, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, - C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0075] In some embodiments, RB1in CyBin Formula (I) is H. In some embodiments, RB1in CyBin Formula (I) is D. In some embodiments, RB1in CyBin Formula (I) is halo. In some embodiments, RB1in CyBin Formula (I) is C1-C6alkyl. In some embodiments, RB1in CyBin Formula (I) is C1-C6haloalkyl. In some embodiments, RB1in CyBin Formula (I) is -O-C1-C6alkyl. In some embodiments, RB1in CyBin Formula (I) is -O-C1-C6haloalkoxyl. In some embodiments, RB1in CyBin Formula (I) is -C3-C8cycloalkyl. In some embodiments, RB1in CyBin Formula (I) is -C3-C10cycloalkenyl. In some embodiments, RB1in CyBin Formula (I) is C6- C10 aryl. In some embodiments, RB1in CyBin Formula (I) is C3-C10heteroaryl. In some embodiments, RB1in CyBin Formula (I) is C3-C10heterocycloalkyl. In other embodiments, RB1in CyBin Formula (I) is C3-C10heterocycloalkenyl. In other embodiments, RB1in CyBin Formula (I) is -OH. In other embodiments, RB1in CyBin Formula (I) is -CN. In other embodiments, RB1in CyBin Formula (I) is -NO2. In other embodiments, RB1in CyBin Formula (I) is -C2-C6 alkenyl. In other embodiments, RB1in CyBin Formula (I) is -C2-C6 alkynyl. In other embodiments, RB1in CyBin Formula (I) is -ORa. In other embodiments, RB1in CyBin Formula (I) is -SRa. In other embodiments, RB1in CyBin Formula (I) is -NRcRd. In other embodiments, RB1in CyBin Formula (I) is -NRaRc. In other embodiments, RB1in CyBin Formula (I) is -C(O)Rb. In other embodiments, RB1in CyBin Formula (I) is -OC(O)Rb. In otherembodiments, RB1in CyBin Formula (I) is -C(O)ORb. In other embodiments, RB1in CyBin Formula (I) is -C(O)NRcRd. In other embodiments, RB1in CyBin Formula (I) is -S(O)Rb. In other embodiments, RB1in CyBin Formula (I) is -S(O)2NRcRd. In other embodiments, RB1in CyBin Formula (I) is -S(O)(=NRb)Rb. In yet other embodiments, RB1in CyBin Formula (I) is - SFs. In yet other embodiments, RB1in CyBin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RB1in CyBin Formula (I) is -P(O)RbRb. In yet other embodiments, RB1in CyBin Formula (I) is -P(O)(ORb)(ORb). In yet other embodiments, RB1in CyBin Formula (I) is - B(ORc)(ORd). In yet other embodiments, RB1in CyBin Formula (I) is -S(O)2Rb. In yet other embodiments, RB1in CyBin Formula (I) is -C(O)NRbORb. In yet other embodiments, RB1in CyBin Formula (I) is -S(O)2ORb. In yet other embodiments, RB1in CyBin Formula (I) is - OS(O)2ORb. In yet other embodiments, RB1in CyBin Formula (I) is -OPO(ORb)(ORb). In yet other embodiments, the C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3- C10 heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0076] In some embodiments, RB1in CyBin Formula (I) is -O-CH3. In some embodiments, RB1in CyBin Formula (I) is -N=S(O)(CH3)2. In other embodiments, RB1in CyBin Formula (I) is -P(O)(CH3)2. In other embodiments, RB1in CyBin Formula (I) is methyl, ethyl or isopropyl. In other embodiments, RB1in CyBin Formula (I) is methyl. In yet other embodiments, RB1in CyBin Formula (I) is ethyl. In yet other embodiments, RB1in CyBin Formula (I) is isopropyl.

[0077] In some embodiments, RB2in CyBin Formula (I) is H, D, halo, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, - C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0078] In some embodiments, RB2in CyBin Formula (I) is H. In some embodiments, RB1in CyBin Formula (I) is D. In some embodiments, RB2in CyBin Formula (I) is halo. In some embodiments, RB2in CyBin Formula (I) is C1-C6alkyl. In some embodiments, RB2in CyBin Formula (I) is C1-C6haloalkyl. In some embodiments, RB2in CyBin Formula (I) is -O-C1-C6alkyl. In some embodiments, RB2in CyBin Formula (I) is -O-C1-C6haloalkoxyl. In someembodiments, RB2in CyBin Formula (I) is -C3-C8cycloalkyl. In some embodiments, RB2in CyBin Formula (I) is -C3-C10cycloalkenyl. In some embodiments, RB2in CyBin Formula (I) is C6- C10 aryl. In some embodiments, RB2in CyBin Formula (I) is C3-C10heteroaryl. In some embodiments, RB2in CyBin Formula (I) is C3-C10heterocycloalkyl. In other embodiments, RB2in CyBin Formula (I) is C3-C10heterocycloalkenyl. In other embodiments, RB2in CyBin Formula (I) is -OH. In other embodiments, RB2in CyBin Formula (I) is -CN. In other embodiments, RB2in CyBin Formula (I) is -NO2. In other embodiments, RB2in CyBin Formula (I) is -C2-C6 alkenyl. In other embodiments, RB2in CyBin Formula (I) is -C2-C6 alkynyl. In other embodiments, RB2in CyBin Formula (I) is -ORa. In other embodiments, RB2in CyBin Formula (I) is -SRa. In other embodiments, RB2in CyBin Formula (I) is -NRcRd. In other embodiments, RB2in CyBin Formula (I) is -NRaRc. In other embodiments, RB2in CyBin Formula (I) is -C(O)Rb. In other embodiments, RB2in CyBin Formula (I) is -OC(O)Rb. In other embodiments, RB2in CyBin Formula (I) is -C(O)ORb. In other embodiments, RB2in CyBin Formula (I) is -C(O)NRcRd. In other embodiments, RB2in CyBin Formula (I) is -S(O)Rb. In other embodiments, RB2in CyBin Formula (I) is -S(O)2NRcRd. In other embodiments, RB2in CyBin Formula (I) is -S(O)(=NRb)Rb. In yet other embodiments, RB2in CyBin Formula (I) is - SFs. In yet other embodiments, RB2in CyBin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RB2in CyBin Formula (I) is -P(O)RbRb. In yet other embodiments, RB2in CyBin Formula (I) is -P(O)(ORb)(ORb). In yet other embodiments, RB2in CyBin Formula (I) is - B(ORc)(ORd). In yet other embodiments, RB2in CyBin Formula (I) is -S(O)2Rb. In yet other embodiments, RB2in CyBin Formula (I) is -C(O)NRbORb. In yet other embodiments, RB2in CyBin Formula (I) is -S(O)2ORb. In yet other embodiments, RB2in CyBin Formula (I) is - OS(O)2ORb. In yet other embodiments, RB2in CyBin Formula (I) is -OPO(ORb)(ORb). In yet other embodiments, the C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3- C10 heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0079] In some embodiments, RB3in CyBin Formula (I) is H, D, halo, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, - C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl,-C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0080] In some embodiments, RB3in CyBin Formula (I) is H. In some embodiments, RB3in CyBin Formula (I) is D. In some embodiments, RB3in CyBin Formula (I) is halo. In some embodiments, RB3in CyBin Formula (I) is C1-C6alkyl. In some embodiments, RB3in CyBin Formula (I) is C1-C6haloalkyl. In some embodiments, RB3in CyBin Formula (I) is -O-C1-C6alkyl. In some embodiments, RB3in CyBin Formula (I) is -O-C1-C6haloalkoxyl. In some embodiments, RB3in CyBin Formula (I) is -C3-C8cycloalkyl. In some embodiments, RB3in CyBin Formula (I) is -C3-C10cycloalkenyl. In some embodiments, RB3in CyBin Formula (I) is C6- C10 aryl. In some embodiments, RB3in CyBin Formula (I) is C3-C10heteroaryl. In some embodiments, RB3in CyBin Formula (I) is C3-C10heterocycloalkyl. In other embodiments, RB3in CyBin Formula (I) is C3-C10heterocycloalkenyl. In other embodiments, RB3in CyBin Formula (I) is -OH. In other embodiments, RB3in CyBin Formula (I) is -CN. In other embodiments, RB3in CyBin Formula (I) is -NO2. In other embodiments, RB3in CyBin Formula (I) is -C2-C6 alkenyl. In other embodiments, RB3in CyBin Formula (I) is -C2-C6 alkynyl. In other embodiments, RB3in CyBin Formula (I) is -ORa. In other embodiments, RB3in CyBin Formula (I) is -SRa. In other embodiments, RB3in CyBin Formula (I) is -NRcRd. In other embodiments, RB3in CyBin Formula (I) is -NRaRc. In other embodiments, RB3in CyBin Formula (I) is -C(O)Rb. In other embodiments, RB3in CyBin Formula (I) is -OC(O)Rb. In other embodiments, RB3in CyBin Formula (I) is -C(O)ORb. In other embodiments, RB3in CyBin Formula (I) is -C(O)NRcRd. In other embodiments, RB3in CyBin Formula (I) is -S(O)Rb. In other embodiments, RB3in CyBin Formula (I) is -S(O)2NRcRd. In other embodiments, RB3in CyBin Formula (I) is -S(O)(=NRb)Rb. In yet other embodiments, RB3in CyBin Formula (I) is - SFs. In yet other embodiments, RB3in CyBin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RB3in CyBin Formula (I) is -P(O)RbRb. In yet other embodiments, RB3in CyBin Formula (I) is -P(O)(ORb)(ORb). In yet other embodiments, RB3in CyBin Formula (I) is - B(ORc)(ORd). In yet other embodiments, RB3in CyBin Formula (I) is -S(O)2Rb. In yet other embodiments, RB3in CyBin Formula (I) is -C(O)NRbORb. In yet other embodiments, RB3in CyBin Formula (I) is -S(O)2ORb. In yet other embodiments, RB3in CyBin Formula (I) is - OS(O)2ORb. In yet other embodiments, RB3in CyBin Formula (I) is -OPO(ORb)(ORb). In yet other embodiments, the C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3- C10 heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0081] In some embodiments, RB4in CyBin Formula (I) is H, D, halo, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl, C3-C 10 heterocycloalkenyl, -OH, -CN, -NO2, - C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, - C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0082] In some embodiments, RB4in CyBin Formula (I) is H. In some embodiments, RB4in CyBin Formula (I) is D. In some embodiments, RB4in CyBin Formula (I) is halo. In some embodiments, RB4in CyBin Formula (I) is C1-C6alkyl. In some embodiments, RB4in CyBin Formula (I) is C1-C6haloalkyl. In some embodiments, RB4in CyBin Formula (I) is -O-C1-C6alkyl. In some embodiments, RB4in CyBin Formula (I) is -O-C1-C6haloalkoxyl. In some embodiments, RB4in CyBin Formula (I) is -C3-C8cycloalkyl. In some embodiments, RB4in CyBin Formula (I) is -C3-C10cycloalkenyl. In some embodiments, RB4in CyBin Formula (I) is C6- C10 aryl. In some embodiments, RB4in CyBin Formula (I) is C3-C10heteroaryl. In some embodiments, RB4in CyBin Formula (I) is C3-C10heterocycloalkyl. In other embodiments, RB4in CyBin Formula (I) is C3-C10heterocycloalkenyl. In other embodiments, RB4in CyBin Formula (I) is -OH. In other embodiments, RB4in CyBin Formula (I) is -CN. In other embodiments, RB4in CyBin Formula (I) is -NO2. In other embodiments, RB4in CyBin Formula (I) is -C2-C6 alkenyl. In other embodiments, RB4in CyBin Formula (I) is -C2-C6 alkynyl. In other embodiments, RB4in CyBin Formula (I) is -ORa. In other embodiments, RB4in CyBin Formula (I) is -SRa. In other embodiments, RB4in CyBin Formula (I) is -NRcRd. In other embodiments, RB4in CyBin Formula (I) is -NRaRc. In other embodiments, RB4in CyBin Formula (I) is -C(O)Rb. In other embodiments, R64in CyBin Formula (I) is -OC(O)Rb. In other embodiments, RB4in CyBin Formula (I) is -C(O)ORb. In other embodiments, RB4in CyBin Formula (I) is -C(O)NRcRd. In other embodiments, RB4in CyBin Formula (I) is -S(O)Rb. In other embodiments, RB4in CyBin Formula (I) is -S(O)2NRcRd. In other embodiments, RB4in CyBin Formula (I) is -S(O)(=NRb)Rb. In yet other embodiments, RB4in CyBin Formula (I) is - SFs. In yet other embodiments, RB4in CyBin Formula (I) is -N=S(O)RbRb. In yet other embodiments, RB4in CyBin Formula (I) is -P(O)RbRb. In yet other embodiments, RB4in CyBin Formula (I) is -P(O)(ORb)(ORb). In yet other embodiments, RB4in CyBin Formula (I) is -B(ORc)(ORd). In yet other embodiments, RB4in CyBin Formula (I) is -S(O)2Rb. In yet other embodiments, RB4in CyBin Formula (I) is -C(O)NRbORb. In yet other embodiments, RB4in CyBin Formula (I) is -S(O)2ORb. In yet other embodiments, RB4in CyBin Formula (I) is - OS(O)2ORb. In yet other embodiments, RB4in CyBin Formula (I) is -OPO(ORb)(ORb). In yet other embodiments, the C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or C3- C10 heterocycloalkenyl are optionally substituted by 1-6 Rfgroups.

[0083] In some embodiments, RB2and RB3in CyBin Formula (I), may, together with the carbon atoms to which they are attached, form a ring structure; or RB3and RB4in CyBin Formula (I), may, together with the carbon atoms to which they are attached, form a ring structure; in CyBin Formula (I), together with the carbon atoms to which they are attached, can form a ring structure. In some embodiments, RB2and RB3, together with the carbon atoms to which they are attached, form a ring structure. In other embodiments, RB3and RB4in CyBin Formula (I), together with the carbon atoms to which they are attached, form a ring structure.

[0084] In some embodiments, each Rfin Formula (I), when present, is independently H, D, oxo, halogen, -OC1-C8alkyl, C1-C8alkyl, haloalkyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -ORa, - SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, - S(O)(=NRb)Rb, -SF5, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); wherein said C1-C8alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd.

[0085] In some embodiments, Rfin Formula (I) is H. In some embodiments, Rfin Formula (I) is D. In some embodiments, Rfin Formula (I) is oxo. In some embodiments, Rfin Formula (I) is halogen. In some embodiments, Rfin Formula (I) is -OC1-C8alkyl. In some embodiments, Rfin Formula (I) is C1-C8alkyl. In some embodiments, the C1-C8alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd. In some embodiments, Rfin Formula I is haloalkyl. In some embodiments, Rfin Formula (I) is -OH. In some embodiments, Rfin Formula (I) is -CN. In some embodiments, Rfin Formula (I) is -NO2. In some embodiments, Rfin Formula (I) is -C2-C6 alkenyl. In some embodiments, Rfin Formula (I) is -C2-C6 alkynyl. In some embodiments, Rfin Formula (I) is aryl. In some embodiments, Rfin Formula (I) is heteroaryl. In some embodiments, Rfin Formula (I) is cycloalkyl. In other embodiments, Rfin Formula (I) is cycloalkenyl. In other embodiments, Rfin Formula (I) is heterocycloalkyl. In other embodiments, Rfin Formula (I) is heterocycloalkenyl. In otherembodiments, Rfin Formula (I) is -ORa. In other embodiments, Rfin Formula (I) is -SRa. In other embodiments, Rfin Formula (I) is -NRcRd. In other embodiments, Rfin Formula (I) is - NRaRc. In other embodiments, Rfin Formula (I) is -C(O)Rb. In other embodiments, Rfin Formula (I) is -OC(O)Rb. In other embodiments, Rfin Formula (I) is -C(O)ORb. In other embodiments, Rfin Formula (I) is -C(O)NRcRd. In yet other embodiments, Rfin Formula (I) is - S(O)Rb. In yet other embodiments, Rfin Formula (I) is -S(O)2NRcRd. In yet other embodiments, Rfin Formula (I) is -S(O)(=NRb)Rb. In yet other embodiments, Rfin Formula (I) is -SFs. In yet other embodiments, Rfin Formula (I) is -P(O)RbRb. In yet other embodiments, Rfin Formula (I) is -P(O)(ORb)(ORb). In yet other embodiments, Rfin Formula (I) is -B(ORc)(ORd). In yet other embodiments, Rfin Formula (I) is -S(O)2Rb. In yet other embodiments, Rfin Formula (I) is - C(O)NRbORb. In yet other embodiments, Rfin Formula (I) is -S(O)2ORb. In yet other embodiments, Rfin Formula (I) is -OS(O)2ORb. In yet other embodiments, Rfin Formula (I) is - OPO(ORb)(ORb).

[0086] In some embodiments, each Rain Formula (I) is independently H, D, -C(O)Rb, - RC)2, --C1oalkyl, - C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0087] In some embodiments, Rain Formula (I) is H. In some embodiments, Rain Formula (I) is D. In some embodiments, Rain Formula (I) is -C(O)Rb. In some embodiments, Rain Formula (I) is -C(O)ORC. In some embodiments, Rain Formula (I) is -C(O)NRcRd. In some embodiments, Rain Formula (I) is -C(=NRb)NRbRc. In some embodiments, Rain Formula (I) is C(=NORb)NRbRc. In some embodiments, Rain Formula (I) is -C(=NCN)NRbRc.

[0088] In other embodiments, Rain Formula (I) is -P(ORC)2, -P(O)RcRb, -P(O)ORcORb, - S(O)Rb, -S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiRb3, and the like. In yet other embodiments, Rain Formula (I) is -C1-C1oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, and the like.

[0089] In some embodiments, each Rbin Formula (I) is independently H, D, -C1-C6alkyl, -C2- C6alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0090] In some embodiments, Rbin Formula (I) is H. In some embodiments, Rbin Formula (I) is D. In some embodiments, Rbin Formula (I) is -C1-C6alkyl. In some embodiments, Rbin Formula (I) is -C2-C6 alkenyl. In some embodiments, Rbin Formula (I) is -C2-C6 alkynyl. Inother embodiments, Rbin Formula (I) is aryl. In other embodiments, Rbin Formula (I) is cycloalkyl. In other embodiments, Rbin Formula (I) is cycloalkenyl. In other embodiments, Rbin Formula (I) is heteroaryl. In other embodiments, Rbin Formula (I) is heterocycloalkyl. In other embodiments, Rbin Formula (I) is heterocycloalkenyl.

[0091] In some embodiments, each Rcor Rdin Formula (I) is independently H, D, -C1-C6alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0092] In some embodiments, Rcor Rdin Formula (I) is H. In some embodiments, Rcor Rdin Formula (I) is D. In some embodiments, Rcor Rdin Formula (I) is -C1-C10 alkyl. In some embodiments, Rcor Rdin Formula (I) is -C2-C6 alkenyl. In some embodiments, Rcor Rdin Formula (I) is -C2-C6 alkynyl. In other embodiments, Rcor Rdin Formula (I) is -OC1-C6alkyl. In other embodiments, Rcor Rdin Formula (I) is -O-cycloalkyl. In other embodiments, Rcor Rdin Formula (I) is aryl. In other embodiments, Rcor Rdin Formula (I) is cycloalkyl. In other embodiments, Rcor Rdin Formula (I) is cycloalkenyl. In other embodiments, Rcor Rdin Formula (I) is heteroaryl. In other embodiments, Rcor Rdin Formula (I) is heterocycloalkyl. In other embodiments, Rcor Rdin Formula (I) is heterocycloalkenyl.

[0093] In yet other embodiments, Rcand Rdin Formula (I), together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group. In yet other embodiments, Rcand Rdin Formula (I) form a monocyclic heterocycloalkyl. In yet other embodiments, Rcand Rdin Formula (I) form a multicyclic heterocycloalkyl. In yet other embodiments, Rcand Rdin Formula (I) form a monocyclic heterocyclo-alkenyl group. In yet other embodiments, Rcand Rdin Formula (I) form a multicyclic heterocyclo-alkenyl group.

[0094] In some embodiments, Cycin Formula (I) is a substituted bicyclyl. In some embodiments, the bicyclyl is substituted with -T-A-R, wherein T, A, and R have the meanings described herein.

[0095] In some embodiments, the compound of Formula (I) is a compound of Formula (la):or a pharmaceutically acceptable salt or solvate thereof; whereinfused bicyclic group ( / .c. , rings Cl and C2 share two atoms and the bonds between those atoms) wherein, ring Cl is an optionally substituted 5-6 membered aryl group or an optionally substituted 5-6 membered heteroaryl group; and ring C2 is a substituted 5-8 membered heterocyclyl group or a substituted 5-8 membered heteroaryl group.

[0096] In some embodiments, ring Cl in Formula (la) is an optionally substituted 5-6 membered aryl group or an optionally substituted 5-6 membered heteroaryl group. In some embodiments, ring Cl in Formula (la) is an optionally substituted 5-6 membered aryl group. In other embodiments, ring Cl in Formula (la)is an optionally substituted 5-6 membered heteroaryl group.

[0097] In some embodiments, ring C2 in Formula (la) is a substituted 5-8 membered heterocyclyl group or a substituted 5-8 membered heteroaryl group. In some embodiments, ring C2 in Formula (la) is a substituted 5-8 membered heterocyclyl group. In other embodiments, ring C2 in Formula (la) is a substituted 5-8 membered heteroaryl group.whereinX1is CRX1or N;X2is CRX2or N;X3is CRX3or N;X4is CRX4or N;X5is CRX5or N;X6is CRX6or N;X7is O, S, C(RX7)2or NRX7;X8is O, S, C(RX8)2or NRX8;X9is O, S or NRX9; p is 0, 1 or 2; q is 0, 1 or 2; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;R2is -T-A-R;T is absent, optionally substituted C1-C6alkyl, -Co-C6alk-, -Co-C6alk-C(0)-Co-C6alk-, - Co-C6alk-O-Co-C6alk-, -Co-C6alk-NRb-Co-C6alk-, optionally substituted Cs-C12cycloalkyl, optionally substituted Cs-C12heterocycloalkyl, -C(O)-, -C(O)NRb-, -NRb-, - C(O)O-, -C(O)NRb-, -S(O)-, -S(O)2NRb-, -S(O)(=NRb)-, -S(O)2-, -C(O)NRbO-, or - S(O)2O-;A is absent, an optionally substituted 5-6 membered aryl group, an optionally substituted 5-6 membered heteroaryl group, an optionally substituted 5-6 membered heterocycloalkyl group, or an optionally substituted 5-6 membered heterocycloalkenyl group, an optionally substituted 5-6 membered cycloalkyl group, or an optionally substituted 5-6 membered cycloalkenyl group;R is absent, H, -CN, -C(O)Rb, -C(O)ORC, -C(O)NRcRd, -C(=NRb)NRbRc, - C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORC)2, -P(O)RcRb, -P(O)ORcORb, -S(O)Rb, - S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiRb3, -C1-C1oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each R3is independently H, D, halo, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1- C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, C3-C10heterocycloalkenyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, - ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, - S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; or two R3groups attached to the same carbon atom form a carbonyl group (i.e., =0); or two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups; or two R3groups attached to adjacent carbon atoms, together with those carbon atoms, form a ring that is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted cycloalkenyl ring, an optionally substituted heterocycloalkyl ring, or an optionally substituted heterocycloalkenyl ring; wherein the ring optionally substituted by 1-6 Rfgroups;RX1, RX2, RX3, RX4, RX5, RX6, RX7RX8and RX9are each independently H, halo, C1-C6alkyl, -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -0Ra, - SRa, -NRcRd, -NRaRc, -C(0)Rb, -0C(0)Rb, -C(0)0Rb, -C(0)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, -SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, - C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); or two RX7or two RX8groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups.

[0099] In some embodiments,embodiments,in Formula (la) isotherin Formulaotherembodiments, other embodiments, in Formulain Formulaother embodiments,yet other embodiments,in Formulayet other embodiments,yet other embodiments, inFormulayet other embodiments,yet other embodiments,

[0100] In some embodiments, X1in Formula (la) is CRX1or N. In some embodiments, X1in Formula (la) is CRX1. In other embodiments, X1in Formula (la) is N.

[0101] In some embodiments, X2in Formula (la) is CRX2or N. In some embodiments, X2in Formula (la) is CRX2. In other embodiments, X2in Formula (la) is N.

[0102] In some embodiments, X3in Formula (la) is CRX3or N. In some embodiments, X3in Formula (la) is CRX3. In other embodiments, X3in Formula (la) is N.

[0103] In some embodiments, X4in Formula (la) is CRX4or N. In some embodiments, X4in Formula (la) is CRX4. In other embodiments, X4in Formula (la) is N.

[0104] In some embodiments, X5in Formula (la) is CRX5or N. In some embodiments, X5in Formula (la) is CRX5. In other embodiments, X5in Formula (la) is N.

[0105] In some embodiments, X6in Formula (la) is CRX6or N. In some embodiments, X6in Formula (la) is CRX6. In other embodiments, X6in Formula (la) is N.

[0106] In some embodiments, X7in Formula (la) is O, S, C(RX7)2 or NRX7. In some embodiments, X7in Formula (la) is C(RX7)2. In some embodiments, X7in Formula (la) is NRX7. In other embodiments, X7in Formula (la) is O. In other embodiments, X7in Formula (la) is S.

[0107] In some embodiments, X8in Formula (la) is O, S, C(RX8)2 or NRX8. In some embodiments, X8in Formula (la) is C(RX8)2. In some embodiments, X8in Formula (la) is NRX8. In other embodiments, X8in Formula (la) is O. In other embodiments, X8in Formula (la) is S.

[0108] In some embodiments, X9in Formula (la) is O, S, or NRX9. In some embodiments, X9in Formula (la) is O. In other embodiments, X9in Formula (la) is S. In other embodiments, X9in Formula (la) is NRX9.

[0109] In some embodiments, p in Formula (la) is 0, 1 or 2. In some embodiments, p in Formula (la) is 0. In other embodiments, p in Formula (la) is 1. In other embodiments, p in Formula (la) is 2.

[0110] In some embodiments, q in Formula (la) is 0, 1 or 2. In some embodiments, q in Formula (la) is 0. In other embodiments, q in Formula (la) is 1. In other embodiments, q in Formula (la) is 2.

[0111] In some embodiments, n in Formula (la) is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In some embodiments, n in Formula (la) is 1. In some embodiments, n in Formula (la) is 2. In some embodiments, n in Formula (la) is 3. In some embodiments, n in Formula (la) is 4. In other embodiments, n in Formula (la) is 5. In other embodiments, n in Formula (la) is 6. In other embodiments, n in Formula (la) is 7. In other embodiments, n in Formula (la) is 8. In yet other embodiments, n in Formula (la) is 9. In yet other embodiments, n in Formula (la) is 10. Inyet other embodiments, n in Formula (la) is 11. In yet other embodiments, n in Formula (la) is 12.

[0112] In some embodiments, R2in Formula (la) is -T-A-R. In some embodiments, R2in Formula (la) is -Co-C6alk-A-R or -Co-C6alk-(CO)-Co-C6alk-A-R. In some embodiments, R2in Formula (la) is -Co-C6alk-A-R. In other embodiments, R2in Formula (la) is -CH2-A-R. In other embodiments, R2in Formula (la) is -Co-C6alk-(CO)-Co-C6alk-A-R. In other embodiments, R2in Formula (la) is -CH2-A-C(O)NRcRd. In yet other embodiments, R2in Formula (la) is -CH2-A- C(O)N(CH3)2. In yet other embodiments, R2in Formula (la) is -C(O)-A-R.

[0113] In some embodiments, T is absent, optionally substituted C1-C6alkyl, -Co-C6alk-, -Co- C6alk-C(0)-Co-C6alk-, -Co-C6alk-O-Co-C6alk-, -Co-C6alk-NRb-Co-C6alk-, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycloalkyl, -C(O)-, -C(O)NRb-, -NRb-, - C(O)O-, -C(O)NRb-, -S(O)-, -S(O)2NRb-, -S(O)(=NRb)-, -S(O)2-, -C(O)NRbO-, or -S(O)2O-.

[0114] In some embodiments, T is absent. In some embodiments, T is optionally substituted C1-6 alkyl. In some embodiments, T is -Co-C6alk-. In some embodiments, T is -Co-C6alk-C(O)- Co-C6alk-. In some embodiments, T is -Co-C6alk-O-Co-C6alk-. In some embodiments, T is -Co- C6alk-NRb-Co-C6alk-. In other embodiments, T is optionally substituted C3-12 cycloalkyl. In other embodiments, T is optionally substituted C3-12 heterocycloalkyl. In other embodiments, T is -C(O)-. In other embodiments, T is -C(O)NRb-. In other embodiments, T is -NRb-. In other embodiments, T is -C(O)O-. In other embodiments, T is -C(O)NRb-. In other embodiments, T is -S(O)-. In yet other embodiments, T is -S(O)2NRb-. In yet other embodiments, T is - S(O)(=NRb)-. In yet other embodiments, T is -S(O)2-. In yet other embodiments, T is - C(O)NRbO-. In yet other embodiments, T is -S(O)2O-.

[0115] In some embodiments, A is absent, an optionally substituted 5-6 membered aryl group, an optionally substituted 5-6 membered heteroaryl group, an optionally substituted 5-6 membered heterocycloalkyl group or an optionally substituted 5-6 membered heterocycloalkenyl group. In some embodiments, A is absent. In some embodiments, A is an optionally substituted 5-6 membered aryl group. In other embodiments, A is an optionally substituted 5-6 membered heteroaryl group. In other embodiments, A is an optionally substituted 5-6 heterocycloalkyl group. In other embodiments, A is an optionally substituted 5-6 membered heterocycloalkenyl group. In yet other embodiments, A is an optionally substituted 5-6 membered cycloalkyl group. In yet other embodiments, A is an optionally substituted 5-6 membered cycloalkenyl group.

[0116] In some embodiments, A is an optionally substituted 6-membered heteroaryl group. In other embodiments, A is an optionally substituted pyridinyl.

[0117] In some embodiments, A is an optionally substituted 5-membered heteroaryl group. In other embodiments, A is an optionally substituted pyrazolyl or thiazolyl. In other embodiments, A is an optionally substituted pyrazolyl. In other embodiments, A is an optionally substituted thiazolyl.

[0118] In some embodiments, A is an optionally substituted 6-membered heterocycloalkyl group. In other embodiments, A is an optionally substituted piperidinyl.

[0119] In some embodiments, A is an optionally substituted 5-membered heterocycloalkyl group. In other embodiments, A is an optionally substituted pyrrolidinyl.

[0120] In some embodiments, A is an optionally substituted 6-membered cycloalkyl group. In other embodiments, A is an optionally substituted cyclohexyl group.

[0121] In some embodiments, A is an optionally substituted 5-membered cycloalkyl group. In other embodiments, A is an optionally substituted cyclopentyl group.

[0122] In some embodiments, A is an optionally substituted 6-membered heterocycloalkenyl group. In other embodiments, A is an optionally substituted 5-membered heterocycloalkenyl group.

[0123] In some embodiments, A is an optionally substituted 6-membered cycloalkenyl group. In other embodiments, A is an optionally substituted 5-membered cycloalkenyl group.

[0124] In some embodiments, R is absent, H, D, -CN, -C(O)Rb, -C(O)ORC, -C(O)NRcRd, - C(=NRb)NRbRc, -C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORC)2, -P(O)RcRb, -P(O)ORcORb, - S(O)Rb, -S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiRb3, -C1-C1oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. In some embodiments, R is absent. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is -CN. In some embodiments, R is -C(O)Rb. In some embodiments, R is -C(O)ORC. In some embodiments, R is -C(O)NRcRd. In some embodiments, R is - C(=NRb)NRbRc. In some embodiments, R is -C(=NORb)NRbRc. In other embodiments, R is - C(=NCN)NRbRc. In other embodiments, R is -P(ORC)2. In other embodiments, R is -P(O)RcRb. In other embodiments, R is -P(O)ORcORb. In other embodiments, R is -S(O)Rb. In other embodiments, R is -S(O)NRcRd. In other embodiments, R is -S(O)2Rb. In other embodiments, R is -S(O)2NRcRd. In other embodiments, R is SiRb3. In other embodiments, R is -C1-C1oalkyl. In other embodiments, R is -C2-C10 alkenyl. In yet other embodiments, R is -C2-C10 alkynyl. In yet other embodiments, R is aryl. In yet other embodiments, R is cycloalkyl. In yet other embodiments, R is cycloalkenyl. In yet other embodiments, R is heteroaryl. In yet other embodiments, R is heterocycloalkyl. In yet other embodiments, R is heterocycloalkenyl.

[0125] In some embodiments, R is H, -CN, -C(O)Rb, -C(O)NRcRd, -S(O)2Rb, or -C1-C1oalkyl, wherein:Rbis H or -C1-C6alkyl; each Rcor Rdis independently H or -C1-C10 alkyl, or Rcand Rd, together with the atom to which they are both attached, form a monocyclic heterocycloalkyl ring that is optionally substituted with 1-3 C1-C6alkyl or fluoro groups. In some embodiments, Rcand Rdare -CH3.

[0126] In some embodiments, R2is -CH2-A-C(O)NRcRd, wherein each Rcor Rdis independently H or -C1-C10 alkyl, or Rcand Rd, together with the atom to which they are both attached, form a monocyclic heterocycloalkyl ring that is optionally substituted with 1-3 C1-C6alkyl or fluoro groups. In some embodiments, Rcand Rdare -CH3., some embodiments, R2is, other embodiments, R2isIn other embodiments, R2isIn other embodiments, R2isIn yet other embodiments, R2isIn yet other embodiments,yet other embodiments,

[0128] In some embodiments,some embodiments, R2is,

[0129] In some embodiments, each R3in Formula (la) is independently H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, - SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, - S(O)(=NRb)Rb, -SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, - C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0130] In some embodiments, each R3in Formula (la) is H. In some embodiments, each R3in Formula (la) is D. In some embodiments, each R3in Formula (la) is halo. In some embodiments, each R3in Formula (la) is C1-C6alkyl. In some embodiments, each R3in Formula (la) is -OC1-C6alkyl. In some embodiments, each R3in Formula (la) is C1-C6haloalkyl. In some embodiments, each R3in Formula (la) is C3-C8cycloalkyl. In some embodiments, each R3in Formula (la) is -C2-C6 alkenyl. In other embodiments, each R3in Formula (la) is -C2-C6 alkynyl. In other embodiments, each R3in Formula (la) is -ORa. In other embodiments, each R3in Formula (la) is -SRa. In other embodiments, each R3in Formula (la) is -NRcRd. In other embodiments, each R3in Formula (la) is -NRaRc. In other embodiments, each R3in Formula (la) is -C(O)Rb. In other embodiments, each R3in Formula (la) is -C(O)ORb. In other embodiments, each R3in Formula (la) is -C(O)NRcRd. In other embodiments, each R3in Formula (la) is - S(O)Rb. In other embodiments, each R3in Formula (la) is -S(O)2NRcRd. In other embodiments, each R3in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, each R3in Formula (la) is -SF5. In yet other embodiments, each R3in Formula (la) is -N=S(O)RbRb. In yet other embodiments, each R3in Formula (la) is -P(O)RbRb. In yet other embodiments, each R3in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, each R3in Formula (la) is - B(ORc)(ORd). In yet other embodiments, each R3in Formula (la) is -S(O)2Rb. In yet other embodiments, each R3in Formula (la) is -C(O)NRbORb. In yet other embodiments, each R3in Formula (la) is S(O)2ORb. In yet other embodiments, each R3in Formula (la) is -OS(O)2ORb. In yet other embodiments, each R3in Formula (la) is -OPO(ORb)(ORb).

[0131] In some embodiments, at least one R3in Formula (la) is H. In some embodiments, at least one R3in Formula (la) is D. In some embodiments, at least one R3in Formula (la) is halo. In some embodiments, at least one R3in Formula (la) is C1-C6alkyl. In some embodiments, atleast one R3in Formula (la) is -OC1-C6alkyl. In some embodiments, at least one R3in Formula (la) is C1-C6haloalkyl. In some embodiments, at least one R3in Formula (la) is C3-C8cycloalkyl. In some embodiments, at least one R3in Formula (la) is -C2-C6 alkenyl. In other embodiments, at least one R3in Formula (la) is -C2-C6 alkynyl. In other embodiments, at least one R3in Formula (la) is -ORa. In other embodiments, at least one R3in Formula (la) is -SRa. In other embodiments, at least one R3in Formula (la) is -NRcRd. In other embodiments, at least one R3in Formula (la) is -NRaRc. In other embodiments, at least one R3in Formula (la) is - C(O)Rb. In other embodiments, at least one R3in Formula (la) is -C(O)ORb. In other embodiments, at least one R3in Formula (la) is -C(O)NRcRd. In other embodiments, at least one R3in Formula (la) is -S(O)Rb. In other embodiments, at least one R3in Formula (la) is - S(O)2NRcRd. In other embodiments, at least one R3in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, at least one R3in Formula (la) is -SFs. In yet other embodiments, at least one R3in Formula (la) is -N=S(O)RbRb. In yet other embodiments, at least one R3in Formula (la) is -P(O)RbRb. In yet other embodiments, at least one R3in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, at least one R3in Formula (la) is -B(ORc)(ORd). In yet other embodiments, at least one R3in Formula (la) is -S(O)2Rb. In yet other embodiments, at least one R3in Formula (la) is -C(O)NRbORb. In yet other embodiments, at least one R3in Formula (la) is S(O)2ORb. In yet other embodiments, at least one R3in Formula (la) is -OS(O)2ORb. In yet other embodiments, at least one R3in Formula (la) is -OPO(ORb)(ORb).

[0132] In some embodiments, two R3groups attached to the same carbon atom form a carbonyl group (i.e., =0).

[0133] In some embodiments, two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups. In some embodiments, the spirocyclic ring that is an optionally substituted cycloalkyl ring. In some embodiments, the spirocyclic ring that is an optionally substituted heterocycloalkyl ring. In other embodiments, the spirocyclic ring that is an optionally substituted cycloalkenyl ring. In other embodiments, the spirocyclic ring that is an optionally substituted heterocycloalkenyl ring.

[0134] In some embodiments, two R3groups attached to adjacent carbon atoms, together with those carbon atoms, form a ring that is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted cycloalkenyl ring, an optionally substituted heterocycloalkyl ring, or an optionally substitutedheterocycloalkenyl ring; wherein the ring optionally substituted by 1-6 Rfgroups. In some embodiments, the ring is an optionally substituted aryl ring. In some embodiments, the ring is an optionally substituted heteroaryl ring. In other embodiments, the ring that is an optionally substituted cycloalkyl ring. In other embodiments, the ring is an optionally substituted heterocycloalkyl ring. In yet other embodiments, the ring that is an optionally substituted cycloalkenyl ring. In yet other embodiments, the ring is an optionally substituted heterocycloalkenyl ring.

[0135] In some embodiments, two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cyclopropyl ring, or any optionally substituted cyclobutyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups. In other embodiments, two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cyclopropyl ring, or any optionally substituted cyclobutyl ring, wherein the ring is optionally substituted by 1-2 -F.

[0136] In some embodiments, RX1in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, - N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0137] In some embodiments, RX1in Formula (la) is H. In some embodiments, RX1in Formula (la) is D. In some embodiments, RX1in in Formula (la) is halo. In some embodiments, RX1in Formula (la) is C1-C6alkyl. In some embodiments, RX1in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX1in Formula (la) is C1-C6haloalkyl. In some embodiments, RX1in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX1in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX1in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX1in Formula (la) is -ORa. In other embodiments, RX1in Formula (la) is -SRa. In other embodiments, RX1in Formula (la) is -NRcRd. In other embodiments, RX1in Formula (la) is - NRaRc. In other embodiments, RX1in Formula (la) is -C(O)Rb. In other embodiments, RX1in Formula (la) is -C(O)ORb. In other embodiments, RX1in Formula (la) is -C(O)NRcRd. In other embodiments, RX1in Formula (la) is -S(O)Rb. In other embodiments, RX1in Formula (la) is - S(O)2NRcRd. In other embodiments, RX1in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX1in Formula (la) is -SFs. In yet other embodiments, RX1in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX1in Formula (la) is -P(O)RbRb. In yet other embodiments, RX1in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX1inFormula (la) is -B(ORc)(ORd). In yet other embodiments, RX1in Formula (la) is -S(O)2Rb. In yet other embodiments, RX1in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX1in Formula (la) is S(O)2ORb. In yet other embodiments, RX1in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX1in Formula (la) is -OPO(ORb)(ORb).

[0138] In some embodiments, RX1in in Formula (la) is H or -OC1-C6alkyl. In some embodiments, RX1in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX1in in Formula (la) is -OCH3, -OCH2CH3, or -OCH(CH3)2. In some embodiments, RX1in in Formula (la) is - OCH3. In other embodiments, RX1in in Formula (la) is -OCH2CH3. In other embodiments, RX1in in Formula (la) is -OCH(CH3)2.

[0139] In some embodiments, RX2in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, - N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0140] In some embodiments, RX2in Formula (la) is H. In some embodiments, RX2in Formula (la) is D. In some embodiments, RX2in in Formula (la) is halo. In some embodiments, RX2in Formula (la) is C1-C6alkyl. In some embodiments, RX2in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX2in Formula (la) is C1-C6haloalkyl. In some embodiments, RX2in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX2in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX2in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX2in Formula (la) is -ORa. In other embodiments, RX2in Formula (la) is -SRa. In other embodiments, RX2in Formula (la) is -NRcRd. In other embodiments, RX2in Formula (la) is - NRaRc. In other embodiments, RX2in Formula (la) is -C(O)Rb. In other embodiments, RX2in Formula (la) is -C(O)ORb. In other embodiments, RX2in Formula (la) is -C(O)NRcRd. In other embodiments, RX2in Formula (la) is -S(O)Rb. In other embodiments, RX2in Formula (la) is - S(O)2NRcRd. In other embodiments, RX2in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX2in Formula (la) is -SFs. In yet other embodiments, RX2in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX2in Formula (la) is -P(O)RbRb. In yet other embodiments, RX2in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX2in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX2in Formula (la) is -S(O)2Rb. In yet other embodiments, RX2in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX2in Formula (la) is S(O)2ORb. In yet other embodiments, RX2in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX2in Formula (la) is -OPO(ORb)(ORb).

[0141] In some embodiments, RX3in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, - N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0142] In some embodiments, RX3in Formula (la) is H. In some embodiments, RX3in Formula (la) is D. In some embodiments, RX3in in Formula (la) is halo. In some embodiments, RX3in Formula (la) is C1-C6alkyl. In some embodiments, RX3in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX3in Formula (la) is C1-C6haloalkyl. In some embodiments, RX3in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX3in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX3in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX3in Formula (la) is -ORa. In other embodiments, RX3in Formula (la) is -SRa. In other embodiments, RX3in Formula (la) is -NRcRd. In other embodiments, RX3in Formula (la) is - NRaRc. In other embodiments, RX3in Formula (la) is -C(O)Rb. In other embodiments, RX3in Formula (la) is -C(O)ORb. In other embodiments, RX3in Formula (la) is -C(O)NRcRd. In other embodiments, RX3in Formula (la) is -S(O)Rb. In other embodiments, RX3in Formula (la) is - S(O)2NRcRd. In other embodiments, RX3in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX3in Formula (la) is -SFs. In yet other embodiments, RX3in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX3in Formula (la) is -P(O)RbRb. In yet other embodiments, RX3in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX3in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX3in Formula (la) is -S(O)2Rb. In yet other embodiments, RX3in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX3in Formula (la) is S(O)2ORb. In yet other embodiments, RX3in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX3in Formula (la) is -OPO(ORb)(ORb).

[0143] In some embodiments, RX4in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, - N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0144] In some embodiments, RX4in Formula (la) is H. In some embodiments, RX4in Formula (la) is D. In some embodiments, RX4in in Formula (la) is halo. In some embodiments, RX4in Formula (la) is C1-C6alkyl. In some embodiments, RX4in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX4in Formula (la) is C1-C6haloalkyl. In some embodiments, RX4in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX4in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX4in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX4in Formula (la) is -ORa. In other embodiments, RX4in Formula (la) is -SRa. In other embodiments, RX4in Formula (la) is -NRcRd. In other embodiments, RX4in Formula (la) is - NRaRc. In other embodiments, RX4in Formula (la) is -C(O)Rb. In other embodiments, RX4in Formula (la) is -C(O)ORb. In other embodiments, RX4in Formula (la) is -C(O)NRcRd. In other embodiments, RX4in Formula (la) is -S(O)Rb. In other embodiments, RX4in Formula (la) is - S(O)2NRcRd. In other embodiments, RX4in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX4in Formula (la) is -SFs. In yet other embodiments, RX4in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX4in Formula (la) is -P(O)RbRb. In yet other embodiments, RX4in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX4in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX4in Formula (la) is -S(O)2Rb. In yet other embodiments, RX4in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX4in Formula (la) is S(O)2ORb. In yet other embodiments, RX4in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX4in Formula (la) is -OPO(ORb)(ORb).

[0145] In some embodiments, RX5in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, - N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0146] In some embodiments, RX5in Formula (la) is H. In some embodiments, RX5in Formula (la) is D. In some embodiments, RX5in in Formula (la) is halo. In some embodiments, RX5in Formula (la) is C1-C6alkyl. In some embodiments, RX5in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX5in Formula (la) is C1-C6haloalkyl. In some embodiments, RX5in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX5in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX5in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX5in Formula (la) is -ORa. In other embodiments, RX5in Formula (la) is -SRa. In other embodiments, RX5in Formula (la) is -NRcRd. In other embodiments, RX5in Formula (la) is - NRaRc. In other embodiments, RX5in Formula (la) is -C(O)Rb. In other embodiments, RX5in Formula (la) is -C(O)ORb. In other embodiments, RX5in Formula (la) is -C(O)NRcRd. In other embodiments, RX5in Formula (la) is -S(O)Rb. In other embodiments, RX5in Formula (la) is - S(O)2NRcRd. In other embodiments, RX4in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX5in Formula (la) is -SFs. In yet other embodiments, RX5in Formula (la) is -N=S(O)RbRb. In yet other embodiments, RX5in Formula (la) is -P(O)RbRb. In yet other embodiments, RX5in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX5in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX5in Formula (la) is -S(O)2Rb. In yet other embodiments, RX5in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX5in Formula (la) is S(O)2ORb. In yet other embodiments, RX5in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX5in Formula (la) is -OPO(ORb)(ORb).

[0147] In some embodiments, RX6in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, - N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0148] In some embodiments, RX6in Formula (la) is H. In some embodiments, RX6in Formula (la) is D. In some embodiments, RX6in in Formula (la) is halo. In some embodiments, RX6in Formula (la) is C1-C6alkyl. In some embodiments, RX6in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX6in Formula (la) is C1-C6haloalkyl. In some embodiments, RX5in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX6in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX6in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX6in Formula (la) is -ORa. In other embodiments, RX6in Formula (la) is -SRa. In other embodiments, RX6in Formula (la) is -NRcRd. In other embodiments, RX6in Formula (la) is - NRaRc. In other embodiments, RX6in Formula (la) is -C(O)Rb. In other embodiments, RX6in Formula (la) is -C(O)ORb. In other embodiments, RX6in Formula (la) is -C(O)NRcRd. In other embodiments, RX6in Formula (la) is -S(O)Rb. In other embodiments, RX6in Formula (la) is - S(O)2NRcRd. In other embodiments, RX6in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX6in Formula (la) is -SFs. In yet other embodiments, RX6in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX6in Formula (la) is -P(O)RbRb. In yet other embodiments, RX6in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX6in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX6in Formula (la) is -S(O)2Rb. In yet other embodiments, RX6in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX6in Formula (la) is S(O)2ORb. In yet other embodiments, RX6in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX6in Formula (la) is -OPO(ORb)(ORb).

[0149] In some embodiments, RX7in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(0)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0150] In some embodiments, RX7in Formula (la) is H. In some embodiments, RX7in Formula (la) is D. In some embodiments, RX7in in Formula (la) is halo. In some embodiments, RX7in Formula (la) is C1-C6alkyl. In some embodiments, RX7in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX7in Formula (la) is C1-C6haloalkyl. In some embodiments, RX7in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX7in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX7in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX7in Formula (la) is -ORa. In other embodiments, RX7in Formula (la) is -SRa. In other embodiments, RX7in Formula (la) is -NRcRd. In other embodiments, RX7in Formula (la) is - NRaRc. In other embodiments, RX7in Formula (la) is -C(O)Rb. In other embodiments, RX7in Formula (la) is -C(O)ORb. In other embodiments, RX7in Formula (la) is -C(O)NRcRd. In other embodiments, RX7in Formula (la) is -S(O)Rb. In other embodiments, RX7in Formula (la) is - S(O)2NRcRd. In other embodiments, RX7in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX7in Formula (la) is -SFs. In yet other embodiments, RX7in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX7in Formula (la) is -P(O)RbRb. In yet other embodiments, RX7in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX7in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX7in Formula (la) is -S(O)2Rb. In yet other embodiments, RX7in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX7in Formula (la) is S(O)2ORb. In yet other embodiments, RX7in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX7in Formula (la) is -OPO(ORb)(ORb).

[0151] In some embodiments, two RX7groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups. In some embodiments, the spirocyclic ring that is an optionally substituted cycloalkyl ring. In some embodiments, the spirocyclic ring that is an optionally substituted heterocycloalkyl ring. In other embodiments, the spirocyclic ring that is an optionally substituted cycloalkenyl ring. In other embodiments, the spirocyclic ring that is an optionally substituted heterocycloalkenyl ring.

[0152] In some embodiments, RX8in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0153] In some embodiments, RX8in Formula (la) is H. In some embodiments, RX8in Formula (la) is D. In some embodiments, RX8in in Formula (la) is halo. In some embodiments, RX8in Formula (la) is C1-C6alkyl. In some embodiments, RX8in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX8in Formula (la) is C1-C6haloalkyl. In some embodiments, RX8in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX8in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX8in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX8in Formula (la) is -ORa. In other embodiments, RX8in Formula (la) is -SRa. In other embodiments, RX8in Formula (la) is -NRcRd. In other embodiments, RX8in Formula (la) is - NRaRc. In other embodiments, RX8in Formula (la) is -C(O)Rb. In other embodiments, RX8in Formula (la) is -C(O)ORb. In other embodiments, RX8in Formula (la) is -C(O)NRcRd. In other embodiments, RX8in Formula (la) is -S(O)Rb. In other embodiments, RX8in Formula (la) is - S(O)2NRcRd. In other embodiments, RX8in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX8in Formula (la) is -SFs. In yet other embodiments, RX8in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX8in Formula (la) is -P(O)RbRb. In yet other embodiments, RX8in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX8in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX8in Formula (la) is -S(O)2Rb. In yet other embodiments, RX8in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX8in Formula (la) is S(O)2ORb. In yet other embodiments, RX8in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX8in Formula (la) is -OPO(ORb)(ORb).

[0154] In some embodiments, two RX8groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups. In some embodiments, the spirocyclic ring that is an optionally substituted cycloalkyl ring. In some embodiments, the spirocyclic ring that is an optionally substituted heterocycloalkyl ring. In other embodiments, the spirocyclic ring that is an optionally substituted cycloalkenyl ring. In other embodiments, the spirocyclic ring that is an optionally substituted heterocycloalkenyl ring.

[0155] In some embodiments, RX9in Formula (la) is H, D, halo, C1-C6alkyl or -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, - C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(0)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb).

[0156] In some embodiments, RX9in Formula (la) is H. In some embodiments, RX9in Formula (la) is D. In some embodiments, RX9in in Formula (la) is halo. In some embodiments, RX9in Formula (la) is C1-C6alkyl. In some embodiments, RX9in in Formula (la) is -OC1-C6alkyl. In some embodiments, RX9in Formula (la) is C1-C6haloalkyl. In some embodiments, RX9in Formula (la) is C3-C8cycloalkyl. In some embodiments, RX8in Formula (la) is -C2-C6 alkenyl. In other embodiments, RX9in Formula (la) is -C2-C6 alkynyl. In other embodiments, RX9in Formula (la) is -ORa. In other embodiments, RX9in Formula (la) is -SRa. In other embodiments, RX9in Formula (la) is -NRcRd. In other embodiments, RX9in Formula (la) is - NRaRc. In other embodiments, RX9in Formula (la) is -C(O)Rb. In other embodiments, RX9in Formula (la) is -C(O)ORb. In other embodiments, RX9in Formula (la) is -C(O)NRcRd. In other embodiments, RX9in Formula (la) is -S(O)Rb. In other embodiments, RX9in Formula (la) is - S(O)2NRcRd. In other embodiments, RX9in Formula (la) is -S(O)(=NRb)Rb. In yet other embodiments, RX9in Formula (la) is -SFs. In yet other embodiments, RX9in Formula (la) is - N=S(O)RbRb. In yet other embodiments, RX9in Formula (la) is -P(O)RbRb. In yet other embodiments, RX9in Formula (la) is -P(O)(ORb)(ORb). In yet other embodiments, RX9in Formula (la) is -B(ORc)(ORd). In yet other embodiments, RX9in Formula (la) is -S(O)2Rb. In yet other embodiments, RX9in Formula (la) is -C(O)NRbORb. In yet other embodiments, RX9in Formula (la) is S(O)2ORb. In yet other embodiments, RX9in Formula (la) is -OS(O)2ORb. In yet other embodiments, RX9in Formula (la) is -OPO(ORb)(ORb).in Formula (la) isin Formula (la) isin Formula (la) isin Formula (la) isyet other embodiments,yet other embodiments,other embodiments,yet other embodiments,in Formula (la) isin Formulaembodiments, some embodiments, in Formulaother embodiments,in Formulaother embodiments,inembodiments,in Formula ( yet other embodiments, inFormula ( yet other embodiments, in Formula (In yet other embodiments,in Formulaembodiments,in Formula ( some embodiments, in Formulain Formulaembodiments,in Formula (other embodiments, in Formulaembodiments,in Formula (other embodiments,in Formulaother embodiments,in Formulayet other embodiments,other embodiments,in Formula

[0163] In some embodiments, CyBin Formula (I) or FormulaIn some embodiments, CyBin Formula (I) or Formulasomeother embodiments, CyBin Formula (I) or Formulaother embodiments, CyBin Formula (I) orIn yet other embodiments, CyBin Formula (I) or Formula

[0164] In some embodiments, B1in CyBin Formula (I) or Formula (la) is CRB1.

[0165] In some embodiments, RB1in CyBin Formula (I) or Formula (la) is -O-C1-C6alkyl or -P(O)RbRb, wherein said -O-C1-C6alkyl is optionally substituted by 1-6 Rfgroups.

[0166] In some embodiments, RB1in CyBin Formula (I) or Formula (la) is -C1-C6alkyl or - O-C1-C6alkyl. In some embodiments, RB1in CyBin Formula (I) or Formula (la) is -O-C1-C6alkyl. In other embodiments, RB1in CyBin Formula (I) or Formula (la) is -O-CH3.

[0167] In some embodiments, RB1in CyBin Formula (I) or Formula (la) is -C1-C6alkyl. In some embodiments, RB1in CyBin Formula (I) or Formula (la) is methyl, trifluoromethyl, ethyl or isopropyl. In other embodiments, RB1in CyBin Formula (I) or Formula (la) is methyl. In other embodiments, RB1in CyBin Formula (I) or Formula (la) is trifluoromethyl. In other embodiments, RB1in CyBin Formula (I) or Formula (la) is ethyl. In other embodiments, RB1in CyBin Formula (I) or Formula (la) is isopropyl.

[0168] In some embodiments, CyBin Formula (I) or FormulaIn other embodiments, CyBin Formula (I) or Formulayet other embodiments, CyBin Formula (I) or Formula (yet other embodiments,CyBin Formula (I) orFormula (

[0169] In some embodiments, CyAin Formula (I) or Formula

[0170] In some embodiments, CyAin Formula (I) or Formula (. In some embodiments, CyAin Formula (I) or Formula (la) is . In some embodiments, CyAin Formula (I) or Formula (la) isn other embodiments, CyAin Formula (I) or Formula (la) is. In other embodiments, CyAin Formula (I) or Formula (la) is . In yet other embodiments, CyAin Formula (I) or Formula (la) is yet other embodiments, CyAin Formula (I) or Formula (la) is

[0171] In some embodiments, CyAin Formula (I) or Formula (

[0172] In some embodiments, CyAin Formula (I) or Formula (. In some embodiments, CyAin Formula (I) or Formula (la) is. In some embodiments, CyAin Formula (I) or Formula (la) isother embodiments, CyAin Formula (I) or Formula (la) is . In other embodiments, CyAin Formula (I) or Formula (la) is . In yet other embodiments, CyAin Formula (I) or Formula (la) is yet other embodiments, CyAin Formula (I) or Formula (la) is

[0173] In some embodiments, CyAin Formula (I) or Formula (

[0174] In some embodiments, CyAin Formula (I) or Formula (Formula (I) or Formula (some embodiments, CyAin Formula (I), other embodiments, CyAin Formula (I) or Formula (la) is . In other embodiments, CyAin Formula (I) or Formula (la) is other embodiments, CyAin Formula (I) or Formula (la) isIn other embodiments, CyAin Formula (I) or Formula (la) is. other embodiments, CyAin Formula (I) or Formula (la) is. In yet other embodiments, CyAin Formula (I) or Formula (la) is yet other embodiments, CyAin Formula (I) or Formula (la) isIn yet other embodiments, CyAin Formula (I) or Formula (la) is

[0175] In some embodiments, CyAin Formula (I) or Formula (

[0176] In some embodiments, CyAin Formula (I) or Formula (CyAin Formula (I) or Formula (some embodiments, CyAinFormula (I) or Formula (some embodiments, CyAin Formula (I)other embodiments, CyAin Formula (I) or Formula

[0177] In some embodiments, R1in CyAin Formula (I) or Formula (la) is H. In some embodiments, R1in CyAin Formula (I) or Formula (la) is C(O)R20. In some embodiments, R1in CyAin Formula (I) or Formula (la) is optionally substituted aryl. In some embodiments, R1in CyAin Formula (I) or Formula (la) is optionally substituted heteroaryl.

[0178] In some embodiments, R1in CyAin Formula (I) or Formula (la) is C1-C6alkyl, C1-C6haloalkyl, or C3-C10heterocycloalkyl, wherein said C1-C6alkyl, C1-C6haloalkyl, C3-C10heterocycloalkyl is optionally substituted by 1-6 Rfgroups. In some embodiments, R1in CyAin Formula (I) or Formula (la) is C1-C6alkyl optionally substituted by 1-6 Rfgroups. In otherembodiments, R1in CyAin Formula (I) or Formula (la) is C1-C6haloalkyl optionally substituted by 1-6 Rfgroups. In other embodiments, R1in CyAin Formula (I) or Formula (la) is C3-C10heterocycloalkyl optionally substituted by 1-6 Rfgroups.

[0179] In some embodiments, R20in CyAin Formula (I) or Formula (la) is a cycloalkyl group. In some embodiments, R20in CyAin Formula (I) or Formula (la) is a cyclopropyl group.

[0180] In yet further embodiments, the compounds of Formula (I) are:6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)-2-methylimidazo[l,2-Z>]pyridazin-8-yl)amino)- 2-methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-3'-oxospiro[cyclopropane-l,r-isoindolin]-2'-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-l-oxo-3,4-dihydrospiro[benzo[c]azepine-5,r-cyclopropan]-2(177)-yl)methyl)- 7V,7V-dimethylpicolinamide;6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-l -oxo-1, 3,4, 5-tetrahydro-2Z7-benzo[c]azepin-2-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-3, 3-dimethyl-l -oxo-3, 4-dihydroisoquinolin-2(lJ7)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-3'-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-2,2-difluoro-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((7-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)- 1 -oxo- 1 ,3 ,4, 5-tetrahydro-2J7-3 ,5 -methanobenzo[c]azepin-2-yl)methyl)-7V,7V- dimethylpicolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-2,2-dimethyl-5-oxo-2,3-dihydrobenzo[ / ][l,4]oxazepin-4(5J7)-yl)methyl)-A,A- dimethylpicolinamide;6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-4-fluoro-l-oxoisoquinolin-2(177)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3 -((2-Aminoimidazo[2, 1 -f\ [ 1 , 2, 4]triazin-4-yl)amino)-2 -methoxyphenyl)- 1 '-oxo- 177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((2-(pyridin-2-ylamino)imidazo[2,l-: / ][l,2,4]triazin-4-yl)amino) phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethylp- icolinamide;6-((6'-(3-((5-(Cyclopropanecarboxamido)pyrazolo[l,5-a]pyrimidin-7-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((2-Aminopyrazolo[l,5-a][l,3,5]triazin-4-yl)amino)-2-methoxyphenyl)-r-oxo- 177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((5-(Cyclopropanecarboxamido)thiazolo[5,4-d]pyrimidin-7-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethylpicolinamide;6-((6'-(3-((5-Aminothiazolo[5,4-J]pyrimidin-7-yl)amino)-2-methoxyphenyl)-r-oxo-177- spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-A,A-dimethylpicolinamide;((6'-(3-((5-Aminothiazolo[5,4-J]pyrimidin-7-yl)amino)-2-methoxyphenyl)-r-oxo-177- spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((2-Aminopyrido[3,2-J]pyrimidin-4-yl)amino)-2-methoxyphenyl)-r-oxo-177- spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)pyrido[3,2-J]pyrimidin-4-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethylpicolinamide;6-((6'-(3-((5-(Cyclopropanecarboxamido)-3J7-imidazo[4,5-Z>]pyridin-7-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;7V-(8-((2-Methoxy-3-(2'-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-r-oxo-2',3'- dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin- 6-yl)cyclopropanecarboxamide;2-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylisonicotinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V- methylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- picolinamide;7V-(8-((3-(2'-((6-(3,3-Difluoropyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-r-oxo-2',3'- dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[l,2- Z>]pyridazin-6-yl)cyclopropanecarboxamide;7V-(8-((3-(2'-((6-Cyanopyridin-2-yl)methyl)-r-oxo-2',3'-dihydro-177-spiro[cyclopropane- l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[l,2-Z>]pyridazin-6-yl)cyclopropane- carboxamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V-ethyl-7V- methylpicolinamide;7V-(8-((2-Methoxy-3-(2'-((l-methyl-177-pyrazol-4-yl)methyl)-r-oxo-2',3'-dihydro-177- spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin-6- yl)cyclopropanecarboxamide;7V-(8-((2-Methoxy-3-(r-oxo-2'-(pyri din-2 -ylmethyl)-2', 3'-dihy dro-177-spiro[cy clo- propane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin-6-yl)cyclopropane- carboxamide;7V-(8-((2-Methoxy-3-(r-oxo-2'-((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2',3'- dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin- 6-yl)cyclopropanecarboxamide;2-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl )-l'-oxo-l' / / -spiro[cyclopropane-l,4'-isoquinolin]-2'(3' / / )-yl)methyl)-AA- dimethylthiazole-4-carboxamide;6'-(3 -((2-Aminoimidazo[2, 1 -f\ [ 1 ,2,4]triazin-4-yl)amino)-2-methoxyphenyl)-2'-((6- (ethylsulfonyl)pyridin-2-yl)methyl)-2',3'-dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-r- one;7V-(4-((3 -(2'-(( 1 -Acetylpiperi din-3 -yl)methyl)- l'-oxo-2', 3 '-dihydro- 177-spiro[cyclo- propane-1, 4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[2, 1 T / ][ 1,2, 4]tri azin-2 - yl)cyclopropanecarboxamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-8'-ethoxy-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- AA-dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl )-l'-oxo-l' / / -spiro[cyclopropane-l,4'-[2,7]naphthyridin]-2'(3' / / )-yl)methyl)-AA- dimethylpicolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-5'-fluoro-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- AA-dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopentane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)- l'-oxo-177-spiro[cy cl obutane- 1,4' -isoquinolin] -2'(377)-yl)methyl)-A,A- dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)-2- methoxyphenyl)-4,4-dimethyl-l -oxo-3, 4-dihydroisoquinolin-2(lH)-yl)methyl)-A,A- dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-l -oxo-3, 4-dihydroisoquinolin-2(lJ7)-yl)methyl)-AA-dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-l-oxoisoquinolin-2(177)-yl)methyl)-AA-dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-4-isopropyl-l-oxo-3,4-dihydroisoquinolin-2(lJ7)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-4-isopropyl-l-oxoisoquinolin-2(lJ7)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((4-Acetyl-6-(3-((6-(cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)- 2-methoxyphenyl)-l-oxoisoquinolin-2(lJ7)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)- 1 -oxophthal azin-2(lJ7)-yl)methyl)-7VTV-dimethylpicolinamide;6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-4-oxoquinazolin-3(4J7)-yl)methyl)-7VTV-dimethylpicolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-3-methyl-7-oxothieno[2,3-c]pyridin-6(7J7)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-3,4,4-trimethyl-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5J7)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-7-oxothieno[2,3-c]pyridin-6(7J7)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5J7)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-4-oxothieno[3,2-c]pyridin-5(4J7)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((2-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-6-oxo-4,6-dihydro-5J7-thieno[2,3-c]pyrrol-5-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- ethoxyphenyl)- l'-oxo-177-spiro[cy cl opropane- 1,4' -isoquinolin] -2'(377)-yl)methyl)-7V, N- dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methyl phenyl )-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V, N- dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)-2- fluorophenyl)-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(4-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)-3- methoxypyri din-2 -yl)-r-oxo-l'H-spiro[cy cl opropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethylpicolinamide;6-((6'-(2-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-3- methoxypyridin-4-yl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-3- methoxypyridin-4-yl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(6-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-5- methoxypyrimidin-4-yl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- A,A-dimethylpicolinamide;6'-(3 -((2-Aminoimidazo[2, 1 -f\ [ 1 ,2,4]triazin-4-yl)amino)-2-methoxy-6-methylphenyl)-2'- ((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2',3'-dihydro-177-spiro[cyclopropane-l,4'- isoquinolin]-l'-one;A-(4-((2 -Methoxy -4-methyl -3-(l'-oxo-2'-((6-(pyrrolidine-l -carbonyl)pyri din-2- yl)methyl)-2',3'-dihydro-r77-spiro[cyclopropane-l,4'-isoquinolin]-6'- yl)phenyl)amino)imidazo[2,l- / |[l,2,4]triazin-2-yl)cyclopropanecarboxamide;6-((6'-(3-((6-Aminoimidazo[l,2-Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r-oxo-177- spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(4-((2-((2,2-Difluoroethyl)amino)imidazo[2,l-: / ][l,2,4]triazin-4-yl)amino)-3- methoxypyri din-2 -yl)-r-oxo-177-spiro[cy cl opropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethylpicolinamide;6-((6'-(3-((2-(l-Fluorocyclopropane-l-carboxamido)imidazo[2,l- / |[l,2,4]triazin-4- yl)amino)-2-m ethoxyphenyl)- r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3 -((2-( 1 -methylcyclopropane- 1 -carboxamido)imidazo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)amino)phenyl)-r-oxo-r77-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((2-(l-(trifluoromethyl)cyclopropane-l-carboxamido)imidazo[2,l- f\ [ 1 ,2,4]triazin-4-yl)amino)phenyl)- 1 '-oxo- 177-spiro[cyclopropane- 1 ,4'-isoquinolin]-2'(3 'H)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(3-((2-(2,2-Difluorocyclopropane-l-carboxamido)imidazo[2,l- / |[l,2,4]triazin-4- yl)amino)-2-m ethoxyphenyl)- r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((2-(spiro[2.2]pentane-l-carboxamido)imidazo[2,l- / |[l,2,4]triazin- 4-yl)amino)phenyl)-r-oxo-r77-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((2-(Cyclobutanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-r77-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3 -((2-(Bicyclo[ 1.1.1 ]pentane-2-carboxamido)imidazo[2, 1 -f\ [ l,2,4]triazin-4- yl)amino)-2-m ethoxyphenyl)- r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(3 -((2-(Bicyclo[ 1.1.1 ]pentane- 1 -carboxamido)imidazo[2, 1 -f\ [ l,2,4]triazin-4- yl)amino)-2-m ethoxyphenyl)- r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(2 -Methoxy-3-((2-(3, 3, 3-trifluoropropanamido)imidazo[2, 1 T / ][ 1,2, 4]triazin-4- yl)amino)phenyl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((2-(2-Cyclopropylacetamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-l'-oxo-l 77-spiro[cyclobutane-l,4'-isoquinolin]-2'(3'77)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-Methoxy-3 -((2-(2-m ethoxy acetamido)imidazo[2, 1 -f\ [ 1 ,2,4]triazin-4- yl)amino)phenyl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((2-(2-Cyanoacetamido)imidazo[2, 1- / 1 [1,2, 4]tri azin-4-yl)amino)-2 -methoxy- phenyl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethylp- icolinamide;Cyclopropyl(4-((3-(2'-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l'-oxo-2',3'-dihydro- l'H-spiro[cyclobutane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[2,l- f] [ 1 , 2, 4]tri azin-2 -yl)carbamate;6-((6'-(2-Methoxy-3 -((6-(pyri din-2 -ylamino)imidazo[ 1 ,2-Z>]pyridazin-8-yl)amino) phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((6-((5-Fluoropyridin-2-yl)amino)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3 -((6-((2,3 -Dihydro-[ 1 ,4]dioxino[2,3 -Z>]pyridin-6-yl)amino)imidazo[ 1,2- Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]- 2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((l-methyl-177-pyrazol-4-yl)amino)imidazo[l,2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((6-methoxypyridazin-3-yl)amino)imidazo[l,2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((l-methyl-177-pyrazol-3-yl)amino)imidazo[l,2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((6-((2,6-Dimethylpyrimidin-4-yl)amino)imidazo[l,2-Z>]pyridazin-8-yl)amino)- 2-methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((5-morpholinopyri din-2 -yl)amino)imidazo[ 1, 2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((6-Acetamidoimidazo[l,2-Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r-oxo- 177-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3 -((6-propionamidoimidazo[ 1 ,2-Z>]pyridazin-8-yl)amino)phenyl)- 1'- oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'J7)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((6-Isobutyramidoimidazo[l,2-Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r- oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'J7)-yl)methyl)-A,A-dimethylpicolinamide; or a pharmaceutically acceptable salt thereof.

[0181] It will be apparent that the compounds of Formula I, including all subgenera described herein, may have multiple stereogenic centers. As a result, there exist multiple stereoisomers(enantiomers and diastereomers) of the compounds of Formula I (and subgenera described herein). The present disclosure contemplates and encompasses each stereoisomer of any compound of Formula I (and subgenera described herein), as well as mixtures of said stereoisomers.

[0182] Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of the disclosure.

[0183] Isotopic variants of the compounds of Formula I (including all subgenera described herein) are also contemplated by the present disclosure.Pharmaceutical Compositions and Methods of Administration

[0184] In some embodiments, the disclosure is directed to pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0185] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0186] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

[0187] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v or v / v.

[0188] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v, or v / v.

[0189] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0190] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w / w, w / v or v / v.

[0191] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g,3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in the range defined by and including any two numbers above).

[0192] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g,0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g,0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g,4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above).

[0193] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0194] The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0195] A pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0196] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same.Pharmaceutical Compositions for Oral Administration.

[0197] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.

[0198] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[0199] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0200] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of theinvention which contain lactose can be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[0201] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0202] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxy-propyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0203] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0204] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration tooccur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0205] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0206] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0207] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0208] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, andmixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0209] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[0210] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[0211] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0212] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di -glycerides; succinylated mono- and diglycerides; citric acid esters of mono- and di -glycerides; and mixtures thereof.

[0213] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl -2 -lacty late, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0214] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0215] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / capryl ate glycerides, polyglyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate,polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE -23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[0216] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; poly oxy ethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0217] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0218] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, s-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate,acetyl tri ethyl citrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, a -caprolactone and isomers thereof, 5-valerolactone and isomers thereof, P-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0219] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[0220] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.

[0221] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0222] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine,ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)-aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0223] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.Pharmaceutical Compositions for Injection.

[0224] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[0225] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0226] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluiditycan be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0227] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery.

[0228] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0229] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[0230] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation.

[0231] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerolmonolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0232] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.

[0233] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.Pharmaceutical Compositions for Inhalation.

[0234] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.Other Pharmaceutical Compositions.

[0235] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis ofTherapeutics, Tenth Edition, McGraw Hill, 2001 ; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty- Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

[0236] Administration of the compounds or pharmaceutical composition of the present invention can be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

[0237] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.

[0238] In some embodiments, a compound of the invention is administered in a single dose.

[0239] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.

[0240] In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0241] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0242] An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0243] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery -inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip / spin coating, spray coating, dip-coating, and / or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in asuitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.

[0244] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5451233; U.S. Pat. No. 5040548; U.S. Pat. No. 5061273; U.S. Pat. No. 5496346; U.S. Pat. No. 5292331; U.S. Pat. No. 5674278; U.S. Pat. No. 3657744; U.S. Pat. No. 4739762; U.S. Pat. No. 5195984; U.S. Pat. No. 5292331 ; U.S. Pat. No. 5674278; U.S. Pat. No. 5879382; U.S. Pat. No. 6344053.

[0245] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.

[0246] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.

[0247] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0248] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.Methods of Use

[0249] The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0250] As used herein, the term "IC50" refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50). EC50 refers to the plasma concentration required for obtaining 50% of a maximum effect in vivo.

[0251] In some aspects, the present disclosure provides a method of modulating JAK2 activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof.

[0252] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0253] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.Treatment of Disorders

[0254] Provided compounds are inhibitors of JAK2 and are therefore useful for treating one or more disorders associated with activity of JAK2 or mutants thereof. Thus, in certain embodiments, the present disclosure provides a method of treating a JAK2 -mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing, to a subject in need thereof. In certain embodiments, the present disclosure provides a method of treating a JAK2 -mediated disorder in a subject comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a subject in need thereof In some embodiments, the subject has a mutant JAK2. In some embodiments, the subject has JAK2 containing a V617F mutations.

[0255] As used herein, the term “JAK2 -mediated” disorders, diseases, and / or conditions means any disease or other deleterious condition in which J AK2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which JAK2, or a mutant thereof, is known to play a role. Such JA.K2 -mediated disorders include, but are not limited to, cellular proliferative disorders (e g. cancer). In some embodiments, the JAK2-mediated disorder is a disorder mediated by a mutant JAK2. In some embodiments, the JAK2 -mediated disorder is a disorder mediated by a JAK2 containing a V617F mutations.

[0256] In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In some embodiments, the present disclosure provides a method for treating a cellular proliferative disease, said method comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0257] In some embodiments, the method of treatmem comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said provided compound in a therapeutically effective amount to treat, suppress and / or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant JAK2. In some embodiments, the subject has JAK2 containing a V617F mutation.

[0258] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and / or prevent the disease state or condition in a subject in need of such treatment. In some embodiments, the subject has a mutant JAK2. In some embodiments, the subject has JAK2 containing a V6I7F mutation.

[0259] Another aspect of the disclosure provides a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either of the foregoing, for the treatment of a disorder described herein. Similarly, the disclosure provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein. C6llular Proliferative Diseases

[0260] In some embodiments, the disorder is a cellular proliferative disease. In some embodiments, the cellular proliferative disease is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a hematopoietic cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cellular proliferative disease is a tumor and / or cancerous cell growth. In some embodiments, the cellular proliferative disease is a tumor. In some embodiments, the cellular proliferative disease is a solid tumor. In some embodiments, the cellular proliferative disease is a cancerous cell growth.

[0261] In some embodiments, the cancer is selected from sarcoma; lung; bronchus; prostate, breast (including sporadic breast cancers and sufferers of Cowvlen disease); pancreas; gastrointestinal; colon; rectum; carcinoma; colon carcinoma; adenoma, colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma, endometrial; melanoma; kidney; renal pelvis, urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); multiple myeloma; esophagus; a leukemia; acute myelogenous leukemia; acute megakaryocytic leukemia; chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia; T-cell acute lymphoblastic leukemia (T-ALL); B-cell acute lymphoblastic leukemia (B-ALL); acute myeloid leukemia (AML); Chronic Myelornonocytic Leukemia (CMML); T-cell large granular lymphocyticleukemia (T-LGL); T-cell prolymphocytic leukemia (T-PLL); brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia, a neoplasia of epithelia! character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; neck; head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; ami Waldenstrom macroglobulinemia.

[0262] In some embodiments, the cancer is selected from lung, bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; endometrial; kidney, renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; a leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; neck; and head. In some embodiments, the cancer is selected from sarcoma; carcinoma; colon carcinoma; adenoma; colorectal adenoma; glioma, glioblastoma; melanoma; multiple myeloma; a carcinoma of the brain; non-Hodgkin lymphoma; villous colon adenoma; a neoplasia, a neoplasia of epithelial character; lymphoma; a mammary carcinoma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.

[0172] In some embodiments, the cancer is selected from lung; bronchus; prostate; breast (including sporadic breast cancers and Cowden disease); pancreas; gastrointestinal; colon; rectum; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland, stomach; gastric; endometrial; kidney; renal pelvis, urinary bladder; uterine corpus; uterine cervix; vagina; ovary (including clear cell ovarian cancer); esophagus; brain; oral cavity and pharynx; larynx, small intestine; neck; and head. In some embodiments, the cancer is a leukemia. In some embodiments, the cancer is acute myelogenous leukemia; chronic myelogenous leukemia, lymphocytic leukemia, or myeloid leukemia.

[0263] In some embodiments, the cancer is breast cancer (including sporadic breast cancers and Cowden disease). In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ER+ / HER2- breast cancer. In some embodiments, the cancer is ER+ / HER2- breast cancer, and the subject is intolerant to, or ineligible for, treatment with alpelisib. In some embodiments, the cancer is sporadic breast cancer. In some embodiments, the cancer is Cowden disease.

[0264] In some embodiments, the cellular proliferative disease has mutant JAK2. In some embodiments, the cellular proliferative disease is a myeloproliferative disorder. In some embodiments, the cancer has mutant JAK2. In some embodiments, the hematopoietic cancer has mutant JAK2. In some embodiments, the myeloproliferative disorder has mutant JAK2.

[0265] In some embodiments, the cancer is adenoma; carcinoma, sarcoma, glioma; glioblastoma; melanoma; multiple myeloma; or lymphoma. In some embodiments, the cancer is a colorectal adenoma or avillous colon adenoma. In some embodiments, die cancer is colon carcinoma; a carcinoma of the brain; a mammary' carcinoma; basal cell carcinoma; or a squamous cell carcinoma. In some embodiments, the cancer is a neoplasia or a neoplasia of epithelial character. In some embodiments, the cancer is non-Hodgkin lymphoma. In some embodiments, the cancer is actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; or Waldenstrom macroglobulinemia.

[0266] In some embodiments, the cellular proliferative disease displays overexpression or amplification of JAK2, or somatic mutation of JAK2.A ddi ti on al Di sord er s

[0267] In some embodiments, the JAK2-mediated disorder is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation. Loftier’s syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonaiy aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophil -related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia greata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, autoimmune haematogical disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven -Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy. Graves’ disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis,hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

[0268] In some embodiments, the JAK2-mediated disorder is polycythemia vera, essential thrombocythemia, or myelofibrosis with myeloid metaplasia. In some embodiments, the JAK2- mediated disorder is asthma, COPD, ARDS, PROS (PI3K-related overgrowth syndrome), venous malformation, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), or bronchopulmonary aspergillosis. In some embodiments, the JAK2-mediated disorder is polyarteritis nodosa (including Churg- Strauss syndrome), eosinophilic granuloma, eosinophil -related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, or scleroderma. In some embodiments, the J AK2 -mediated disorder is vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, or autoimmune baematogical disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia). In some embodiments, the JAK2-mediated disorder is systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, or autoimmune inflammatory' bowel disease (e.g. ulcerative colitis and Crohn's disease).

[0269] In some embodiments, the JAK2 -mediated disorder is endocrine opthalmopathy, Graves’ disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, or psoriatic arthritis. In some embodiments, the JAK2-mediated disorder is glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, or reperfusion injuries. In some embodiments, the JAK2 -mediated disorder is retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

[0270] In some embodiments, the J.AK2 -mediated disorder is myelofibrosis (MF), polycythemia Vera (PV), essential thrombocythemia (ET), acute megakaryocytic leukemia, T- cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), T-cell large granular lymphocytic leukemia (T-LGL), T-cell prolymphocyiic leukemia (T-PLL), or graft versus host disease (GVHD).Synthesis

[0271] Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[0272] The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0273] Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0274] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,JH or13C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0275] The expressions, “ambient temperature,” “room temperature,” and “r.t ” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, forexample, a temperature from about 20 °C to about 30 °C.

[0276] Compounds of the invention can be prepared using numerous preparatory reactions known in the literature. The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

[0277] The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein.Synthesis

[0278] Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[0279] The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents can be selected by the skilled artisan.

[0280] Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0281] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,!H or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0282] The expressions, “ambient temperature,” “room temperature,” and “r.t ” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.

[0283] Compounds of the invention can be prepared using numerous preparatory reactions known in the literature. The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

[0284] The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein.EXAMPLESGeneral Synthetic Procedures

[0285] Compounds of Formula (I) can be prepared as shown in Scheme 1. Compounds 1-1 where Y1is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M1is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)s, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)-palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)), to give compounds 1-3. Coupling of compounds 1-3 with compounds 1-4 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) can provide compounds of Formula (I).

[0286] Alternatively, compounds 1-1 can be coupled with compounds 1-4, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to afford compounds 1-6. Compounds 1-6 where Y1is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M1is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II)), to give compounds of Formula (I).Scheme 1Buchwald-Hartwig, or SNAr CyASuzki, Stille, or Negishi

[0287] Compounds of Formula (IA) can be prepared as shown in Scheme 2. Compounds 2-1 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 2-2, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithiumbis(trimethylsilyl)-amide to provide compounds 2-3. Coupling of compounds 2-3 where Y1is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with compounds 1-2 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)-palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)) can provide compounds 2-4. Reaction of compounds 2-4 where Y3is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with amines 2-5, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) can provide compounds of Formula (IA).

[0288] Alternatively, reaction of compounds 2-3 where Y3is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with amines 2-5, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)3, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) can furnish compounds 2-6. Coupling of compounds 2-6 where Y1is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with compounds 1-2 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenyl- phosphine)palladium(O)), or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II)) can afford compounds of Formula (IA).Scheme 22-3 2-4Buchwald-Hartwig or SNArFormula (IA)

[0289] Compounds of Formula (IAa) can be prepared as shown in Scheme 3. Compounds 3- 1 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 2-2, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide) to provide compounds 3-2. Reaction of thioethers 3-2 where Rais alkyl (e.g., methyl, ethyl, isopropyl) under oxidative conditions (e.g., in the presence of an oxidant such as mCPBA) can provide sulfones 3-3. Sulfones 3-3 can react with protected amines 3-4 (e.g., p-methoxybenzyl-amine), under nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to afford compounds 3-5.Compounds 3-5 where Y1is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M1is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presenceof a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [l,l'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(II)), to give compounds 3-6. Deprotection reaction of compounds 3-6 can afford compounds of Formula (lAa).Scheme 3Formula (lAa)

[0290] Compounds of Formula (IB) and Formula (IBa) can be prepared as shown in Scheme 4. Compounds 4-1 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 2-2, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 4-2. Compounds 4-2 where Y3is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with protected amines 3-4 (e.g., p-methoxybenzylamine), under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 4-3. Compounds 4-3 where Y1is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M1is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)3, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as K3PO4), or standardStille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenyl- phosphine)palladium(O)), or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II)), to give compounds 4-4. The deprotection reaction of compounds 4-4 can afford compounds of Formula (IBa). Coupling of amines of Formula (IBa) with acids 4-5 using standard amide coupling conditions (e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine), or acylation of amines of Formula (IBa) with compounds 4-6 where Yais halogen (e.g., F, Cl, Br, or I) can afford compounds of Formula (IB).Scheme 4deprotectionacylation or amide couplingFormula (IB)

[0291] Compounds of Formula (IC) can be prepared as shown in Scheme 5. Compounds 2-2 where Y1is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with compounds 1-2 where M1is a boronic acid, boronate ester, potassium trifluoroborate, or an appropriately substituted metal, such as Sn(Bu)s, or ZnCl, under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloro-palladium(II) and a base, such as K3PO4), or standard Stille conditions (e.g., in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0)), or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)-palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)), to give compounds 5-1. Compounds 5- 2 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react withamines 5-1, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 5-3. Compounds 5-3 where Y3is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with protected amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds of Formula (IC).Scheme 5

[0292] Compounds of Formula (ID) can be prepared as shown in Scheme 6. Compounds 6-1 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 5-1, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)-amide) to provide compounds 6-2. Compounds 6-2 where Y3is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with protected amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G3, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds of Formula (IC).Scheme 6Formula (ID)

[0293] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 7. Compound 7-1 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 7-2 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and a base, such as potassium acetate).

[0294] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 8. Alkylation of nitriles 8-1 with suitable compounds 8-2 where Yais halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 8-3. Reduction of nitriles 8-3 where Rais alkyl (e.g., methyl, ethyl, isopropyl) under standard conditions, such as in the presence of a reducing agent (e.g., borane tetrahydrofuran complex), can provide the cyclized product compounds 8-4. Alkylation of amides 8-4 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 8-6. Compound 8-6 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 8-7 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)3, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [ 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base, such as potassium acetate).Scheme 8

[0295] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 9. Alkylation of nitriles 8-1 with suitable compounds 9-1 where two Yaare independently halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) and where m = 0, 1, 2, 3, etc., in the presence of a base, such as sodium hydride, can provide compounds 9-2. Reduction of nitriles 9-2 where Rais alkyl (e.g., methyl, ethyl, isopropyl) under standard conditions, such as in the presence of a reducing agent (e.g., borane tetrahydrofuran complex), can provide the cyclized product compounds 9-3. Alkylation of amides 9-3 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 9-4. Compound 9-4 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 9-5 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).Scheme 99-5

[0296] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 10. Nucleophilic aromatic substitution of compounds 10-1 where Ybis halogen (e.g., F or Cl) with suitable nitriles 10-2 where m and n are independently 1, 2, etc., and where W1is O, or CRbRc, in the presence of a base, such as KHMDS, can provide compounds 10-3. Esterification of acids 10-3 under standard conditions can provide the esters 10-4.Reduction of nitriles 10-4 under standard conditions, such as in the presence of a reducing agent (e.g., borane tetrahydrofuran complex), can provide the cyclized product compounds 10-5.Scheme 10

[0297] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 11. Alkylation of 11-1 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 11-2. Compound 11-2 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 11-3 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).Scheme 11

[0298] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 12. Oxidation of compounds 12-1 in the presence of an oxidant, such as DDQ, can provide compounds 12-2. Alkylation of 12-2 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 12-3. Compound 12-3 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 12-4 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).Scheme 12

[0299] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 13. Alkylation of amides 13-1 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 13-2. Compound 13-2 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 13-3 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and a base, such as potassium acetate).Scheme 13

[0300] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 14. Alkylation of compounds 14-1 with compounds 9-1 where two Yaare independently halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) and where m = 0, 1, 2, 3, etc., in the presence of a base, such as sodium hydride, can provide compounds 14-2. Reduction of compounds 14-2 under standard conditions, such as in the presence of a reducing agent (e.g., borane tetrahydrofuran complex), can provide the compounds 14-3. Reaction of compounds 14-3 with standard reagent (such as triphosgene) can provide the compounds 14-4. Cyclization of compounds 14-4 under standard conditions, such as in the presence of a Lewis acid (e.g., AlCh), can provide the compounds 14-5. Alkylation of amides 14-5 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 14-6. Under standard conditions, such as in the presence of NBS, the compounds 14-7 can be obtained. Compound 14- 7 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 14-8 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)3, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II) and a base, such as potassium acetate).Scheme 1414-7 14-8

[0301] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 15. Halogenation of alcohols 15-1, in the presence of an electrophilic halogenating reagent, such as thionyl chloride or phosphorus bromide, or sulfonylation reagent, such as methanesulfonyl chloride, can provide compounds 15-2 where Ybis a halogen (e.g. F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) and CyDis a heteroaromatic ring (e.g. pyridine, pyrazine, pyrimidine, pyrazole, thiazole, etc.) or a saturated heterocyclic (e.g. piperidine, pyrrolidine, etc.). Nucleophilic substitution of the compounds 15-2 with a suitable amide bicycle 8-4 in the presence of a base, such as sodium hydride, can furnish tertiary amides 15-3. Hydrolysis of esters 15-3 with a suitable base, such as LiOH, NaOH, or KOH, can give carboxylic acids 15-4. Coupling of amines 15-5 with acids 15-4 using standard amide coupling conditions (e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine) can provide the compounds 15-6.Scheme 154

[0302] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 16. Halogenation of alcohols 16-1, in the presence of an electrophilic halogenating, such as thionyl chloride or phosphorus bromide, or sulfonylation reagent, such as methanesulfonyl chloride, can provide compounds 16-2 where Ybis a halogen (e.g. F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) Nucleophilic substitution of the compounds 16-2 with a suitable amide bicycle 8-4 in the presence of a base, such as sodium hydride, can furnish tertiary amides 16-3. Hydrolysis of esters 16-3 with a suitable base, such as LiOH, NaOH, or KOH, can give carboxylic acids 16-4. Coupling of amines 15-5 with acids 16-4 using standard amide coupling conditions (e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine) can provide the compounds 16-5.Scheme 16

[0303] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 17. Condensation of amines 15-5 with esters 17-1 using a Lewis acid, suchas MgCh, at elevated temperatures can produce amides 17-2. Halogenation of alcohols 17-2, in the presence of an electrophilic halogenating, such as thionyl chloride or phosphorus bromide, or sulfonylation reagent, such as methanesulfonyl chloride, can provide compounds 17-3 where Ybis a halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs).Scheme 17R1? _RCNHHalogenation

[0304] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 18. Protection of alcohols 18-1 with a suitable protecting group, such as a silyl protecting group (TBS, TBDPS, TIPS, etc), can provide protected alcohols 18-2. Hydrolysis of esters 18-2 with a suitable base, such as LiOH, NaOH, or KOH, can give carboxylic acids 18- 3. Coupling of amines 15-5 with carboxylic acids 18-3 using standard amide coupling conditions (e.g., in the presence of a coupling reagent such as HATU, and an optional base such as triethylamine) can furnish amides 18-4. Deprotection of the protected alcohols 18-4 with suitable conditions (e.g. HC1 deprotection of TBS protected alcohols) can provide the deprotected alcohols 18-5. Halogenation of alcohols 18-5, in the presence of an electrophilic halogenating, such as thionyl chloride or phosphorus bromide, or sulfonylation reagent, such as methanesulfonyl chloride, can provide compounds 18-6 where Ybis a halogen (e.g. F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs).Scheme 18

[0305] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 19. Compounds 19-1 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 19-2, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)3, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 19-3 where M1is a metal (e.g. B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl). Compounds 19-3 where Y3is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to provide compounds 19-4.Scheme 19

[0306] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 20. Compounds 20-1 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 5-1, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)s, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as potassium tert-butoxide or lithium bis(trimethylsilyl)amide) to provide compounds 20-2 where Y1is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs). Compounds 20-2 where Y3is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with protected amines 3-4 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as N,N- diisopropylethylamine at elevated temperatures) to provide the compounds 20-3. Deprotection of compounds 20-3 with suitable deprotection conditions (e.g. TFA deprotection of a PMB or DMB protecting group) can furnish the compounds 20-4. Coupling of compounds 20-4 with acids 4-5 using standard amide coupling conditions (e.g., in the presence of a coupling reagent such asHATU, and an optional base such as triethylamine), or acylation of amines 20-4 with compounds 4-6 where Yais a halogen (e.g., F, Cl, Br, or I) can afford compounds 20-5.Scheme 20

[0307] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 21. Compounds 21-1 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with protected amines 3-4 (e.g. tert-butyl carbamate), under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)s, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to give compounds 21-2. Compounds 21-2 where Y3is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as N,N- diisopropylethylamine at elevated temperatures) to provide the compounds 21-3. Deprotection of compounds 21-3 with suitable deprotection conditions (e.g. TFA deprotection of a Boc, PMB, or DMB protecting group) can furnish the compounds 21-4. Compounds 21-5 where Ycis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with compounds 21-4, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, a ligand such as BrettPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as CS2CO3 atelevated temperatures or lithium bis(trimethylsilyl)amide) to afford compounds 21-6 where Y1is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs).Scheme 21

[0308] Compounds of Formula (ICa) can be prepared as shown in Scheme 22. Compounds 22-1 can be protected with protecting groups such as THP with suitable conditions (e.g., catalytic pyridinium p-toluenesulfonate and 3,4-dihydro-2H-pyran at elevated temperatures) to provide the compounds 22-2. Compounds 22-2 where Y2is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 5-1, under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)s, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as lithium bis(trimethylsilyl)amide) to give compounds 22-3. Compounds 22-3 where Y3is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can react with amines 2-5 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as Pd2(dba)3, ligand, such as XantPhos, and a base, such as CS2CO3 or K3PO4) or nucleophilic aromatic substitution conditions (e.g., in the presence of a base such as 7\(7V-diisopropylethylamine at elevated temperatures or lithium bis(trimethylsilyl)amide) to afford the compounds 22-4. Deprotection of the compounds 22-4 can be performed under suitable conditions (e.g., TFA deprotection of a THP, PMB, or Boc protecting group) to furnish compounds of Formula (ICa).Scheme 22

[0309] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 23. Alkylation of ester 23-1 with compounds 9-1 where two Yaare independently halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) and where m = 0, 1, 2, 3, etc., in the presence of a base, such as sodium hydride, can provide compounds 23-2. Reduction of esters 23-2 under standard conditions, such as in the presence of a reducing agent (e.g., DIBAL), can provide the compounds 23-3. Reaction of compounds 23-3 with appropriate reagent (e.g., SOCh, PBrs, or mesyl chloride) can provide the compounds 23-4 where YDis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs). Compounds 23-5 can be prepared by treating 23-4 with standard reagent (such as NaCN). Reduction of nitriles 23-5 under standard conditions, such as in the presence of a reducing agent (e.g., borane tetrahydrofuran complex), can provide the amine product compounds 23-6. Reaction of compounds 23-6 with standard reagent (such as triphosgene) can provide the isocyantes 23-7. Cyclization of compounds 23-7 under standard conditions, such as in the presence of a Lewis acid (e.g., A1CL), can provide the compounds 23-8. Alkylation of compounds 23-8 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 23-9. Compound 23-9 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 23-10 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladiumcatalyst, such as [l,l'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) and a base, such as potassium acetate).Scheme 2323-10

[0310] Intermediates for the synthesis of compounds provided herein can be prepared as described in Scheme 24. The reaction of aromatic nitriles 24-1 with Ti(Oi-Pr)4 and EtMgBr can provide amines 24-2. Cyclization of 24-2 in the presence of a Lewis acid can provide compounds 24-3. Alkylation of the compounds 24-3 with suitable compounds 8-5 where Ybis halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base, such as sodium hydride, can provide compounds 24-4. Compounds 24-4 where Y4is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be converted to the appropriate metal 24-5 (e.g., M1is B(OH)2, Bpin, BF3K, Sn(Bu)s, or ZnCl) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base, such as potassium acetate).Scheme 24Intermediate 1. 6-(Chloromethyl)-7V,7V-dimethylpicolinamide

[0311] Step 1. 6-(Hydroxymethyl)-N,N-dimethylpicolinamide

[0312] To a solution of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (2.0 g, 12.0 mmol) in THF (50 mL) was added MgCh (3.42 g, 35.9 mmol) and dimethylamine (15.0 mL, 29.9 mmol, 2M in THF). The recti on mixture was stirred at 65 °C for 18 h then cooled and extracted with DCM, which was then dried over N,a2S conOd4ensed, and used directly in the next step. LCMS calcd. for C9H13N2O2 [M+H]+: m / z = 181.1; Found: 181.1.

[0313] Step 2. 6-(Chloromethyl)-N,N-dimethylpicolinamide

[0314] To a solution 6-(hydroxymethyl)-7\(7V-dimethylpicolinamide (2.30 g, 12.8 mmol) in DCM (30 mL) at 0 °C was added SOCh (1.82 g, 15.3 mmol), and the reaction was stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure and used crude in the next step. LCMS calcd. for C9H12CIN2O [M+H]+: m / z = 199.1; Found: 199.1.Intermediate 2. 6-((6'-Bromo-l '-oxo- 1 ' / / -spiro| cyclopropane- 1.4'-isoquinolin|-2'(3' / / )- yl)methyl)-7V,7V-dimethylpicolinamide

[0316] To a solution of methyl 4-bromo-2-(cyanomethyl)benzoate (13.0 g, 51.2 mmol) in DMSO (200 mL) was added NaH 60% dispersion in mineral oil (6.14 g, 153 mmol). After stirring at 25°C for 0.5 h, l-bromo-2-chloroethane (6.39 mL, 76.8 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was poured into water and filtered. The filtered solids were dried under vacuo and purified by SiCL FCC to afford the title compound (10.5 g, 73% yield) as a white solid. LCMS calcd. for C12H11BrNO2[M+H]+: m / z = 280.0 / 282.0; Found: 280.7 / 282.8.

[0317] Step 2. 6’-Bromo-2 ', 3 '-dihydro- 1 'H-spiro[ cyclopropane- 1, 4 '-isoquinolin ]-l '-one

[0318] To a solution of methyl 4-bromo-2-(l-cyanocyclopropyl)benzoate (10.0 g, 35.7 mmol) and cobalt(II) chloride (9.27 g, 71.4 mmol) in MeOH (200 mL) was added NaBFL (6.75 g, 178 mmol) slowly at 0 °C. The reaction mixture was stirred at 15 °C for 1 h, then poured into ice water and acidified to pH 6 with 1 M HC1 (aq). The mixture was extracted with DCM (3x50 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, condensed, and purified by SiCL FCC: 0-5% MeOH / DCM to afford the title compound (6.0 g, 67% yield) as a white solid. LCMS calcd. for C1 1H1 1BrNO [M+H]+: m / z =252.0 / 254.0;Found:251.9 / 253.9.

[0319] Step 3. 6-((6'-Bromo-r-oxo-rH-spiro[cyclopropane-l ,4'-isoquinolin]-2'(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0320] To a solution of 6'-bromo-2',3'-dihydro-1H / -spiro[cyclopropane-l,4'-isoquinolin]-l'- one (520 mg, 2.06 mmol) and Intermediate 1 (819 mg, 4.13 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil) (247 mg, 6.19 mmol) under N2 at 0 °C. The resulting mixture was stirred at 0 °C for 2 h, then quenched with sat. NH4CI (aq.). The reaction mixture was extracted with EtOAc (3x50 ml), and the combined organic layers were washed with brine, dried over Na2SC>4, concentrated, and purified by SiO2FCC: 0-100% EtOAc / hexane to afford the title compound (970 mg, 2.34 mmol) as a yellow oil. LCMS calcd. for C2oH2iBrN302 [M+H]+: m / z =414.1 / 416.1; Found: 414.0 / 415.9.Intermediate 3. N-(8-((2-Methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl) amino)imidazo[l,2-b]pyridazin-6-yl)cyclopropanecarboxamide

[0321] Step 1. 6- Chlor o-N-(2-methoxy-3-(4, 4, 5, 5-tetramethyl-l, 3,2-dioxaborolan-2- yl)phenyl)imidazo[ 1, 2-b ]pyridazin-8-amine

[0322] To a solution of 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (1.0 g, 4.01 mmol), 8-bromo-6-chloroimidazo[l,2-Z>]pyridazine (933 mg, 4.01 mmol) in 1,4- dioxane (30 mL) was added Pd2(dba)3(735 mg, 0.80 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (929 mg, 1.61 mmol) and CS2CO3 (3.92 g, 12.0 mmol) under N2, and the reaction was stirred at 100 °C for 16 h. The reaction mixture was directly concentrated andpurified by SiO2FCC: 5-50% EtOAc / hexanes to afford the title compound (500 mg, 29% yield) as a yellow solid. LCMS calcd. for C19H23BCIN4O3 [M+H]+: m / z = 401.2; Found: 401.5.

[0323] Step 2. N-( 8-( ( 2-Methoxy-3-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl)amino) imidazo[ 1, 2-b ]pyridazin-6-yl) cyclopropanecarboxamide

[0324] To a solution of 6-chloro-A-(2-m ethoxy-3 -(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl)imidazo[l,2-Z>]pyridazin-8-amine (300 mg, 0.75 mmol) in 1,4-di oxane (15 mL) was added cyclopropanecarboxamide (319 mg, 3.74 mmol), Brettphos (80.4 mg, 0.15 mmol), Brettphos-Pd-G3 (136 mg, 0.15 mmol) and CS2CO3 (731 mg, 2.25 mmol). The mixture was stirred at 100°C under N2 for 16 h. The mixture was concentrated and purified by SiCL FCC: 5-50% EtOAc / hexanes to afford the title compound (150 mg, 45% yield) as a yellow solid.LCMS calcd. for C23H29BN5O4 [M+H]+: m / z = 450.2; Found: 450.2.Intermediate 4. 4-7V-(3-bromo-2-methoxyphenyl)-2-7V-[(2,4-dimethoxyphenyl)methyl] imidazo[2,l- / ][l,2,4]triazine-2,4-diamine

[0325] Step 1. N-(3-Bromo-2-methoxyphenyl)-2-chloroimidazo[2,l-J] ' [l,2,4]triazin-4-amine

[0326] To a solution of 3 -bromo-2 -methoxy aniline (153 mg, 0.76 mmol) and 2,4- dichloroimidazo[2,l-: / ][l,2,4]triazine (130 mg, 0.69 mmol) in THF (2.5 mL) was added potassium tert-butoxide (0.83 mL, 0.83 mmol, 1 M in THF). The reaction was stirred at rt for 10 mins and at 50 °C for 30 mins. The reaction was cooled to rt, poured into brine, and extracted with DCM / MeOH= 20 / 1 (3x). The combined organic phase was dried over Na2SO4, condensed, and the residue was slurried 2x in 1 : 1 EtOAc / heptanes to give the title compound(170 mg, 70% yield) as a pale-yellow solid. LCMS calcd. for CnHioBrCINsO [M+H]+: m / z = 354.0 / 356.0; Found: 354.1 / 356.1.

[0327] Step 2. N4-(3-Bromo-2-methoxyphenyl)-2-N-[(2,4- dimethoxyphenyl)methyl ]imidazo[ 2, l-f][ 1, 2, 4 ]triazine-2, 4-diamine

[0328] A solution of A-(3-bromo-2-methoxyphenyl)-2-chloroimidazo[2,l-: / ][l,2,4]triazin-4- amine (130 mg, 0.37 mmol) and 2,4-dimethoxybenzylamine (613 mg, 3.67 mmol) in NMP (2.5 mL) was stirred at 95 °C for 2 h under N2. The reaction was cooled to rt and directly purified by prep-HPLC on C18 column (30 x 250 mm, 10 pm, 25-65% MeCN / H2O (w / 0.1% TFA)). The desired fractions were collected and concentrated to give the title compound (105 mg, 59% yield) as a white TFA salt. LCMS calcd. for C21H22BrN6O3[M+H]+: m / z = 487.1 / 485.1; Found: 486.9 / 485.0.Intermediate 5: \4-(4-((3-bromo-2-met hoxyphenyl)amino)imidazo|2.1 - / ] 11.2.4| triazin-2- yl)cyclopropanecarboxamide

[0329] Step 1. N4-( 3-Bromo-2-methoxyphenyl)imidazo[ 2, l-f][ 1, 2, 4 ]triazine-2, 4-diamine

[0330] To a cold solution of Nv-(3-bromo-2-methoxyphenyl)-2-A-[(2,4-dimethoxyphenyl)- methyl]imidazo[2, 1 -f\ [1, 2, 4]triazine-2, 4-diamine (105 mg, 0.22 mmol) in DCM (2.0 mL) was added 2.0 mL of TFA. The reaction was stirred at rt for 1 h, then directly condensed and resuspended in DCM and sat. NaHCCL (aq). The mixture was extracted 3x with DCM / MeOH (v / v=10 / l). The combined organic phase was dried over Na2SO4 and condensed to yield the title compound (65 mg, 90% yield) as white solids. LCMS calcd. for C12H12BrN6O [M+H]+: m / z = 337.0 / 335.0; Found: 337.0 / 335.0.

[0331] Step 2. N4-( 4-( ( 3-bromo-2-methoxyphenyl)amino)imidazo[ 2, l-f][ 1, 2, 4 ]triazin-2- yl) cyclopropanecarboxamide

[0332] A mixture of AfV-(3-bromo-2-methoxyphenyl)imidazo[2, l: / ][ l ,2,4]triazine-2,4- diamine (55 mg, 0.16 mmol) in DCM (6.0 mL) with pyridine (0.08 mL, 0.98 mmol) was cooled to 0 °C and cyclopropanecarbonyl chloride (21.0 mg, 0.2 mmol) in DCM was added dropwise. The reaction was slowly warmed to rt and stirred for 1 h. The reaction was quenched with MeOH and stirred another 20 mins. The reaction mixture was directly condensed, taken up in DCM, poured into sat. NH4CI (aq) and extracted 3x with DCM / MeOH (v / v=15 / l). The combined organic phase was dried over Na2SO4, condensed, and purified by prep-HPLC on C18 column (30 x 250 mm, 10 pm, 8-55% MeCN / (0.1% TFA (aq))). The desired fractions were collected, concentrated, and poured into sat. NaHCCL (aq) and extracted 3x with DCM / MeOH (v / v=15 / l). The combined organic phase was dried over Na2SO4and condensed to afford the title compound (46 mg, 70% yield) as white solids. LCMS calcd. for C16Hi6BrNeO2 [M+H]+: m / z = 403.0 / 405.0; Found 403.0 / 405.0.Intermediate 6. 6-(bromomethyl)-A,7V-dimethylpicolinamide

[0333] Phosphorus tribromide (1.76 mL, 18.8 mmol) was added to a stirring solution of 6- (hydroxymethyl)-A,A-dimethylpicolinamide (3.04 g, 16.9 mmol) in chloroform (45 mL) at 0 °C. The reaction mixture warmed to rt and stirred for 1.5 hours. The product mixture was then cooled to 0 °C, diluted with sat. K2CO3 (aq) (100 mL) and extracted with DCM (3 x 80 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by SiO2FCC: 0- 10% MeOH / DCM to obtain the title compound (2.9 g, 71% yield) as a red oil. LCMS calcd. for C9Hi2BrN2O [M+H]+: m / z = 243.0 / 245.0; Found: 242.9 / 244.9Intermediate 7. A,A-dimethyl-6-((l'-oxo-6'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1 ' / / -spiro [cyclobutane-l,4'-isoquinolin] -2'(3'F / )-yl)methyl)picolinamide

[0334] Step 1. Methyl 4-bromo-2-(l-cyanocyclobutyl)benzoate

[0335] To a solution of methyl 4-bromo-2-(cyanomethyl)benzoate (1.00 g, 3.94 mmol) in DMF (12 mL) was added NaH 60% dispersion in mineral oil (203 mg, 8.46 mmol) and 1,3 -dibromopropane (0.40 mL, 3.94 mmol) at 0°C under N2. The reaction was stirred at rt for 2 h. Then the reaction mixture was quenched with sat. NH4CI (aq.) (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by trituration with 10: 1 heptane / EtOAc to afford the title compound (881 mg, 76% yield) as a white solid. 'H NMR (300 MHz, CDCI3) 6 7.74 (d, J= 8.3 Hz, 1H), 7.51 (dd, J= 8.2, 1.9 Hz, 1H), 7.45 (d, J= 2.0 Hz, 1H), 3.90 (s, 3H), 2.94 - 2.86 (m, 2H), 2.57 - 2.36 (m, 4H).

[0336] Step 2. 6'-Bromo-2 ', 3 '-dihydro- 1 'H-spiro[ cyclobutane- 1, 4 '-isoquinolin ]-l '-one

[0337] The title compound was prepared using procedures analogous to Intermediate 2 Step 2 with appropriate starting materials and commercial reagents. LCMS calcd. for CnHnBrNO [M+H]+: m / z =266.0; Found 266.1.XH NMR (300 MHz, CDC13) 8 7.93 (d, J= 8.2 Hz, 1H), 7.65 (d, J= 1.9 Hz, 1H), 7.49 (dd, J = 8.3, 1.9 Hz, 1H), 2.9 (s, 2H), 2.39 - 2.27 (m, 2H), 2.20 - 2.00 (m, 4H).

[0338] Step 3. 6-((6'-Bromo-r-oxo-rH-spiro[cyclobutane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0339] To a solution of 6'-bromo-2',3'-dihydro-17 / -spiro[cyclobutane-l,4'-isoquinolin]-l'-one (166 mg, 0.62 mmol) in DMF (3 mL) was added NaH (15 mg, 0.62 mmol, 60% in mineral oil) and Intermediate 6 (197 mg, 0.81 mmol) at 0°C under N2. The resulting mixture was stirred at 25°C for 2 h. Then the mixture was poured into water and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by trituration with EtOAc (100%) to afford the title compound (262 mg, 98% yield) as a colorless liquid. LCMS calcd. for C2iH23BrN3O2[M+H]+: m / z = 428.1; Found 428.3. 'H NMR (300 MHz, CDCI3) 8 7.96 (d, J = 8.3 Hz, 1H), 7.74 (t, J= 7.7 Hz, 1H), 7.58 - 7.45 (m, 3H), 6.99 (d, J= 1.9 Hz, 1H), 4.90 (s, 2H), 3.62 (s, 2H), 3.12 (s, 3H), 3.01 (s, 3H), 2.32 - 2.17 (m, 2H), 2.02 - 1.91 (m, 4H).

[0340] Step 4. N,N-dimethyl-6-((r-oxo-6'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-rH- spiro[ cyclobutane- 1, 4 '-isoquinolin ]-2 '( 3 'H) -yl)methyl)picolinamide

[0341] A vial was charged with 6-((6'-bromo-l'-oxo-17 / -spiro[cyclobutane-l,4'-isoquinolin]- 2'(377)-yl)methyl)-A,A-dimethylpicolinamide (142 mg, 0.330 mmol), bis(pinacolato)diboron (211 mg, 0.830 mmol), potassium pivalate (233, 1.66 mmol), and Pd(dppf)C12 • DCM (81.5 mg, 0.100 mmol). The mixture was dissolved in 1,4-dioxane (5 mL), sparged with N2 gas for 5 minutes, sealed, and heated to 100 °C for 1 h. The product mixture was diluted with DCM (10 mL) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain the crude title compound. The residue obtained was used in the next step without further purification and a quantitative yield was assumed. LCMS calcd. for C27H35BN3O4 [M+H]+: m / z = 476.3; Found: 476.2.Intermediate 8. 2'-((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-6'-(4,4,5,5- t el r:imethyl-1.3.2-dioxaborolan-2-yl)-2'.3'-dihydro-l ' / / -spiro [cyclopropane- 1.4'- isoquinolin]-l'-one

[0342] Step 1. (6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(pyrrolidin-l- yl)methanone

[0343] HATU (1.54 g, 4.04 mmol) and DIPEA (2.92 mL, 16.8 mmol) were added in sequence to a stirring solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinic acid (900 mg, 3.37 mmol) and pyrrolidine (239 mg, 3.37 mmol) in DMF (9 mL) at room temperature for 2 hours. The product mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried with Na2SO4, filtered, concentrated, and purified by SiO2FCC: 5-50% EtOAc / heptane to obtain the title compound (1.0 g, 93%). LCMS calcd. for C17H29N2O2Si [M+H]+: m / z = 321.2; Found: 320.8.

[0344] Step 2. (6-(hydroxymethyl)pyridin-2-yl)(pyrrolidin-l-yl)methanone

[0345] HC1 (4 mL, 16 mmol, 4 M in 1,4-di oxane) was added to a stirring solution of (6- (((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(pyrrolidin-l-yl)methanone (230 mg, 0.718 mmol) at room temperature. The reaction mixture was stirred for 1 hour. The product mixture was concentrated under reduced pressure. The residue obtained was used without further purification. LCMS calcd. for C11H15N2O2 [M+H]+: m / z = 207.1; Found: 207.2.

[0347] The title compound was prepared using procedures analogous to Intermediate 1 Step2 with appropriate starting materials and commercial reagents. LCMS calcd. for C11H14CIN2O [M+H]+: m / z = 225.1; Found: 225.1.

[0348] Step 4. 6'- bromo-2 '-( ( 6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2 ', 3 '-dihydro-1 'H-spiro[cyclopropane-l,4'-isoquinolin]-l '-one

[0349] The title compound was prepared using procedures analogous to Intermediate 2 Step 3 with appropriate starting materials and commercial reagents. LCMS calcd. for C22H23BrN3O2 [M+H]+: m / z = 440.1 / 442.1; Found: 440.2 / 442.0.

[0350] Step 5. 2'-((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-6'-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-2 ', 3 '-dihydro- 1 'H-spiro[ cyclopropane- 1, 4 '-isoquinolin ]-l '-one

[0351] A vial was charged with 6'-bromo-2'-((6-(pyrrolidine-l-carbonyl)pyri din-2 - yl)methyl)-2',3'-dihydro-l 7 / -spiro[cyclopropane-l,4'-isoquinolin]-l'-one (350 mg, 0.795 mmol), bis(pinacolato)diboron (606 mg, 2.38 mmol), KOAc (234 mg, 2.38 mmol), and Pd(dppf)C12 (57.7 mg, 0.0795 mmol). The mixture was dissolved in 1,4-dioxane (7 mL). The reaction mixture was sparged with N2 gas for 5 minutes then sealed. The sealed reaction mixture was heated to 100 °C and stirred for 2 h. The product mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO,4concentrated, and purified by SiCL FCC eluting with EtOAc to obtain the title compound (360 mg, 93%).Intermediate 9. A(A-dimethyl-6-((l'-oxo-6'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1 ' / / -spiro|cycloprop:ine-1.4'-isoquinolin|-2'(3' / / )-yl)methyl)picolinamide

[0352] The title compound was prepared using procedures analogous to Intermediate 8 Step 5 with appropriate starting materials and commercial reagents. LCMS calcd. for C26H33BN3O4 [M+H]+: m / z = 462.2; Found: 462.1.Example 1. 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2- / >]pyridazin-8-yl)amino)- 2-methoxyphenyl)-l'-oxo-l'Z7-spiro[cyclopropane-l,4'-isoquinolin]-2'(3tH)-yl)methyl)-7V,7V- dimethylpicolinamide

[0353] Step 1. 6-((6'-(3-Amino-2-methoxyphenyl)-r-oxo-rH-spiro[cyclopropane-l,4'- isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N-dimethylpicolinamide

[0354] To a solution of Intermediate 2 (770 mg, 1.86 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(dppf)C12 (269 mg, 0.370 mmol), K2CO3 (770 mg, 5.58 mmol) and 2- methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (601 mg, 2.42 mmol). The resulting mixture was stirred at 100 °C under N2 for 2 h. The reaction mixture was diluted in water and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine, dried over Na2SO,4concentrated, and purified by SiCL FCC: 0-5% MeOH / EtOAc to afford the title compound (800 mg, 94% yield) as a yellow solid. LCMS calcd. for C27H29N4O3 [M+H]+: m / z = 457.2; Found: 456.9.

[0355] Step 2. 6-( (6'-( 3-( f 6-Chloroimidazo[ 1, 2-b ]pyridazin-8-yl)amino)-2-methoxyphenyl)-l oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N-dimethylpicolinamide

[0356] To a solution of 6-((6'-(3-amino-2 -methoxyphenyl)- l'-oxo-17 / -spiro[cy cl opropane- l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide (600 mg, 1.31 mmol) in 1,4- dioxane (12 mL) was added 8-bromo-6-chloroimidazo[l,2-Z>]pyridazine (458 mg, 1.97 mmol), CS2CO3 (1.29 g, 3.95 mmol), Pd2(dba)3 (240 mg, 0.26 mmol) and Xantphos (152 mg, 0.260 mmol). The resulting mixture was stirred at 100°C under N2 for 24 h. The reaction mixture was filtered, concentrated, and purified by SiO2FCC: 0-10% MeOH / DCM, then further purified byprep-HPLC on a C18 column (20-70% MeCN in 0.1% TFA(aq.)) to afford the title compound (340 mg, 43% yield) as a yellow TFA salt. LCMS calcd. for C33H31CIN7O3 [M+H]+: m / z = 608.2; Found: 608.2.

[0357] Step 3. 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0358] To a solution of 6-((6'-(3-((6-chloroimidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-r-oxo-17 / -spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethylpicolinamide (150 mg, 0.247 mmol) in 1,4-dioxane (5 mL) was added cyclopropanecarboxamide (105 mg, 1.23 mmol), CS2CO3 (242 mg, 0.740 mmol), Brettphos (27.0 mg, 0.0493 mmol) and Brettphos-Pd-G3 (45.0 mg, 0.049 mmol). The resulting mixture was stirred at 100 °C under N2 for 18 h. The reaction mixture was concentrated, and the crude was purified by SiCL FCC: 0-10% MeOH / DCM, then further purified by prep-HPLC on a C18 column (20-70% MeCN in 0.1% TFA(aq)) to afford the TFA salt of the title compound (23.0 mg, 14% yield) as a white solid. LCMS calcd. for C37H37N8O4 [M+H]+: m / z = 657.3; Found: 657.2. 'H NMR (400 MHz, DMSO-tL) 8 10.96 (s, 1H), 9.14 (s, 1H), 8.13 (s, 1H), 7.99 (d, J= 8.0 Hz, 1H), 7.87 (d, J= 7.8 Hz, 1H), 7.83 (s, 1H), 7.50 (d, J= 8.5 Hz, 2H), 7.41 (q, J= 8.1, 6.4 Hz, 3H), 7.29 (d, J= 6.3 Hz, 2H), 7.18 (s, 1H), 4.81 (s, 2H), 3.53 (s, 2H), 3.30 (s, 3H), 2.95 (s, 3H), 2.86 (s, 3H), 1.96 - 1.92 (m, 1H), 1.12 (d, J= 6.1 Hz, 2H), 0.95 (d, J= 5.2 Hz, 2H), 0.79 (d, J= 6.1 Hz, 4H).Example 2. 6-((6'-(3-((6-(cyclopropanecarboxamido)-2-methylimidazo[l,2- / >]pyridazin-8- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'Er)- yl)methyl)-7V,7V-dimethylpicolinamide

[0359] The title compound was prepared as the TFA salt using procedures analogous to Example 1 Steps 1-3 with 8-bromo-6-chl oro-2 -methylimidazo[l,2-Z>]pyridazine replacing 8- bromo-6-chloroimidazo[l,2-Z>]pyridazine in Step 2. LCMS calcd. for C38H39N8O4 [M+H]+: m / z = 671.30; Found: 671.20.XH NMR (400 MHz, DMSO-t / e) 8 10.99 (s, 1H), 9.05 (s, 1H), 8.01 - 7.96 (m, 2H), 7.88 (t, J= 7.8 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J= 8.1 Hz, 1H), 7.41 (q, J= 8.4, 6.7 Hz, 3H), 7.29 (d, J= 6.0 Hz, 2H), 7.18 (s, 1H), 4.81 (s, 2H), 3.52 (s, 2H), 3.29 (s, 3H), 2.95 (s, 3H), 2.86 (s, 3H), 2.44 (s, 3H), 1.95 - 1.91 (m, 1H), 1.12 (d, J= 6.2 Hz, 2H), 0.95 (d, J= 5.1 Hz, 2H), 0.79 (d, J= 6.2 Hz, 4H).Example 3. 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2- / >]pyridazin-8-yl)amino)-2-methoxyphenyl)-l'H-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide

[0360] Step 1: 6' -Bromo-2',3'-dihydro-l'H-spiro [cyclopropane- 1 ,4'-isoquinoline]

[0361] To a stirring solution of BH3 THF (4.0 mL, 4.0 mmol, 1 M in THF) was added 6'- bromo-2',3'-dihydro-r / Z-spiro[cyclopropane-l,4'-isoquinolin]-T-one (200 mg, 0.79 mmol) and the reaction was stirred overnight at 50 °C. The reaction mixture was directly concentrated and purified by prep-LCMS (20-70% MeCN in (0.1% TFA (aq)) to afford the title compound (100 mg, 53% yield) as a white TFA salt. LCMS calcd. for CnHnBrN [M+H]+: m / z = 238.1. Found: 238.9.

[0362] Step 2. 6-((6'-Bromo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N-dimethylpicolinamide

[0363] To a stirring solution of 6'-bromo-2',3'-dihydro-17 / -spiro[cyclopropane-l,4'- isoquinoline] (134 mg, 0.56 mmol) and 6-formyl-7\(7V-dimethylpicolinamide (100 mg, 0.56 mmol) in DMSO (2 mL) was added sodium triacetoxyborohydride (595 mg, 2.81 mmol) and the reaction mixture was stirred at rt overnight. The reaction was quenched with water, then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, condensed, and purified by prep-LCMS to afford the title compound (50 mg, 22% yield) as a white solid. LCMS calcd. for C2oH23BrN30 [M+H]+: m / z = 400.1; Found: 400.9.

[0364] Step 3. 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl) amino) -2 -methoxyphenyl)-! 'H-spiro[ cyclopropane- 1,4' -isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N- dimethylpicolinamide

[0365] To a solution of 6-((6'-bromo-17 / -spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-A,A-dimethylpicolinamide (20.0 mg, 0.05 mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was added K2CO3 (21 mg, 0.15 mmol), Intermediate 3 (22.4 mg, 0.05 mmol), and Pd(dppf)C12 (3.7 mg, 0.005 mmol), and the reaction was stirred at 110 °C under N2 for 2 h. The reaction mixture was then cooled, filtered, condensed under vacuum, and purified by prep-HPLC (20-70% MeCN in 0.1% TFA (aq)) to afford the TFA salt of the title compound (2.5 mg, 8% yield). LCMS calcd. for C37H39N8O3 [M+H]+: m / z = 643.3; Found: 644.6.Example 4. 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2- / >]pyridazin-8-yl)amino)- 2-methoxyphenyl)-3'-oxospiro[cyclopropane-l,r-isoindolin]-2'-yl)methyl)-A,A- dimethylpicolinamide

[0366] Step 1. 6-((6'-Bromo-3'-oxospiro[cyclopropane-l,r-isoindolin]-2'-yl)methyl)-N,N- dimethylpicolinamide

[0367] The title compound was prepared using procedures analogous to Intermediate 2 Step 3 with 6'-bromospiro[cyclopropane-l,l'-isoindolin]-3'-one replacing 6'-bromo-2',3'-dihydro-177- spiro[cyclopropane-l,4'-isoquinolin]-l'-one. LCMS calcd. for 19H19BrN3O [M+H]+: m / z = 400.1; Found: 400.1.

[0368] Step 2. 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8- yl)amino)-2-methoxyphenyl)-3'-oxospiro[cyclopropane-l,l'-isoindolin]-2'-yl)methyl)-N,N- dimethylpicolinamide

[0369] A vial containing 6-((6'-bromo-3'-oxospiro[cyclopropane-l,l'-isoindolin]-2'- yl)methyl)-A,A-dimethylpicolinamide (12.5 mg, 0.03 mmol), Intermediate 3 (20 mg, 0.03 mmol), K3PO4 (13.2 mg, 0.06 mmol), 1,4-dioxane (1 mL), and water (0.1 mL) was charged with XPhos Pd G2 (1.2 mg, 0.0016 mmol), sparged with N2, sealed, and heated to 90 °C. After 1 hour, the reaction mixture was cooled, filtered, and purified by prep-LCMS (5 pm, 30 x 100 nm, Waters CSH-Phenyl -Hexyl, 15.4-35.4% MeCN in water (0.1% TFA), 12 min) to afford the TFA salt of the title compound (3.0 mg, 15% yield). LCMS calcd. for C36H35N8O4[M+H]+: m / z = 643.3; Found: 643.3.Example 5. 6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2- / >]pyridazin-8-yl)amino)-2-methoxyphenyl)-l-oxo-3,4-dihydrospiro[benzo[c]azepine-5,r-cyclopropan]-2(lH)- yl)methyl)-\, \-dimethylpicolinamide

[0370] The title compound was prepared as the TFA salt using procedures analogous to Example 4 Steps 1-2 with 7-bromo-3,4-dihydrospiro[benzo[c]azepine-5,r-cyclopropan]-l(2J7)- one replacing 6'-bromospiro[cyclopropane-l,l'-isoindolin]-3'-one. LCMS calcd. for C38H39N8O4 [M+H]+: m / z = 671.3; Found:671.3 .Example 6. 6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2- / >]pyridazin-8-yl)amino)-2-methoxyphenyl)- 1-oxo- 1.3.4.5-tetrahydro-2 / / -beiizo|c|:izepiii-2-yl)methyl)-\, \- dimethylpicolinamide

[0371] Step 1. (E)-6-Bromo-3,4-dihydronaphthalen-l(2H)-one oxime

[0372] A mixture of 6-bromo-3,4-dihydronaphthalen-l(2J7)-one (500 mg, 2.22 mmol), NaOAc (364 mg, 4.44 mmol), and hydroxylamine HC1 (170 mg, 2.44 mmol) in EtOH (5 mL) was refluxed at 75 °C for 2 h. Water was added to the cooled reaction mixture, and the precipitated solids were filtered out and dried in vacuo to afford the title compound (493 mg, 92% yield). LCMS calcd. for C1oHnBrNO [M+H]+: m / z = 240.0; Found: 239.8.

[0373] Step 2. 7-Bromo-2,3,4,5-tetrahydro-lH-benzo[c]azepin-l-one

[0374] (E)-6-Bromo-3,4-dihydronaphthalen-l(2H )-one oxime (497 mg, 2.1 mmol) was taken up in SOCh (5.0 mL, 69 mmol) and heated to 50 °C. After 2 h, the reaction was directly condensed, taken up in EtOAc, and washed with sat. NaHCOi (aq). The organic layer was washed with water and brine, dried over Na2SO4, condensed, and purified by SiO2FCC to afford the title compound (303 mg, 61% yield). LCMS calcd. for C10H1BrNO [M+H]+: m / z = 240.0; Found: 239.7.

[0375] Step 3. 6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)- 2-methoxyphenyl)-l -oxo-1, 3,4, 5-tetrahydro-2H-benzo[c]azepin-2-yl)methyl)-N,N- dimethylpicolinamide

[0376] The title compound was prepared as the TFA salt using procedures analogous to Intermediate 2 Step 3 and Example 1 Steps 1-3. LCMS calcd. for C36H37N8O4 [M+H]+: m / z = 645.3; Found: 645.4. 'HNMR (400 MHz, DMSO-t / e) 8 10.89 (s, 1H), 9.04 (s, 1H), 8.07 (s, 1H), 7.88 (t, J= 7.8 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J= 7.9 Hz, 1H), 7.52 (dd, J= 7.9, 1.6 Hz, 1H), 7.47 (s, 2H), 7.42 (dd, J= 7.4, 2.7 Hz, 3H), 7.29 - 7.25 (m, 2H), 4.81 (s, 2H), 3.31 (s, 3H), 3.27 (t, J= 6.2 Hz, 2H), 2.95 (s, 3H), 2.88 (s, 3H), 2.77 (t, J= 7.0 Hz, 2H), 1.92 (td, J= 5.8, 2.4 Hz, 1H), 1.85 (q, J= 6.7 Hz, 2H), 0.76 (dq, J= 5.8, 3.3 Hz, 4H).Example 7. 6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / ] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-3,3-dimethyl-l-oxo-3,4-dihydroisoquinolin-2(lZ7)-yl)methyl)- 7V,7V-dimethylpicolinamide

[0377] Step 1. 6-((6-Bromo-3,3-dimethyl-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)methyl)-N,N-dimethylpicolinamide

[0378] The title compound was prepared using procedures analogous to Intermediate 2 Step 3, with 6-bromo-3,3-dimethyl-3,4-dihydroisoquinolin-l(2J7)-one replacing 6'-bromo-2',3'- dihydro-17 / -spiro[cyclopropane-l,4'-isoquinolin]-r-one. LCMS calcd. for C2oH23BrN302 [M+H]+: m / z = 416.1; Found: 416.0.

[0379] Step 2. 6-((3,3-Dimethyl-l-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinolin-2(lH)-yl)methyl)-N,N-dimethylpicolinamide

[0380] The title compound was prepared using a procedure analogous to Intermediate 8 Step 5. LCMS calcd. for C26H35BN3O4 [M+H]+: m / z = 464.3; Found: 464.1.

[0381] Step 3. 6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l-f] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-3, 3 -dimethyl- 1 -oxo- 3, 4-dihydroisoquinolin-2( lH)-yl)methyl)-N,N- dimethylpicolinamide

[0382] A solution of 6-((3,3-dimethyl-l-oxo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,4-dihydroisoquinolin-2(177)-yl)methyl)-A,A-dimethylpicolinamide (27 mg, 0.058 mmol), Intermediate 5 (17.7 mg, 0.044 mmol), K2CO3 (12.1 mg, 0.088 mmol), and Pd(dppf)C12'DCM (3.6 mg, 0.004 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was degassed with N2 for 1 min, then sealed under N2 and heated to 80 °C. After 40 hours, the reaction mixture was cooled, filtered, diluted in DMSO and MeOH and purified on prep-HPLC (5 pm, 30 x 100 nm, Waters CSH-C18, 31.3-51.3% MeCN in water (0.1% TFA), 5 min) to afford the TFA salt of the title compound (1.0 mg, 3% yield) as a fluffy white powder. LCMS calcd. for C36H38N9O4 [M+H]+: m / z = 660.3; Found: 660.3.Examples 8 - 11

[0383] Examples 8 - 11 are shown below in Table 1. Examples 8 - 11 were prepared as TFA salts using procedures analogous to those used in Example 7 with the appropriate starting materials and commercial reagents.Table 1. Examples 8 - 11Example 12. 6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / ] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-4-fluoro-l-oxoisoquinolin-2(lH)-yl)methyl)-7V,7V- dimethylpicolinamide

[0384] Step 1. 4- bromo-N-methoxybenzamide

[0385] To a vigorously stirring mixture of K2CO3 (318 mg, 2.30 mmol) and O- methylhydroxyl-amine HC1 (114 mg, 1.37 mmol) in EtOAc (8 mL) and water (4 mL) at 0 °C was added 4-bromobenzoyl chloride (250 mg, 1.14 mmol) and the reaction was allowed to warm to ambient temperature. After stirring well for 5 hours, the layers were allowed to separate and the organic layer was set aside. The aqueous layer was washed with EtOAc (2 x 10 mL), and the combined organic layers were dried over Na2SO4and condensed to yield the crude title compound (250 mg, 95% yield) as white crystals. LCMS calcd. for CsELBrbTCL [M+H]+: m / z = 229.9 / 231.9; Found: 229.9 / 231.9.

[0386] Step 2. 6- bromo-4, 4-difluoro-3-hydroxy-3, 4-dihydroisoquinolin-l(2H)-one

[0387] A reaction vessel was charged with 4-bromo-A-methoxybenzamide (250 mg, 1.09 mmol), 2,2-difluorovinyl 4-methylbenzenesulfonate (380 pL, 2.17 mmol), NaOAc (178 mg, 2.17 mmol), tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (45.2 mg, 0.05 mmol), and finally water (8.7 mL), and it was sealed and stirred at 80 °C overnight. After the reaction mixture cooled, it was filtered, partially condensed, and extracted with EtOAc. The organic layer was dried over Na2SO4, condensed, and purified by SiO2 FCC: 0-100%EtOAc / hexanes to afford the title compound (228 mg, 76% yield) as a red solid. LCMS calcd. for C9H7BrF2NO2 [M+H]+: m / z = 278.0 / 280.0; Found: 277.7 / 279.8.

[0388] Step 3. 6- bromo-4, 4-difluoro-3, 4-dihydroisoquinolin-l(2H)-one

[0389] To a suspension of 6-bromo-4,4-difluoro-3 -hydroxy-3, 4-dihydroisoquinolin- 1(277)- one (228 mg, 0.82 mmol) in DCM (8 mL) was added methanesulfonic acid (1.48 mL, 3.28 mmol) and the starting material went into solution. Triethylsilane (917 pL, 5.74 mmol) was then added slowly, and the reaction was allowed to stir at rt. After 6 hours, more methanesulfonic acid (1.48 mL, 3.28 mmol) and triethylsilane (917 pL, 5.74 mmol) were added and the reaction was stirred overnight. The reaction was quenched with dropwise addition of sat. NaHCCh (aq), then extracted with DCM (3 x 10 mL). The combined organics were washed with brine, dried over Na2SO4, condensed, and purified by SiCL FCC: 0-100% EtOAc / hexanes to afford the title compound (132 mg, 61% yield) as a light peach-colored solid. LCMS calcd. for CLFLB^NO [M+H]+: m / z = 262.0 / 264.0; Found: 261.8 / 263.9.

[0390] Step 4. 6-((6-bromo-4-fluoro-l-oxoisoquinolin-2(lH)-yl)methyl)-N,N- dimethylpicolinamide

[0391] To a stirring solution of 6-bromo-4,4-difluoro-3,4-dihydroisoquinolin-l(277)-one (50.0 mg, 0.19 mmol) and Intermediate 6 (46.4 mg, 0.19 mmol) in DMF (1 mL) at 0 °C was added NaH (60% in mineral oil, 16.8 mg, 0.42 mmol). The reaction was allowed to warm to ambient temperature and stirred for 1 h. LCMS showed complete reaction, as well as quantitative elimination of a fluorine. The reaction was quenched with water and extracted with EtOAc (3 x 3 mL). The combined organics were dried over Na2SO4, condensed, and purified by SiO2FCC: 0- 10% MeOH / DCM to afford the title compound (51.5 mg, 67% yield) as a tan solid. LCMS calcd. for C18Hi6BrFN3O2 [M+H]+: m / z = 404.0 / 406.0; Found: 404.0 / 406.0.

[0392] Step 5. 6-((6-(3-((2-(cyclopropanecarboxamido)imidazo[2, 1-j] [ l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)-4-fluoro-l-oxoisoquinolin-2(lH)-yl)methyl)-N,N- dimethylpicolinamide

[0393] The title compound was prepared as the TFA salt using procedures analogous to those described for Example 7 Steps 2-3. LCMS calcd. for C34H31FN9O4 [M+H]+: m / z = 648.2; Found:648.2.Example 13. 6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / ] [l,2,4]triazin-4- yl)amino)-2-methoxyphenyl)- 1 '-oxo- 1 ' / / -spiro [cyclopropane- 1 ,4'-isoquinolin]-2'(3'Z / )- yl)methyl)-\, \ dimethylpicolinamide

[0394] A mixture of Intermediate 5 (15 mg, 0.04 mmol), Intermediate 9 (19 mg, 0.04 mmol), K3PO4 (24 mg, 0.11 mmol) in 1,4-di oxane (0.80 mL) and water (0.16 mL) was purged with N2 for 1 min and was added XPhos Pd G3 (6 mg, 0.01 mmol) and was further purged with N2 for 1 min. The reaction was stirred at 90 °C overnight. The reaction was cooled to rt and was poured into brine and was extracted 3x by DCM / MeOH (v / v=15 / l). The combined organic phase was dried over Na2SO4and purified by prep-HPLC on C18 column (30 x 250 mm, 10 pM, 8-55% MeCN / EEO (w / 0.1% TFA)). The desired fractions were collected, concentrated, and freeze- dried to give the TFA salt of the title compound (12.5 mg, 51% yield) as white solids. LCMS calcd. for C36H36N9O4 [M+H]+: m / z = 658.3; Found: 658.4.Example 14. 6-((6'-(3-((2-Aminoimidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-! '-oxo- 1 ' / / -spiro [cyclopropane- 1.4'-isoquinolin|-2'(37 / )-yl)methyl)-\, \ dimethylpicolinamide

[0395] Step 1. 6-((6'-(3-((2-((2,4-Dimethoxybenzyl)amino)imidazo[2,l-f][l,2,4]triazin-4- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0396] The title compound as the TFA salt was prepared using the procedure analogous to that described for Example 13 with appropriate starting materials. LCMS calcd. for C41H42N9O5 [M+H]+: m / z = 740.3; Found: 740.5.

[0397] Step 2. 6-((6'-(3-((2-Aminoimidazo[2,l-f][l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N- dimethylpicolinamide

[0398] To a solution of 6-((6'-(3-((2-((2,4-dimethoxybenzyl)amino)imidazo[2,l- f\ [ 1 , 2, 4]triazin-4-yl)amino)-2-m ethoxyphenyl)- 1 '-oxo- 17 / -spiro[cyclopropane- 1 ,4'-isoquinolin]- 2'(3'7 / )-yl)methyl)-A A-dimethylpicolinamide (140 mg, 0.19 mmol) in cold DCM (2 mL) was added TFA (1.0 mL, 0.19 mmol). The reaction was stirred at rt for 1 h. The solvent wasremoved. The residue was purified by prep-HPLC on C18 column (30 x 250 mm, 10 pM, 8-40% MeCN / TfcO (w / 0.1% TFA)). The desired fractions were collected and concentrated. A small portion was freeze-dried to give 6.5 mg product as a TFA salt. The remaining part was poured into sat. NaHCCh (aq) and extracted by DCM / MeOH (v / v=10 / l) three times. The combined organic phase was dried over Na2SO4and condensed to afford the title compound (94 mg, 84% yield) as colorless viscous solids. LCMS calcd. for C32H32N9O3 [M+H]+: m / z = 590.3; Found: 590.6.1H NMR (300 MHz, CD3OD) 5 8.64 (dd, J = 8.0, 1.8 Hz, 1H), 8.10 (d, J= 8.1 Hz, 1H), 7.93 (t, J= 7.8 Hz, 1H), 7.77 (d, J= 1.4 Hz, 1H), 7.64 (d, J = 1.4 Hz, 1H), 7.59 (dd, J= 8.1, 1.6 Hz, 1H), 7.51 (t, J= 7.1 Hz, 2H), 7.28 (t, J= 7.9 Hz, 1H), 7.24 (d, J= 1.4 Hz, 1H), 7.21 (dd, J= 7.8, 1.8 Hz, 1H), 4.93 (s, 2H), 3.61 (s, 2H), 3.47 (s, 3H), 3.10 (s, 3H), 2.99 (s, 3H), 1.16 (t, J= 5.7 Hz, 2H), 1.02 (t, J= 5.7 Hz, 2H).Example 15. 6-((6'-(2-Methoxy-3-((2-(pyridin-2-ylamino)imidazo[2,l- / | [l,2,4]triazin-4- yl)amino)phenyl)-l '-oxo-1 ' / / -spiro [cyclopropane-1, 4'-isoquinolin]-2'(3' / / )-yl)methyl)-A,A- dimethylpicolinamide

[0399] A mixture of 6-((6'-(3-((2-aminoimidazo[2,l-: / ][l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-l '-oxo-1 H-spiro[cy cl opropane-1, 4'-isoquinolin]-2'(3 H)-yl)methyl)-A,A- dimethylpicolinamide (22 mg, 0.04 mmol), 2-bromopyridine (7 mg, 0.04 mmol), CS2CO3 (37 mg, 0.11 mmol), and Xantphos Pd G3 (5.3 mg, 0.01 mmol) in 1,4-dioxane (2 mL) was purged with N2 for 2 mins. The reaction was stirred at 100 °C overnight. The reaction was poured into brine and was extracted 3x by DCM / MeOH (v / v=15 / l). The combined organic phase was dried over Na2SO4, condensed, and purified by prep-HPLC on C18 column (30 x 250 mm, 10 pM,10- 50% MeCN / H2O (w / 0.1% TFA)). The desired fractions were collected, concentrated, andfreeze-dried to give the title compound (14.5 mg, 58% yield) as its TFA salt. LCMS ealed. for C37H35N10O3 [M+H]+: m / z = 667.3; Found: 667.7. *H NMR (300 MHz, CD3OD) 5 8.46 (dd, J= 7.1, 2.5 Hz, 1H), 8.38 - 8.26 (m, 2H), 8.19 - 8.10 (m, 2H), 7.97 (t, J= 7.8 Hz, 1H), 7.75 (d, J= 1.1 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.55 (t, J = 7.1 Hz, 2H), 7.48 - 7.34 (m, 3H), 7.27 (d, J= 1.4 Hz, 1H), 4.97 (s, 2H), 3.65 (s, 2H), 3.54 (s, 3H), 3.13 (s, 3H), 3.03 (s, 3H), 1.19 (t, J= 5.7 Hz, 2H), 1.06 (t, J = 5.7 Hz, 2H).Example 16. 6-((6'-(3-((5-(Cyclopropanecarboxamido)pyrazolo[l,5-a]pyrimidin-7- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'Er)- yl)methyl)-7V,7V-dimethylpicolinamide

[0400] Step 1. N-(3-Bromo-2-methoxyphenyl)-5-chloropyrazolo[l,5-a]pyrimidin-7-amine

[0401] To a solution of 3 -bromo-2 -methoxy aniline (500 mg, 2.47 mmol) in EtOH (6 mL) was added 5,7-dichloropyrazolo[l,5-a]pyrimidine (1.16 g, 6.19 mmol), followed by cone. HC1 (1 mL). The reaction was stirred at 80 °C for 22 h. Then the reaction mixture was basified to pH 7 by adding 1 M NaOH and concentrated under reduced pressure. The residue was purified by SiO2FCC: (0-50% EtOAc / hexane) to afford the title compound (717 mg, 82% yield) as a white solid. LCMS ealed. for CnHnBrCMO [M+H]+: m / z = 355.0 / 353.0; Found: 353.2 / 355.3.

[0402] Step 2. N-( 7-( ( 3-Bromo-2-methoxyphenyl)amino)pyrazolo[ 1, 5 -a ]pyrimidin-5- yl) cyclopropanecarboxamide

[0403] To a solution of Av-(3-bromo-2-methoxyphenyl)-5-chloropyrazolo[l,5-a]pyrimidin-7- amine (500 mg, 1.41 mmol) in 1,4-dioxane (10 mL) was added cyclopropanecarboxamide (361 mg, 4.24 mmol), Pd2(dba)s (259 mg, 0.28 mmol), Xantphos (346 mg, 0.42 mmol) and CS2CO3 (2.3 g, 7.07 mmol). The resulting mixture was purged with N2, and the mixture was stirred at 120°C for 22 h. The mixture was concentrated to give a residue. Then the reside was poured into water and extracted with ethyl acetate (60 ml). The organic layer was washed with a sat. NaHCO3(50 ml, aq) and brine (50 ml), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by prep-HPLC on C18 column (30 x 250 mm, 10 pM, 0- 60% MeCN / ThO (w / 0.05% formic acid)) to afford the title compound (32.2 mg, 6% yield) as an off- white solid as its formate salt. LCMS calcd. for C17H17BrN5O [M+H]+: m / z = 402.1 / 404.1; Found: 404.0.

[0404] Step 3. 6-((6'-(3-((5-(cyclopropanecarboxamido)pyrazolo[l,5-a]pyrimidin-7- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0405] To a mixture of 7V-[7-(3-bromo-2-methoxyanilino)pyrazolo[l,5-a]pyrimidin-5- yl]cyclopropanecarboxamide (30 mg, 0.07 mmol), Intermediate 9 (36 mg, 0.08 mmol), and K3PO4 (63 mg, 0.3 mmol) in 1,4-dioxane (2 mL) and water (0.40 mL) was added Xphos Pd G3 (32 mg, 0.04 mmol) and Xphos (18 mg, 0.04 mmol). The mixture was purged with N2 for 1 min. The reaction was stirred at 90 °C overnight. The remaining boronic ester starting material was turned into boronic acid by adding 1 N HC1 and stirred at rt for 20 mins. The resulting reaction mixture was poured into a saturated aqueous NaHCCL solution and was extracted by DCM / MeOH (v / v=10 / l) three times. The combined organic phase was dried over Na2SO4, condensed, and purified by prep-HPLC on C18 column (30 x 250 mm, 10 pM, 8- 55% MeCN / H2O (w / 0.1% TFA)). The desired fractions were collected, concentrated, and freeze- dried to give the title compound (6.0 mg, 12% yield) as white solids as its TFA salt. LCMS calcd. for C37H37N8O4[M+H]+: m / z = 657.3; Found: 657.5. 'H NMR (300 MHz, CD3OD) 5 8.17- 8.05 (m, 2H), 7.93 (t, J= 7.8 Hz, 1H), 7.61 (dd, J= 8.1, 1.6 Hz, 1H), 7.57 - 7.43 (m, 4H), 7.39 (t, J= 7.8 Hz, 1H), 7.24 (d, J= 1.6 Hz, 1H), 6.55 - 6.41 (m, 2H), 4.93 (s, 2H), 3.61 (s, 2H), 3.42 (s, 3H), 3.09 (s, 3H), 2.99 (s, 3H), 1.82 7.7, 3.9 Hz, 1H), 1.23 - 1.14 (m, 2H), 1.12 - 0.94 (m, 6H).Example 17. 6-((6'-(3-((2-Aminopyrazolo[l,5-a][l,3,5]triazin-4-yl)amino)-2- methoxyphenyl)-l'-oxo-ltH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'Er)-yl)methyl)-7V,7V- dimethylpicolinamide

[0406] Step 1. N-( 3-Bromo-2-methoxyphenyl) -2-(methylthio)pyrazolo[ 1, 5 -a ][ 1, 3, 5 ]triazin-4- amine

[0407] Lithium bis(trimethylsilyl)amide (6.23 mL, 6.23 mmol, 1 M in THF) was added dropwise to a stirring solution of 3 -bromo-2-methoxy aniline (289 pL, 2.20 mmol) and 4-chloro- 2-(methylthio)pyrazolo[l,5-a][l,3,5]triazine (500 mg, 2.49 mmol) in THF (25 mL) at 0 °C. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight at room temperature. The product mixture was diluted with EtOAc (100 mL) and water (100 mL). The diluted product mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by SiO2FCC: 0-50% EtOAc / heptane to obtain the title compound (680 mg, 75%). LCMS calcd. for C13Hi3BrN5OS [M+H]+: m / z = 366.0 / 368.0; Found: 366.2 / 368.2.

[0408] Step 2. N-( 3-Bromo-2-methoxyphenyl) -2-(methylsulfonyl)pyrazolo[ 1, 5- a ][ 1, 3, 5 ]triazin-4-amine

[0409] meto-Chloroperoxybenzoic acid (283 mg, 1.64 mmol) was added to a stirring solution of 7V-(3-bromo-2-methoxyphenyl)-2-(methylthio)pyrazolo[l,5-a][l,3,5]triazin-4-amine (300 mg, 0.819 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was allowed to gradually warm to rt. The reaction mixture was stirred at rt for 2 h. The product mixture was diluted with EtOAc (20 mL) and water (20 mL). The diluted product mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by SiO2 FCC: 0-70% EtOAc / heptane to obtain the title compound (300 mg, 92%). LCMS calcd. for CoHoBrNsOsS [M+H]+: m / z = 398.0 / 400.0; Found: 398.2 / 400.3.

[0410] Step 3. N4-( 3-Bromo-2-methoxyphenyl)-N2-(2, 4-dimethoxybenzyl)pyrazolo[ 1, 5- a ][ 1, 3, 5 ]triazine-2, 4-diamine

[0411] DIPEA (115 pL, 0.663 mmol) was added to a stirring solution of 2,4- dimethoxybenzylamine (145 pL, and 0.964 mmol) and 7V-(3-bromo-2-methoxyphenyl)-2- (methylsulfonyl)pyrazolo[l,5-a][l,3,5]triazin-4-amine (120 mg, 0.301 mmol) in 1,4-dioxane (5 mL). The reaction mixture was heated to 45 °C and stirred for 5 hours. The product mixture was concentrated under reduced pressure and purified by SiO2FCC: 0-5% MeOH / DCM to obtain the title compound (145 mg, 99%). LCMS calcd. for C2iH22BrNeO3 [M+H]+: m / z = 485.1 / 487.1; Found: 485.1 / 487.1

[0412] Step 4. 6-((6'-(3-((2-((2,4-Dimethoxybenzyl)amino)pyrazolo[ 1 ,5-a] [ 1 ,3,5]triazin-4- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0413] The title compound was prepared using the procedure analogous to that described for Example 13 with appropriate starting materials and commercial reagents. LCMS calcd. for C41H42N9O5 [M+H]+: m / z = 740.3; Found: 740.5

[0414] Step 5. 6-((6'-(3-((2-Aminopyrazolo[l,5-a][l,3,5]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N- dimethylpicolinamide

[0415] Trifluoroacetic acid (1 mL) was added to stirring solution of 6-((6'-(3-((2-((2,4- dimethoxybenzyl)amino)pyrazolo[l,5-a][l,3,5]triazin-4-yl)amino)-2-methoxyphenyl)-r-oxo- rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-7V,7V-dimethylpicolinamide (40 mg, 0.054 mmol) and anisole (100 pL, 0.92 mmol) in DCM (1 mL). The reaction mixture was stirred for 2 hours at room temperature. The product mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (20 mL) and washed with a sat NaHCO3 (aq) solution (2 x 15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue obtained was purified with prep-HPLC on a C18 column (15-50% MeCN in 0.05% formic acid (aq)) to give the title compound (1.3 mg, 3.5%) as the formic acid salt. LCMS calcd. for C32H32N9O3 [M+H]+: m / z = 590.3; Found: 590.6.Example 18. 6-((6'-(3-((5-(Cyclopropanecarboxamido)thiazolo[5,4-d]pyrimidin-7- yl)amino)-2-methoxyphenyl)-l '-oxo-1 ' / / -spiro [cyclopropane- 1, 4'-isoquinolin ] -2'(3' / / )- yl)methyl)-\,A-dimethylpicolinamide

[0416] Step 1. 6-((6'-(3-((5-Chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)-2-methoxyphenyl)-1 '-oxo-1 'H-spiro[ cyclopropane- 1 ,4'-isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N-dimethylpicolinamide

[0417] To a solution of 5,7-dichloro-[l,3]thiazolo[5,4-J]pyrimidine (50.0 mg, 0.24 mmol) and 6-((6'-(3-amino-2-methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-A,A-dimethylpicolinamide (111 mg, 0.24 mmol) in DMF (1 mL) was added DIPEA (157 mg, 1.21 mmol) and the reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was cooled to rt, poured into water (10 mL), and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered, concentrated, and purified by SiO2FCC: 0-5% MeOH / DCM to give the title compound (100 mg, 66% yield) as a light yellow solid.JH NMR (400 MHz, CDCh) 5 9.02 (s, 1H), 8.89 (s, 1H), 8.75 (dd, J= 8.3, 1.5 Hz, 1H), 8.22 (d, J= 8.1 Hz, 1H), 7.84 (t, J= 7.6 Hz, 1H), 7.61-7.51 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 7.17-7.10 (m, 2H), 4.99 (s, 2H), 3.51 (s, 2H), 3.48 (s, 3H), 3.16 (s, 3H), 3.05 (s, 3H), 1.13 (d, J= 6.1 Hz, 2H), 0.92 (d, J= 5.5 Hz, 2H).

[0418] Step 2. 6-((6'-(3-((5-(Cyclopropanecarboxamido)thiazolo[5,4-d]pyrimidin-7- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0419] The title compound as the TFA salt was prepared using the procedure analogous to that described for Example 1 Step 3 with appropriate starting materials and commercial reagents. LCMS calcd. for C36H35N8O4S [M+H]+: m / z = 675.2; Found: 675.2. 'HNMR (400 MHz, DMSO-t / e) 8 10.85 (s, 1H), 9.23 (s, 1H), 9.12 (s, 1H), 8.86 (dd, J= 8.1, 1.6 Hz, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.91 (t, J= 7.8 Hz, 1H), 7.56 (dd, J= 8.0, 1.6 Hz, 1H), 7.44 (td, J= 8.0, 1.0 Hz, 2H), 7.25 (d, J= 7.9 Hz, 1H), 7.21-7.15 (m, 2H), 4.84 (s, 2H), 3.55 (s, 2H), 3.42 (s, 3H), 2.98 (s, 3H), 2.90 (s, 3H), 2.23-2.15 (m, 1H), 1.19-1.11 (m, 2H), 1.02-0.95 (m, 2H), 0.88-0.77 (m, 4H).Example 19. 6-((6'-(3-((5-Aminothiazolo[5,4-< / ]pyrimidin-7-yl)amino)-2-methoxyphenyl)- r-oxo-r / / -spiro|cyclopropane-1.4'-isoquinolin|-2'(3' / / )-yl)methyl)-\, \ dimethylpicolinamide

[0420] Step 1. tert-Butyl(7-( ( 3-(2'-( ( 6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l '-oxo-2 3 '- dihydro- rH-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)thiazolo[5, 4- d]pyrimidin-5-yl) carbamate

[0421] The title compound was prepared using a procedure analogous to Example 1 Step 3 using the appropriate intermediates and commercial reagents.

[0422] Step 2. 6-( (6'-( 3-((5-Aminothiazolo [ 5, 4-d]pyrimidin- 7 -yl) amino) -2 -methoxyphenyl)-! '- oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N-dimethylpicolinamide

[0423] The title compound as the TFA salt was prepared using a procedure analogous to Example 14 Step 2 using the appropriate intermediates and commercial reagents. LCMS calcd. for C32H31N8O3S [M+H]+: m / z = 607.2; Found: 607.2.Example 20. 6-((6'-(3-((5-Aminothiazolo[5,4-< / ]pyrimidin-7-yl)amino)-2-methoxyphenyl)- l'-oxo-ltH-spiro[cyclobutane-l,4'-isoquinolin]-2'(3tH)-yl)methyl)-7V,7V- dimethylpicolinamide

[0424] Step 1. 6-((6'-(3-Amino-2-methoxyphenyl)-r-oxo-rH-spiro[cyclobutane-l,4'- isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N-dimethylpicolinamide

[0425] 3 -Bromo-2 -methoxyaniline (63.8 mg, 0.316 mmol), potassium carbonate (43.6 mg, 0.316 mmol), and Pd(dppf)C12 • CH2CI2 (12.9 mg, 0.0158 mmol) was added to a vial charged with Intermediate 7 (75 mg, 0.158 mmol). The mixture was dissolved in 1,4-dioxane (1 mL) and water (200 pL). The reaction mixture was sparged with N2 gas for 5 minutes and sealed. The sealed reaction mixture was heated to 80 °C and stirred for 4 hours. The product mixture was diluted with DCM (10 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel flash column chromatography with a gradient of 0-10% MeOH / DCM to afford the title compound (69 mg, 93%). LCMS calcd. for C28H31N4O3 [M+H]+: m / z = 471.2; Found: 471.1.

[0426] Step 2. 6-((6'-(3-((5-Chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)-2-methoxyphenyl)-

[0427] The title compound was prepared using a procedure analogous to Example 18Step 1 using the appropriate intermediates and commercial reagents. LCMS calcd. for C33H31CIN7O3S [M+H]+: m / z = 640.2; Found: 640.2.

[0428] Step 3. 6-( (6'-( 3-((5-Aminothiazolo [ 5, 4-d]pyrimidin- 7 -yl) amino) -2 -methoxyphenyl)-! '- oxo-1 'H-spiro[ cyclobutane- 1, 4 '-isoquinolin ]-2 '( 3 'H) -yl)methyl) -N,N-dimethylpicolinamide

[0429] The title compound as the TFA salt was prepared using a procedure analogous to Example 1 Step 3 using the appropriate intermediates and commercial reagents. LCMS calcd. for C33H33N8O3S [M+H]+: m / z = 621.3; Found: 621.3.Example 21. 6-((6'-(3-((2-Aminopyrido[3,2-J|pyrimidin-4-yl)amino)-2-methoxyphenyl)-l'- oxo-17f-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'Er)-yl)methyl)-7V,7V-dimethylpicolinamide

[0430] Step 1. N-( 3-Bromo-2-methoxyphenyl) -2-chloropyrido[ 3, 2-d]pyrimidin-4-amine

[0431] A mixture of 2,4-dichloropyrido[3,2-t / ]pyrimidine (300 mg, 1.5 mmol), 3-bromo-2- methoxy aniline (606 mg, 3.0 mmol), and DIPEA (0.78 mL, 4.5 mmol) in 1 -butanol (5 mL) was heated at 50 °C overnight. The precipitate was filtered, washed with minimum amount of methanol and was collected as the title compound (432.8 mg, 79% yield) as an off-white solid.1H NMR (300 MHz, CDCI3) 6 10.07 (s, 1H), 9.05 - 8.68 (m, 2H), 8.16 (dd, J= 8.5, 1.5 Hz, 1H), 7.79 (dd, J= 8.5, 4.3 Hz, 1H), 7.38 (dd, J= 8.1, 1.5 Hz, 1H), 7.19 (t, J= 8.2 Hz, 1H), 4.04 (s, 3H).

[0432] Step 2. N4-(3-Bromo-2-methoxyphenyl)-N2-(2,4-dimethoxybenzyl)pyrido[3,2- d]pyrimidine-2, 4-diamine

[0433] A mixture of 2,4-dimethoxybenzylamine (183 mg, 1.1 mmol), 7V-(3-bromo-2- methoxyphenyl)-2-chloropyrido[3,2-J]pyrimidin-4-amine (200 mg, 0.6 mmol) and DIPEA (0.19 mL, 1.1 mmol) in 1-butanol (2.7 mL) was heated at 90 °C for 17 h. The reaction was cooled to rt and was filtered to collect the precipitate. The precipitate was washed with minimum amount of methanol and dried on the funnel for 15 min. The off-white solid was collected as the title compound (232 mg, 85% yield). 'H NMR (300 MHz, CDC13) 8 9.80 (s, 1H), 8.82 (d, J = 8.2 Hz, 1H), 8.45 (dd, J = 4.2, 1.5 Hz, 1H), 7.79 (s, 1H), 7.52 (dd, J = 8.5, 4.2 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.27 - 7.25 (m, 1H), 7.07 (t, J = 8.2 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 5.55 (s, 1H), 4.71 (d, J = 5.9 Hz, 2H), 4.01 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H).

[0434] Step 3. 6-((6'-(3-((2-Aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methoxyphenyl)-r- oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-N,N-dimethylpicolinamide

[0435] The title compound was prepared as the TFA salt using procedures analogous to Example 13 Step 1 and Example 14 Step 2 using the appropriate intermediates and commercial reagents. LCMS calcd. for C34H33N8O3 [M+H]+: m / z = 601.3; Found: 601.5.XH NMR (300 MHz, CD3OD) 5 8.76 (d, J = 3.2 Hz, 1H), 8.70 (dd, J = 7.1, 2.7 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.99 - 7.81 (m, 3H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.26 (s, 1H), 4.94 (s, 2H), 3.62 (s, 2H), 3.51 (s, 3H), 3.10 (s, 3H), 2.99 (s, 3H), 1.19 - 1.14 (m, 2H), 1.09 - 0.99 (m, 2H).Example 22. 6-((6'-(3-((2-(Cyclopropanecarboxamido)pyrido[3,2-J|pyrimidin-4-yl)amino)- 2-methoxyphenyl)-l'-oxo-l'Z7-spiro[cyclopropane-l,4'-isoquinolin]-2'(3tH)-yl)methyl)-7V,7V- dimethylpicolinamide

[0436] To a mixture of 6-((6'-(3-((2-aminopyrido[3,2-J]pyrimidin-4-yl)amino)-2- methoxyphenyl)-r-oxo-17 / -spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide (21.0 mg, 0.03 mmol), cyclopropanecarboxylic acid (6.0 mg, 0.07 mmol) and 1 -methylimidazole (0.02 mL, 0.24 mmol) in MeCN (0.35 mL) was added chloro-7V,7V,7V,7V- tetramethylformamidinium hexafluorophosphate (11.8 mg, 0.04 mmol) in a single portion. To this mixture was added DMF (2 mL) to aid solubility. The mixture was then heated at 60°C for 48 h. The reaction was purified by reverse phase chromatography to give the title compound (5.3 mg, 23% yield) as an off-white solid as the TFA salt. LCMS calcd. for C38H37N8O4 [M+H]+: m / z = 669.3; Found: 669.5. *H NMR (300 MHz, CD3OD) 5 9.00 (dd, J = 4.4, 1.4 Hz, 1H), 8.52 (dd, J = 6.1, 3.6 Hz, 1H), 8.44 (dd, J = 8.6, 1.4 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.05 (dd, J = 8.6, 4.4 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.66 (dd, J = 8.1, 1.6 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.48 - 7.40 (m, 2H), 7.29 (d, J = 1.6 Hz, 1H), 4.97 (s, 2H), 3.65 (s, 2H), 3.54 (s, 3H), 3.13 (s, 3H), 3.03 (s, 3H), 2.16 - 1.99 (m, 1H), 1.30 - 1.03 (m, 8H).Example 23. 6-((6'-(3-((5-(Cyclopropanecarboxamido)-3Z7-imidazo[4,5- / >]pyridin-7- yl)amino)-2-methoxyphenyl)-l'-oxo-l'H-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'Er)- yl)methyl)-7V,7V-dimethylpicolinamide

[0437] Step 1. 5, 7-Dichloro-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridine

[0438] Pyridinium / ?-toluenesulfonate (127 mg, 0.505 mmol) was added to a stirring solution of 5,7-dichloro-3H-imidazo[4,5-b]pyridine (950 mg, 5.05 mmol) and 3,4-dihydro-2H-pyran (1.28 g, 15.2 mmol) in THF (10 mL) at rt. The reaction mixture was heated to 70 °C and stirred for 1 hr. The product mixture was concentrated under reduced pressure. The residue obtained was purified by SiO2FCC: DCM to obtain the title compound (600 mg, 44%).JH NMR (400 MHz, CDC13) 8 8.28 (s, 1H), 7.32 (d, J= 0.7 Hz, 1H), 5.79 (dd, J= 10.7, 2.5 Hz, 1H), 4.16 (dp, J = 11.7, 1.8 Hz, 1H), 3.78 (td, J = 11.7, 2.8 Hz, 1H), 2.13 (dt, J= 14.8, 2.8 Hz, 1H), 2.06 (td, J= 7.1, 3.8 Hz, 1H), 1.97 (qd, J= 12.1, 3.6 Hz, 1H), 1.86 - 1.68 (m, 2H), 1.68 - 1.61 (m, 1H

[0439] Step 2. 6-((6'-(3-((5-Chloro-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridin- 7-yl)amino)-2-methoxyphenyl)-l '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0440] The title compound was prepared using procedures analogous to Example 1 Step 2 using the appropriate intermediates and commercial reagents.

[0441] Step 3. 6-((6'-(3-((5-(Cyclopropanecarboxamido)-3-(tetrahydro-2H-pyran-2-yl)-3H- imidazo[ 4, 5-b Jpyridin- 7 -yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane-1, 4 '- isoquinolin ]-2 '( 3 'H)-yl)methyl)-N,N-dimethylpicolinamide

[0442] The title compound was prepared using procedures analogous to Example 16 Step 2 using the appropriate intermediates and commercial reagents.1H NMR (400 MHz, DMSO-t / 6) 5 10.45 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H) 7.95 (d, J= 8.0 Hz, 1H), 7.85 (t, J= 7.8 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J= 7.8 Hz, 1H), 7.42 - 7.32 (m, 3H), 7.23 - 7.08 (m, 3H), 5.59 (d, J= 10.5 Hz, 1H), 4.78 (s, 2H), 3.99 (d, J= 13.5 Hz, 1H), 3.66 - 3.53 (m, 1H), 3.48 (s, 2H), 3.25 (s, 3H) 2.93(s, 3H), 2.84 (s, 3H), 2.23 (q, J= 12.4 Hz, 1H), 2.07 - 1.85 (m, 3H), 1.71 - 1.49 (m, 3H), 1.09 (s, 2H), 0.91 (s, 2H), 0.79 - 0.63 (m, 4H).

[0443] Step 4. 6-((6'-(3-((5-(Cyclopropanecarboxamido)-3H-imidazo[4,5-b]pyridin-7- yl) amino) -2 -methoxyphenyl)-! '-oxo-1 'H-spiro[ cyclopropane- 1 ,4' -isoquinolin ]-2 '(3'H)- yl)methyl)-N,N-dimethylpicolinamide

[0444] 6-((6'-(3-((5-(Cyclopropanecarboxamido)-3-(tetrahydro-2J / -pyran-2-yl)-3JT- imidazo[4,5-Z>]pyridin-7-yl)amino)-2-methoxyphenyl)-r-oxo-17 / -spiro[cyclopropane-l,4'- isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide (15 mg, 0.020 mmol) was dissolved in TFA (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours. The product mixture was concentrated under reduced pressure. The residue obtained was purified by prep- HPLC (20-70% MeCN / H2O (w / 0.1% TFA)) to obtain the title compound (8.6 mg, 65%) as the TFA salt. ‘HNMR (400 MHz, DMSO-t / 6) 5 10.78 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 7.98 (d, J= 8.0 Hz, 1H), 7.86 (t, J= 7.8 Hz, 1H), 7.60 (s, 1H), 7.49 (dd, J= 8.0, 1.6 Hz, 1H), 7.44 - 7.35 (m, 3H), 7.31 - 7.18 (m, 2H), 7.15 (d, J= 1.6 Hz, 1H), 4.79 (s, 2H), 3.50 (s, 2H), 3.29 (s, 3H), 2.94 (s, 3H), 2.85 (s, 3H), 1.93 (p, J= 6.3 Hz, 1H), 1.10 (q, J= 4.6 Hz, 2H), 0.93 (q, J= 4.5 Hz, 2H), 0.84 - 0.73 (m, 4H). LCMS calcd. for C37H37N8O4 [M+H]+: m / z = 657.3; Found: 657.4.Example 24. 7V-(8-((2-Methoxy-3-(2'-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-l'- oxo-2', 3 Mlihydro- l ' / / -spiro | cyclopropane- 1.4'-isoquinolin]-6'- yl)phenyl)amino)imidazo[l,2- / >]pyridazin-6-yl)cyclopropanecarboxamide

[0445] Step 1. Methyl 6-(chloromethyl)picolinate

[0446] The title compound was prepared using procedures analogous to Intermediate 1 Step 2 using the appropriate intermediates and commercial reagents. LCMS calcd. for CsFLQNCL [M+H]+: m / z = 186.0; Found: 186.0.

[0447] Step 2. Methyl 6-((6'-bromo-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)picolinate

[0448] The title compound was prepared using the procedure analogous to that described for Intermediate 2 Step 3 replacing Intermediate 1 with methyl 6-(chloromethyl)picolinate. LCMS calcd. forC19H18BrN2O3 [M+H]+: m / z = 401.0; Found: 401.4.

[0449] Step 3. 6-((6'-Bromo-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)- yl)methyl)picolinic acid

[0450] To a solution of methyl 6-((6'-bromo-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]- 2'(377)-yl)methyl)picolinate (200 mg, 0.50 mmol) in THF (4 mL) and water (2 mL) was added LiOH FLO (105 mg, 2.49 mmol), and the reaction mixture was stirred at room temperature for 16 h. The mixture was purified by prep-HPLC to give the title compound (100 mg, 52% yield) as a white solid. LCMS calcd. for C18H16BrN2O3[M+H]+: m / z = 387.0; Found: 387.0.

[0451] Step 4. 6'-Bromo-2 '-( 66-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-2 3 '-dihydro-1 'H-spiro[cyclopropane-l,4'-isoquinolin]-l '-one

[0452] The title compound was prepared using the procedure analogous to that described for Intermediate 8 Step 1 with appropriate starting materials and commercial reagents. LCMS calcd. for C22H23BrN3O3[M+H]+: m / z = 456.1; Found: 456.1.

[0453] Step 5. N-(8-((2-Methoxy-3-(2'-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-r- oxo-2',3'-dihydro-l'H-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2- b]pyridazin-6-yl)cyclopropanecarboxamide

[0454] The title compound as the TFA salt was prepared using the procedure analogous to that described for Example 3 Step 3 with appropriate starting materials and commercial reagents. LCMS calcd. for C39H39N8O5[M+H]+: m / z = 699.3; Found: 699.2. *H NMR (400 MHz, DMSO- d6) 5 10.82 (s, 1H), 8.99 (s, 1H), 8.00 (s, 1H), 7.92 - 7.88 (m, 2H), 7.64 (s, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 7.27 (d, J= 4.7 Hz, 2H), 7.19 (s, 1H), 5.31 - 5.28 (m, 2H), 4.81 (s, 2H), 3.57 (s, 3H), 3.53 (s, 2H), 3.29 (s, 8H), 1.43 (s, 1H), 1.12 (s, 2H), 0.95 (s, 2H), 0.83 - 0.78 (m, 4H).Examples 25 - 29

[0455] Examples 25 - 29 are shown below in Table 2. Examples 8 - 11 were prepared in accordance with the synthetic protocols set forth in Example 24 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.Table 2. Examples 25 - 29Example 30. 6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2- / >]pyridazin-8- yl)amino)-2-methoxyphenyl)-l'-oxo-l'ZZ-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'ZZ)- yl)methyl)-7V-ethyl-7V-methylpicolinamide

[0456] Step 1. Methyl 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinate

[0457] To a solution of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (15.0 g, 89.7 mmol) and imidazole (18.3 g, 269 mmol) in DCM (200 mL) was added TBSC1 (14.9 g, 98.7 mmol) at 0°C. After 2 h at RT, the reaction was poured into sat. NH4CI (aq.) and extracted with EtOAc (3x 20 mL). The combined organic layers were washed with brine (20 mL), dried withNa2SO4, filtered, and concentrated under vacuum to give the titled compound (18 g, 71% yield) as a yellow oil. LCMS calcd. for C14H24NO3 Si+H]+: m / z = 282.1; Found 282.2.

[0459] The title compound was prepared using the procedure analogous to that described for Example 24 Step 3-4 replacing methyl 6-((6'-bromo-l'-oxo-177-spiro[cyclopropane-l,4'- isoquinolin]-2'(377)-yl)methyl)picolinate with methyl 6-(((terLbutyldimethylsilyl)oxy)methyl)- picolinate. LCMS calcd. for C16H29N2O2Si [M+H]+: m / z = 309.2; Found 308.9.

[0460] Step 3. N-Ethyl-6-(hydroxymethyl)-N-methylpicolinamide

[0461] To a mixture of 6-(((terLbutyldimethylsilyl)oxy)methyl)-7V-ethyl-7V- methylpicolinamide (320 mg, 1.04 mmol) in 1,4-dioxane (0.5 mL) was added 40% HC1 in 1,4- dioxane (1 mL, 1.04 mmol). After 1 h, the reaction was complete and concentrated under reduced pressure. Crude was used in the next step without additional purification and a quantitative yield was assumed. LCMS calcd. for C10H15N2O2 [M+H]+: m / z = 195.1; Found 195.2.

[0462] Step 4. 6-(Chloromethyl)-N-ethyl-N-methylpicolinamide

[0463] The title compound was prepared using the procedure analogous to that described for Intermediate 1 Step 2 replacing 6-(hydroxymethyl)-7\(A-dimethylpyridine-2-carboxamide with A-ethyl-6-(hydroxymethyl)-A-methylpyridine-2...

Claims

What is claimed:

1. A compound of F ormula (I) :or a pharmaceutically acceptable salt or solvate thereof, whereinA2is CRA2or N;A3is CRA3or N;A4is O, S or NRA4;A5is CRA5or N;R1is H, OH, NH2, -NRcRd, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, - S(O)(=NRb)Rb, -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -C(O)R20, -OC1-C6alkyl, C1-C6alkyl, C1- C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl or Cs-C1o hetero-cycloalkenyl; wherein said -OC1-C6alkyl, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C3-C10cycloalkenyl, aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; wherein R20is C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6- C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl, or C3-C10heterocycloalkenyl, wherein said - C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, or C3-C10heterocycloalkenyl, are optionally substituted by 1-6 Rfgroups;RA1, RA2, RA3, RA4and RA5are each independently H, halo, -CN, C1-C6alkyl, -OC1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, - NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, - SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb);B2is CRB2or N;B3is CRB3or N;B4is CRB4or N;RB1, RB2, RB3, and RB4are each independently H, halo, C1-C6alkyl, C1-C6haloalkyl, -O- C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, C3-C10heterocycloalkenyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, - S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), - B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3- C10 cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C 10 heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; or RB2and RB3, may, together with the carbon atoms to which they are attached, form a ring structure; or RB3and RB4, may, together with the carbon atoms to which they are attached, form a ring structure; each Rfis independently H, oxo, halogen, -OC1-C8alkyl, C1-C8alkyl, haloalkyl, -OH, - CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, - C(O)ORb, -C(O)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -P(O)RbRb, - P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or - OPO(ORb)(ORb); wherein said C1-C8alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd; each Rais independently H, -C(O)Rb, -C(O)ORC, -C(O)NRcRd, -C(=NRb)NRbRc, - C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORC)2, -P(O)RcRb, -P(O)ORcORb, -S(O)Rb, -S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiR\ -C1-C1oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each Rb, is independently H, -C1-C6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;each Rcor Rdis independently H, -C1-C1o alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1- C6alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or Rcand Rd, together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group; andCycis a substituted bicyclyl.

2. The compound of claim 1 that is a compound of Formula (la):or a pharmaceutically acceptable salt or solvate thereof; whereinfused bicyclic group (i.e. , rings Cl and C2 share two atoms and the bonds between those atoms) wherein, ring Cl is an optionally substituted 5-6 membered aryl group or an optionally substituted 5-6 membered heteroaryl group; and ring C2 is a substituted 5-8 membered heterocyclyl group or a substituted 5-8 membered heteroaryl group.X1is CRX1or N;X2is CRX2or N;X3is CRX3or N;X4is CRX4or N;X5is CRX5or N;X6is CRX6or N;X7is O, S, C(RX7)2or NRX7;X8is O, S, C(RX8)2or NRX8;X9is O, S or NRX9; p is 0, 1 or 2; q is 0, 1 or 2; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;R2is -T-A-R;T is absent, optionally substituted C1-C6alkyl, -Co-C6alk-, -Co-C6alk-C(0)-Co-C6alk-, - Co-C6alk-O-Co-C6alk-, -Co-C6alk-NRb-Co-C6alk-, optionally substituted Cs-C12cycloalkyl, optionally substituted Cs-C12heterocycloalkyl, -C(O)-, -C(O)NRb-, -NRb-, - C(O)O-, -C(O)NRb-, -S(O)-, -S(O)2NRb-, -S(O)(=NRb)-, -S(O)2-, -C(O)NRbO-, or - S(O)2O-;A is abent, an optionally substituted 5-6 membered aryl group, an optionally substituted 5-6 membered heteroaryl group, an optionally substituted 5-6 membered heterocycloalkyl group, or an optionally substituted 5-6 membered heterocycloalkenyl group, an optionally substituted 5-6 membered cycloalkyl group, or an optionally substituted 5-6 membered cycloalkenyl group;R is abent, H, -CN, -C(O)Rb, -C(O)ORC, -C(O)NRcRd, -C(=NRb)NRbRc, - C(=NORb)NRbRc, -C(=NCN)NRbRc, -P(ORC)2, -P(O)RcRb, -P(O)ORcORb, -S(O)Rb, - S(O)NRcRd, -S(O)2Rb, -S(O)2NRcRd, SiRb3, -C1-C1oalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each R3is independently H, halo, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C10heteroaryl, C3-C10heterocycloalkyl, C3-C10heterocycloalkenyl, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, - ORa, -SRa, -NRcRd, -NRaRc, -C(O)Rb, -OC(O)Rb, -C(O)ORb, -C(O)NRcRd, -S(O)Rb, - S(0)2NRcRd, -S(O)(=NRb)Rb, -SFs, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, -S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); wherein said C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -C3-C8cycloalkyl, -C3-C10cycloalkenyl, C6-C1o aryl, C3-C 10 heteroaryl, C3-C10heterocycloalkyl or C3-C10heterocycloalkenyl are optionally substituted by 1-6 Rfgroups; or two R3groups attached to the same carbon atom form a carbonyl group (i.e., =0); or two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups; or two R3groups attached to adjacent carbon atoms, together with those carbon atoms, form a ring that is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted cycloalkenyl ring, an optionally substituted heterocycloalkyl ring, or an optionally substituted heterocycloalkenyl ring; wherein the ring optionally substituted by 1-6 Rfgroups;RX1, RX2, RX3, RX4, RX5, RX6, RX7and RX8are independently H, halo, C1-C6alkyl, -OC1- C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -0Ra, -SRa, -NRcRd, -NRaRc, -C(0)Rb, -0C(0)Rb, -C(0)0Rb, -C(0)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(0)(=NRb)Rb, -SF5, -N=S(O)RbRb, -P(O)RbRb, -P(O)(ORb)(ORb), -B(ORc)(ORd), -S(O)2Rb, -C(O)NRbORb, - S(O)2ORb, -OS(O)2ORb, or -OPO(ORb)(ORb); or two RX7or two RX8groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups.

4. The compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, wherein7. The compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, wherein9. The compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim13. The compound of claim 2 or claim 3, wherein14. The compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, whereinThe compound of claim 2 or claim 3, wherein19. The compound of claim 2 or claim 3, wherein20. The compound of claim 2 or claim22. The compound of any one of claims 3 to 21, wherein two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, an optionally substituted heterocycloalkyl ring, an optionally substituted cycloalkenyl ring, or an optionally substituted heterocycloalkenyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups.

23. The compound of claim 22, wherein two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cycloalkyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups.

24. The compound of claim 22 or claim 23, wherein two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cyclopropyl ring, or anyoptionally substituted cyclobutyl ring, wherein the ring is optionally substituted by 1-6 Rfgroups.

25. The compound of any one of claims 22-24, wherein two R3groups attached to the same carbon atom form a spirocyclic ring that is an optionally substituted cyclopropyl ring, or any optionally substituted cyclobutyl ring, wherein the ring is optionally substituted by 1-2 -F.

27. The compound of claim 26, wherein29. The compound of any one of the preceding claims, wherein X1is CRX1.

30. The compound of claim 29, wherein RX1is H or -OC1-C6alkyl.

31. The compound of claim 30, wherein RX1is -OC1-C6alkyl.

32. The compound of claim 31, wherein RX1is -OCH3, -OCH2CH3, or -OCH(CH3)2.

33. The compound of any one of claims 2-25, wherein Cl is 5-membered heteroaryl ring.

36. The compound of claim 35, wherein37. The compound of claim 35, wherein38. The compound of claim 35, wherein39. The compound of claim 35, wherein40. The compound of claim 35, wherein41. The compound of claim 35, wherein42. The compound of claim 35, wherein43. The compound of any one of the preceding claims, wherein RB1is -C1-C6alkyl or -O-C1- C6alkyl, wherein said -C1-C6alkyl and -O-C1-C6alkyl are optionally substituted by 1-6 Rfgroups.

44. The compound of claim 43, wherein RB1is -O-C1-C6alkyl.

45. The compound of claim 44, wherein RB1is -O-CH3.

46. The compound of claim 43, wherein RB1is -C1-C6alkyl optionally substituted by 1-6 Rfgroups.

47. The compound of claim 46, wherein RB1is methyl, trifluoromethyl, ethyl or isopropyl.

49. The compound of any one of the preceding claims, wherein50. The compound of claim 49, wherein51. The compound of claim 49 or claim 50, wherein52. The compound of claim 50 or claim 51, wherein53. The compound of any one of claims 50-52, wherein at least one of RA1, RA2, or RA3is H.

54. The compound of any one of claims 50-53, wherein each of RA1, RA2, or RA3is H.

55. The compound of any one of claims 1-48, wherein57. The compound of claim 55 or claim 56, wherein58. The compound of claim 55 or claim 56, wherein59. The compound of claim 55 or claim 56, wherein60. The compound of claim 55 or claim 56, wherein61. The compound of any one of claims 56-60, wherein at least one of RA1, RA2, or RA3is H.

62. The compound of any one of claims 56-61, wherein each of RA1, RA2, or RA3is H.

63. The compound of any one of claims 1-48, wherein65. The compound of claim 63 or claim 64, wherein66. The compound of claim 63 or claim 64, wherein67. The compound of claim 63 or claim 64, wherein68. The compound of claim 63 or claim 64, wherein69. The compound of claim 63 or claim 64, wherein70. The compound of claim 63 or claim 64, wherein71. The compound of any one of claims 64-70, wherein at least one of RA1, RA2, or RA4is H.

72. The compound of any one of claims 64-71, wherein each of RA1, RA2, or RA4is H.

73. The compound of any one of claims 1-48, wherein74. The compound of claim 73, wherein76. The compound of claim 73 or claim 74, wherein77. The compound of claim 73 or claim 74, wherein78. The compound of claim 73 or claim 74, wherein79. The compound of claim 73 or claim 74, wherein80. The compound of claim 73 or claim 74, wherein81. The compound of claim 73 or claim 74, wherein82. The compound of claim 73 or claim 74, wherein83. The compound of any one of claims 73-82, wherein at least one of RA1, RA2, RA3, or RA5is H.

84. The compound of any one of claims 73-83, wherein each of RA1, RA2, RA3, or RA5is H.

85. The compound of any one of the preceding claims, wherein R1is H.

86. The compound of any one of claims 1-84, wherein R1is C(O)R20.

87. The compound of claim 86, wherein R20is C1-C6alkyl, C1-C6haloalkyl, or C3-C8cycloalkyl, wherein said - C1-C6alkyl, C1-C6haloalkyl, or C3-C8cycloalkyl, is optionally substituted by 1-6 Rfgroups.

88. The compound of claim 87, wherein R20is a C3-C8cycloalkyl group.

89. The compound of claim 88, wherein R20is a cyclopropyl group.

90. The compound of claim 88, wherein R20is a cyclobutyl group.o o91. The compound of any one of claims 87-90, wherein R192. The compound of any one of claims 1-84, wherein R1is C1-C6alkyl, C1-C6haloalkyl, or C3-C10heterocycloalkyl, wherein said C1-C6alkyl, C1-C6haloalkyl, C3-C10heterocycloalkyl is optionally substituted by 1-6 Rfgroups.

93. The compound of claim 92, wherein R1is94. The compound of any one of claims 1-84, wherein R1is optionally substituted aryl.

95. The compound of any one of claims 1-84, wherein R1is optionally substituted heteroaryl.

96. The compound of claim 95, wherein R1is optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl.

97. The compound of claim 96, wherein R1is98. The compound of any one of the preceding claims, wherein R2is -Co-C6alk-A-R.

99. The compound of claim 98, wherein R2is -CH2-A-R.

100. The compound of any one of claims 1-97, wherein R2is -Co-C6alk-(CO)-Co-C6alk-A-R.

101. The compound of claim 100, wherein R2is -C(O)-A-R.

102. The compound of any one of claims 98-101, wherein A is a 6-membered heteroaryl group.

103. The compound of claim 102, wherein A is pyridinyl.

104. The compound of any one of claims 98-101, wherein A is a 5-membered heteroaryl group.

105. The compound of claim 104, wherein A is pyrazolyl or thiazolyl.

106. The compound of claim any one of claims 98-101, wherein A is an optionally substituted 6-membered heterocycloalkyl group.

107. The compound of claim 106, wherein A is piperidinyl.

108. The compound of claim any one of claims 98-101, wherein A is an optionally substituted5-membered heterocycloalkyl group.

109. The compound of claim 108, wherein A is pyrrolidinyl.

110. The compound of claim any one of claims 98-101, wherein A is an optionally substituted6- membered cycloalkyl group.

111. The compound of claim 110, wherein A is cyclohexyl.

112. The compound of claim any one of claims 98-101, wherein A is an optionally substituted 5- membered cycloalkyl group.

113. The compound of claim 112, wherein A is cyclopentyl.

114. The compound of claim any one of claims 98-101, wherein A is an optionally substituted6- membered heterocycloalkenyl group.

115. The compound of claim any one of claims 98-101, wherein A is an optionally substituted5- membered heterocycloalkenyl group.

116. The compound of claim any one of claims 98-101, wherein A is an optionally substituted6- membered cycloalkenyl group.

117. The compound of claim any one of claims 98-101, wherein A is an optionally substituted 5- membered cycloalkenyl group.

118. The compound of any one of claims 98-117, wherein R is H, -CN, -C(O)Rb, -C(O)NRcRd, -S(O)2Rb, or -C1-C1oalkyl, wherein:Rbis H or -C1-C6alkyl; each Rcor Rdis independently H or -C1-C1o alkyl, or Rcand Rd, together with the atom to which they are both attached, form a monocyclic heterocycloalkyl ring that is optionally substituted with 1-3 C1-C6alkyl or fluoro groups.

119. The compound of any one of claims 3-97, wherein R2is -CH2-A-C(O)NRcRd, wherein each Rcor Rdis independently H or -C1-C1o alkyl, or Rcand Rd, together with the atom to which they are both attached, form a monocyclic heterocycloalkyl ring that is optionally substituted with 1-3 C1-C6alkyl or fluoro groups.

120. The compound of claim 119, wherein Rcand Rdare -CH3.

122. The compound of any one of claims 3-97, wherein123. The compound of any one of the preceding claims that is:6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V, N- dimethyl-picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)-2-methylimidazo[l,2-Z>]pyridazin-8-yl)amino)- 2-methoxyphenyl)-T-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethyl-picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy-phenyl)-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-3'-oxospiro[cy cl opropane-1, r-isoindolin]-2'-yl)methyl)-7V, 7V-dimethyl- picolinamide;6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l -oxo-3, 4-dihydrospiro[benzo[c]azepine-5,l'-cyclopropan]-2(lJ7)-yl)methyl)- 7V,7V-dimethylpicolinamide;6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-l-oxo-l,3,4,5-tetrahydro-2J7-benzo[c]azepin-2-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-3, 3-dimethyl-l -oxo-3, 4-dihydroisoquinolin-2(177)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-3'-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-2,2-difluoro-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((7-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)- 1 -oxo- 1 ,3 ,4, 5-tetrahydro-27 / -3 ,5 -methanobenzo[c]azepin-2-yl)methyl)-7V,7V- dimethylpicolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-2,2-dimethyl-5-oxo-2,3-dihydrobenzo[ / ][l,4]oxazepin-4(5J7)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-4-fluoro-l-oxoisoquinolin-2(177)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3 -((2-Aminoimidazo[2, 1 -f\ [ 1 , 2, 4]triazin-4-yl)amino)-2 -methoxyphenyl)- 1 '-oxo- 177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((2-(pyridin-2-ylamino)imidazo[2,l-: / ][l,2,4]triazin-4-yl)amino) phenyl)-! '-oxo-l '7 / -spiro[cyclopropane-l,4'-isoqiiinolin]-2'(3'7 / )-yl)rnethyl)-MA-dirnethylp- icolinamide;6-((6'-(3-((5-(Cyclopropanecarboxamido)pyrazolo[l,5-a]pyrimidin-7-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)rnethyl)-A, N- dimethyl-picolinamide;6-((6'-(3-((2-Aminopyrazolo[l,5-a][l,3,5]triazin-4-yl)amino)-2-methoxyphenyl)-r-oxo- 177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((5-(Cyclopropanecarboxamido)thiazolo[5,4-d]pyrimidin-7-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethyl-picolinamide;6-((6'-(3-((5-Aminothiazolo[5,4-t / ]pyrimidin-7-yl)amino)-2-methoxyphenyl)-l'-oxo-l'7 / - spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-A,A-dimethylpicolinamide;((6'-(3-((5-Aminothiazolo[5,4-J]pyrimidin-7-yl)amino)-2-methoxyphenyl)-r-oxo-177- spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((2-Aminopyrido[3,2-J]pyrimidin-4-yl)amino)-2-methoxyphenyl)-r-oxo-177- spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)pyrido[3,2-J]pyrimidin-4-yl)amino)-2- methoxy -phenyl)-l'-oxo-l 77-spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)methyl)-A, TV- dimethyl-picolinamide;6-((6'-(3-((5-(Cyclopropanecarboxamido)-3J7-imidazo[4,5-Z>]pyridin-7-yl)amino)-2- methoxyphenyl )-l '-oxo-l '7 / -spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethyl-picolinamide;A-(8-((2-Methoxy-3-(2'-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-r-oxo-2',3'- dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin- 6-yl)cyclopropanecarboxamide;2-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-! '-oxo-l '7 / -spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)methyl)-A,A- dimethyl-isonicotinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy-phenyl)-r-oxo-177-spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)methyl)-7V- methylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)methyl)- picolinamide;7V-(8-((3-(2'-((6-(3,3-Difluoropyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-r-oxo-2',3'- dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[l,2- Z>]pyridazin-6-yl)cyclopropanecarboxamide;7V-(8-((3-(2'-((6-Cyanopyridin-2-yl)methyl)-r-oxo-2',3'-dihydro-177-spiro[cyclopropane- l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[l,2-Z>]pyridazin-6-yl)cyclopropane- carboxamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opropane-1, 4'-isoquinolin]-2'(377)-yl)methyl)-7V-ethyl -N- methyl-picolinamide;7V-(8-((2-Methoxy-3-(2'-((l-methyl-177-pyrazol-4-yl)methyl)-r-oxo-2',3'-dihydro-177- spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin-6-yl)cyclo- propanecarboxamide;A-(8-((2-Methoxy-3-(l'-oxo-2'-(pyri din-2 -ylmethyl)-2', 3'-dihy dro-177-spiro[cy clo- propane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin-6-yl)cyclopropane- carboxamide;7V-(8-((2-Methoxy-3-(r-oxo-2'-((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2',3'- dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-6'-yl)phenyl)amino)imidazo[l,2-Z>]pyridazin- 6-yl)cyclopropanecarboxamide;2-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethyl -thi azol e-4 -carb oxami de;6'-(3 -((2-Aminoimidazo[2, 1 -f\ [ 1 ,2,4]triazin-4-yl)amino)-2-methoxyphenyl)-2'-((6-(ethyl- sulfonyl)pyridin-2-yl)methyl)-2',3'-dihydro-177-spiro[cyclopropane-l,4'-isoquinolin]-r-one;7V-(4-((3 -(2'-(( 1 -Acetylpiperi din-3 -yl)methyl)- l'-oxo-2', 3 '-dihydro- 177-spiro[cyclo- propane-1, 4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[2, 1 T / ][ 1,2, 4]triazin-2- yl)cyclopropane-carboxamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy-phenyl)-8'-ethoxy-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- TV,TV-dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opropane-l,4'-[2,7]naphthyridin]-2'(377)-yl)methyl)-TV, N- dimethyl-picolinamide;6-((6'-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-5'-fluoro-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- TV,TV-dimethylpicolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opentane-l,4'-isoquinolin]-2'(377)-yl)methyl)-TV, N- dimethyl-picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl obutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-TV, N- dimethyl-picolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)-2- methoxy -phenyl)-4,4-dimethyl-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)methyl)-TV,TV- dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-l-oxo-3,4-dihydroisoquinolin-2(lJ7)-yl)methyl)-TV,TV-dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy-phenyl)-l-oxoisoquinolin-2(lJ7)-yl)methyl)-7VTV-dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-4-isopropyl-l -oxo-3, 4-dihydroisoquinolin-2(lJ7)-yl)methyl)-7V, TV- dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-4-isopropyl-l-oxoisoquinolin-2(lJ7)-yl)methyl)-TV,TV-dimethylpicolinamide;6-((4-Acetyl-6-(3-((6-(cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)- 2-methoxyphenyl)-l-oxoisoquinolin-2(lJ7)-yl)methyl)-TV,TV-dimethylpicolinamide;6-((6-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)- 1 -oxophthal azin-2(177)-yl)methyl)-TVTV-dimethylpicolinamide;6-((7-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-4-oxoquinazolin-3(4J7)-yl)methyl)-TVTV-dimethylpicolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy-phenyl)-3-methyl-7-oxothieno[2,3-c]pyridin-6(7J7)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxyphenyl)-3,4,4-trimethyl-7-oxo-4,7-dihydrothieno[2,3-c]pyridin-6(5J7)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-7-oxothieno[2,3-c]pyridin-6(7J7)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-7-oxo-4,7-dihydrothieno[2, 3 -c]pyridin-6(5J7)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((2-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-4-oxothieno[3,2-c]pyridin-5(4J7)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((2-(3-((2-(Cyclopropanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxyphenyl)-6-oxo-4,6-dihydro-5J7-thieno[2,3-c]pyrrol-5-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2-ethoxy- phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2 -methyl- phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((6-(Cy cl opropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)-2 -fluoro- phenyl)-r-oxo-rH-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(4-((6-(Cyclopropanecarboxamido)imidazo[l,2-b]pyridazin-8-yl)amino)-3- methoxy -pyri din-2 -yl)-r-oxo-l'H-spiro[cy cl opropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V, N- dimethyl-picolinamide;6-((6'-(2-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-3- methoxy -pyri din-4-yl)-l'-oxo-177-spiro[cy cl opropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V, N- dimethyl-picolinamide;6-((6'-(2-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-3- methoxy-pyridin-4-yl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethyl-picolinamide;6-((6'-(6-((6-(Cyclopropanecarboxamido)imidazo[l,2-Z>]pyridazin-8-yl)amino)-5- methoxy -pyrimidin-4-yl)-l'-oxo-l 77-spiro[cy cl opropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- A,A-dimethyl-picolinamide;6'-(3 -((2-Aminoimidazo[2, 1 -f\ [ 1 ,2,4]triazin-4-yl)amino)-2-methoxy-6-methylphenyl)-2'- ((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2',3'-dihydro-177-spiro[cyclopropane-l,4'- isoquinolin]-l'-one;A-(4-((2 -Methoxy -4-methyl -3-(l'-oxo-2'-((6-(pyrrolidine-l -carbonyl)pyri din-2- yl)methyl)-2',3'-dihydro-r77-spiro[cyclopropane-l,4'-isoquinolin]-6'- yl)phenyl)amino)imidazo[2,l- / |[l,2,4]triazin-2-yl)cyclopropanecarboxamide;6-((6'-(3-((6-Aminoimidazo[l,2-Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r-oxo-177- spiro[cyclopropane-l,4'-isoquinolin]-2'(3'77)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(4-((2-((2,2-Difluoroethyl)amino)imidazo[2,l-: / ][l,2,4]triazin-4-yl)amino)-3- methoxy-pyri din-2 -yl)-r-oxo-177-spiro[cy cl opropane-l,4'-isoquinolin]-2'(3'77)-yl)methyl)-A,A- dimethyl-picolinamide;6-((6'-(3-((2-(l-Fluorocyclopropane-l-carboxamido)imidazo[2,l- / |[l,2,4]triazin-4- yl)amino)-2-m ethoxyphenyl)- r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3 -((2-( 1 -methylcyclopropane- 1 -carboxamido)imidazo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)amino)phenyl)-r-oxo-r77-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)- A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((2-(l-(trifluoromethyl)cyclopropane-l-carboxamido)imidazo[2,l- f\ [ 1 ,2,4]triazin-4-yl)amino)phenyl)- 1 '-oxo- 177-spiro[cyclopropane- 1 ,4'-isoquinolin]-2'(377)- yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((2-(2,2-Difluorocyclopropane-l-carboxamido)imidazo[2,l- / |[l,2,4]triazin-4- yl)amino)-2 -methoxyphenyl)- r-oxo-l'77-spiro[cyclopropane-l,4'-isoquinolin]-2'(3 '77)- yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((2-(spiro[2.2]pentane-l-carboxamido)imidazo[2,l- / |[l,2,4]triazin- 4-yl)amino)phenyl)-l'-oxo-r77-spiro[cyclopropane-l,4'-isoquinolin]-2'(3'77)-yl)methyl)-A,A- dimethylpicolinamide;6-((6'-(3-((2-(Cyclobutanecarboxamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- methoxy -phenyl)-l'-oxo-177-spiro[cy cl opropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V, N- dimethyl-picolinamide;6-((6'-(3 -((2-(Bicyclo[ 1.1.1 ]pentane-2-carboxamido)imidazo[2, 1 -f\ [ l,2,4]triazin-4- yl)amino)-2-m ethoxyphenyl)- r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(3 -((2-(Bicyclo[ 1.1.1 ]pentane- 1 -carboxamido)imidazo[2, 1 -f\ [ l,2,4]triazin-4- yl)amino)-2-m ethoxyphenyl)- r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)- yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(2 -Methoxy-3-((2-(3, 3, 3-trifluoropropanamido)imidazo[2, 1 T / ][ 1,2, 4]triazin-4- yl)amino)phenyl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethyl-picolinamide;6-((6'-(3-((2-(2-Cyclopropylacetamido)imidazo[2,l- / |[l,2,4]triazin-4-yl)amino)-2- m ethoxy -phenyl)- 1' -oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(3'77)-yl)methyl)-7V,7V- dimethyl-picolinamide;6-((6'-(2-Methoxy-3 -((2-(2-m ethoxy acetamido)imidazo[2, 1 -f\ [ 1 ,2,4]triazin-4-yl)amino) phenyl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethyl- picolinamide;6-((6'-(3-((2-(2-Cyanoacetamido)imidazo[2, 1- / 1 [1,2, 4]tri azin-4-yl)amino)-2 -methoxy- phenyl)-r-oxo-177-spiro[cyclobutane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V-dimethylp- icolinamide;Cyclopropyl(4-((3-(2'-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l'-oxo-2',3'-dihydro- l'H-spiro[cyclobutane-l,4'-isoquinolin]-6'-yl)-2-methoxyphenyl)amino)imidazo[2,l- f] [ 1 , 2, 4]tri azin-2 -yl)carbamate;6-((6'-(2-Methoxy-3 -((6-(pyri din-2 -ylamino)imidazo[ 1 ,2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethyl-picolinamide;6-((6'-(3-((6-((5-Fluoropyridin-2-yl)amino)imidazo[l,2-Z>]pyridazin-8-yl)amino)-2- methoxy -phenyl)-r-oxo-177-spiro[cy cl opropane-l,4'-isoquinolin]-2'(3'77)-yl)methyl)-7V, N- dimethyl-picolinamide;6-((6'-(3 -((6-((2,3 -Dihydro-[ 1 ,4]dioxino[2,3 -Z>]pyridin-6-yl)amino)imidazo[ 1,2- Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r-oxo-r77-spiro[cyclopropane-l,4'-isoquinolin]- 2'(3'77)-yl)methyl)-7V,7V-dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((l -methyl -1 J7-pyrazol-4-yl)amino)imidazo[l,2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((6-methoxypyridazin-3-yl)amino)imidazo[l,2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((l-methyl-l / / -pyrazol-3-yl)amino)imidazo[l,2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((6-((2,6-Dimethylpyrimidin-4-yl)amino)imidazo[l,2-Z>]pyridazin-8-yl)amino)- 2-methoxyphenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(2-Methoxy-3-((6-((5-morpholinopyri din-2 -yl)amino)imidazo[ 1, 2-Z>]pyridazin-8- yl)amino)phenyl)-r-oxo-177-spiro[cyclopropane-l,4'-isoquinolin]-2'(377)-yl)methyl)-7V,7V- dimethylpicolinamide;6-((6'-(3-((6-Acetamidoimidazo[l,2-Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r-oxo- 17 / -spiro[cyclopropane-l,4'-isoquinolin]-2'(3'H)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(2-Methoxy-3 -((6-propionamidoimidazo[ 1 ,2-Z>]pyridazin-8-yl)amino)phenyl)- T- oxo-17 / -spiro[cyclopropane-l,4'-isoquinolin]-2'(3'J7)-yl)methyl)-A,A-dimethylpicolinamide;6-((6'-(3-((6-Isobutyramidoimidazo[l,2-Z>]pyridazin-8-yl)amino)-2-methoxyphenyl)-r- oxo-17 / -spiro[cyclopropane-l,4'-isoquinolin]-2'(3'J7)-yl)methyl)-A,A-dimethylpicolinamide; or a pharmaceutically acceptable salt thereof.

124. The compound of any one of the preceding claims in the form of a pharmaceutically acceptable salt.

125. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier.

126. A method of inhibiting a JAK2 enzyme in a sample in vivo or in vitro, by contacting a JAK2 enzyme with a compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, or a composition of claim 125.

127. The method of claim 126, wherein the inhibiting of a JAK2 enzyme comprises reducing the activity of the JAK2 enzyme by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.

128. The method of claim 126, wherein the inhibiting of a JAK2 enzyme comprises reducing the activity of the JAK2 enzyme by at least 1-fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20- fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.

129. A method of degrading a JAK2 enzyme in a sample in vivo or in vitro, by contacting a JAK2 enzyme with a compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, or a composition of claim 125.

130. The method of claim 129, wherein the degrading of a JAK2 enzyme comprises reducing the activity of the JAK2 enzyme by at least 1%, 2%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., relative to a reference standard.

131. The method of claim 129, wherein the degrading of a JAK2 enzyme comprises reducing the activity of the JAK2 enzyme by at least 1-fold, 1.5-fold, 2-fold, 3-fold, 5-fold, 10-fold, 20- fold, 30-fold, 50-fold, 100-fold, or more, e.g., relative to a reference standard.

132. A method of treating a JAK2 -mediated disorder in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, or a composition of claim 125.

133. The method of claim 132, wherein the JAK2 -mediated disorder is a disorder mediated by a JAK2 containing a V617F mutation.

134. The method of any one of claims 132-133, wherein the JAK2 -mediated disorder is a proliferative disease.

135. The method of any one of claims 132-134, wherein the proliferative disease displays overexpression or amplification of JAK2, or somatic mutation of JAK2.

136. The method of any one of claims 132-134, wherein the JAK2 -mediated disorder is myelofibrosis (MF), polycythemia Vera (PV), essential thrombocythemia (ET), acute megakaryocytic leukemia, T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), T-cell large granular lymphocytic leukemia (T-LGL), T-cell prolymphocytic leukemia (T-PLL), or graft versus host disease (GVHD).

137. The method of any one of claims 132-136, wherein the method comprises the steps of:(i) identifying a subject in need of such treatment;(ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and(iii) administering said provided compound in a therapeutically effective amount to treat, suppress and / or prevent the disease state or condition in a subject in need of such treatment.

138. A method of inhibiting an activity of the V617F variant of JAK2 kinase, comprising contacting the kinase with a compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, or a composition of claim 125.

139. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, or a composition of claim 125.

140. The method of claim 139, wherein the cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer, skin cancer, and brain cancer.141 . The method of claim 139, wherein the cancer is a hematological cancer.

142. The method of claim 139, wherein the cancer is selected from leukemia, lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin’s or non-Hodgkin’s lymphoma, a myeloproliferative neoplasm), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

143. A method of treating a myeloproliferative disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, or a composition of claim 125.

144. The method of claim 143, wherein the myeloproliferative disorder is selected from polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post- essential thrombocythemia myelofibrosis, post polycythemia vera myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, and systemic mast cell disease.

145. A method of treating myelodysplastic syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, or a composition of claim 125.

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