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 in the inhibition of a JAK2 enzyme and preparation, are also described.

Description

105807.005059 PCT ApplicationJAK2 INHIBITORS AND THEIR USE AS PHARMACEUTICALS

[0001] This application claims the benefit of U. S. Provisional Application Nos. 63 / 730,023, filed December 10, 2024, and 63 / 843,353, filed July 14, 2025, the entireties of which are incorporated by reference herein.TECHNICAL FIELD

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

[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- 1 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationJAK2 inhibitors can result in anemia and thrombocytopenia and these toxicities are consistent with 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 orN-oxide thereof, whereineach of Wi, W2, and W3 is independently N or CRs;each Z is independently O, S, SO2, NR4, NR9 or C(Rs)2, wherein at least 3 Z are C(Rs)2 and wherein at least one Z is NR4;each Rs is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb;or any two Rs groups attached to the same carbon form =0;or any two Rs groups attached to the same carbon form a 3-6 membered spirocycloalkyl or spiroheterocycloalkyl ring;or any two Rs groups attached to adjacent carbon atoms form a 3-6 membered cycloalkyl or heterocycloalkyl ring;each R4 is independently -L1-! -!;each R9is independently H, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl,- 2 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationspiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl, -C(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) or -S(O)2Rb; wherein each of -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl can be optionally substituted by 1-6 Rf groups;each L1is independently absent, or is independently -(CRcRd)p-, -(CRaRc)pO-, -S(O)-, -S(O)2-, -C(=O)-, -C(=O)O-, -C(=O)NRa-, -S(=O)NRa-, -S(=O)2NRa-, or aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;each L2is independently absent, or is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;each L3is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb;p is 1, 2, 3 or 4;each Xi, X2, X3, X4, and Xe is independently N or CR10;each Rio is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -ORa, -SRa, -NRcRd, -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) or -S(O)2Rb;Ri is H, D, -Ci-Cealkyl, -Ci-Cehaloalkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, -NHR5;Rs is H, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;Re is H, D, -OH, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl or spiroheterocycloalkenyl;R7 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -C2-Cealkenyl, or cycloalkyl;each Rais independently H, -Ci-Cioalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;each Rb, is independently H, D, -Ci-Ce alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;- 3 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationeach Rcor Rdis independently H, D, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OCi-Cealkyl, -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;wherein any of the -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl and spiroheterocycloalkenyl groups in any of R1-R10 and L1-! is optionally substituted by 1-6 Rfgroups; andeach Rfis independently H, D, oxo, halogen, Ci-Cs alkoxy, Ci-Cs alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, -OH, -CN, -NO2, -C2-6 alkenyl, -C2-6 alkynyl, Ce-io aryl, C5-12 heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, C3-8 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)RcRd, -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 Ci-C8alkyl is optionally substituted by 1-6 groups selected from D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd.

[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. Certain 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 “Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl. “Co alkyl” refers to a covalent bond.- 4 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[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 straight -or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 6 carbons atoms (“Ci-Ce”), in the group. Examples of alkyl groups include methyl (Me, Cialkyl), ethyl (Et, C2alkyl), n-propyl (Csalkyl), isopropyl (Csalkyl), butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tertpentyl (Csalkyl), hexyl (Cealkyl), isohexyl (Cealkyl), 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, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, and Ci-C6haloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-Cealkyl)2, -S(O)2NH(Ci-C6alkyl), and -S(O)2N(Ci-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 (“Cs-Ce”). 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 (Ce), 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 - 5 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationwherein the cycloalkyl group is substituted, the cycloalkyl group can be substituted with 1, 2, or 3 substituents independently selected from -OH, -CN, amino, halo, Ci-Cealkyl, Ci-Cealkoxy, Ci-C6haloalkyl, and Ci-C6haloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-C6alkyl)2, -S(O)2NH(Ci-C6alkyl), and -S(O)2N(Ci-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-Ce”). Cycloalkenyl groups of the disclosure include monocyclic groups, as well as multi cyclic 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 (i.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 (Ce), 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, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, and Ci-C6haloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-C6alkyl)2, -S(O)2NH(Ci-C6alkyl), and -S(O)2N(Ci-Cealkyl)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,- 6 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationthe cyclic groups can share one common atom (i.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, ooxaspiro[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, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, and Ci-Cehaloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-C6alkyl)2, -S(O)2NH(Ci-Cealkyl), and -S(O)2N(Ci-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 ( / .<?., 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,- 7 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application[f, or for example a dihydroisoquinolinone such as 3,4-dihydroisoquinolin-l(2H)- Oone, 'T-, or in which the partially saturated ring is fused to a heteroaryl group,such as, for example, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine,N, 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, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, and Ci-C6haloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-Cealkyl)2, -S(O)2NH(Ci-C6alkyl), and -S(O)2N(Ci-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, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, and Ci-C6haloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-C6alkyl)2, -S(O)2NH(Ci-C6alkyl), and -S(O)2N(Ci-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.105807.005059\4925-4900-9536.3105807.005059 PCT Application

[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 ring atoms. 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, Ci-Cealkyl, Ci-Cealkoxy, Ci-C6haloalkyl, and Ci-C6haloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-C6alkyl)2, -S(O)2NH(Ci-C6alkyl), and -S(O)2N(Ci-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 “spirocycloalkyl” when used alone or as part of a substituent group refers to a cycloalkyl ring that shares one carbon atom with another cycloalkyl ring.

[0022] The term “spirocycloalkenyl” when used alone or as part of a substituent group refers to a cycloalkenyl ring that shares one carbon atom with another cycloalkyl or cycloalkenyl ring.

[0023] The term “spiroheterocycloalkyl” when used alone or as part of a substituent group refers to a heterocycloalkyl ring that shares one carbon atom with another cycloalkyl or heterocycloalkyl ring.

[0024] The term “spiroheterocycloalkenyl” when used alone or as part of a substituent group refers to a heterocycloalkenyl ring that shares one carbon atom with another cycloalkyl, heterocycloalkyl, or heterocycloalkenyl ring.

[0025] When a range of carbon atoms is used herein, for example, Ci-Ce, all ranges, as well as individual numbers of carbon atoms are encompassed, for example, “C1-3” includes C1-3, Ci-2, C2.3, Ci, C2, and C3. The term “Ci-ealk” refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, -CH2-, -CH(CHs)-, -CH(CH -CH2-, and -C(CH3)2-. The term “-Coalk-” refers to a bond.

[0026] The term “Co-Cealk” 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 “-Cialk-”, for example, refers to a -CH2-. The term “-Coalk-” refers to a bond.

[0027] Unless otherwise specified, in those embodiments wherein the -Ci-Cealkyl, -C1-C10 alkyl, -Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cioalkenyl, -C2-Cealkynyl, -C2-Cioalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are substituted, they can be optionally substituted with 1, 2, or 3 substituents independently selected - 9 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationfrom -OH, -CN, amino, halo, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, and Ci-Cehaloalkoxy, -C(O)NH(Ci-C6alkyl), -C(O)N(Ci-C6alkyl)2, -OC(O)NH(Ci-C6alkyl), -OC(O)N(Ci-C6alkyl)2, -S(O)2NH(Ci-Cealkyl), and -S(O)2N(Ci-C6alkyl)2. In other embodiments, the -Ci-Cealkyl, -Ci-Cio alkyl, -Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cioalkenyl, -C2-Cealkynyl, -C2-Cioalkynyl, 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, orNRcRd; or the -Ci-Cealkyl, -C1-C10 alkyl, -Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cioalkenyl, -C2-Cealkynyl, -C2-Cioalkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl groups are optionally substituted by 1-6 Rfgroups.

[0028] 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.

[0029] As used herein, “hydroxylalkyl” refers to an alkyl group substituted by OH.

[0030] 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.

[0031] Compounds of the invention may also include tautomeric forms. All tautomeric forms are encompassed.

[0032] 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.

[0033] 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.

[0034] 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 - 10 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationseparation 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 least about 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] A “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.- 11 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0039] “Subject” includes humans. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0040] “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.

[0041] “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.

[0042] 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.

[0043] 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 CS')-stereoi somers 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 - 12 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationenantiomers, are encompassed by that structure. Where more than one chiral center exists in a structure, 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.

[0044] The disclosure is directed to compounds of Formula I:or a pharmaceutically acceptable salt or solvate orN-oxide thereof, whereineach of Wi, W2, and W3 is independently N or CRs;each Z is independently O, S, SO2, NR4, NR9 or C(Rs)2, wherein at least 3 Z are C(Rs)2 and wherein at least one Z is NR4;each Rs is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb;or any two Rs groups attached to the same carbon form =0;or any two Rs groups attached to the same carbon form a 3-6 membered spirocycloalkyl or spiroheterocycloalkyl ring;or any two Rs groups attached to adjacent carbon atoms form a 3-6 membered cycloalkyl or heterocycloalkyl ring;each R4 is independently -L1-! -!;each R9is independently H, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl, -C(O)Rb, -C(O)ORb, -C(0)NRcRd, -S(O)Rb, -S(O)2NRcRd, -S(O)(=NRb)Rb, -SF5, -P(O)RbRb, -P(O)(ORb)(ORb), -B(0Rc)(0Rd) or -S(O)2Rb; wherein each of -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, - 13 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationheteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl can be optionally substituted by 1-6 Rf groups;each L1is independently absent, or is independently -(CRcRd)p-, -(CRaRc)pO-, -S(O)-, -S(O)2-, -C(=O)-, -C(=O)O-, -C(=O)NRa-, -S(=O)NRa-, -S(=O)2NRa-, or aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;each L2is independently absent, or is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;each L3is independently absent or is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb;p is 1, 2, 3 or 4;each Xi, X2, X3, X4, and Xe is independently N or CR10;each Rio is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -ORa, -SRa, -NRcRd, -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) or -S(O)2Rb;Ri is H, D, -Ci-Cealkyl, -Ci-Cehaloalkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, -NHR5;Rs is H, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;Re is H, D, -OH, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl or spiroheterocycloalkenyl;R7 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -C2-Cealkenyl, or cycloalkyl;each Rais independently H, -Ci-Cioalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;each Rb, is independently H, D, -Ci-Ce alkyl, -C2-Ce alkenyl, -C2-Ce alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;each Rcor Rdis independently H, D, -C1-C10 alkyl, -C2-Ce alkenyl, -C2-Ce alkynyl, -OCi-Cealkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;- 14 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor 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;wherein any of the -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl and spiroheterocycloalkenyl groups in any of R1-R10 and L1-! is optionally substituted by 1-6 Rfgroups; andeach Rfis independently H, D, oxo, halogen, Ci-Cs alkoxy, Ci-Cs alkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, -OH, -CN, -NO2, -C2-6 alkenyl, -C2-6 alkynyl, Ce-io aryl, C5-12 heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, C3-8 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)RcRd, -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 Ci-C8alkyl is optionally substituted by 1-6 groups selected from D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd.

[0045] In some embodiments, each Wi, W2, and W3 in Formula (I) is independently N or CRs.

[0046] In some embodiments, Wi in Formula (I) is N. In other embodiments, Wi in Formula (I) is CR8.

[0047] In some embodiments, W2 in Formula (I) is N. In other embodiments, W2 in Formula (I) is CR8.

[0048] In other embodiments, W3 in Formula (I) is N. In other embodiments, W3 in Formula (I) is CR8.

[0049] In yet other embodiments, at least one of Wi, W2, and W3 is CRs. In yet other embodiments, each Wi, W2, and W3 is CRs.

[0050] In some embodiments, each Z in Formula (I) is independently O, S, SO2, NR4, NR9 or C(R8)2, wherein at least 3 Z are C(Rs)2 and wherein at least one Z is NR4.

[0051] In some embodiments, three Z are C(Rs)2. In other embodiments, four Z are C(Rs)2. In other embodiments, each Z is C(Rs)2.

[0052] In some embodiments, one Z in Formula (I) is O and four Z are C(Rs)2. In some embodiments, one Z in Formula (I) is O, one Z is NR4 and three Z are C(Rs)2. In other embodiments, two Z in Formula (I) are O and three Z are C(Rs)2.

[0053] In some embodiments, one Z in Formula (I) is S and four Z are C(Rs)2. In some embodiments, one Z in Formula (I) is S, one Z is NR4 and three Z are C(Rs)2. In other embodiments, two Z in Formula (I) are S and three Z are C(Rs)2.- 15 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0054] In some embodiments, one Z in Formula (I) is SO2 and four Z are C(Rs)2. In some embodiments, one Z in Formula (I) is SO2, one Z is NR4 and three Z are C(Rs)2. In other embodiments, two Z in Formula (I) are SO2 and three Z are C(Rs)2.

[0055] In some embodiments, one Z in Formula (I) is NR4 and four Z are C(Rs)2. In some embodiments, one Z in Formula (I) is NR4, one Z is NR9 and three Z are C(Rs)2. In other embodiments, two Z in Formula (I) are SO2 and three Z are C(Rs)2.

[0056] In some embodiments, Rs in Formula (I) is H, D, halogen, -OH, -CN, -NO2, -Ci-Ce alkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, 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) or -S(O)2Rb

[0057] In some embodiments, Rs in Formula I is H. In some embodiments, Rs in Formula I is D. In some embodiments, Rs in Formula I is halogen. In some embodiments, Rs in Formula I is -OH. In some embodiments, Rs in Formula I is -CN. In some embodiments, Rs in Formula I is -NO2. In some embodiments, Rs in Formula I is Ci-Ce alkyl. In some embodiments, Rs in Formula I is Ci-Cs alkoxide. In some embodiments, Rs in Formula I is -C2-C6 alkenyl. In some embodiments, Rs in Formula I is -C2-C6 alkynyl. In some embodiments, Rs in Formula I is aryl. In some embodiments, Rs in Formula I is heteroaryl. In other embodiments, Rs in Formula I is cycloalkyl. In other embodiments, Rs in Formula I is cycloalkenyl. In other embodiments, Rs in Formula I is heterocycloalkyl. In other embodiments, Rs in Formula I is heterocycloalkyl. In other embodiments, Rs in Formula I is ORa. In other embodiments, Rs in Formula I is SRa. In other embodiments, Rs in Formula I is -NRcRd. In other embodiments, Rs in Formula I is -NRaRc. In other embodiments, Rs in Formula I is -C(O)Rb. In other embodiments, Rs in Formula I is -OC(O)Rb. In other embodiments, Rs in Formula I is -C(O)ORb. In yet other embodiments, Rs in Formula I is -C(O)NRcRd. In yet other embodiments, Rs in Formula I is -S(O)Rb. In yet other embodiments, Rs in Formula I is -S(O)2NRcRd. In yet other embodiments, Rs in Formula I is -S(O)(=NRb)Rb. In yet other embodiments, Rs in Formula I is -SF5. In yet other embodiments, Rs in Formula I is -P(O)RbRb. In yet other embodiments, Rs in Formula I is -P(O)(ORb)(ORb). In yet other embodiments, Rs in Formula I is -B(ORc)(ORd). In yet other embodiments, Rs in Formula I is -S(O)2Rb.

[0058] In yet other embodiments, any two Rs groups attached to the same carbon form =0. In yet other embodiments, any two Rs groups attached to the same carbon form a 3-6 membered spirocycloalkyl or spiroheterocycloalkyl ring. In yet other embodiments, any two Rs groups attached to adjacent carbon atoms form a 3-6 membered cycloalkyl or heterocycloalkyl ring.- 16 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0059] In some embodiments, each R4 in Formula (I) is independently -L1-! -!.

[0060] In some embodiments, each R9 in Formula (I) is independently H, D, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl, -C(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) or -S(O)2Rb.

[0061] In some embodiments, R9 in Formula I is H. In some embodiments, R9 in Formula I is D. In some embodiments, R9 in Formula I is Ci-Ce alkyl. In some embodiments, R9 in Formula I is -C2-C6 alkenyl. In some embodiments, R9 in Formula I is -C2-C6 alkynyl. In some embodiments, R9 in Formula I is aryl. In some embodiments, R9 in Formula I is heteroaryl. In other embodiments, R9 in Formula I is cycloalkyl. In other embodiments, R9 in Formula I is cycloalkenyl. In other embodiments, R9 in Formula I is heterocycloalkyl. In other embodiments, R9 in Formula I is heterocycloalkyl. In other embodiments, R9 in Formula I is heterocycloalkenyl. In other embodiments, R9 in Formula I is spirocycloalkyl. In other embodiments, R9 in Formula I is spiroheterocycloalkyl. In other embodiments, R9 in Formula I is spirocycloalkenyl. In other embodiments, R9 in Formula I is spiroheterocycloalkenyl. In other embodiments, R9 in Formula I is -C(O)Rb. In other embodiments, R9 in Formula I is -C(O)ORb. In yet other embodiments, R9 in Formula I is -C(O)NRcRd. In yet other embodiments, R9 in Formula I is -S(O)Rb. In yet other embodiments, R9 in Formula I is -S(O)2NRcRd. In yet other embodiments, R9 in Formula I is -S(O)(=NRb)Rb. In yet other embodiments, R9 in Formula I is -SF5. In yet other embodiments, R9 in Formula I is -P(O)RbRb. In yet other embodiments, R9 in Formula I is -P(O)(ORb)(ORb). In yet other embodiments, R9 in Formula I is -B(ORc)(ORd). In yet other embodiments, R9 in Formula I is -S(O)2Rb.

[0062] In some embodiments, each of -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl in R9 can be optionally substituted by 1-6 Rf groups.

[0063] In some embodiments, each L1in Formula (I) is independently absent, or is independently -(CRcRd)P-, -(CRaRc)PO-, -O-, -S-, -S(O)-, -S(O)2-, -C(=O)-, -NRa-, -OC(=O)-, -C(=O)O-, -NRaC(O)-, -C(=O)NRa-, -OC(=O)N(Ra)-, -NRaC(O)O-, -S(=O)NRa-, -NRaS(O)-, -S(=O)2NRa-, or -NRaS(O)2-, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl.

[0064] In some embodiments, L1in Formula (I) is absent. In some embodiments, L1in Formula (I) is -(CRcRd)p-. In some embodiments, L1in Formula (I) is -(CRaRc)pO-. In some - 17 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationembodiments, L1in Formula (I) is -O-. In some embodiments, L1in Formula (I) is -S-. In some embodiments, L1in Formula (I) is -S(O)-. In some embodiments, L1in Formula (I) is -S(O)2-. In some embodiments, L1in Formula (I) is -C(=O)-. In some embodiments, L1in Formula (I) is -NRa-. In other embodiments, L1in Formula (I) is -OC(=O)-. In other embodiments, L1in Formula (I) is -C(=O)O-. In other embodiments, L1in Formula (I) is -NRaC(O)-. In other embodiments, L1in Formula (I) is -C(=O)NRa-. In other embodiments, L1in Formula (I) is -OC(=O)N(Ra)-. In other embodiments, L1in Formula (I) is -NRaC(O)O-. In other embodiments, L1in Formula (I) is -S(=O)NRa-. In other embodiments, L1in Formula (I) is -NRaS(O)-. In yet other embodiments, L1in Formula (I) is -S(=O)2NRa-. In yet other embodiments, L1in Formula (I) is -NRaS(O)2-. In yet other embodiments, L1in Formula (I) is aryl. In yet other embodiments, L1in Formula (I) is heteroaryl. In yet other embodiments, L1in Formula (I) is cycloalkyl. In yet other embodiments, L1in Formula (I) is cycloalkenyl. In yet other embodiments, L1in Formula (I) is heterocycloalkyl. In yet other embodiments, L1in Formula (I) is heterocycloalkenyl.

[0065] In some embodiments, L1in Formula (I) is -(CRcRd)p-. In some embodiments, L1in Formula (I) is -CH2-.

[0066] In some embodiments, p in Formula (I) is 1, 2, 3 or 4. In some embodiments, p in Formula (I) is 0. In some embodiments, p in Formula (I) is 1. In some embodiments, p in Formula (I) is 2. In other embodiments, p in Formula (I) is 3. In other embodiments, p in Formula (I) is 4.

[0067] In some embodiments, each L2in Formula (I) is independently absent, or is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl.

[0068] In some embodiments, L2in Formula (I) is absent. In some embodiments, L2in Formula (I) is aryl. In some embodiments, L2in Formula (I) is heteroaryl. In other embodiments, L2in Formula (I) is cycloalkyl. In other embodiments, L2in Formula (I) is cycloalkenyl. In yet other embodiments, L2in Formula (I) is heterocycloalkyl. In yet other embodiments, L2in Formula (I) is heterocycloalkenyl.

[0069] In some embodiments, L2in Formula (I) is phenyl or pyridyl. In some embodiments, L2in Formula (I) is phenyl. In other embodiments, L2in Formula (I) is pyridyl.

[0070] In some embodiments, L3in Formula (I) is independently absent, or is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Ce alkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, 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) or -S(O)2Rb- 18 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0071] In some embodiments, L3in Formula (I) is absent. In some embodiments, L3in Formula I is H. In some embodiments, L3in Formula I is D. In some embodiments, L3in Formula I is halogen. In some embodiments, L3in Formula I is -OH. In some embodiments, L3in Formula I is -CN. In some embodiments, L3in Formula I is -NO2. In some embodiments, L3in Formula I is Ci-Ce alkyl. In some embodiments, L3in Formula I is Ci-Cs alkoxide. In some embodiments, L3in Formula I is -C2-C6 alkenyl. In some embodiments, L3in Formula I is -C2-Ce alkynyl. In some embodiments, L3in Formula I is aryl. In some embodiments, L3in Formula I is heteroaryl. In other embodiments, L3in Formula I is cycloalkyl. In other embodiments, L3in Formula I is cycloalkenyl. In other embodiments, L3in Formula I is heterocycloalkyl. In other embodiments, L3in Formula I is heterocycloalkyl. In other embodiments, L3in Formula I is ORa. In other embodiments, L3in Formula I is SRa. In other embodiments, L3in Formula I is -NRcRd. In other embodiments, L3in Formula I is -NRaRc. In other embodiments, L3in Formula I is -C(O)Rb. In other embodiments, L3in Formula I is -OC(O)Rb. In other embodiments, L3in Formula I is -C(O)ORb. In yet other embodiments, L3in Formula I is -C(O)NRcRd. In yet other embodiments, L3in Formula I is -S(O)Rb. In yet other embodiments, L3in Formula I is -S(O)2NRcRd. In yet other embodiments, L3in Formula I is -S(O)(=NRb)Rb. In yet other embodiments, L3in Formula I is -SF5. In yet other embodiments, L3in Formula I is -P(O)RbRb. In yet other embodiments, L3in Formula I is -P(O)(ORb)(ORb). In yet other embodiments, L3in Formula I is -B(ORc)(ORd). In yet other embodiments, L3in Formula I is -S(O)2Rb.

[0072] In some embodiments, L3in Formula (I) is H or -Ci-Cealkyl. In some embodiments, L3in Formula (I) is H or CH3. In some embodiments, L3in Formula (I) is H. In some embodiments, L3in Formula (I) is CH3.

[0073] In some embodiments, L3in Formula (I) is -C(O)NRcRdwherein Rcand Rdare each independently -C1-C10 alkyl; or Rcand Rd, together with the atom to which they are both attached, form a monocyclic or multi cyclic heterocycloalkyl.

[0074] In some embodiments, L3in Formula (I) is -C(O)NRcRdwherein Rcand Rdare each independently -C1-C10 alkyl. In other embodiments, L3in Formula (I) is -C(O)NRcRdwherein Rcand Rdare each independently -C1-C10 alkyl; or Rcand Rd, together with the atom to which they are both attached, form a monocyclic or multi cyclic heterocycloalkyl.

[0075] In some embodiments, L3in Formula (I) is -C(O)NRcRdand at least one of Rcand Rdis methyl.

[0076] In some embodiments, each Xi, X2, X3, X4, and Xe in Formula (I) is independently N or CR10.- 19 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0077] In some embodiments, Xi in Formula (I) is N. In some embodiments, Xi in Formula (I) is CR10. In other embodiments, Xi in Formula (I) is CH.

[0078] In some embodiments, X2 in Formula (I) is N. In other embodiments, X2 in Formula (I) is CR10.

[0079] In some embodiments, X3 in Formula (I) is N. In other embodiments, X3 in Formula (I) is CR10.

[0080] In some embodiments, X4 in Formula (I) is N. In other embodiments, X4 in Formula (I) is CR10.

[0081] In some embodiments, X2 in Formula (I) is N and X4 in Formula (I) is N.

[0082] In other embodiments, Xe in Formula (I) is N. In other embodiments, Xe in Formula (I) CR10.

[0083] In some embodiments, each of X2, X3, and X4 in Formula (I) is CH. In some embodiments, Xe in Formula (I) is CH.

[0084] In some embodiments, Rio in Formula (I) is H, D, halogen, -OH, -CN, -NO2, -Ci-Ce alkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, -ORa, -SRa, -NRcRd, -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) or -S(O)2Rb.

[0085] In some embodiments, Rio in Formula I is H. In some embodiments, Rio in Formula I is D. In some embodiments, Rio in Formula I is halogen. In some embodiments, Rio in Formula I is -OH. In some embodiments, Rio in Formula I is -CN. In some embodiments, Rio in Formula I is -NO2. In some embodiments, Rio in Formula I is Ci-Ce alkyl. In some embodiments, Rio in Formula I is Ci-Cs alkoxide. In some embodiments, Rio in Formula I is -C2-C6 alkenyl. In some embodiments, Rio in Formula I is -C2-C6 alkynyl. In some embodiments, Rio in Formula I is aryl. In some embodiments, Rio in Formula I is heteroaryl. In other embodiments, Rio in Formula I is cycloalkyl. In other embodiments, Rio in Formula I is cycloalkenyl. In other embodiments, Rio in Formula I is heterocycloalkyl. In other embodiments, Rio in Formula I is heterocycloalkyl. In other embodiments, Rio in Formula I is ORa. In other embodiments, Rio in Formula I is SRa. In other embodiments, Rio in Formula I is -NRcRd. In other embodiments, Rio in Formula I is -C(O)Rb. In other embodiments, Rio in Formula I is -OC(O)Rb. In other embodiments, Rio in Formula I is -C(O)ORb. In yet other embodiments, Rio in Formula I is -C(O)NRcRd. In yet other embodiments, Rio in Formula I is -S(O)Rb. In yet other embodiments, Rio in Formula I is -S(O)2NRcRd. In yet other embodiments, Rio in Formula I is -S(O)(=NRb)Rb. In yet other embodiments, Rio in Formula I is -SF5. In yet other embodiments, Rio in Formula I - 20 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationis -P(O)RbRb. In yet other embodiments, Rio in Formula I is -P(O)(ORb)(ORb). In yet other embodiments, Rio in Formula I is -B(ORc)(ORd). In yet other embodiments, Rio in Formula I is -S(O)2Rb

[0086] In some embodiments, Ri in Formula (I) is H, D, -Ci-Cealkyl, -Ci-Cehaloalkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, -NHR5.

[0087] In some embodiments, Ri in Formula I is H. In some embodiments, Ri in Formula I is D. In some embodiments, Ri in Formula I is Ci-Ce alkyl. In some embodiments, Ri in Formula I is Ci-Cs haloalkyl. In other embodiments, Ri in Formula I is Ci-Cs alkoxide. In other embodiments, Ri in Formula I is -C2-C6 alkenyl. In other embodiments, Ri in Formula I is -C2-Ce alkynyl.

[0088] In some embodiments, Ri is methyl optionally substituted by 1-6 D atoms. In other embodiments, Ri is methyl substituted by at least one D atom.

[0089] In some embodiments, Ri in Formula I is -NHR5. In some embodiments, R5 in Formula (I) is H, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl.

[0090] In some embodiments, R5 in Formula I is H. In some embodiments, R5 in Formula I is Ci-Ce alkyl. In some embodiments, R5 in Formula I is Ci-Cs alkoxide. In some embodiments, Rs in Formula I is -C2-C6 alkenyl. In some embodiments, R5 in Formula I is -C2-C6 alkynyl. In some embodiments, R5 in Formula I is aryl. In some embodiments, R5 in Formula I is heteroaryl. In other embodiments, R5 in Formula I is cycloalkyl. In other embodiments, R5 in Formula I is cycloalkenyl. In other embodiments, R5 in Formula I is heterocycloalkyl. In other embodiments, R5 in Formula I is heterocycloalkenyl.

[0091] In some embodiments, R5 is methyl optionally substituted by 1-6 D atoms. In some embodiments, R5 is methyl substituted by at least one D atom. In some embodiments, R5 in Formula I is methyl or CD3. In some embodiments, R5 in Formula I is CD3.

[0092] In some embodiments, Re in Formula (I) is H, D, -OH, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl or spiroheterocycloalkenyl.

[0093] In some embodiments, Re in Formula I is H. In some embodiments, Re in Formula I is D. In some embodiments, Re in Formula I is -OH. In some embodiments, Re in Formula I is Ci-Ce alkyl. In some embodiments, Re in Formula I is Ci-Cs alkoxide. In some embodiments, Re in Formula I is -C2-C6 alkenyl. In some embodiments, Re in Formula I is -C2-C6 alkynyl. In some embodiments, Re in Formula I is aryl. In some embodiments, Re in Formula I is heteroaryl. In other embodiments, Re in Formula I is cycloalkyl. In other embodiments, Re in Formula I is - 21 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationcycloalkenyl. In other embodiments, Re in Formula I is heterocycloalkyl. In other embodiments, Re in Formula I is heterocycloalkenyl. In yet other embodiments, Re in Formula I is spirocycloalkyl. In yet other embodiments, Re in Formula I is spiroheterocycloalkyl. In yet other embodiments, Re in Formula I is spiroheterocycloalkenyl.

[0094] In some embodiments, Re in Formula (I) is -Ci-Cealkyl, cycloalkyl or spirocycloalkyl, wherein the -Ci-Cealkyl, cycloalkyl and spirocycloalkyl are optionally substituted by 1-6 Rf groups. In some embodiments, Re in Formula (I) is -Ci-Cealkyl optionally substituted by 1-6 Rf groups. In other embodiments, Re in Formula (I) is cycloalkyl optionally substituted by 1-6 Rf groups. In other embodiments, Re in Formula (I) is spirocycloalkyl optionally substituted by 1-6 Rf groups.

[0095] In some embodiments, Re in Formula (I) is cyclopropyl optionally substituted by 1-6 Rf groups. In some embodiments, Re in Formula (I) is fluorine substituted cyclopropane.

[0096] In some embodiments, Re in Formula (I) is -Ci-Cealkyl optionally substituted by 1-6 Rf groups.

[0097] In some embodiments, R? in Formula (I) is H, D, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -C2-Cealkenyl, or cycloalkyl.

[0098] In some embodiments, R7 in Formula I is H. In some embodiments, R7 in Formula I is D. In some embodiments, R7 in Formula I is -Ci-Ce alkyl. In some embodiments, R7 in Formula I is -Ci-Ce haloalkyl. In some embodiments, R?in Formula I is -C2-C6 alkenyl. In other embodiments, R?in Formula I is cycloalkyl.

[0099] In some embodiments, each Rain Formula I is independently H, D, -Ci-Cioalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0100] In some embodiments, Rain Formula I is H. In some embodiments, Rain Formula I is D. In some embodiments, Rain Formula I is -Ci-Cioalkyl. In some embodiments, Rain Formula I is -C2-C10 alkenyl. In some embodiments, Rain Formula I is -C2-C10 alkynyl. In other embodiments, Rain Formula I is aryl. In other embodiments, Rain Formula I is cycloalkyl. In other embodiments, Rain Formula I is cycloalkenyl. In yet other embodiments, Rain Formula I is heteroaryl. In yet other embodiments, Rain Formula I is heterocycloalkyl. In yet other embodiments, Rain Formula I is heterocycloalkenyl.

[0101] In some embodiments, each Rbin Formula I is independently H, D, -Ci-Ce alkyl, -C2-Ce alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.- 22 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0102] In some embodiments, Rbin Formula I is H. In some embodiments, Rbin Formula I is D. In some embodiments, Rbin Formula I is -Ci-Ce alkyl. In some embodiments, Rbin Formula I is -C2-C6 alkenyl. In some embodiments, Rbin Formula I is -C2-C6 alkynyl. In other 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.

[0103] In some embodiments, each Rcor Rdin Formula I is independently H, D, -Ci-Ce alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0104] 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 -OCi-Cealkyl. 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.

[0105] 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.

[0106] In some embodiments, each Rfin Formula I, when present, is independently H, D, oxo, halogen, Ci-Cs alkoxide, Ci-Cs alkyl, 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 Ci-Cs alkyl is optionally substituted by 1-6 R groups selected from H, D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd.- 23 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0107] 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 Ci-Cs alkoxide. In some embodiments, Rfin Formula I is Ci-Cs alkyl. In some embodiments, the Ci-Cs alkyl 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 other embodiments, 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 -SF5. 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).

[0108] In some embodiments, the compound of Formula (I) is a compound of Formula (II):- 24 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, Wi, W2, W3, Xi, X2, X3, X4, Xe, and Z are as defined herein.

[0109] In some embodiments, the compound of Formula (I) is a compound of Formula (III), Formula (IV) or Formula (V):or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, R4, Re, R7, Rs, R9, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0110] In some embodiments, the compound of Formula (I) is a compound of Formula (III):or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, R4, Re, R7, Rs, R9, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0111] In other embodiments, the compound of Formula (I) is a compound of Formula (IV):- 25 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, R4, Re, R7, Rs, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0112] In yet other embodiments, the compound of Formula (I) is a compound of Formula (V):or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, R4, Re, R7, Rs, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0113] In some embodiments, the compound of Formula (I) is a compound of Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), or Formula (XV):- 26 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application- 27 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, R9, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein; and whereinL1is absent, -(CRcRd)P-, -S(O)-, -S(O)2-, or-C(=O)-;L2is absent, aryl or heteroaryl; andL3is H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb;wherein any of the -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl groups of L2and L3are optionally substituted by 1-6 Rf groups.

[0114] In some embodiments, the compound of Formula (I) is a compound of Formula (VI)or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, R9, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.- 28 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0115] In some embodiments, the compound of Formula (I) is a compound of Formula (VII)(VII),or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, R9, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0116] In some embodiments, the compound of Formula (I) is a compound of Formula (VIII)(VIII),or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, R9, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0117] In some embodiments, the compound of Formula (I) is a compound of Formula (XIX)- 29 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0118] In other embodiments, the compound of Formula (I) is a compound of Formula (X)(X),or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0119] In other embodiments, the compound of Formula (I) is a compound of Formula (XI)- 30 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(XI),or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, R9, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0120] In other embodiments, the compound of Formula (I) is a compound of Formula (XII)or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0121] In other embodiments, the compound of Formula (I) is a compound of Formula (XIII)- 31 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationo. LTL2\ iRBRoII i8W1 / > W2O HN X'or a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0122] In yet other embodiments, the compound of Formula (I) is a compound of Formula (XIV)o,,N DR8V \ / K8RNs43W^W2Y3O HN X2f y^ x6oor a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0123] In yet other embodiments, the compound of Formula (I) is a compound of Formula (XV)- 32 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor a pharmaceutically acceptable salt or solvate orN-oxide thereof; wherein Ri, Re, R7, Rs, Li, L2, L3, Wi, W2, W3, Xi, X2, X3, X4, and Xe are as defined herein.

[0124] In some embodiments, the compound of Formula (I) is a compound that is:6-(Cyclopropanecarboxamido)-4-((3-(l-ethyl-4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-l / Z-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-isopropyl-2-oxo-2,3,4,5-tetrahydro-l / Z-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cyclopropanecarboxamido)-4-((3-(4-(3-(dimethylcarbamoyl)-2-fluorobenzyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-l / Z-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cyclopropanecarboxamido)-4-((3-(l-cyclopropyl-4-((6-(dimethylcarbamoyl)pyridin- 2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-l / Z-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(2-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-oxo-2, 3,4, 5-tetrahydro-l / Z-benzo[c]azepin-7 -yl)-2-methoxyphenyl)amino)-7V-methylpyridazine- 3 -carboxamide;6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-5-oxo-2, 3,4, 5-tetrahydrobenzo[ / ][l, 4]oxazepin-8-yl)-2 -methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-6-fluoro-5-oxo-2,3,4,5-tetrahydrobenzo[ / ][l,4]oxazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;- 33 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l-methyl-5-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-ethyl-5-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-isopropyl-5-oxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-A-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-A-methylpyridazine-3-carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-ethyl-2,5-dioxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-A-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-isopropyl-2,5-dioxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-A-methylpyridazine-3-carboxamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;3-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-2-fluoro-A, A-dimethylbenzamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2-fluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;- 34 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-! -(cyanomethyl )-2-oxo-l, 2, 3, 5-tetrahydro-4 / / -benzo[< ][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(oxetan-3-yl)-2-oxo-l,2,3,5-tetrahydro-4Z7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-4 / / -benzo[e] [ 1,4] diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lA,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4 / 7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(3-((5-Acetyl-2-(spiro[2.2]pentane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4Z7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(A)-6-((8-(3-((5-Acetyl-2-(spiro[2.2]pentane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4Z7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((15,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4 / 7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lA,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4 / 7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lS,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4 / 7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-cyclopropyl-2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the compound of Formula (I) is a compound that is:- 35 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4Z7-pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4 / 7-pyri do[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2-fluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4Z7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4Z7-pyrido[3,2-e] [ 1,4]di azepi n-4-yl )methyl )-M A-di methyl pi col i nami de;6-((8-(3-((5-acetyl-2-((l£,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l -isopropyl -2-oxo-l, 2,3, 5-tetrahydro-4Z7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-isobutyl-2-oxo-l,2,3,5-tetrahydro-4Z7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the compound of Formula (I) is a compound that is:6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -cyclobutyl-2-oxo- 1,2,3, 5-tetrahydro-4Z7-benzo[e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(l-fluoropropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4A-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 2-oxo-l-(thiazol-5-ylmethyl)-l,2,3,5-tetrahydro-4J7-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(cyclopropylmethyl)-2-oxo-l,2,3,5-tetrahydro-4J7-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;- 36 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -cyclopentyl -2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[<?] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -((5)-tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4 / 7-benzofe] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-2-oxo- 1 -(OS') -tetrahydrofuran -3 -yl)- 1,2,3,5 -tetrahydro-4 / 7-benzofe] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((LS',2 / )-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5 -fluoro-2-methoxyphenyl)- 1 -(2-fluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4 / 7-benzofe] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lA,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lA,2A)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-m ethoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4Z / -pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15',25 -2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-m ethoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4Z / -pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lA,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-2-oxo- 1 -((5)-tetrahydrofuran-3 -yl)- 1,2,3,5 -tetrahydro-4 / / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5 -fluoro-2-methoxyphenyl)- 1 -(2-fluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4 / / -py ri do[3,2-e\ [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;- 37 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]-diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5 -fluoro-2-methoxyphenyl)- 1 -cyclobutyl -2-oxo- 1, 2, 3, 5 -tetrahy dro-4 / / -py ri do[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-6-fluoro-2-oxo-l-((5)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4JH-benzofe] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((l£,27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -( / )-tetrahydrof uran-3 -yl)- 1,2,3, 5 -tetrahy dro-4 / / -benzofe] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2-fluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-6-fluoro-2-methoxy-phenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4#-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-((l£,27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-((lJR,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxy-5-(trifluoromethyl)phenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lJR,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxy-5-(trifluoromethyl)phenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lJR,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l-((5)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;- 38 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-((15',27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 2-methoxyphenyl)-2-oxo-l-((5)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15',27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-2-oxo- 1 -(CS’)-tetrahydrof iiran-3 -yl)- 1,2,3,5 -tetrahydro-4 / / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2-fluoro-2-methylpropyl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy -phenyl)- 1 -(2 -methoxy -2 -methylpropyl)-2-oxo- 1,2, 3,5 -tetrahydro-4 / / -pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-isobutyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-7V,7V-dimethylbenzamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V-methyl-7V-(2,2,2-trifluoroethyl)picolinamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(3-hydroxypyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lJH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxy-phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2, 3, 4, 5-tetrahydro-lJH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2 -methoxyphenyl)-amino)pyridin-2-yl)cyclopropanecarboxamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V-(2,2-difluoroethyl)-7V-methylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V-(2-hydroxyethyl)-7V-methylpicolinamide;- 39 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-7V-(tert-butyl)-7V-methylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l -methyl -2-oxo-l, 2,3, 5-tetrahydro-4 / / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy -phenyl)- l-methyl-2-oxo-l, 2,3, 5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-methyl-2-oxo-l,2,3,5-tetrahydro-4#-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 2-methoxyphenyl)-6-fluoro-l -methyl -2-oxo-l, 2,3, 5-tetrahydro-4 -benzo[e][l, 4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy -phenyl)-6-fluoro-l -methyl -2-oxo-l, 2,3, 5-tetrahydro-4 -benzo[e][l, 4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 6-fluoro-l-methyl-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l -methyl -2-oxo-l, 2,3, 5-tetrahydro-4 -benzo[e][l, 4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15',27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l -methyl -2-oxo-l, 2,3, 5-tetrahydro-4 -benzo[e][l, 4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;- 40 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxy-5-methyl-phenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxy-5-(trifluoromethyl)phenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-4-fluoro-2-methoxy -phenyl)- l-methyl-2-oxo-l, 2,3, 5-tetrahydro-4Z / -benzo[e][l, 4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;(?)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxy-phenyl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;(5)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxy-phenyl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4#-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-ethyl-2-oxo-l,2,3,5-tetrahydro-4#-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-((ls,3s)-3-cyanocyclobutyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -( 1 -cyanoethyl)-2-oxo- 1,2,3, 5-tetrahydro-4 / / -benzo[c] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;- 41 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxy-5-(trifluoromethyl)phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-ethyl-7-fluoro-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -(2-cyanoethyl)-2-oxo- 1,2,3, 5-tetrahydro-4 -benzo[e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-methyl-2-oxo-l,2,3,5-tetrahydro-4#-pyrido[4,3-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-((15',27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 2-methoxyphenyl)-l -(2 -methoxy ethyl)-2-oxo-l, 2,3, 5-tetrahydro-4Z / -pyrido[4,3-e][l,4]diazepin- 4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l -methyl -2-oxo-l, 2,3, 5-tetrahydro-4Z / -pyrido[4,3-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4#-pyrido[4,3-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[4,3-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-(2,2-difluoropropyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;(?)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxy-phenyl)-l-(l-methoxypropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;(5)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxy-phenyl)-2-oxo- 1 -(tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-47 / -benzo[c] [ 1,4] diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;- 42 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-cyclobutyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyri din-2 -yl)-6-fluoro-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3,5 -tetrahydro-4 / / -benzofe] [ 1,4]di azepi n-4-yl )methyl )-M A-di methyl pi col i nami de;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(2,2-difluoroethyl)-6-fluoro-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-ethyl-6-fluoro-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4 -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4J7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(2-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-4-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[e][l,4]diazepin-4-yl)methyl)-Af, Af-dimethyl-picolinamide;6-((8-(4-((5-acetyl-2-((lA,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 3-methoxypyridin-2-yl)-l -methyl -2-oxo-l, 2,3, 5-tetrahydro-4 / / -benzo[e][l, 4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15,25)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lA,2A)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-(8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lJH-pyrido[3,2-e][l,4]diazepine-4-carbonyl)-7V,7V-dimethylpicolinamide;-43 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-acetyl-2-((15',27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 3-methoxypyridin-2-yl)-2-oxo-l-((5)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]-diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(2-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 4-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(2-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-4-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;(5)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((15',27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 3-methoxypyridin-2-yl)-l -cyclobutyl -2-oxo-l, 2,3, 5-tetrahydro-4J7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;(5)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyri din-2 -yl)-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4 / / -benzofe] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4J7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(4-((5-acetyl-2-((15,25)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((15',27?)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;-44 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-acetyl-2-((17?,27?)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l -isopropyl -2-oxo-l, 2, 3, 5-tetrahydro-4 / / -pyrido[3,2-c][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((15,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l -isopropyl -2-oxo-l, 2, 3, 5-tetrahydro-4 / / -pyrido[3,2-c][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((l£,27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l -isopropyl -2-oxo-l, 2, 3, 5-tetrahydro-4 / / -pyrido[3,2-c][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((17?,27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((2-(cyclopropanecarboxamido)-5-propionylpyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((l£,27?)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 3-methoxypyridin-2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-chloro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-7V,7V-dimethylpicolinamide;(7?)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(l-methoxypropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;(17?,2S)-7V-(5-acetyl-4-((5-fluoro-2-methoxy-3 -(l-methyl-4-((6-(morpholine-4-carbonyl)-pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)phenyl)amino)-pyri din-2 -yl)-2-fluorocy cl opropane-1 -carboxamide;- 45 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application7V-(5-acetyl-4-((3-(4-((6-(3,3-difluoropyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;N-(5 -acetyl-4-((3 -( 1 -ethyl -4-(( 1 -methyl - 17 / -py razol -4-yl)methyl)-2-oxo-2, 3,4, 5 -tetrahydro-l#-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-ethyl-4-((6-((3a7?,6a7?)-hexahydro-lJ / -furo[3,4-c]pyrrole-5-carbonyl)-pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)-amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-ethyl-4-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;7V-(4-((3-(4-([l,2,4]triazolo[l,5-a]pyridin-5-ylmethyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro- I / / -benzofc] [1, 4]diazepin-8-yl)-2-methoxyphenyl)amino)-5-acetylpyri din-2 -yl)cy cl opropane-carboxamide;7V-(4-((3-(4-([l,2,4]triazolo[l,5-a]pyridin-8-ylmethyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-lJH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-5-acetylpyri din-2 -yl)cy cl opropane-carboxamide;7V-(5-acetyl-4-((3-(l-ethyl-4-(imidazo[l,5-a]pyridin-8-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-ethyl-4-(imidazo[l,2-a]pyridin-8-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-ethyl-2-oxo-4-(pyrazolo[l,5-a]pyridin-7-ylmethyl)-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-ethyl-4-(imidazo[l,2-a]pyridin-5-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-ethyl-4-((6-(methylsulfonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-17 / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane-carboxamide;- 46 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application7V-(5-acetyl-4-((3-(l-ethyl-4-(isoquinolin-l-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-17 -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyri din-2 -yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(4-((4-cyanopyridin-2-yl)methyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-17 / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyri din-2 -yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-(imidazo[l,5-a]pyridin-8-ylmethyl)-2-oxo- 2,3,4,5-tetrahydro-17 -pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-(imidazo[l,2-a]pyridin-8-ylmethyl)-2-oxo- 2,3,4,5-tetrahydro-17 -pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane-carboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-(3-(difluoromethyl)-2-fluorobenzyl)-2-oxo- 2,3,4,5-tetrahydro-17 -pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;7V-(5-acetyl-4-((3-(4-(3-chlorobenzyl)-l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-17 -pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-17 -pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-pyridin-2-yl)cyclopropanecarboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-((6-oxo-l,6-dihydropyridin-2-yl)methyl)-2,3,4,5-tetrahydro-17 -pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(difluoromethyl)pyridin-2-yl)methyl)-2-oxo-2, 3,4, 5-tetrahydro-l#-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydro-lJ / -pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane-carboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-lJ / -pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane-carboxamide;7V-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(hydroxymethyl)pyridin-2-yl)methyl)-2-oxo-2, 3,4, 5-tetrahydro-l#-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;-47 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationA-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-(thiazol-4-ylmethyl)-2,3,4,5-tetrahydro-l -pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane-carboxamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A-methoxy-A-methylpicolinamide;3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy -phenyl)-l -(2, 2-difluoroethyl)-2-oxo-l, 2,3, 5-tetrahydro-4 / / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V-methoxy-7V-methylbenzamide;A-(5-acetyl-4-((3-(4-((6-aminopyridin-2-yl)methyl)-l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-l / / -pyrido[3,2-< ][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;A-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(3-methylureido)pyridin-2-yl)methyl)-2-oxo-2, 3,4, 5-tetrahydro-l#-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;A-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-((A-methylsulfamoyl)amino)pyri din-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-U / -pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxy-phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;A-(5-Acetyl-4-((2-methoxy-3-(l -methyl -2-oxo-4-((6-(tetrahydrofuran-2-yl)pyri din-2-yl)methyl)-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;A-(5- Acetyl -4-((2-m ethoxy-3 -(4-((6-(3 -m ethoxy oxetan-3 -yl)pyri din-2 -yl)methyl)- 1 -methyl-2-oxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclopropane-carboxamide;A-(5-Acetyl-4-((3-(4-((6-acetylpyridin-2-yl)methyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-l -benzo[e] [ 1,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyri din-2 -yl)cyclopropanecarboxamide;6-(2-(8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[c][l,4]diazepin-4-yl)propan-2-yl)-A, A-dimethyl-picolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(tert-butyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;- 48 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(5)-6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxy-phenyl)- 1 -( 1 -acetylpyrrolidin-3 -yl)-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)- 1 -(azeti din-3 -yl)-2-oxo- 1,2,3, 5-tetrahydro-4 -benzo[e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-2-yl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((15,25)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-2-yl)-2-oxo-l-((5)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4#-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(2-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-4-yl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(bicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2,3,5-tetrahydro-4Jff-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(3-fluorobicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(bicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2-oxabicyclo[2.1. l]hexan-4-yl)-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isobutyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;- 49 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-l-cyclopentyl-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lA,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(CS')-tetrahy dro-2 / / -py ran -3 -yl)- 1,2,3,5 -tetrahydro-4 / / -pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(sec-butyl)-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(A)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(sec-butyl)-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((l£,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 3-methoxypyridin-2-yl)-l-((?)-sec-butyl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;5-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-A, A-dimethylbicyclo[3.1.1 ]heptane-l -carboxamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-cyclopentyl-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-2-oxo-l-propyl-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-2-oxo-l-(pentan-3-yl)-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-cyclohexyl-2-oxo-l,2,3,5-tetrahydro-4J7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-cyclohexyl-2-oxo-l,2,3,5-tetrahydro-4J7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;-50 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(tetrahydro-2 / / -pyran-4-yl )- 1,2,3, 5 -tetrahydro-4 / / -benzofe] [ 1,4]di azepi n-4-yl )methyl )-M A-di methyl pi col i nami de;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxy -phenyl)- 1 -(2-hy droxy-2-methylpropyl)-2-oxo- 1,2,3, 5 -tetrahy dro-4 / / -benzofe] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-cyclopropyl-2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;3-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[e][l,4]diazepin-4-yl)methyl)-2-methoxy -N, A-di methyl -benzamide;3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -ethyl-2-oxo- 1,2,3, 5-tetrahydro-4 A-benzo[e] [ 1,4]diazepin-4-yl)methyl)-A, N,2-trimethylbenzamide;6-(8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lJ / -pyrido[3,2-e][l,4]diazepine-4-carbonyl)-A, A-dimethylpicolinamide;5-(8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lJ / -pyrido[3,2-e][l,4]diazepine-4-carbonyl)-A, A-dimethylbicyclo[3.1.1]heptane-l -carboxamide;6-((l-(4-(lJH-Pyrazol-l-yl)phenyl)-8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((l-(6-(lJH-Pyrazol-l-yl)pyridin-3-yl)-8-(3-((5-acetyl-2-(cyclopropanecarboxamido)-pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4A-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(pyri din-3 -yl)- 1,2,3, 5-tetrahydro-4 A-benzo[e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-(6-methoxypyridin-3-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;- 51 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2-fluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(3,4-difluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 2-oxo-l-(quinolin-7-yl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-2-oxo-l-(quinolin-6-yl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(5-fluoropyridin-2-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(3-fluoropyridin-4-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2,4-difluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(4-cyanophenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 2-oxo-l-phenyl-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(3-chlorophenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(3-fluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;-52 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(6-methylpyridin-3-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-2-oxo-l-(quinolin-3-yl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(4-fluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 2-oxo-l-(thiazol-5-yl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-2-oxo-l-(pyridin-2-yl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-2-oxo-l-(pyridin-4-yl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-(5-fluoropyridin-3-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- l-(2-methoxypyridin-4-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide;7V-(5-acetyl-4-((2-methoxy-3 -(4-((6-(morpholine-4-carbonyl)pyri din-2 -yl)methyl)-2-oxo- l-(pyridin-3-yl)-2,3,4,5-tetrahydro-lJ -benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclo-propanecarboxamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(methylsulfonyl)-2-oxo-l,2,5-tetrahydro-4J7-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-6-cyano-l -isopropyl -2-oxo-l, 2, 3, 5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-7V, N-dimethylpicolinamide;- 53 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(5)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(l,l-difluoropropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(A)-6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxy-pyridin-2-yl)-l-(l,l-difluoropropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2-e] [ 1,4]di azepi n-4-yl Jmethyl )-M A-di methyl pi col i nami de;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-6-(ethylamino)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[2,3-e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-6-ethoxy-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-6-ethoxy-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-6-methoxy-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-6-chloro-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)sulfonyl)-A, A-dimethylpicolinamide;7V-(5-Acetyl-4-((2-methoxy-3-(l -methyl -4-((6-(morpholine-4-carbonyl)pyridin-2-yl)sulfonyl)-2-oxo-2,3,4,5-tetrahydro-U / -benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(pyri din-3 -yl)- 1,2,3, 5-tetrahydro-4 / / -benzo[e] [ 1,4]diazepin-4-yl)sulfonyl)-A, A-dimethyl-picolinamide;-54 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(A)-6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxy-phenyl)-! -ethyl -3-methyl-2-oxo-l, 2,3, 5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxy-phenyl)-! -ethyl -3 -methyl -2-oxo- 1, 2,3, 5-tetrahydro-4Z / -benzo[e][l,4]diazepin-4-yl)methyl)-A, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-5-methyl-2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[c][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)-5-(2-fluoroacetyl)pyridin-4-yl)amino)-2-methoxy-phenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)-5-(2,2-difluoroacetyl)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(3-((3-Acetyl-6-(cyclopropanecarboxamido)pyridazin-4-yl)amino)-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4 / / -benzo[c][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)-5-oxo-5,6-dihydro-l,6-naphthyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(2-cyclopropylacetamido)pyridin-4-yl)amino)-5-fluoro-2 -methoxy-phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lA,2A)-2-(trifluoromethyl)cyclopropane-l-carboxamido)pyridin- 4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido-[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(3-((5-acetyl-2-(2,2-difluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-pyrido[3,2-e] [ 1,4]-diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;- 55 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(A)-6-((8-(3-((5-acetyl-2-(2,2-difluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(2,2-dimethylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e][l,4]-diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((5-((l-((3',6'-dihydroxy-3-oxo-37 / -spiro[isobenzofuran-l,9'-xanthen]-5-yl)amino)-l-thioxo-5,8,ll-trioxa-2-azatridecan-13-yl)carbamoyl)pyridin-2-yl)amino)-4-((3-(l-(l-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)azeti din-3 -yl)-l / / -pyrazol -4-yl)-2-methoxyphenyl)amino)-A-methylpyridazine-3-carboxamide;or a pharmaceutically acceptable salt thereof.

[0127] In yet further embodiments, the compounds of Formula (I) are in the form of a pharmaceutically acceptable salt.

[0128] In yet further embodiments, disclosed is a pharmaceutical composition comprising a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0129] 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.

[0130] Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of the disclosure.

[0131] 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

[0132] In some embodiments, the disclosure is directed to pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt or solvate thereof.

[0133] 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 - 56 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationcoordination 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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 - 57 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationapproximately 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.

[0138] 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.

[0139] 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).

[0140] 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).

[0141] 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.

[0142] 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,- 58 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationfrom 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.

[0143] 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.

[0144] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same.Pharmaceutical Compositions for Oral Administration.

[0145] 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.

[0146] 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.

[0147] 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.- 59 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationCompressed 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.

[0148] 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 the invention 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.

[0149] 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.

[0150] 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 - 60 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationgum, 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.

[0151] 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.

[0152] 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 to occur 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.

[0153] 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.

[0154] 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- 61 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0155] 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.

[0156] 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, and mixtures 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.

[0157] 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.

[0158] 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.

[0159] 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;- 62 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationsuccinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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- 63 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationoleate, 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.

[0164] 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; polyoxyethylated 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.

[0165] 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.

[0166] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, - 64 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationpropylene 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, 6-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.

[0167] 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.

[0168] 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.

[0169] 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,- 65 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationviscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0170] 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.

[0171] 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.

[0172] 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.- 66 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0173] 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.

[0174] 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 fluidity can 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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 - 67 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationdelivery 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.

[0179] 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, glycerol monolaurate, 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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 - 68 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationfor 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 of Therapeutics, 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.

[0184] 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.

[0185] 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.

[0186] In some embodiments, a compound of the invention is administered in a single dose.

[0187] 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.

[0188] 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.- 69 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationIn 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.

[0189] 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.

[0190] 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.

[0191] 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 - 70 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationstent 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 a suitable 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.

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.- 71 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationMethods of Use

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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- 72 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0202] 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.

[0203] As used herein, the term “JAK2 -mediated” disorders, diseases, and / or conditions means any disease or other deleterious condition in which JAK2 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 JAK2 -mediated disorders include, but are not limited to, cellular proliferative disorders (e.g. cancer). In some embodiments, the J AK2 -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.

[0204] 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

[0205] In some embodiments, the method of treatment 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.- 73 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0206] 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 V617F mutation.

[0207] 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.Cellular Proliferative Diseases

[0208] 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.

[0209] In some embodiments, the cancer is selected from sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden 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 Myelomonocytic Leukemia (CMML); T-cell large granular lymphocytic leukemia (T-LGL); T-cell proly phocytic leukemia (T-PLL); brain; a carcinoma of the brain;- 74 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationoral cavity and pharynx; larynx; small intestine, 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; neck; head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom macroglobulinemia.

[0210] 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.

[0211] 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.

[0212] In some embodiments, the cellular proliferative disease has mutant JAK2. In some embodiments, the cellular proliferative disease is a myeloproliferative disorder. In some- 75 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationembodiments, the cancer has mutant JAK2. In some embodiments, the hematopoietic cancer has mutant JAK2. In some embodiments, the myeloproliferative disorder has mutant JAK2.

[0213] 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, the 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 macroglobulinernia.

[0214] In some embodiments, the cellular proliferative disease displays over express! on or amplification of JAK2, or somatic mutation of JAK2.Additional Disorders

[0215] In some embodiments, the J AK2 -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 pneumoni, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary 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,- 76 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationsuch as diabetic retinopathy or hyperbaric oxygen -induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.

[0216] In some embodiments, the J AK2 -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 JAK2 -mediated disorder is vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, or autoimmune haematogical 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).

[0217] 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 J AK2-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.

[0218] In some embodiments, 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- 77 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationgranular lymphocytic leukemia (T-LGL), T-cell prolymphocytic leukemia (T-PLL), or graft versus host disease (GVHD).Synthesis

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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 - 78 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationorganic chemistry to prepare various compounds of the invention. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.

[0225] 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 ProceduresIntermediate 1. 4-((3-Bromo-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-7V-methylpyridazine-3-carboxamideBrO HN

[0226] Step 1. Lithium 4, 6-dichloropyridazine-3-carboxylateO Cl

[0227] To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (1.00 g, 4.83 mmol) in MeCN (5.0 mL) and water (0.75 mL) was added LiBr (1.26 g, 14.5 mmol) and DIPEA (1.87 g, 14.5 mmol). The reaction was stirred at 25 °C for 3h. Then the reaction mixture was filtered, and the filter cake was washed with MeCN (5 mL). The filter cake was dried under reduced pressure to afford the title compound (1.00 g, 5.03 mmol, 104% yield) as a white solid, which was used in the next step directly without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H).

[0228] Step 2. 4, 6-Dichloro-N-methylpyridazine-3-carboxamideO Cl

[0229] To a solution of lithium 4,6-dichloropyridazine-3-carboxylate (1.00 g, 5.03 mmol) in DCM (15 mL) was added methylamine hydrochloride (815 mg, 12.1 mmol) and pyridine (1.91 g, 24.2 mmol) at 0 °C under N2. Then to the mixture was added POCI3 (3.70 g, 24.15 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 3h. Then the mixture was poured into water and extracted with DCM (30 mL). The organic layer was washed with a - 79 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationsaturated solution of NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by trituration with hexane: EtOAc=10:l to afford the title compound (720 mg, 3.49 mmol, 72.3% yield) as a white solid.JH NMR (400 MHz, DMSO-d6) δ 9.08 - 8.81 (m, 1H), 8.96 - 8.90 (m, 1H), 2.83 (d, J= 4.7 Hz, 3H).

[0230] Step 3. 4-((3-Bromo-2-methoxyphenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

[0231] To a solution of 4,6-dichloro-A-methylpyridazine-3-carboxamide (500 mg, 2.43 mmol) in THF (10 mL) was added 3 -bromo-2 -methoxy aniline (490 mg, 2.43 mmol). The mixture was purged with N2 three times and then to the mixture was added lithium hexamethyldisilazide (5.6 mL, 7.28 mmol, 1.3 M in THF) at -10 °C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into a saturated solution of NH4CI (20 mL). The mixture was extracted with DCM (20 mL x 2). 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 hexane: EtOAc=5: 1 to afford the title compound (510 mg, 1.37 mmol, 56.6% yield) as a white solid. LCMS calc, for CisHisBrCllS Ch [M+H]+: m / z =370.98; Found:371.1.

[0232] Step 4. 4-((3-Bromo-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0233] To a solution of 4-(3 -bromo-2 -m ethoxyanilino)-6-chl oro-A-methylpyridazine-3-carboxamide (500 mg, 1.35 mmol) in 1,4-dioxane (10 mL) and water (2.0 mL) was added cyclopropanecarboxamide (343 mg, 4.04 mmol), Pd2(dba)3(123 mg, 0.13 mmol), dppf (149 mg, 0.27 mmol) and K3PO4 (857 mg, 4.04 mmol). The resulting mixture was purged with N2 three times, and the mixture was stirred at 110 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (5-50% EtOAc / hexane) to afford the title compound (210 mg, 0.50 mmol, 37% yield) as a yellow solid. LCMS calc, for Ci7Hi9BrN5O3 [M+H]+: m / z = 420.06; Found: 420.1.1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 11.02 (s, 1H), 9.18 (d, J = 4.9 Hz, 1H), 8.13 (s, 1H), 7.45 (ddd, J= 12.6, 8.1, 1.2- 80 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationHz, 2H), 7.16 (t, J= 8.1 Hz, 1H), 3.73 (s, 3H), 2.85 (dd, J= 8.9, 4.8 Hz, 3H), 2.29 - 1.98 (m, 1H), 0.83 (dd, J= 8.5, 4.6 Hz, 4H).Intermediate 2. 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)-7V-methylpyridazine-3-carboxamide

[0234] To a solution of 4-((3-bromo-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-7V-methylpyridazine-3-carboxamide (Int. 1) (1.00 g, 2.38 mmol) in 1,4-dioxane (15.0 mL) was added bis(pinacolato)diboron (1.20 g, 4.73 mmol), Pd(dppf)C12 (174 mg, 0.238 mmol) and KO Ac (700 mg, 7.13 mmol). The resulting mixture was purged with N2 three times, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with EtOAc (20 mL) and filtered and extracted with EtOAc (50 mL). The organic layer was then washed with brine (100 mL), dried overNa2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc / hexane) to afford the title compound (660 mg, 1.41 mmol, 59% yield) as a yellow solid. LCMS calc, for C23H31BN5O5 [M+H]+: m / z = 468.24; Found: 468.3.Intermediate 3. V-(5-Acetyl-4-((3-bromo-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane-carboxamideBr

[0235] Step 1. l-(4-((3-Bromo-2-methoxyphenyl)amino)-6-chloropyridin-3-yl)ethan-l-one- 81 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0236] To a solution of l-(4,6-dichloro-3-pyridinyl)ethanone (2.2 g, 11.6 mmol) in ethanol (40 mL) was added 3 -bromo-2 -methoxy aniline (2.34 g, 11.6 mmol) and HC1 (11.6 mL, 139 mmol, 12 M in water) under N2. The resulting mixture was stirred at 80 °C for 3 hours. The reaction mixture was quenched by adding sat. Na2CO3(aq) (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na₂SO₄U, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (5-45% EtOAc / Hexanes) to yield the title compound (1.89 g, 46% yield) as a yellow solid. LCMS calc, for CuHisBrC Ch [M+H]+: m / z = 354.9 / 356.9; Found 355.0 / 357.0.

[0237] In an alternative preparation, to a solution of l-(4,6-dichloro-3-pyridinyl)ethanone (4.5 g, 24 mmol) in ethanol (90 mL) was added 3 -bromo-2 -methoxy aniline (4.8 g, 24 mmol) and HC1 (18 mL, 24 mmol) under N2. The resulting mixture was stirred at 80 °C for 15 h. The reaction mixture was quenched by adding water and extracted with EtOAc (3 x 50 mL). the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude, which was purified by prep-HPLC on a Cl 8 column (20-70% MeCN in 0.1% TFA(aq), pH = 2) to obtain the title compound (4.3 g, 51% yield) as a yellow solid. LCMS calc, for Ci4Hi3BrClN2O2 [M+H]+: m / z = 354.9 / 356.9; Found 355.0 / 357.0.

[0238] Step 2. N-(5-Acetyl-4-((3-bromo-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane-carboxamide

[0239] To a solution of l-(4-((3 -bromo-2 -methoxyphenyl)amino)-6-chloropyri din-3 -yl)ethan-1-one (5.0 g, 14 mmol) in 1,4-di oxane (100 mL) and water (10 mL) was added cyclopropanecarboxamide (5.9 g, 70 mmol), dppf (1.6 g, 2.8 mmol), K3PO4 (8.9 g, 42 mmol) and Pd2(dba)3( 1.3 g, 1.4 mmol) under N2. The resulting mixture was stirred at 110 °C for 14 hours. The reaction mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-50% EtOAc / Hexanes) to obtain the title compound (5.6 g, 99% yield) as a yellow solid.LCMS calc, for Ci8Hi9BrN3O3[M+H]+: m / z = 404.1 / 406.1; Found 404.1 / 406.1.Intermediates 4-6.- 82 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0240] Intermediates 4-6 shown below in Table 1 were prepared in accordance with the synthetic protocols set forth in Int. 3 Steps 1-2 using appropriate intermediates, as well as commercial starting materialsTable 1. Intermediate 4-6Intermediate Name Structure Analytical Data Br7V-(5-acetyl-4-((3-bromo- LCMS calc, for 5-fluoro-2- O CisHisBrFNsCh 4 methoxyphenyl)- [M+H]+: m / z = amino)pyridin-2-yl)cyclo-0422.1 / 424.1; Found: propanecarb oxami de 422.1 / 424.0"NBr7V-(5-acetyl-4-((3-bromo- LCMS calc, for 4-fluoro-2- O CisHisBrFNsCh 5 methoxyphenyl)- [M+H]+: m / z = amino)pyridin-2-yl)cyclo- ^ r ii0422.1 / 424.1; Found: propanecarb oxami de 422.1 / 424.1"NBr7V-(5-acetyl-4-((3-bromo- LCMS calc, for 6-fluoro-2- O CisHisBrFNsCh 6 methoxyphenyl)- [M+H]+: m / z = amino)pyridin-2-yl)cyclo- AA % 422.1 / 424.1; Found: propanecarb oxami de 421.9 / 423.9"N

[0241] Intermediate 7.7V-(5-Acetyl-4-((3-bromo-2-methoxy-5-(trifluoromethyl)phenyl)-amino)pyridin-2-yl)cyclopropanecarboxamide

[0242] Step 1. l-Bromo-2-methoxy-3-nitro-5-(trifluoromethyl)benzene- 83 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationBr

[0243] Potassium carbonate (125 mg, 0.9 mmol) and dimethyl sulfate (114 mg, 0.9 mmol) were added in sequence to a stirring solution of 2-bromo-6-nitro-4-(trifluoromethyl)phenol (129 mg, 0.45 mmol) in acetone (5 mL). The reaction mixture was heated to reflux for 2 hours. The product mixture was filtered through celite and concentrated under reduced pressure to yield the title compound (99 mg, 73% yield) which was used without further purification.JH NMR (400 MHz, CDC13) 88.05 (d, J= 3.0 Hz, 2H), 4.08 (s, 3H).

[0244] Step 2. 3-Bromo-2-methoxy-5-(trifluoromethyl)anilineBr

[0245] Iron (92 g, 1.65 mmol) and ammonium chloride (176 mg, 3.3 mmol) were added to a stirring solution of l-bromo-2-m ethoxy-3 -nitro-5-(trifluoromethyl)benzene (99 mg, 0.33 mmol) in ethanol (5 mL) and water (2.5 mL). The reaction mixture was heated to 80 °C for 2 hours. The product mixture was filtered and concentrated under reduced pressure. The residue obtained was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (5-30% EtOAc / Hexanes) to yield the title compound (60 mg, 67% yield). LCMS calc, for CsHvBrFsNO [M+H]+: m / z = 270.0 / 272.0; Found: 270.0 / 272.1

[0246] Step 3. l-(4-((3-Bromo-2-methoxy-5-(trifluoromethyl)phenyl)ammo)-6-chloropyridm-3-yl)ethan-l-one

[0247] To a solution of l-(4,6-dichloro-3-pyridinyl)ethanone (352 mg, 1.85 mmol) in ethanol (5 mL) was added 3 -bromo-2 -methoxy aniline (500 mg, 1.85 mmol) and HC1 (2.5 mL, 60 mmol, 12.1 M in isopropyl acetate) under N2. The resulting mixture was stirred at 75 °C for 16 h. The reaction mixture was quenched by adding water and was extracted with EtOAc (3 x 50 mL). The - 84 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationcombined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (10-20% EtOAc / Hexanes) to yield the title compound (500 mg, 64% yield). LCMS calc, for Ci5Hi2BrClF3N2O2[M+H]+: m / z = 423.0 / 425.0; Found: 423.0 / 424.9

[0248] Step 4. N-(5-Acetyl-4-((3-bromo-2-methoxy-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl) cyclopropanecarboxamide

[0249] The title compound was prepared in accordance with the synthetic protocols set forth in Int.3 Step 2 using appropriate intermediates, as well as commercial starting materials. LCMS calc, for Ci9Hi8BrF3N3O3 [M+H]+: m / z = 472.0 / 474.0; Found: 472.2 / 474.2Intermediate 8. 7V-(5-Acetyl-4-((3-bromo-2-methoxy-5-methylphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

[0250] Step 1. l-Bromo-2-methoxy-5-methyl-3-nitrobenzeneBr

[0251] lodomethane (1.4 mL, 22.6 mmol) was added to a stirring solution of 2-bromo-4-methyl-6-nitrophenol (3.5 g, 15.1 mmol) and potassium carbonate (6.25 g, 45.3 mmol) in DMF (150 mL) at rt. The reaction mixture was heated to 60 °C for 16 hours. The product mixture was diluted with water (100 mL) resulting in precipitation of the product. The suspension was filtered, and the filter cake was dried under reduced pressure to yield the title compound (3.2 g, 86% yield). LCMS calc, for C8H9BrNO3[M+H]+: m / z = 246.0 / 248.0; Found: 246.0 / 247.0

[0252] Step 2. N-(5-Acetyl-4-((3-bromo-2-methoxy-5-methylphenyl)amino)pyridin-2-yl) cyclopropanecarboxamide

[0253] The title compound was prepared using procedures analogous to Intermediate 7 Steps 2 through 4 using appropriate intermediates and commercial starting materials. LCMS calc, for Ci9H2iBrN3O3[M+H]+: m / z = 418.1 / 420.1; Found: 418.0 / 419.9- 85 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationIntermediate 9. (l»S,21?)-7V-(5-Acetyl-4-((3-bromo-2-methoxyphenyl)amino)pyridin-2-yl)-2-fluorocyclopropane-l-carboxamideBrO HN

[0254] Step 1. tert-Butyl (5-acetyl-4-( ( 3-bromo-2 -methoxyphenyl) amino)pyridm-2-y I) carbamateBr

[0255] To a solution of l-(4-((3-bromo-2-methoxyphenyl)amino)-6-chloropyri din-3 -yl)ethan- 1-one (500 mg, 1.4 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added tert-butyl carbamate (820 mg, 7.0 mmol), dppf (160 mg, 0.28 mmol), K3PO4 (900 mg, 4.2 mmol) and Pd2(dba)3 (130 mg, 0.14 mmol) under N2. The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was quenched by adding water (50 mL) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified directly by silica gel column chromatography (3:1 hexane; EtOAc;) to obtain the title compound (266 mg, 43% yield). LCMS calc, for Ci9H23BrN3O4 [M+H]+: m / z = 436.1; Found: 436.2.

[0256] Step 2. l-(6-Amino-4-((3-bromo-2-methoxyphenyl)amino)pyridin-3-yl)ethan-l-one

[0257] To a solution of tert-butyl (5-acetyl-4-((3-bromo-2-methoxyphenyl)amino)pyridin-2-yl)carbamate (260 mg, 0.60 mmol) in DCM (3 mL) was added trifluoroacetic acid (3 mL, 0.6 mmol) under N2 at rt. The resulting mixture was stirred for 1 hour. The reaction mixture was- 86 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationconcentrated under reduced pressure to obtain the TFA salt of title compound (170 mg, 85% yield). LCMS calc, for CwHisBrNsCh [M+H]+: m / z = 336.1; Found 336.1.

[0258] Step 3. (lS,2R)-N-(5-Acetyl-4-((3-bromo-2-methoxyphenyl)amino)pyridin-2-yl)-2-fluorocyclopropane-1 -carboxamide

[0259] To a solution of l-(6-amino-4-((3-bromo-2-methoxyphenyl)amino)pyri din-3 -yl)ethan- 1-one (30 mg, 0.09 mmol) in pyridine (1.2 mL) was added (lA,25)-2-fluorocyclopropane-l- carboxylic acid (9.3 mg, 0.09 mmol) under N2 at rt. Then, POCI3 (68 mg, 0.45 mmol) was added under N2 at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched by adding water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (26 mg, 69% yield). LCMS calc, for CisHisBrFNsOs [M+H]+: m / z = 422.1; Found: 422.2.Intermediates 10-15

[0260] Intermediates 10-15 shown below in Table 2 were prepared in accordance with the synthetic protocols set forth in Int. 9 Steps 1-3 using appropriate starting materials, as well as commercial starting materialsTable 2. Intermediates 10-15Analytical Intermediate Name StructureDataLCMS calc, for (lA,2S)-A-(5-acetyl-4-((3- Ci8Hi7BrF2N3 bromo-5-fluoro-2-methoxy- O3[M+H]+: phenyl)amino)pyridin-2-yl)-2- m / z = fluorocyclopropane-1- 440.0 / 442.0; carb oxami deFound:440.0 / 442.0.LCMS calc, for (15,2A)-A-(5-acetyl-4-((3- Ci8Hi7BrF2N3 bromo-5-fluoro-2-methoxy- O3[M+H]+: phenyl)amino)pyridin-2-yl)-2- m / z = fluorocyclopropane-1- 440.0 / 442.0; carb oxami deFound:440.0 / 442.0.- 87 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationBr LCMS calc, (17?,2S)-7V-(5-acetyl-4-((3- for bromo-2-methoxyphenyl)- Ci8Hi8BrFN3O 12 amino)pyridin-2-yl)-2- 3 [M+H]+: m / z fluorocyclopropane-1- = 422.1 / 424.1;carb oxami de Found:422.1 / 424.1Br LCMS calc, (17?,27?)-7V-(5-acetyl-4-((3- / -0for bromo-2-methoxyphenyl)- CigFLiBrNsCL amino)pyridin-2-yl)-2- 0 HN [M+H]+: m / z = methylcyclopropane-1- 418.1 / 420.1;carb oxami de Found:418.2 / 420.2Br LCMS calc, (15,25)-#-(5-acetyl-4-((3- for bromo-2-methoxyphenyl)- CigH^iBrNsCh 14 amino)pyridin-2-yl)-2- 0 HN [M+H]+: m / z = methylcyclopropane-1- 418.1 / 420.1;carb oxami de Found:418.2 / 420.2.LCMS calc, (l / ?,2S)-7V-(5-acetyl-4-((3- for bromo-2-m ethoxy-5 - Ci9Hi? BrF4N3 (trifluoromethyl)phenyl)amin O3[M+H]+:15o)-pyridin-2-yl)-2- m / z = fluorocyclo-propane-1- 490.0 / 492.0;carb oxami de Found:490.0 / 491.9.Intermediate 16.7V-(5-Acetyl-4-((2-chloro-3-methoxypyridin-4-yl)amino)pyridin-2-yl)cyclo-propanecarboxamide

[0261] Step 1. 2 -Chloro-4-iodo-3-methoxypyridine- 88 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationCl

[0262] Sodium methoxide (899 pL, 4.86 mmol, 5.4 M in methanol) was added to a stirring solution of 2-chloro-3-fluoro-4-iodopyridine (500 mg, 1.94 mmol) in methanol (3.3 mL) at 0 °C. The reaction mixture was heated to 45 °C for 16 hours. The product mixture was diluted with sat. NaHCO3 (aq) solution (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-50% EtOAc / Hexanes) to yield the title compound (255 mg, 49% yield). LC-MS calc, for CeFkClINO [M+H]+: m / z = 269.9; Found: 269.9

[0263] Step 2. l-(6-Chloro-4-((2,4-dimethoxybenzyl)amino)pyridin-3-yl)ethan-l-one

[0264] Tri ethylamine (440 pL, 3.2 mmol) and 2,4-dimethoxybenzylamine (356 pL, 2.4 mmol) were added in sequence to a stirring solution of l-(4,6-dichloro-3-pyridinyl)ethanone (300 mg, 1.6 mmol) in MeCN (4 mL) at rt. The reaction mixture was stirred for 16 hours. The resulting slurry was filtered, and the solid was washed with MeCN (2 x 2 mL). The solid was dried under reduced pressure to yield the title compound (506 mg, 100% yield). LC-MS calc, for Ci6Hi8ClN2O3 [M+H]+: m / z = 321.1; Found: 321.1

[0265] Step 3. N-(5-Acetyl-4-((2,4-dimethoxybenzyl)amino)pyridin-2-yl)cyclopropane-carboxamide- 89 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0266] The title compound was prepared in accordance with the synthetic protocols set forth in Int. 3 Step 2 using appropriate intermediates, as well as commercial starting materials. LC-MS calc, for C20H24N3O4 [M+H]+: m / z = 370.2; Found: 370.2

[0267] Step 4. N-(5-Acetyl-4-aminopyridin-2-yl)cyclopropanecarboxamide

[0268] Trifluoroacetic acid (600 pL) was added to a stirring solution of V-(5-acetyl-4-((2,4- dimethoxybenzyl)amino)pyri din-2 -yl)cy cl opropanecarboxamide (222 mg, 0.6 mmol) in DCM (8 mL) at rt. The reaction mixture was stirred for 2 hours. The product mixture was diluted with sat. NaHCO3 (aq) solution and extracted with a 3:1 CHCl3 / iPrOH mixture (3 x 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (130 mg, 99% yield) which was used without further purification. LC-MS calc, for C11H 4N3O2 [M+H]+: m / z = 220.1; Found: 220.1

[0269] Step 5. N-(5-Acetyl-4-((2-chloro-3-methoxypyridin-4-yl)amino)pyridin-2-yl)cyclo-propanecarboxamide

[0270] A 20 mL scintillation vial was charged with 7V-(5-acetyl-4-aminopyridin-2-yl)cyclo-propanecarboxamide (3.54 g, 16.1 mmol), 2-chloro-4-iodo-3-methoxypyridine (4.35 g, 16.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (2.96 g, 3.2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.87 g, 3.2 mmol), and cesium carbonate (15.8 g, 48.4 mmol). The mixture was dissolved in 1,4-dioxane (71 mL), was sparged with nitrogen gas for 5 minutes and sealed. The reaction mixture was heated to 100 °C for 3 hours. The product mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-100% EtOAc / Hexanes) to yield the title compound (1.79 g, 31% yield). LC-MS calc, for C17H18CIN4O3 [M+H]+: m / z = 361.1; Found: 361.0Intermediate 17. (l»S,21?)-A-(5-Acetyl-4-((2-chloro-3-methoxypyridin-4-yl)amino)pyridin-2-yl)-2-fluorocyclopropane-l-carboxamide- 90 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationCl

[0271] Step 1. l-(6-Amino-4-((2-chloro-3-methoxypyridm-4-yl)ammo)pyridm-3-yl)ethan-lone

[0272] Sodium hydroxide (450 pL, 22.2 mmol, 4 M in water) was added to a stirring solution of A-(5-acetyl-4-((2-chl oro-3 -methoxypyridin-4-yl)amino)pyri din-2 -yl)cyclopropanecarboxamide (Int. 16) (800 mg, 2.22 mmol) in 1,4-dioxane (4.5 mL) and water (500 pL). The reaction mixture was heated to 100 °C for 24 hours. The product mixture was diluted with sat. NaHCO3 (aq) solution (20 mL) and extracted with a 10:1 DCM / MeOH mixture (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (431 mg, 66% yield) which was used without further purification. LCMS calc, for C13H14CIN4O2 [M+H]+: m / z = 293.1; Found: 293.2.

[0273] Step 2. (lS,2R)-N-(5-Acetyl-4-((2-chloro-3-methoxypyridin-4-yl)amino)pyridin-2-yl)-2-fluorocyclopropane-l -carboxamide

[0274] Phosphorus (V) oxychloride (1.11 mL, 12 mmol) was added to a stirring solution of 1-(6-amino-4-((2-chloro-3-methoxypyridin-4-yl)amino)pyridin-3-yl)ethan-l-one (700 mg, 2.39 mmol) and (15,2A)-2-fluorocyclopropane-l-carboxylic acid (249 mg, 2.39 mmol) in pyridine (10 mL) at 0 °C. The reaction mixture was stirred for 20 minutes. The product mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-66% EtOAc / Hexanes) to yield the title compound (672 mg, 74% yield). LCMS calc, for C17H17CIFN4O3 [M+H]+: m / z = 379.1; Found: 379.2.Intermediate 18. N-(5-Acetyl-4-chloropyridin-2-yl)cyclopropanecarboxamide- 91 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationO Cl

[0275] A 40 mL scintillation vial was charged with l-(4,6-dichloropyridin-3-yl)ethan-l-one (300 mg, 1.6 mmol), cyclopropanecarboxamide (134 mg, 1.6 mmol), tris(dibenzylideneacetone)-dipalladium (0) (72 mg, 0.079 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (91 mg, 0.16 mmol), and cesium acetate (909 mg, 4.7 mmol). The reaction mixture was dissolved in 1,4-di oxane (5 mL), sparged with nitrogen gas for 5 minutes, and sealed. The reaction mixture was heated to 85 °C for 2 hours. The product mixture was diluted with water (60 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-5% MeOH / DCM) to yield the title compound (340 mg, 90% yield). LC-MS calc, for C11H12CIN2O2 [M+H]+: m / z = 239.1; Found: 239.0.Intermediate 19. (lR,2S)-N-(5-Acetyl-4-chloropyridin-2-yl)-2-fluorocyclopropane-l-carboxamideO ClY d O

[0276] Step 1. tert-Butyl (5-acetyl-4-chloropyridin-2-yl)carbamateO ClH

[0277] A 40 mL scintillation vial was charged with l-(4,6-dichloropyridin-3-yl)ethan-l-one (500 mg, 2.6 mmol), tert-butyl carbamate (308 mg, 2.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (120 mg, 0.13 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (152 mg, 0.26 mmol), and cesium acetate (1.52 g, 7.9 mmol). The reaction mixture was dissolved in 1,4-dioxane (8.7 mL), sparged with nitrogen gas for 5 minutes, and sealed. The reaction mixture was heated to 85 °C for 2 hours. The product mixture was diluted with water (60 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-100% EtOAc / Hexane) to yield the title- 92 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationcompound (548 mg, 77% yield). LC-MS calc, for CsHsCllShCh [M+H-C4Hs]+: m / z = 215.0; Found: 215.1

[0278] Step 2. l-(6-Amino-4-chloropyridin-3-yl)ethan-l-oneO ClY iN NH2

[0279] Hydrochloric acid (7.6 mL, 30.4 mmol, 4.0 M in 1,4-dioxane) was added to a stirring solution of tert-butyl (5-acetyl-4-chloropyridin-2-yl)carbamate (548 mg, 2.0 mmol) in DCM (10 mL). The reaction mixture was stirred at rt for 24 hours. The product mixture was diluted with sat. Na2CC>3 (aq) (60 mL) and was extracted with a 3:1 CHCl3 / iPrOH mixture (3 x 60 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound (305 mg, 88% yield). LC-MS calc, for C7H8CIN2O [M+H]+: m / z = 171.0; Found: 171.0

[0280] Step 3. (lR,2S)-N-(5-Acetyl-4-chloropyridin-2-yl)-2-fluorocyclopropane-l-carboxamide

[0281] Phosphorus (V) oxychloride (100 pL, 1.1 mmol) was added dropwise to a stirring solution of 7-(6-amino-4-chloropyridin-3-yl)ethan-l-one (76 mg, 0.45 mmol) and (l / ?,2A')-2-fluorocyclopropane-1 -carboxylic acid (53 mg, 0.51 mmol) in pyridine (3 mL) at 0 °C. The reaction mixture was stirred for 30 minutes. The product mixture was quenched with sat.Na2CC>3 (aq) (20 mL) and extracted with a 3:1 CHCl3 / iPrOH mixture (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-5% MeOH / DCM) to yield the title compound (90 mg, 79% yield). LC-MS calc, for C11H11CIFN2O2 [M+H]+: m / z = 257.0; Found: 257.0Intermediates 20-22

[0282] Intermediates 20-22 shown below in Table 3 were prepared in accordance with the synthetic protocols set forth in Int. 19 Step 3 using appropriate intermediates, as well as commercial starting materials.Table 3. Intermediates 20-22Intermediate Name Structure LCMS Data- 93 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(15,27?)-#-(5-acetyl- O Cl LC-MS calc, for 4-chloropyridin-2- C11H11CIFN2O2 20 yl)-2-fluorocyclo- O[M+H]+: m / z = 257.0; propane-1- N Found: 257.0 carb oxami de H( 1R,2R)-N~(5 -acetyl - O Cl LC-MS calc, for 4-chloropyridin-2- C12H14CIN2O2 21 yl)-2 -methylcyclo- o[M+H]+: m / z = 253.1; propane- 1- N N Found: 253.1 carb oxami de H( 1 S, 2S)-N-(5 -acetyl - O Cl LC-MS calc, for 4-chloropyridin-2- C12H14CIN2O2 22 yl)-2 -methylcyclo- [M+H]+: m / z = 253.1; propane- 1- Found: 253.1 carb oxami deIntermediate 23. 6-(Bromomethyl)-7V,7V-dimethylpicolinamide|f^|1O

[0283] Step 1. 6-(Hydroxymethyl)-N, N-dimethylpicolinamideo

[0284] To a solution of methyl 6-(hydroxymethyl)picolinate (2.0 g, 12.0 mmol) in THF (22 mL) was added MgCh (1.7 g, 17.9 mmol) and dimethylamine (20 mL, 40 mmol, 2 M in THF) in sequence. The rection mixture was stirred at 70 °C for 24 hours. The product mixture was diluted with sat. Na2CO3 (aq) (100 mL) and extracted with a 3:1 CHCl3 / iPrOH mixture (5 x 150 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (2.1 g, 97% yield) which was used without further purification. LCMS calc, for C9H13N2O2 [M+H]+: m / z = 181.1; Found: 181.1.

[0285] In an alternative procedure, 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 rection mixture was stirred at 65 °C for 18 h then cooled and extracted with DCM, which was then dried over Na2SO4, condensed, and used directly in the next step. LCMS calcd. for C9H13N2O2 [M+H]+: m / z = 181.1; Found: 181.1.- 94 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0286] Step 2. 6-(Bromomethyl)-N, N-dimethylpicolinamide

[0287] 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, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-100% EtOAc / Hexanes) to yield the title compound (2.9 g, 71% yield). LCMS calc, for CyH^Br^O [M+H]+: m / z = 243.0 / 245.0; Found: 242.9 / 244.9Intermediate 24. 6-Formyl- A, TV-dim ethylpicolinamide

[0288] Step 1. 6-Formyl-N, N-dimethylpicolinamide

[0289] 2-Iodoxybenzoic acid (6.66 g, 16.6 mmol) was added to a stirring solution of 6-(hydroxymethyl)-A,7V-dimethylpicolinamide (2.0 g, 11 mmol) in MeCN (25 mL). The reaction mixture was heated to 55 °C and stirred for 2 hours. The product mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-100% EtOAc / Hexane) to yield the title compound (1.75 g, 88% yield). LC-MS calc, for C9H11N2O2 [M+H]+: m / z = 179.1; Found: 179.1.Intermediate 25. 8-B101110- 1.3.4.5-tetialiydio-2 / / -benzo|c| [l,4]diazepin-2-oneBr

[0290] Step 1. tert-Butyl ( 2-amino-4-bromobenzyl)glycinate

[0291] 2 -Amino-4-bromobenzaldehyde (30 mg, 0.15 mmol) and tert-butyl glycinate (110 mg, 0.83 mmol) were dissolved in DMSO (1.5 mL) and stirred at rt for an hour followed by the - 95 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationaddition of sodium triacetoxyborohydride (180 mg, 0.83 mmol) in one portion. The reaction mixture was stirred overnight at rt. After completion, it was diluted with MeOH and purified by prep HPLC (0.1% formic acid in water and MeCN). The pure fractions were concentrated, basified with NaHCO3 (aq) and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (47 mg, 99% yield). LCMS calc, for CnThoBrlShCh [M+H]+: m / z = 315.1; Found: 315.1.

[0292] Step 2. 8-Bromo-l, 3, 4, 5-tetrahydro-2H-benzo[e] [ 1, 4 ]diazepin-2-one

[0293] To tert-butyl (2-amino-4-bromobenzyl)glycinate (2.7 g, 8.5 mmol) in DCM (6 mL) was added trifluoroacetic acid (6 mL, 78 mmol) dropwise. After overnight, the reaction was concentrated under reduced pressure. The residue obtained was dissolved in toluene (20 mL) and the reaction was concentrated again to dryness under reduced pressure (repeated 2x). The resulting residue was dissolved in anhydrous toluene (20 mL) and refluxed at 120 °C. After 2 hours, the reaction was complete and cooled to rt. The crude was purified by FCC (0-25% MeOFLDCM) to yield the title compound (2.1 g, quant, yield).JH NMR (300 MHz, MeOD) 6 7.46 (dd, J= 8.1, 1.8 Hz, 1H), 7.42 (s, 1H), 7.38 (t, J= 2.4 Hz, 1H), 4.29 (s, 2H), 3.74 (s, 2H).Intermediate 26. 6-((8-Br()ino-2-oxo- 1.2.3.5-tetr:ihydro-4 / / -benzo|c| [l,4]diazepin-4-yl)inethyl)-\.\-diinethylpicolinamide

[0294] A mixture of 8-bromo-l,3,4,5-tetrahydro-2J / -benzo[e][l,4]diazepin-2-one (520 mg, 2.2 mmol) and 6-formyl-7V,7V-dimethylpicolinamide (Int.24) (380 mg, 2.2 mmol) in DCM (15 mL) was stirred at rt for 1 hour, followed by the addition of sodium triacetoxyborohydride (1.4 g, 6.5 mmol). After stirring overnight, the reaction was poured into sat. NaHCO3 (aq) and extracted 3x (DCM / MeOH (v / v=15 / l)). The combined organic phase was washed with brine and dried over Na2SO4, filtered and condensed. The crude was purified by FCC (0-10% MeOH / DCM) to yield the title compound (610 mg, 70% yield). LCMS calc, for CixFLoBr^Ch [M+H]+: m / z = 403.1; Found: 403.1.- 96 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationIntermediate 27. ( )-6-((8-Bromo-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4Z7-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamideBr

[0295] Cesium carbonate (4.85 g, 14.9 mmol) was added to a stirring solution of 6-((8-bromo-2-oxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide (3.00 g, 7.4 mmol) and 3 -iodotetrahydrofuran (2.21 g, 11.2 mmol) in DMF (150 mL) and the resulting reaction mixture was sealed and stirred at 80 °C for 2 days. The cooled reaction mixture was then poured into water and extracted with EtOAc. The combined extracts were washed with brine, dried, condensed, and purified with a DAICEL CHIRAL PAK IC column (250 mm x 30 mm, 10 pM) by using 35% CC>2 / (20% MeCN / iPrOH) with a flow rate of 100 mL / min. to afford the title compound (669 mg, 19% yield). LC-MS calc, for C22H26BrN4O3 [M+H]+: m / z = 473.1 / 475.1. Found: 473.1 / 475.0.Intermediate 28. 6-((8-Br()ino-2-oxo- 1.2.3.5-tetrahydro-4 / / -pyrido|3.2- | [l,4]diazepin-4-yl)methyl)-\.\ dimethylpicolinamide

[0296] Step 1. tert-Butyl ( ( 3-amino-5-bromopyridm-2-yl)methyl)glycmate

[0297] Borane dimethyl sulfide complex (4.3 mL, 45.5 mmol) was added dropwise to a stirring solution of 3-amino-5-bromopicolinonitrile (3.0 g, 15.2 mmol) in THF (36 mL). The - 97 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationreaction mixture was heated to 50 °C and stirred for 1 hour. The product mixture was cooled to 0 °C and quenched with dropwise addition of methanol (10 mL). The diluted product mixture was concentrated under reduced pressure. The residue obtained was dissolved in THF (36 mL). The mixture was cooled to 0 °C and triethylamine (6.3 mL, 45.5 mmol) and tert-butyl 2-bromoacetate (2.13 mL, 14.4 mmol) were added sequentially. The reaction mixture was stirred overnight and allowed to warm to rt. The product mixture was diluted with EtOAc (100 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-50% EtOAc / Hexanes) to yield the title compound (1.55 g, 32% yield). LC-MS calc, for Ci2Hi9BrN3O2 [M+H]+: m / z = 316.1 / 318.1; Found: 316.0 / 318.0.

[0298] Step 2. tert-Butyl N-( ( 3-amino-5-bromopyridin-2-yl)methyl)-N-( 6- (dimethylcarbamoyl)-pyridin-2-yl)methyl)glycinateBr

[0299] Potassium carbonate (2.03 g, 14.7 mmol) was added to a stirring solution of tert-butyl ((3-amino-5-bromopyridin-2-yl)methyl)glycinate (1.55 g, 4.9 mmol) and 6-(bromomethyl)-A, A-dimethylpicolinamide (Int. 23) (1.19 g, 4.9 mmol) in MeCN (16 mL). The reaction mixture was heated to 50 °C and stirred for 3 hours. The product mixture was diluted with EtOAc (80 mL). The diluted product mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-10% MeOH / DCM) to yield the title compound (1.93 g, 82% yield). LC-MS calc, for C2iH29BrN5O3[M+H]+: m / z = 478.1 / 480.1; Found: 478.1 / 480.1.

[0300] Step 3. 6-((8-Bromo-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0301] Sodium hydride (303 mg, 7.6 mmol, 60% dispersion in mineral oil) was added to a stirring solution of tert-butyl N-((3-amino-5-bromopyridin-2-yl)methyl)-N-((6-(dimethyl-carbamoyl)pyridin-2-yl)methyl)glycinate (1.21 g, 2.53 mmol) in THF (24 mL). The reaction mixture was heated to 60 °C and stirred for 3 hours. The product mixture was diluted with sat. NaHCO3(aq) solution (100 mL) and extracted with a 3:1 CHCl3 / iPrOH mixture (3 x 100 mL).- 98 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationThe combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-10% MeOH / DCM) to yield the title compound (1.0 g, 98% yield). LC-MS calc, for CnHwBrNsCh [M+H]+: m / z = 404.1 / 406.1; Found: 404.1 / 406.1.Intermediate 29-30

[0302] Intermediates 29-30 shown below in Table 4 were prepared in accordance with the synthetic protocols set forth in Int. 28 Steps 1-3 using appropriate intermediates, as well as commercial starting materials.Table 4. Intermediate 29-30Intermediate Name Structure Analytical DataLCMS calc, for 6-((8-bromo-6-fluoro-2- CisHi9BrFN4O2 oxo- 1,2, 3, 5 -tetrahy dro-4 / 7- [M+H]+: m / z = 29 benzofe] [ 1,4]diazepin-4- 421.1 / 423.1; yl)methyl)-7V,7V- Found: dimethylpicolinamide 421.1 / 423.1.LCMS calc, for 6-((8-bromo-7 -fluoro-2 - CisHi9BrFN4O2 oxo- 1,2, 3, 5 -tetrahy dro-47 / - [M+H]+: m / z = benzofe] [ 1,4]diazepin-4- 421.1 / 423.1; yl)methyl)-7V,7V- Found: dimethylpicolinamide421.1 / 423.1.Intermediate 31. 6-((8-Chloro-2-oxo-2.3-dihydro- 1 / / -pyrido|4.3-c| [l,4]diazepin-4(5ZZ)-yl)niethyl)-\.\ diniethylpicolinaniide

[0303] Step 1. tert-Butyl ( ( 4-amino-6-chloropyridm-3-yl)methyl)glycinate- 99 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationoCl

[0304] To a solution of 4-amino-6-chloronicotinaldehyde (391 mg, 2.5 mmol) and tert-butyl glycinate (984 mg, 7.5 mmol) in DMSO (10 mL) was added sodium triacetoxyborohydride (2.65 g, 12.5 mmol). The recti on mixture was stirred at 25 °C overnight. The product mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (0-10% MeOH / DCM) to give the title compound (600 mg, 88% yield). LCMS calc, for C12H19CIN3O2 [M+H]+: m / z = 272.1; Found: 272.2.

[0305] Step 2. tert-Butyl N-( ( 4-amino-6-chloropyridin-3-yl)methyl)-N-( 6- (dimethylcarbamoyl)-pyridin-2-yl)methyl)glycinate

[0306] To a solution of tert-butyl ((4-amino-6-chl oropyri din-3 -yl)methyl)glycinate (300 mg, 1.1 mmol) and 6-(bromomethyl)-7V,7V-dimethylpicolinamide (Int. 23) (295 mg, 1.21 mmol) in acetonitrile (5 mL) was added potassium carbonate (458 mg, 3.31 mmol). The reaction mixture was stirred at 50 °C overnight. The product mixture was diluted with water and was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by prep-HPLC (20-70% MeCN in 0.1% TFA (aq), pH=2) to give the title compound (120 mg, 25% yield). LCMS calc, for C21H29CIN5O3 [M+H]+: m / z = 434.19; Found: 434.26.1H NMR (400 MHz, Chloroform ) 8 8.20 (s, 1H), 7.95 (s, 1H), 7.44 (s, 1H), 7.38 (s, 1H), 6.56 (s, 1H), 4.28 - 4.11 (m, 2H), 3.98 (s, 2H), 3.62 (s, 2H), 3.17 (s, 3H), 2.99 (s, 3H), 1.47 (s, 9H).

[0307] Step 3. N-( ( 4-Amino-6-chloropyridin-3-yl)methyl) -N-(( 6-(dimethylcarbamoyl)pyridin-2-yl)methyl)glycine- 100 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0308] To a solution of tert-butyl 7V-((4-amino-6-chl oropyri din-3 -yl)methyl)-7V-((6-(dimethyl-carbamoyl)pyridin-2-yl)methyl)glycinate (200 mg, 0.46 mmol) was added trifluoroacetic acid (3.0 mL). The reaction mixture was stirred at 50 °C for two hours. The product mixture was concentrated to dryness to afford the crude product which was used directly in the next step. LCMS calc, for C17H21CIN5O3 [M+H]+: m / z = 378.1; Found: 378.1.

[0309] Step 4. 6-((8-Chloro-2-oxo-2, 3-dihydro- lH-pyrido[4, 3-e] [l,4]diazepin-4(5H)~ yl)methyl)-N, N-dimethylpicolinamide

[0310] To a solution of 7V-((4-amino-6-chloropyri din-3 -yl)m ethyl)-7V-((6-(dimethylcarbamoyl)-pyridin-2-yl)methyl)glycine (55.0 mg, 0.15 mmol) and, V-diisopropylethylamine (22.6 mg, 0.17 mmol) in DMF (5 mL) was added 2-(7-Azabenzotriazol-l-yl)-7V,7V,7V'7V'-tetramethyluronium hexafluorophosphate (60.9 mg, 0.16 mmol). The reaction mixture was stirred at 15 °C for two hours. The product mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Ethyl acetate) to give the title compound (25.0 mg, 48 % yield) LCMS calc, for C17H19CIN5O2 [M+H]+: m / z = 360.1; Found: 360.0. 'HNMR (400 MHz, Chloroform- ) 88.35 (s, 1H), 7.98 (s, 1H), 7.79 (t, J= 7.7 Hz, 1H), 7.52 (d, J= 7.7 Hz, 1H), 7.41 - 7.37 (m, 1H), 6.87 (s, 1H), 4.03 (s, 2H), 3.91 (s, 2H), 3.88 (s, 2H), 3.12 (s, 3H), 3.01 (s, 3H).Intermediate 32. tert-Butyl 8-bromo-2-oxo- 1,2,3, 5-tetrahydro-4H-pyrido [3,2-e] [l,4]diazepine-4-carboxylateN HN N- 101 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0311] Step 1. tert-Butyl N-( ( 3-amino-5-bromopyridin-2-yl)methyl)-N-( tert-butoxycarbonyl)-glycinate

[0312] Di-tert-butyl dicarbonate (959 pL, 4.17 mmol) was added to a stirring solution of tertbutyl ((3-amino-5-bromopyridin-2-yl)methyl)glycinate (1.2 g, 3.8 mmol) and / ' / . / ' / -diisopropyl-ethylamine (991 pL, 5.69 mmol) in DCM (20 mL) at rt. The reaction mixture was stirred for 2 hours. The product mixture was diluted with water (60 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-0.3% MeOH / DCM) to yield the title compound (1.58 g, 82% yield). LCMS calc.for Ci7H27BrN3O4[M+H]+: m / z = 416.1 / 418.2; Found: 416.2 / 418.2

[0313] Step 2. N-( ( 3-Amino-5-bromopyridin-2-yl)methyl) -N-( tert-butoxycarbonyl) glycine

[0314] Sodium hydroxide (1.2 g, 30 mmol) was added to a stirring solution of tert-butyl N-((3-amino-5-bromopyridin-2-yl)methyl)-7V-(tert-butoxycarbonyl)glycinate (2.5 g, 6.0 mmol) in MeOH (8 mL), water (8 mL), and THF (8 mL). The reaction mixture was stirred at rt for 16 hours. The product mixture was concentrated under reduced pressure. The residue obtained was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (2.0 g, 92% yield) which was used without further purification. LCMS calc.for Ci3Hi9BrN3O4[M+H]+: m / z = 360.1 / 362.1; Found: 359.7 / 361.6

[0315] Step 3. tert-Butyl 8-bromo-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2-e ][ 1, 4 diazepine-4-carboxylate

[0316] Pyridine (1.12 mL, 13.9 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (639 mg, 3.33 mmol) and 4-dimethylaminopyridine (34 mg, 0.28 mmol) were added in sequence to a stirring solution of N-((3-amino-5-bromopyridin-2-yl)methyl)-N-(tert-butoxycarbonyl)glycine - 102 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(1.0 g, 2.78 mmol) in 1,2-di chloroethane (15 mL). The reaction mixture was heated to 40 °C and stirred for 1 hour. The product mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-50% EtOAc) to yield the title compound (674 mg, 71% yield). LCMS calc, for Ci3Hi7BrN3O3 [M+H]+: m / z = 342.0 / 344.0; Found: 342.2 / 344.2Intermediate 33. (S)-6-((8-Bromo-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H- pyrido[3,2-e] [l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide and (R)-6-((8-bromo-2- oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0317] Step 1. (S)-6-((8-Bromo-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[ 3, 2-e ][ 1, 4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide and (R)-6-((8-bromo-2-oxo- l-( tetrahydrofuran-3-yl)-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2-e ][ 1, 4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0318] (R)-3-Iodotetrahydrofuran (612 mg, 3.1 mmol) was added to a stirring solution of 6- ((8-bromo-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide (Int.28) (250 mg, 0.62 mmol) and cesium carbonate (604 mg, 1.9 mmol) in DMF (3 mL). The reaction mixture was heated to 60 °C for 2 hours. The reaction mixture was cooled to rt, and (A)-3 -iodotetrahydrofuran (612 mg, 3.1 mmol) and cesium carbonate (604 mg, 1.9 mmol) were added sequentially to the reaction mixture. The reaction mixture was heated to 60 °C for 2 hours. The product mixture was diluted with brine (60 mL) and extracted with a 3: 1 CHCL / iPrOH mixture (3 x 60 mL). The combined organic layers were dried over MgSO4, - 103 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationfiltered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-5% MeOH / DCM) to yield a mixture of the title compounds (169 mg, 58% yield). LC-MS calc, for C2iH25BrN5O3[M+H]+: m / z = 474.1 / 476.1; Found: 474.1 / 476.1

[0319] Step 2. (S)-6-((8-Bromo-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[ 3, 2-e ][ 1, 4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide and (R)-6-((8-bromo-2-oxo- l-( tetrahydrofuran-3-yl)-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2-e ][ 1, 4 ]diazepin-4-yl)methyl)-N, N- dimethylpicolinamide

[0320] The mixture of (S)-6-((8-bromo-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro- 4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide and (R)-6-((8-bromo-2- oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)- N, N-dimethylpicolinamide was purified via chiral separation (Lux Cellulose-3, 30 mL / min of 70:15:15 Hexanes / IPA / MeOH) to yield (S)-6-((8-bromo-2-oxo-l-(tetrahydrofuran-3-yl)-l, 2,3,5- tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide (83 mg, Peak A, 49% yield) and (R)-6-((8-bromo-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H- pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide (33 mg, PeakB, 20% yield). LC-MS calc, for C2iH25BrN5O3[M+H]+: m / z = 474.1 / 476.1; Found: 474.1 / 476.1Intermediate 34. (5)-6-((8-Bromo-6-fluoro-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5- tetr:iliydro-4 / / -benzo|c||L4|di:izepiii-4-yl)inetliyl)-\.\-diinethylpicolinainideBr

[0321] Step 1. (S)-6-((8-Bromo-6-fluoro-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro- 4H-benzo[e] [l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide and (R)-6-((8-bromo-6-fluoro-2-oxo-l-( tetrahydrofuran-3-yl)-l, 2, 3, 5-tetrahydro-4H-benzo[ e][ 1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide- 104 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0322] The title compounds were prepared using synthetic protocols set forth in Int.33 Step 1 using appropriate intermediates and commercial starting materials. LCMS calc, for C22H25BrFN4O3 [M+H]+: m / z = 491.1 / 493.1; Found: 491.1 / 493.1.

[0323] Step 2. (S)-6-((8-Bromo-6-fluoro-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-benzo[ e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0324] The mixture of (5)-6-((8-bromo-6-fluoro-2-oxo-l-(tetrahydrofuran-3-yl)-l, 2,3,5-tetrahydro-47 / -benzo[c] [ 1,4]di azepi n-4-yl (methyl )- / f, A-dim ethyl pi coli nami de and (A)-6-((8-bromo-6-fluoro-2-oxo- 1 -(tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-47 / -benzo[c] [ 1,4] diazepin-4-yl (methyl )-M A-di methyl pi col inami de was purified via chiral separation (Lux Cellulose-3, 30 mL / min of 70:15:15 Hexanes / IPA / MeOH) to yield (5)-6-((8-bromo-6-fluoro-2-oxo-l-(tetrahydrofuran-3 -yl)- 1,2,3, 5-tetrahydro-47 / -benzo[c] [ 1,4]diazepin-4-yl)methyl)-A,7V-dimethylpicolinamide (62 mg, Peak A, 55% yield) LCMS calc, for C22H2sBrFN4O3 [M+H]+: m / z = 491.1 / 493.1; Found: 491.1 / 493.1.Example 1. 6-(Cyclopropanecarboxamido)-4-((3-(l-ethyl-4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lZ7-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl) amino)- / V-methylpyridazine-3-carboxamide

[0325] Step 1. 6-((8-Bromo-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e] [l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide- 105 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0326] 6-((8-Bromo-2-oxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide (62 mg, 150 pmol), cesium carbonate (100 mg, 308 pmol) and iodoethane (48 mg, 310 pmol) in DMSO (1 mL) were stirred at rt for 1.5 h. The reaction was partitioned between EtOAc (25 mL) and water (25 mL). The organic phase was separated and further washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (15-75% MeCN in H2O w / 0.1% TFA) to yield the title compound as yellow solid (43 mg, 65% yield). LCMS calc, for C2oH24BrN4C>2 [M+H]+: m / z = 431.1; Found: 431.2.

[0327] Step 2. 6-(Cyclopropanecarboxamido)-4-((3-(l-ethyl-4-((6-(methylcarbamoyl)pyridin-2-yl)methyl)-2-oxo-2, 3, 4, 5-tetrahydro-lH-benzo[e] [ 1, 4 ]diazepin-8-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide

[0328] 6-((8-Bromo-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4J7-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide (20 mg, 46 pmol), 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)-A-methylpyridazine-3-carboxamide (Int. 2) (43 mg, 93 pmol) and XPhos Pd G2 (3.4 mg, 4.0 pmol) were added to a vial with 1,4-di oxane (1 mL) followed by the addition of potassium phosphate tribasic (30 mg, 140 pmol) and water (0.2 mL). The mixture was purged with N2 and then stirred at 95 °C for 6 hours. After completion, the reaction was quenched with water, extracted with DCM and condensed. The crude was purified by prep-HPLC (0.02% formic acid in water and MeCN) to yield the title compound as the formic salt (16 mg, 50% yield). LCMS calc, for C37H42N9O5 [M+H]+: m / z = 692.3; Found: 692.4.Examples 2-3

[0329] Examples 2-3 are are shown in Table 5 below and were prepared in accordance with the synthetic protocols set forth in Example 1 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.Table 5. Examples 2-3- 106 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data (LCMS Ex. Name Structureand / or NMR)6-(cyclopropanecarboxamido)-4- ((3-(4-((6-(dimethyl- carbamoyl)pyridin-2-yl)methyl)- LCMS calc, for C38H44N9O5 1 -i sopropy 1 -2 -oxo-2, 3, 4, 5 - 2 [M+H]+: m / z = 706.3; Found tetrahydro-l / Z-benzofe]- 706.8.[ 1,4]diazepin-8-yl)-2 -methoxy - phenyl)amino)-7V-methyl- pyri dazine-3 -carb oxami de^^ IZ IZ>°= / / o o / x xpjoo / \ / = / = / \ # A / / 6 C c A y y e iz zz y A — — —\ / O \o==6-(cyclopropanecarbox-amido)- 4-((3 -(4-(3 -(dimethyl- r o) X * < ' <carbamoyl)-2 -fluorobenzyl)- 1 - LCMS calc, for C38H42FN8O5 3 ethyl-2-oxo-2,3,4,5-tetrahydro- o o [M+H]+: m / z = 709.3 Found 1 / / -benzofc] [ 1,4]diazepin-8-yl)- 709.4.2-methoxyphenyl)amino)-7V- methylpyridazine-3 -carboxamideExample 4. 6-(Cyclopropanecarboxamido)-4-((3-(l-cyclopropyl-4-((6-(dimethylcarbamoyl)-pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lZ7-benzo[e][l,4]diazepin-8-yl)-2-methoxy-phenyl)amino)-7V-methylpyridazine-3-carboxamide- 107 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0330] Step 1. 6-((8-Bromo-l-cyclopropyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[ e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0331] Cyclopropylboronic acid (43 mg, 0.5 mmol), cupric acetate (45 mg, 0.25 mmol), cesium carbonate (120 mg, 0.37 mmol), 6-((8-bromo-2-oxo-l,2,3,5-tetrahydro-4JT-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide (100 mg, 0.25 mmol) and 4-(dimethylamino)pyridine (91 mg, 0.74 mmol) were added to anhydrous toluene (2 mL). It was stirred at 100 °C. After overnight, the reaction was diluted in water and extracted with EtOAc. The organic layer was concentrated and purified by FCC (40-90% Hep: EtOAc) to yield the titled compound (48 mg, 33% yield). LCMS calc, for C2iH24BrN4C>2 [M+H]+: m / z = 443.1 / 445.1; Found: 445.1.

[0332] Step 2. 6-(Cyclopropanecarboxamido)-4-((3-(l-cyclopropyl-4-((6-(dimethylcarbamoyl)-pyridin-2-yl)methyl)-2-oxo-2, 3, 4, 5 -tetrahydro- lH-benzo[ e] [1,4 [diazepin-8-yl)-2-methoxyphenyl) amino)-N-methylpyridazine-3-carboxamide

[0333] XPhos Pd G2 (2.0 mg, 2.5 pmol), cesium acetate (15 mg, 0.08 mmol), 6-((8-bromo-l-cyclopropyl-2-oxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethyl-picolinamide (11 mg, 0.03 mmol), and 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)-7V-methylpyridazine-3-carboxamide (Int. 2) (16 mg, 0.03 mmol) were added in 1,4-dioxane (0.9 mL) and water (0.1 mL) under N2. After stirring at 100 °C overnight, it was purified by prep-TLC (80% Hep: EtOAc) followed by prep- - 108 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationHPLC (15-35% MeCN in water with 0.05% TFA) to yield the title compound as the TFA salt (2.8 mg, 16% yield). LCMS calc, for C38H42N9O5 [M+H]+: m / z = 704.3; Found: 704.7.Example 5. 6-(Cyclopropanecarboxamido)-4-((3-(2-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)- 1 -oxo-2, 3,4, 5-tetrahydro- lZ / -benzo[c]azepin-7-yl)-2-methoxyphenyl)amino)-A-methylpyridazine-3-carboxamideN

[0334] Step 1. 6-((7-Bromo-l-oxo-l,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)methyl)-N, N-dimethylpicolinamide

[0335] To a solution of 7-bromo-2,3,4,5-tetrahydro-2-benzazepin-l-one (270 mg, 1.1 mmol) in DMF (5 mL) at 0 °C was added NaH, 60% dispersion mineral oil, (89 mg, 2.2 mmol). After 30 min at 0 °C, 6-(chloromethyl)-A, A-dimethylpyridine-2-carboxamide;hydrochloride (390 mg 1.6 mmol) was added and then stirred at rt overnight. The reaction was then slowly quenched with water and extracted with EtOAc followed by DCM. The combined organic layer was then dried over Na2SO4, filtered and concentrated. The crude was purified by SiCh FCC (10-30% Hex: EtOAc) to yield the title compound as a yellow solid (295 mg, 66% yield). LCMS calc, for Ci9H2iBrN3O2[M+H]+: m / z = 402.1; Found: 401.9.

[0336] Step 2. 6-(Cyclopropanecarboxamido)-4-((3-(2-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l -oxo-2, 3, 4, 5-tetrahydro- lH-benzo[ c ] azepin- 7 -yl) -2 -methoxyphenyl) amino) -N-methylpyridazine-3-carboxamide- 109 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0337] To a solution of 6-((7-bromo-l-oxo-l,3,4,5-tetrahydro-2J / -benzo[c]azepin-2-yl)methyl)-A, A-dimethylpicolinamide (20 mg, 50 pmol), 6-(cyclopropanecarbonylamino)-4-[2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)anilino]-A-methylpyridazine-3-carboxamide (Int. 2) (28 mg, 60 pmol), Pd(dppf)C12 (3.6 mg, 5.0 pmol) and K2CO3 (14 mg, 99 pmol) in 1,4-di oxane (2 mL) and water (0.4 mL) then stirred at 100 °C. After 2 h, the reaction was cooled to rt, filtered and concentrated. The crude was diluted with water and extracted with DCM (10 mL x 3). The combined organic phase was washed with brine (sat.) (20 mL x 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by TLC, followed by prep-HPLC to yield the title compound (10 mg, 29% yield) as the formate salt. LCMS calc, for C36H39N8O5 [M+H]+: m / z = 663.3; Found: 663.4.Examples 6-7

[0338] Examples 6-7 are shown below in Table 6 and were prepared in accordance with the synthetic protocols set forth in Example 5 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.Table 6. Examples 6-7Analytical Data (LCMS Ex. Name Structureand / or NMR) / -O6-(cyclopropanecarboxamido)- 4-((3-(4-((6-(dimethyl- carbamoyl)pyridin-2- yl)methyl)-5-oxo-2,3,4,5- LCMS calc, for 6 tetrahydro-benzo[ / ] [1,4]- C35H37N8O6 [M+H]+: m / z = oxazepin-8-yl)-2- 665.3; Found 665.2. methoxyphenyl)amino)-A- methylpyridazine-3- Ocarb oxami deNH \7- 110 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data (LCMS Ex. Name Structureand / or NMR) LCMS calc, for C35H36FN8O6 [M+H]+: m / z = 683.3; Found: 683.2. 'H NMR (400 MHz, DMSO- 6-(cyclopropanecarboxamido)- d6) d 11.29 (s, 1H), 10.91 (s, 4-((3-(4-((6-(dimethyl- 1H), 9.10 (q, J= 4.7 Hz, carbamoyl)pyridin-2- 1H), 8.08 (s, 1H), 7.89 (t, J yl)methyl)-6-fluoro-5-oxo- = 7.8 Hz, 1H), 7.43 (td, J= 7 2, 3,4, 5 -tetrahy dro- 8.7, 2.8 Hz, 3H), 7.30 - 7.23 benzof / ] [ 1,4]oxazepin-8-yl)-2- (m, 3H), 7.12 (s, 1H), 4.84 methoxyphenyl)amino)-7V- TJ (s, 2H), 4.26 (t, J = 5.4 Hz, methylpyridazine-3- O 2H), 3.65 (t, J= 5.5 Hz, carb oxami de 2H), 3.35 (s, 3H), 2.95 (s,3H), 2.89 (s, 3H), 2.80 (d, J N N x~7H V = 4.7 Hz, 3H), 2.05 -2.00(m, 1H), 0.82 - 0.75 (m,4H).Example 8. 6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l-methyl-5-oxo-2,3,4,5-tetrahydro-lZ7-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide

[0339] Step 1. 4-Bromo-2-( ( 2-( ( tert-butoxycarbonyl) amino) ethyl) amino)benzoic acidBocHNBr- Ill - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0340] A mixture of 4-bromo-2 -fluorobenzoic acid (2.0 g, 9.13 mmol) and A-boc-ethylenediamine (4.4 g, 27.0 mmol) in NMP (8 mL) stirred at 120 °C for 16 h. The reaction was then cooled to rt, poured into IM HC1 solution (20 mL), and extracted with EtOAc (40 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.3 g, quant, yield). LCMS calc, for CgHnBr^CL [M-Boc+H]+: m / z = 259.0; Found: 259.3.

[0341] Step 2. 2-((2-Aminoethyl)amino)-4-bromobenzoic acidHN

[0342] To a solution of 4-bromo-2-((2-(( / c / 7-butoxycarbonyl)amino)ethyl)amino)benzoic acid (3.3 g, 9.1 mmol) in EtOAc (25 mL) was added 4 M HC1 in dioxane (50 mL) dropwise at 0 °C. After 2 h at rt, the reaction was condensed to yield the title compound (3.7 g, quant, yield).LCMS calc, for C9Hi2BrN2O2 [M+H]+: m / z = 259.0; Found: 259.3.

[0343] Step 3. 8 -bromo- 1, 2, 3, 4-tetrahydro-5H-benzo[e] [ 1, 4 ]diazepin-5-one

[0344] To a solution of 2-((2-aminoethyl)amino)-4-bromobenzoic acid (500 mg, 1.9 mmol) andHATU (1.1 g, 2.9 mmol) in DCM (5 mL) was added DIPEA (1 mL, 5.8 mmol). After 2 h at rt, the reaction was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC (2% MeOH / DCM) to yield the title compound as a white solid (300 mg, 65% yield). LCMS calc, for C9HioBrN20 [M+H]+: m / z = 240.9; Found: 240.8.

[0345] Step 4. 8-Bromo-l -methyl- 1, 2, 3, 4-tetrahydro-5H-benzo[ e][ 1,4 ]diazepin-5-oneN- 112 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0346] To a mixture of 8-bromo-l,2,3,4-tetrahydro-5J / -benzo[e][l,4]diazepin-5-one (75 mg, 0.31 mmol), formaldehyde (47 mg, 0.62 mmol), AcOH (0.1 mL, 0.31 mmol) andNaBHsCN (39 mg, 0.62 mmol) was added MeOH (1 mL). The reaction was stirred for 1 h, then concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (5-75% EtOAc / hexane) to yield the title compound (30 mg, 38% yield). LCMS calc, for CioHi2BrN20 [M+H]+: m / z = 255.0; Found: 255.2.

[0347] Step 5. 6-( (8-Bromo-l-methyl-5-oxo-l, 2, 3, 5-tetrahydro-4H-benzo[ e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0348] The title compound was synthesized by a procedure analogous to that outlined in Example 5 Step 1 with appropriate starting materials. LCMS calc, for CigEfeBrlSECh [M+H]+: m / z = 417.1; Found: 416.9.

[0349] Step 6. 6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l-methyl-5-oxo-2, 3, 4, 5-tetrahydro- IH-benzo [e] [ 1, 4 ]diazepin-8-yl)-2-methoxyphenyl) amino)-N-methylpyridazine-3-carboxamide

[0350] The title compound, as the formate salt, was synthesized by a procedure analogous to that outlined in Example 5 Step 2 with appropriate starting materials. LCMS calc, for C36H40N9O5 [M+H]+: m / z = 678.3; Found: 678.5. 'H NMR (400 MHz, DMSO-tL) 6 11.30 (s, 1H), 10.96 (s, 1H), 9.13 (d, J= 4.9 Hz, 1H), 8.16 (s, 1H), 7.91 (d, J= 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 - 7.44 (m, 1H), 7.44 (s, 1H), 7.42 (d, J= 2.0 Hz, 1H), 7.27 (d, J= 7.7 Hz, 1H), 7.25 - 7.21 (m, 2H), 7.13 - 7.11 (m, 1H), 4.84 (s, 2H), 3.57 - 3.54 (m, 2H), 3.38 (s, 3H), 3.26 -3.23 (m, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.83 (d, J= 4.8 Hz, 3H), 2.80 (s, 3H), 2.07 (d, J= 5.3 Hz, 1H), 0.83 - 0.79 (m, 4H).Examples 9-10

[0351] Examples 9-10 are shown below in Table 7 and were prepared in accordance with the synthetic protocols set forth in Example 8 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.Table 7. Examples 9-10- 113 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data (LCMS Ex. Name Structureand / or NMR) LCMS calc, for C37H42N9O5 [M+H]+: m / z = 692.3; Found 692.3. 'H NMR (400 MHz, DMSO-tC) 6 11.29 (s, 1H), 10.95 (s, 1H), 9.12 (d, J 6-(cyclopropanecarbox- = 4.9 Hz, 1H), 8.13 (s, 1H), amido)-4-((3 -(4-((6- \ / — N 7.88 (t, J = 7.8 Hz, 1H), 7.52 (dimethyl-carbamoyl)pyridin- (d, J = 7.8 Hz, 1H), 7.46 - 2-yl)methyl)-l-ethyl-5-oxo- 7.40 (m, 3H), 7.25 (t, J= 7.8 9 2, 3,4, 5 -tetrahydro- \H- Hz, 1H), 7.20 (dd, J= 7.7, benzofe] [ 1,4]diazepin-8-yl)- 1.7 Hz, 1H), 7.15 - 7.09 (m, 2-methoxyphenyl)amino)-7V- Tj 2H), 4.82 (s, 2H), 3.53 (t, J methylpyridazine-3- ^ IZ = 5.5 Hz, 2H), 3.35 (s, 3H),\o / =carb oxami de 3.25 - 3.11 (m, 4H), 2.97 (s,3H), 2.91 (s, 3H), 2.82 (d, J A \ z O z y z—x e,NH v = 4.7 Hz, 3H), 2.05 (h, J== / \ # \\ 5.8 Hz, 1H), 1.09 (t, J = 7.0Hz, 3H), 0.84 - 0.75 (m,4H).>°°u 'o LCMS calc, for C38H44N9O5 [M+H]+: m / z = 706.3; Found 705.9. 'H NMR (400 MHz, DMSO-tC) 6 11.27 (s, 1H), 10.92 (s, 1H), 9.11 (q, J = 4.8 Hz, 1H), 8.14 (s, 1H), 6-(cyclopropanecarbox- 7.86 (t, J = 7.8 Hz, 1H), 7.50 amido)-4-((3 -(4-((6- (d, J = 7.9 Hz, 1H), 7.42 (dimethyl-carbamoyl)pyridin- (dd, J= 7.7, 3.0 Hz, 3H), 2-yl)methyl)- 1 -i sopropyl-5 - 7.26 - 7.15 (m, 3H), 7.06 10 oxo-2, 3,4, 5 -tetrahydro- 1H- (dd, J = 8.0, 1.4 Hz, 1H), benzofe] [ 1,4]diazepin-8-yl)- 4.80 (s, 2H), 3.79 (p, J= 6.5 2-methoxyphenyl)amino)-7V- Hz, 1H), 3.55 (t, J= 5.6 Hz, methylpyridazine-3- 2H), 3.35 (s, 3H), 3.22 (t, J carb oxami de= 5.5 Hz, 2H), 2.96 (s, 3H), 2.90 (s, 3H), 2.81 (d, J= 4.8 Hz, 3H), 2.08 - 2.01 (m, 1H), 1.14 (d, J = 6.4 Hz, 6H), 0.78 (h, J = 3.1 Hz,4H).Example 11. 6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide- 114 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0352] Step 1. 7-Bromo-l-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dioneBr

[0353] To a solution of 7-bromo-U / -3,l-benzoxazine-2, 4-dione (1.0 g, 4.1 mmol) in DMF (10 mL) cooled to 0 °C by ice-bath under nitrogen was added NaH, 60% dispersion mineral oil, (180 mg, 4.5 mmol) in batches. After the addition, the mixture was stirred at 0 °C for 30 mins. Mel (1.2 g, 8.3 mol) was added dropwise and left to stir at rt for 1 h. The reaction was slowly quenched with NH4CI (aq) (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (1.1 g, quant, yield) as a yellow solid. LCMS calc, for C9H7BrNO3[M+H]+: m / z = 255.9 / 257.9; Found 255.5 / 257.8.

[0354] Step 2. 8-Bromo-l-methyl-3, 4-dihydro-lH-benzo[ e] [1,4 ]diazepine-2, 5-dioneBr

[0355] To a mixture of 7-bromo-l-methyl-2J / -benzo[t ][l,3]oxazine-2,4(177)-dione (1.8 g, 7.1 mmol) and glycine (0.58 g, 7.7 mmol) in DMF (10 mL) was added Et3N (2.1 g, 21 mmol). The mixture was stirred at 60 °C for 1 h. The reaction was complete and purified by prep-HPLC on a C18 column (20-70% MeCN in 0.1% TFA(aq), pH = 2) to yield the title compound (140 mg, 53% yield). LCMS calc, for CioHioBrN202 [M+H]+: m / z = 268.9 / 270.9; Found: 268.9.- 115 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0356] Step 3. 6-((8-Bromo-l-methyl-2,5-dioxo-l,2,3,5-tetrahydro-4H- benzo[ e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0357] The title compound was synthesized by a procedure analogous to that outlined in Example 5 Step 1 with appropriate starting materials. LCMS calc, for CigEEoBrlS Ch [M+H]+: m / z = 431.1 / 433.1; Found: 431.1 / 433.1.

[0358] Step 4. 6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l-methyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH-benzo[e] [ 1, 4 ]diazepin-8-yl)-2-methoxy-phenyl)amino)-N-methylpyridazine-3-carboxamide

[0359] The title compound, as the TFA salt, was synthesized by a procedure analogous to that outlined in Example 5 Step 2 with appropriate starting materials. LCMS calc, for C36H38N9O6 [M+H]+: m / z = 692.3; Found: 692.5. *HNMR (400 MHz, DMSO-tL) 8 11.34 (s, 1H), 11.00 (s, 1H), 9.17 (q, J= 4.7 Hz, 1H), 8.18 (s, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.83 (d, J= 8.1 Hz, 1H), 7.61 (d, J= 1.6 Hz, 1H), 7.52 (ddd, J= 9.2, 7.4, 2.3 Hz, 2H), 7.45 (d, J= 7.6 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 4.92 (s, 2H), 4.28 (d, J= 15.2 Hz, 1H), 3.85 (d, J= 15.3 Hz, 1H), 3.41 (s, 3H), 3.33 (s, 3H), 2.98 (s, 3H), 2.92 - 2.82 (m, 6H), 2.09 (dd, J= 8.9, 4.0 Hz, 1H), 0.83 (t, J= 5.5 Hz, 4H).Example 12

[0360] Example 12 is shown below in Table 8 and was prepared in accordance with the synthetic protocols set forth in Example 11 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.Table 8. Example 12Analytical Data Ex. Name Structure(LCMS and / or NMR)- 116 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-(cyclopropanecarboxamido)- 4-((3-(4-((6-(dimethyl- carbamoyl)pyridin-2- LCMS calc, for yl)methyl)-l-ethyl-2,5-dioxo- C37H40N9O6 [M+H]+:12 2,3,4,5-tetrahydro-17 / -benzo[e]m / z = 706.3; Found [ 1,4]diazepin-8-yl)-2- 706.5. methoxyphenyl)amino)-7V- methylpyridazine-3- carb oxami deExample 13. 6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l-isopropyl-2,5-dioxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide

[0361] Step 1. Methyl ((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)glycinate

[0362] To a mixture of glycine methyl ester; hydrochloride (540 mg, 6.1 mmol) and 6- (chloromethyl)-7V,7V-dimethylpyridine-2-carboxamide (1.0 g, 5.1 mmol) was added K2CO3 (1.1 g, 7.6 mmol) and KI (84 mg, 0.51 mmol) in MeCN (10 mL). The reaction mixture was stirred at 80 °C. After 4 h, the reaction was purified by silica gel column chromatography (50-100% ethyl acetate / hexanes) to yield the title compound (730 mg, 58% yield). LCMS calc, for Ci2Hi8N3O3 [M+H]+: m / z = 252.1; Found: 252.0.- 117 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0363] Step 2. Methyl N-(4-bromo-2-nitrobenzoyl)-N-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl) glycinate

[0364] Methyl ((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)glycinate (270 mg, 1.1 mmol), 4-bromo-2-nitrobenzoic acid (260 mg, 1.1 mmol), HATU (610 mg, 1.6 mmol) and DIPEA (700 mg, 5.4 mmol) were dissolved in DMA (3 mL). The reaction mixture was stirred at rt for 1 h. LCMS showed the reaction was complete. Then the mixture was poured into water and extracted with EtOAc (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (hexane: ethyl acetate = 0:1) to yield the title compound (107 mg, 21% yield). LCMS calc, for CigEEoBrlSUOe [M+H]+: m / z = 479.4 / 481.1; Found 479.1 / 480.9.

[0365] Step 3. 6-( (8-Bromo-2, 5-dioxo-l, 2, 3, 5-tetrahydro-4H-benzo [ e][ 1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0366] Methyl A-(4-bromo-2-nitrobenzoyl)-A-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl) glycinate (90 mg, 0.19 mmol), Fe (52 mg, 0.94 mmol) and NH4CI (100 mg, 1.9 mmol) were dissolved in ethanol (1 mL) and water (0.25 mL). The mixture was stirred at 80 °C for 1 h. Then the mixture was poured into water and extracted with EtOAc (5 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (hexane: ethyl acetate = 0: 1) to yield the title compound (47 mg, 60% yield). LCMS calc, for CisHisBr^Os [M+H]+: m / z = 417.1 / 419.1; Found 417.0 / 419.0.

[0367] Step 4. 6-((8-Bromo- l-isopropyl-2, 5-dioxo-l, 2, 3, 5-tetrahydro-4H-benzo[ e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide- 118 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0368] 6-((8-Bromo-2,5-dioxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide (130 mg, 0.31 mmol), CS2CO3 (310 mg, 0.94 mmol) and 2-iodopropane (160 mg, 0.94 mmol) were dissolved in DMF (1 mL). The reaction mixture was stirred at rt for 16 hrs. Then the mixture was poured into water and extracted with EtOAc (5 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (hexane: ethyl acetate = 0: 1) to yield the title compound (60 mg, 42% yield). LCMS calc, for C2iH24BrN4C>3 [M+H]+: m / z = 459.1 / 461.1; Found 459.0 / 461.0.

[0369] Step 5. 6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-l-isopropyl-2, 5-dioxo-2, 3, 4, 5-tetrahydro-lH-benzo[ e][ 1,4 ]diazepin-8-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide

[0370] The title compound, as the TFA salt, was synthesized by a procedure analogous to that outlined in Example 5 Step 2 with appropriate starting materials. LCMS calc, for C38H42N9O6 [M+H]+: m / z = 720.3; Found: 720.3. 'H NMR (400 MHz, DMSO-tL) 6 11.35 (s, 1H), 10.98 (s, 1H), 9.17 (d, J= 4.6 Hz, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.56 (s, 2H), 7.52 (dd, J = 7.4, 1.6 Hz, 1H), 7.45 (d, J= 7.6 Hz, 1H), 7.31 (s, 3H), 4.91 (s, 2H), 4.16 (s, 2H), 3.71 (d, J = 15.0 Hz, 1H), 3.41 (s, 3H), 2.98 (s, 3H), 2.93 (s, 3H), 2.86 (d, J= 4.6 Hz, 3H), 1.41 (d, J= 6.6 Hz, 3H), 1.25 (d, J= 6.8 Hz, 3H), 1.23 (s, 1H), 0.82 (t, J= 5.8 Hz, 4H).Example 14. 6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l.2.3.5-tetrahydro-4 / / -benzo|c|| 1,4]diazepin-4-yl)methyl)- \.\-diinethylpicolinainide- 119 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0371] Step 1. 6-( ( 1 -Ethyl-2-oxo-8-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l, 2, 3, 5-tetrahydro-4H-benzo[ e][l,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolmamide„BXO O

[0372] To a microwave tube was added 6-((8-bromo-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4Z7-benzo[e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide (170 mg, 0.4 mmol) and a magnetic stir bar. The starting material was dissolved in 1,4-dioxane (3 mL) and to this was added bis-(pinacolato)diboron (200 mg, 0.79 mmol) and potassium acetate (120 mg, 1.2 mmol), respectively. The reaction was bubbled with N2 and to this was added dichloro 1,1'-bisdiphenylphosphino)-ferrocene palladium (II) dichloromethane (32 mg, 0.1 mmol). The vessel was degassed and filled with N2 (3x). The reaction was heated to 95 °C and allowed to stir overnight. The crude material was filtered through a celite pad and concentrated. The sample was pushed forward without purification (188 mg, quant, yield). LCMS calc, for C26H36BN4O4 [M+H]+: m / z = 479.3; Found: 479.5.

[0373] Step 2. 6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l, 2, 3, 5-tetrahydro-4H-benzo[e] [ 1, 4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0374] To a solution of 7V-(5-acetyl-4-((3-bromo-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide (Int. 3) (61 mg, 0.15 mmol) in dioxane (2 mL) and water (100 pL) was added 6-((l-ethyl-2-oxo-8-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-l, 2, 3, 5-tetrahydro- - 120 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application47 / -benzo[c][l,4]diazepin-4-yl)methyl)-Af, Af-dimethylpicolinamide (60 mg, 0.13 mmol), cesium acetate (72 mg, 0.38 mmol), Xphos Pd G2 (10 mg, 0.01 mmol). The solution was purged with N2 for 1 minute. The reaction was stirred at 90 °C for 16 h. Then the reaction mixture was quenched with water, and the water phase was washed with DCM (10 mL x 3). The combined organic phase was dried over Na2SO4, filtered and concentrated with reduced pressure. The residue was purified by prep-HPLC on a C18 column (5-50% MeCN in 0.1% TFA (aq), pH = 2) to afford the title compound (3.0 mg, 3.5% yield) as a white TFA salt. LCMS calc, for C38H42N7O5 [M+H]+: m / z = 676.3; Found: 676.8. *HNMR (300 MHz, MeOD) 6 8.81 (s, 1H), 8.10 (t, J= 7.8 Hz, 1H), 7.84 (s, 1H), 7.75 - 7.66 (m, 4H), 7.57 (ddd, J= 12.6, 7.8, 1.8 Hz, 2H), 7.45 (t, J= 7.8 Hz, 1H), 6.90 (s, 1H), 4.71 (s, 2H), 4.50 (s, 2H), 4.14 (d, J= 7.5 Hz, 2H), 3.82 (s, 2H), 3.51 (s, 3H), 3.18 (s, 3H), 3.09 (s, 3H), 2.74 (s, 3H), 1.85 (tt, J= 7.7, 4.5 Hz, 1H), 1.30 (t, J= 7.1 Hz, 3H), 1.10 (ddt, J= 17.1, 7.8, 3.1 Hz, 4H). / Oy z 'i0Examples 15-35 \ / = / # \\zG iz 7 \ \ — —\ J ) / O==.

[0375] Examples 15-35 are shown below in Table 9 and were prepared in accordance with the et forth in Example 14 using the approT X) >synthetic protocols s pr <iate intermediates, as well as commercial starting materials. The following compounds are TFA 0 salts unless otherwise noted.Table 9. Examples 15-35Analytical Data Ex. Name Structure(LCMS and / or NMR)3-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py ridin-4-yl)amino)-2- LCMS calc, for methoxyphenyl)- 1 -ethyl -2- C39H42FN6O5 [M+H]+: 15oxo- 1,2, 3, 5 -tetrahy dro-47 / - m / z = 693.3; Found: benzofe] [ 1,4]diazepin-4- 693.4. yl)methyl)-2-fluoro-A, A- dimethylbenzamide- 121 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR) LCMS calc, for C38H41FN7O5 [M+H]+: m / z = 694.3; Found: 694.7.XH NMR (300 MHz, MeOD) 88.80 (s, 1H), 8.06 (t, J= 7.8 Hz, 6-((8-(3-((5-acetyl-2- 1H), 7.83 (s, 1H), 7.75 - (cy cl opropanecarb oxami do)py r o7.54 (m, 5H), 7.52 - idin-4-yl)amino)-2- 7.38 (m, 2H), 7.08 (s, methoxyphenyl)- 1 -(2- 1H), 4.79 (d, J = 4.7 Hz, 16 fluoroethyl)-2-oxo- 1,2, 3, 5 - Q ' / \\ Vo==' 1H), 4.64 (t, J= 4.7 Hz, tetrahydro-4 / 7- V 7 (\ / > / V ZX - - _ V / / Z \ / - / 1H), 4.43 (s, 2H), 4.39 benzofe] [ 1,4]diazepin-4- (s, 1H), 4.30 (s, 1H), yl)methyl)-7V,7V- A \Z O-z~Vo 4.25 (s, 2H), 3.62 (s, dimethylpicolinamide2H), 3.49 (s, 3H), 3.18 VXo z(s, 3H), 3.08 (s, 3H), / / / / \C c iz p — 2.73 (s, 3H), 1.83 (td, J / k \ \O== = 7.8, 4.0 Hz, 1H), 1.07(ddd, J= 17.3, 6.8, 3.1 r o * < Hz, 4H).o6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py r LCMS calc, for idin-4-yl)amino)-2- C38H40F2N7O5 [M+H]+: methoxyphenyl)-l-(2,2- m / z = 712.3; Found:17 difluoroethyl)-2-oxo- 1,2, 3, 5 - 712.7.tetrahydro-4 / 7- benzofe] [ 1,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 122 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR) 6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py ridin-4-yl)amino)-2- LCMS calc, for methoxyphenyl)-2-oxo- 1 - C38H39F3N7O5 [M+H]+:18 (2,2,2-trifluoroethyl)-l,2,3,5- o O m / z = 730.3; Found:tetrahydro-47 / - 730.8.rx.benzofe] [ 1,4]diazepin-4- yl)methyl)-7V,7V- (( y O Z A Q== / X—r.= G— J? o ' '"dimethylpicolinamide 7 L X C / ) / ZT - - _ / Z _v / / \ V V \ 7 C / ) / ZI - - _ _ / z A / \ _ / / / ^ \z o Z G z—p r \ I\QO<L=° LCMS calc, for C38H39N8O5 [M+H]+: m / z = 687.3; Found: / r-Cj 687.7.XH NMR (300 6-((8-(3-((5-acetyl-2- -< N-A0MHz, MeOD) 88.77 (s, (cy cl opropanecarb oxami do)py r0< 1.--4; 1H), 8.04 (t, J= 7.8 Hz, idin-4-yl)amino)-2- NC^N'Y^x1H), 7.82 (d, J= 1.5 Hz, methoxyphenyl)- 1 - 1H), 7.76 - 7.50 (m, 19 (cy anomethyl)-2-oxo- 1,2, 3, 5 - 6H), 7.42 (t, J= 7.8 Hz, tetrahydro-47 / - 1H), 6.83 (s, 1H), 5.02 benzofe] [ 1,4]diazepin-4- (s, 2H), 4.42 (s, 2H),O HN'Z'^yl)methyl)-7V,7V-Z4.26 (s, 2H), 3.67 (s, dimethylpicolinamide •AA02H), 3.49 (s, 3H), 3.15(s, 3H), 3.05 (s, 3H), 2.71 (s, 3H), 1.80 (td, J = 1.1, 3.9 Hz, 1H), 1.19 - 0.94 (m, 4H).6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py r LCMS calc, for idin-4-yl)amino)-2- C39H42N7O6 [M+H]+: methoxyphenyl)- 1 -(oxetan-3 - 20 m / z = 704.3; Found:yl)-2-oxo- 1,2, 3, 5 -tetrahy dro- 704.7.47Lbenzo[c] [ 1,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 123 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR)6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py ridin-4-yl)amino)-2- LCMS calc, for methoxyphenyl)-2-oxo- 1 - C40H44N7O6 [M+H]+:21 (tetrahy drofuran-3 -yl)- 1,2, 3, 5 - O m / z = 718.3; Found:tetrahydro-47 / - 718.7. benzofe] [ 1,4]diazepin-4- yl)methyl)-A, A- ( O Z=— G? 'dimethylpicolinamide 7 V \ C / ) / ZI - - _ _ / Z / \ _ / / A< Q ° ° LCMS calc, for C38H41FN7O5 [M+H]+: m / z = 694.3; Found: 694.7.XH NMR (400 MHz, DMSO-tL) 6 11.12 (s, 1H), 11.02 (s, z-O 1H), 8.83 (s, 1H), 8.01 z-NNV6-((8-(3-((5-Acetyl-2-((15,2A)-0(s, 1H), 7.91 (s, 1H), 2-fluorocyclopropane-l- °< 1 hl 7.68 (s, 1H), 7.63 (d, J = carb oxami do)py ri din-4- 7.8 Hz, 1H), 7.55 (d, J = yl)amino)-2-methoxyphenyl)- 7.1 Hz, 3 H), 7.48 - 7.46 22 l-ethyl-2-oxo-l, 2,3,5- (m, 1H), 7.29 - 7.26 (m, tetrahydro-47 / - 2H), 4.83 (dt, J = 64.7, benzofe] [ 1,4]diazepin-4- Tj 4.6 Hz, 1H), 4.45 (s,Oyl)methyl)-A, A- 2H), 4.22 (s, 2H), 3.96 dimethylpicolinamide (d, J = 7.2 Hz, 2H), 3.781 „F(s, 1H), 3.34 (s, 3H), N N H V 2.99 (s, 3H), 2.91 (s,3H), 2.62 (s, 3H), 2.54 (d, J = 7.6 Hz, 1H), 1.52 - 1.47 (m, 1H), 1.18 (d, J = 6.6 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H).- 124 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR) / —(5)-6-((8-(3-((5-acetyl-2- / -N; N-A0(spiro[2.2]pentane-l- °< 1 -Z LCMS calc, for carb oxami do)py ri din-4- C40H43N7O5 [M+H]+: yl)amino)-2-methoxyphenyl)- m / z = 702.3; Found 23 l-ethyl-2-oxo-l, 2,3,5- O 702.7.tetrahydro-47 / - benzofe] [ 1,4]diazepin-4- T jOyl)methyl)-7V,7V- c AAdimethylpicolinamide ■AA ) / ) l G zi ' —\1 _ _ / / Z / \ / _ AN0A. ArN S\ ° H VA ° ° LCMS calc, for C40H43N7O5 [M+H]+: m / z = 702.3; Found 702.7.XH NMR (400 MHz, DMSO-tL) 6 11.04 (s, 1H), 10.85 (s, 1H), 8.79 (s, 1H), 8.00 (7?)-6-((8-(3-((5-acetyl-2- (s, 1H), 7.88 (s, 1H), (spiro[2.2]pentane-l- 7.68 (s, 1H), 7.62 (d, J = carb oxami do)py ri din-4- 7.8 Hz, 1H), 7.53 (d, J= yl)amino)-2-methoxyphenyl)- 5.4 Hz, 3 H), 7.49 (d, J= 24 l-ethyl-2-oxo-l, 2,3,5- 7.5 Hz, 1H), 7.32 - 7.28 tetrahydro-47 / - (m, 2H), 4.41 (s, 1H), benzofe] [ 1,4]diazepin-4- 4.19 (s, 2H), 3.96 (d, J= yl)methyl)-7V,7V- 7.3 Hz, 2H), 3.69 (s, dimethylpicolinamide 2H), 3.34 (s, 4H), 2.99(s, 3H), 2.90 (s, 3H), 2.61 (s, 3H), 2.32 -2.29 (m, 1H), 1.33 (d, J= 3.8 Hz, 2H), 1.10 (t, 7.1 Hz, 3H), 0.83 (d, J= 8.5 Hz, 2H), 0.69 (d, J = 3.8 Hz, 1H).- 125 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR) LCMS calc, for C38H41FN7O5 [M+H]+: m / z = 694.3; Found: 694.7.XH NMR (400 MHz, DMSO-tL) 6 11.15 (s, 1H), 11.03 (s, 1H), 8.83 (s, 1H), 8.01 o o(t, J = 7.8 Hz, 1H), 7.88 6-((8-(3-((5-acetyl-2-((U?,2S)- (s, 1H), 7.69 (s, 1H), 2-fluorocyclopropane-l- ' o• ' 7.63 (d, J= 7.8 Hz, 1H), carb oxami do)py ri din-4- 7.56 (d, J = 6.8 Hz, 3H),y> <\ / >y> <\ / > / / I ZI I zx - - - -x- -x / \ \ \ / \ \ ° °==yl)amino)-2-methoxyphenyl)- _ _ _ _ / / / / Z \ Z \ _ / _ / V / V / 7.49 - 7.46 (m, 1H), 25 l-ethyl-2-oxo-l, 2,3,5- 7.28 (d, J = 4.4 Hz, 2H), tetrahydro-47 / - )) V V\\ ° ° 4.83 (dt, J = 64.8, 4.5 benzofe] [ 1,4]diazepin-4- Hz, 1H), 4.50 (s, 2H),AA ° ° ° °yl)methyl)-7V,7V- 4.27 (s, 2H), 3.96 (d, J= dimethylpicolinamide 7.3 Hz, 2H), 3.79 - 3.75(m, 2H), 3.34 (s, 3H), 2.99 (s, 3H), 2.91 (s, 3H), 2.61 (d, J= 12.2 Hz, 3H), 2.55 - 2.50 (m, 1H), 1.53 - 1.48 (m, 1H), 1.21 - 1.16 (m, 1H), 1.10 (t, J= 7.1 Hz,3H).6-((8-(3-((5-acetyl-2-((17?,27?)- 2-fluorocyclopropane-l- carb oxami do)py ri din-4- LCMS calc, for yl)amino)-2-methoxyphenyl)- C38H41FN7O5 [M+H]+:26 l-ethyl-2-oxo-l, 2,3,5- m / z = 694.3; Found:tetrahydro-47 / - 694.7. benzofe] [ 1,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 126 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR) LCMS calc, for C38H41FN7O5 [M+H]+: m / z = 694.3; Found: 694.7.XH NMR (400 MHz, DMSO-t / e) 6 11.04 (d, J= 11.7 Hz, 2H), 8.81 (s, 1H), 8.00 6-((8-(3-((5-acetyl-2-((15,2S)- o(t, J = 7.8 Hz, 1H), 7.89 2-fluorocyclopropane-l- (s, 1H), 7.69 (s, 1H), carb oxami do)py ri din-4- 7.62 (d, J= 7.8 Hz, 1H), yl)amino)-2-methoxyphenyl)- 7.58 - 7.46 (m, 4H), 27 l-ethyl-2-oxo-l, 2,3,5- _ _ ( / / / v z \ _ 7.30 (d, J= 7.4 Hz, 2H), tetrahydro-4 / 7- 4.89 (dq, J = 66.2, 5.3 benzofe] [ 1,4]diazepin-4- ~l o) V\ ° Hz, 1H), 4.46 (s, 2H), yl)methyl)-7V,7V- 4.23 (s, 2H), 3.96 (d, J= dimethylpicolinamide A^ ° °x- 2o7.3 Hz, 2H), 3.78 (s, / = / / / V\,cyiz y) \ — — / v, 1H), 3.34 (s, 5H), 2.99 \o= (s, 3H), 2.90 (s, 3H),2.62 (s, 3H), 2.17 (p, J = T <6.9 Hz, 1H), 1.63 - 1.49 (m, 1H), 1.21 - 1.05 (m,5H).6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py ridin-4-yl)amino)-2- LC-MS calc, for methoxyphenyl)-l-cyclobutyl- C40H44N7O5 [M+H]+:282-oxo- 1,2, 3, 5 -tetrahy dro-4 / 7- m / z = 702.3; Found: benzofe] [ 1,4]diazepin-4- 702.5 yl)methyl)-7V,7V- dimethylpicolinamide- 127 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR)6-((8-(3-((5-acetyl-2- / -N<^TNX(cy cl opropanecarb oxami do)py ridin-4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 -( 1 -0C39H43FN7O5 [M+H]+:29 fluoropropan-2-yl)-2-oxo- m / z = 708.3; Found: 1,2, 3, 5 -tetrahy dro-47 / - _ Zo^T j 708.7 benzofe] [ 1,4]diazepin-4- yl)methyl)-7V,7V- O ( / \ O==dimethylpicolinamide _ _ / Z \ V / / _, / SrL\ “ ° 8%z- ^ LC-MS calc, for C40H41N8O5S [M+H]+: m / z = 745.3; Found: 745.6.XH NMR (400 MHz, DMSO-t / r,) 6 11.07 (d, J= 7.5 Hz, 6-((8-(3-((5-acetyl-2- 2H), 8.97 (s, 1H), 8.86 (cy cl opropanecarb oxami do)py r (s, 1H), 7.98 (d, J= 10.0 idin-4-yl)amino)-2- Hz, 2H), 7.81 (d, J= methoxyphenyl)-2-oxo- 1 - 14.3 Hz, 2H), 7.62 30 (thiazol-5-ylmethyl)-l, 2,3,5- (d, J = 7.8 Hz, 1H), 7.52 tetrahydro-47 / - (dd, J= 13.4, 8.8 Hz, benzofe] [ 1,4]diazepin-4- 4H), 7.31 (dd, J= 13.2, yl)methyl)-7V,7V- 7.7 Hz, 2H), 5.42 (s, dimethylpicolinamide 2H), 4.26 (s, 2H), 3.88(s, 2H), 3.47 (s, 2H), 3.34 (s, 3H), 3.02 (s, 3H), 2.94 (s, 3H), 2.66 (s, 3H), 2.01 (d, J= 7.9 Hz, 1H), 0.82 (t, J= 6.6 Hz, 4H).- 128 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR)6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py ridin-4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 - C40H44N7O5 [M+H]+:31 (cyclopropylmethyl)-2-oxo- m / z = 702.3; Found: 1,2, 3, 5 -tetrahy dro-47 / - 702.5 benzofe] [ 1,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamideY o o ojyff 'ii o zno z\ / =\ / = / / / A / V / / ,C iz y / G iz) \ — A \ — \ 7 / — - \ \oo==6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)py r 1 <i <idin-4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 - Z^ ^C41H46N7O5 [M+H] 3+:2 cyclopentyl-2-oxo-l, 2,3,5- m / z = 716.4; Found: tetrahydro-47 / - 716.7 benzofe] [ 1,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamideLC-MS calc, for C40H43FN7O6 [M+H]+: m / z = 736.3; Found:736.6.Z-N " AJ6-((8-(3-((5-acetyl-2-((U?,2S)-XH NMR (400 MHz, 2-fluorocyclopropane-l- °=< ) or xDMSOWo) 6 11.13 (s, carb oxami do)py ri din-4- 1H), 11.04 (s, 1H), 8.84 yl)amino)-2-methoxyphenyl)- (s, 1H), 8.03 - 7.91 (m, 33 2-oxo- 1 -((A') -tetrahy drofuran-3 - 2H), 7.62 (d, J = 7.8 Hz, yl)- 1,2, 3, 5 -tetrahy dro-47 / - 1H), 7.54 (dt, J = 7.8, benzofe] [ 1,4]diazepin-4- O 2.1 Hz, 4H), 7.48 yl)methyl)-7V,7V- (dd, J= 7.8, 1.7 Hz, dimethylpicolinamide1H), 7.32 - 7.21 (m, 'W zE F 2H), 4.93 -4.87 (m,NH " V' 1H), 4.36 (s, 4H), 4.19(s, 2H), 3.93 (s, 2H),3.64 (d, J= 8.2 Hz, 1H),- 129 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationAnalytical Data Ex. Name Structure(LCMS and / or NMR) 3.42 (s, 2H), 3.33 (s, 3H), 2.99 (s, 3H), 2.91 (s, 3H), 2.63 (s, 3H), 2.57 - 2.50 (m, 1H), 2.36 - 1.68 (m, 2H), 1.50 (dddd, J = 20.5, 10.0, 6.4, 3.4 Hz, 1H), 1.19 (dq, J= 12.9, 6.4 Hz, 1H).6-((8-(3-((5-acetyl-2-((U?,2S)- z-N " ANZ2-fluorocyclopropane-l- ) or xcarb oxami do)py ri din-4- yl)amino)-5 -fluoro-2- LC-MS calc, for methoxyphenyl)-2-oxo- 1 -((5)- C40H42F2N7O6 [M+H]+:34tetrahy drofuran-3 -yl)- 1,2, 3, 5 - m / z = 754.3; Found:tetrahydro-47 / - 754.2. benzofe] [ 1,4]diazepin-4- Oyl)methyl)-7V,7V- dimethylpicolinamide'W zE FNH LC-MS calc, for C38H39F3N7O5 [M+H]+: m / z = 730.3; Found: 730.2.XH NMR (400 6-((8-(3-((5-acetyl-2-((15,27?)- r^Jl! MHz, CDCI3) 6 13.13 (s,Z-N N-A / 1H), 11.66 (s, 1H), 8.69 2-fluorocyclopropane-l- °=< )x(s, 1H), 8.20 (s, 1H), carb oxami do)py ri din-4- 7.93 (t, J= 7.8 Hz, 1H), yl)amino)-5 -fluoro-2-fv 7.69 - 7.52 (m, 5H), methoxyphenyl)- 1 -(2- 35 7.13 (ddd, J= 53.3, 8.4, fluoroethyl)-2-oxo- 1,2, 3, 5 - 3.0 Hz, 2H), 4.92 -4.01 tetrahydro-47 / - X I (m, 9H), 3.94 (s, 2H), benzofe] [ 1,4]diazepin-4- O3.35 (s, 3H), 3.15 (s, yl)methyl)-7V,7V- 3H), 3.04 (s, 3H), 2.69 dimethylpicolinamide... F (s, 3H), 2.51 (ddt, J= N N A— 7H V 16.7, 10.1, 6.1 Hz, 1H),1.63 (dtd, J= 17.5, 6.9, 3.3 Hz, 1H), 1.40 (dq, J = 12.9, 6.5 Hz, 1H).- 130 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationExample 36. 6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5- fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2- e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide

[0376] Step 1. 6-((8-Bromo-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2- e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0377] To a stirring solution of 6-((8-bromo-2-oxo-l,2,3,5-tetrahydro-4 / / -pyrido[3,2- e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide (Int.28) (170 mg, 0.42 mmol) in DMF (2 mL) was added cesium carbonate (411 mg, 1.26 mmol) and l,l-difluoro-2 -iodoethane (111 pL, 1.26 mmol) sequentially. The reaction mixture was stirred for 5 hours. The product mixture was diluted with sat. brine (aq) (30 mL) and extracted with a 3:1 CHCl3 / iPrOH mixture (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0- 10% MeOH / DCM) to yield the title compound (183 mg, 93% yield). LC-MS calc, for C19H21BrF2N5O2[M+H]+: m / z = 468.1 / 470.1; Found: 468.1 / 470.1.

[0378] Step 2. 6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2, 2-difluoroethyl)-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2- e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0379] A 20 mL scintillation vial was charged with bis(pinacolato)diboron (73 mg, 0.29 mmol), potassium pivalate (81 mg, 0.58 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloro- - 131 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationpalladium(II) complex with di chloromethane (16 mg, 0.019 mmol), and 6-((8-bromo-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethyl-picolinamide (90 mg, 0.19 mmol). The mixture was dissolved in 1,4-dioxane (1 mL), was sparged with nitrogen gas for 5 minutes and sealed. Then the reaction mixture was heated to 95 °C for 50 minutes. The mixture was cooled to rt, and A-(5-acetyl-4-((3-bromo-5-fluoro-2-methoxyphenyl)-amino)pyri din-2 -yl)cy cl opropanecarboxamide (Int. 4) (81 mg, 0.19 mmol), potassium carbonate (42 mg, 0.3 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with di chloromethane (8.2 mg, 0.01 mmol), 1,4-dioxane (1 mL) and water (500 pL) were added to the reaction mixture sequentially. The mixture was sparged with nitrogen gas for 5 minutes and sealed. The reaction mixture was heated to 80 °C for 3 hours. The product mixture was diluted with MeCN (7 mL), filtered, and purified directly by prep-HPLC on a C18 column (18.5-38.5% MeCN in 0.2% TFA(aq)) to afford the TFA salt of the title compound (80 mg, 43% yield). LC-MS calc, for C37H38F3N8O5 [M+H]+: m / z = 731.3; Found: 731.3.XH NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 11.17 (s, 1H), 8.89 (s, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.24 (d, J= 1.9 Hz, 1H), 8.02 (s, 1H), 8.00 (t, J= 7.7 Hz, 1H), 7.62 (d, J= 7.9 Hz, 1H), 7.52 (d, J= 7.8 Hz, 1H), 7.48 (dd, J= 9.7, 3.0 Hz, 1H), 7.31 (dd, J= 9.0, 3.0 Hz, 1H), 6.32 (tt, J= 54.8, 4.3 Hz, 1H), 4.51 - 4.38 (m, 2H), 4.23 (s, 2H), 4.12 (s, 2H), 3.48 (s, 2H), 3.38 (s, 3H), 3.02 (s, 3H), 2.95 (s, 3H), 2.67 (s, 3H), 2.03 (p, J= 6.6 Hz, 1H), 0.91 - 0.79 (m, 4H).Examples 37 to 63

[0380] Examples 37-63 are shown below in Table 10 and were prepared in accordance with the synthetic protocols set forth in Example 36 using appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.Table 10. Example 37-63Analytical Data (LCMS Ex. Name Structureand / or NMR)- 132 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- ((15,27?)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 - C37H38F3N8O5 [M+H]+: m / z 37 (2,2-difluoroethyl)-2- = 731.3; Found: 731.3.oxo-1, 2,3,5- tetrahydro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((ltf,2S)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 - C37H38F3N8O5 [M+H]+: m / z 38 (2,2-difluoroethyl)-2- = 731.3; Found: 731.2.oxo-1, 2,3,5- tetrahydro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-N, N- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((lR,2R)-2- methylcyclopropane- 1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 - C38H41F2N8O5 [M+H]+: m / z (2,2-difluoroethyl)-2- = 727.3; Found: 727.3 oxo-1, 2,3,5- tetrahydro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 133 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- ((15,2S)-2- methylcyclopropane- 1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 - C38H41F2N8O5[M+H]+: m / z 40 (2,2-difluoroethyl)-2- = 727.3; Found: 727.3 oxo-1, 2,3,5- tetrahydro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide LC-MS calc, for C39H42FN8O6 [M+H]+: m / z = 737.3; Found: 737.3. 'H NMR (400 MHz, DMSO-t / e) (5)-6-((8-(3-((5-acetyl- 6 11.17 (s, 1H), 11.09 (s,2- 1H), 8.89 (s, 1H), 8.73 (d, J (cyclopropanecarboxa = 1.9 Hz, 1H), 8.09 (s, 1H), mido)pyridin-4- 8.04 - 7.89 (m, 2H), 7.65 - yl)amino)-5 -fluoro-2- 7.58 (m, 1H), 7.52 (d, J= 7.7 methoxyphenyl)-2- Hz, 1H), 7.47 (dd, J= 9.8, oxo-1- 3.0 Hz, 1H), 7.23 (dd, J= (tetrahy drofuran-3 -yl)- 9.0, 3.0 Hz, 1H), 4.96 (s, 1,2, 3, 5 -tetrahydro-47 / - 1H), 4.21 (s, 2H), 4.11 (s, pyrido[3,2- 2H), 4.01 - 3.92 (m, 2H), e][l,4]diazepin-4- 3.88 (s, 1H), 3.68 (q, J= 7.8 yl)methyl)-7V,7V- Hz, 1H), 3.39 (s, 3H), 3.35 dimethylpicolinamide (s, 2H), 3.02 (s, 3H), 2.95 (s,3H), 2.67 (s, 3H), 2.36 - 2.20 (m, 1H), 2.04 (dt, J= 12.5, 6.3 Hz, 2H), 1.01 - 0.74 (m, 4H).- 134 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- ((17?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-5 -fluoro- LC-MS calc, for 2-methoxyphenyl)-2- C39H41F2N8O6 [M+H]+: m / z 42 oxo- 1 -((5)- = 755.3; Found: 755.3 tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamideLC-MS calc, for C37H39F2N8O5 [M+H]+: m / z = 713.3; Found: 713.3.1H NMR (400 MHz, DMSO- 6-((8-(3-((5-acetyl-2- d6) δ 11.19 (s, 1H), 11.18 (s, (cyclopropanecarboxa 1H), 8.88 (s, 1H), 8.74 (d, J mido)pyridin-4- = 1.8 Hz, 1H), 8.19 (d, J= yl)amino)-5 -fluoro-2- 1.9 Hz, 1H), 8.05 - 7.95 (m, methoxyphenyl)- 1 -(2- 2H), 7.63 (d, J= 7.9 Hz, 43 fluoroethyl)-2-oxo- 1H), 7.54 (d, J= 7.7 Hz, 1,2, 3, 5 -tetrahy dro-47 / - 1H), 7.48 (dd, J = 9.7, 3.0 pyrido[3,2- Hz, 1H), 7.30 (dd, J= 9.0, e][l,4]diazepin-4- 3.0 Hz, 1H), 4.65 (dt, J= yl)methyl)-7V,7V- 47.3, 4.8 Hz, 2H), 4.39 - dimethylpicolinamide 4.19 (m, 6H), 3.57 (s, 2H),3.39 (s, 2H), 3.02 (s, 2H), 2.95 (s, 2H), 2.66 (s, 3H), 2.02 (ddd, J= 12.5, 7.2, 5.3 Hz, 1H), 0.89 - 0.80 (m, 4H).6-((8-(3-((5-acetyl-2- ((U?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- LC-MS calc, for 4-yl)amino)-5 -fluoro- C37H38F3N8O5 [M+H]+: m / z 2-methoxyphenyl)- 1 - = 731.3; Found: 731.3 (2-fluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 135 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- ((17?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- LC-MS calc, for 4-yl)amino)-5 -fluoro- C37H37F4N8O5 [M+H]+: m / z 2-methoxyphenyl)- 1 - = 749.3; Found: 749.3 45 (2,2-difluoroethyl)-2- oxo-1, 2,3,5- tetrahydro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((15,27?)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-5 -fluoro- 2-methoxyphenyl)- 1 - LC-MS calc, for (2,2-difluoroethyl)-2- C37H37F4N8O5 [M+H]+: m / z oxo-1, 2,3,5- = 749.3; Found: 749.5 tetrahydro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((15,2 / ?)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-5 -fluoro- LC-MS calc, for 2-methoxyphenyl)- 1 - C38H41F2N8O5 [M+H]+: m / z isopropyl-2-oxo- = 727.3; Found: 727.4 1,2, 3, 5 -tetrahy dro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 136 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationLC-MS calc, for C39H45N8O5 [M+H]+: m / z = 705.4; Found: 705.3.1H NMR (300 MHz, CDCI3) 5 11.37 (s, 6-((8-(3-((5-acetyl-2- 1H), 10.81 (s, 1H), 8.70-8.60 (cyclopropanecarboxa(m, 2H), 8.30-8.25 (m, 1H), mido)pyridin-4- 8.25-8.20 (m, 1H), 7.95-7.90 yl)amino)-2- (m, 1H), 7.85-7.80 (m, 1H), methoxyphenyl)- 1 - 7.70-7.65 (m, 1H), 7.60-7.50 48 isobutyl-2-oxo- (m, 2H), 7.40-7.35 (m, 1H), 1,2, 3, 5 -tetrahy dro-4 / 7- 4.12 (s, 2H), 4.04 (s, 2H), pyrido[3,2- 3.87 (d, J = 6.4 Hz, 2H), 3.45 e][l,4]diazepin-4- (s, 3H), 3.34 (s, 2H), 3.16 (s, yl)methyl)-7V,7V- 3H), 3.13 (s, 3H), 2.70 (s, dimethylpicolinamide3H), 2.00 - 1.90 (m, 1H), 1.85-1.80 (m, 1H), 1.15-1.05 (m, 2H), 1.00-0.95 (m, 2H), 0.95 (d, J = 6.4 Hz, 4H).6-((8-(3-((5-acetyl-2- ((U?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-5 -fluoro- LC-MS calc, for 2-methoxyphenyl)- 1 - 49 C39H41F2N8O5 [M+H]+: m / z cyclobutyl-2-oxo- = 739.3; Found: 739.3.1,2, 3, 5 -tetrahy dro-4 / 7- pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((U?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-5 -fluoro- LC-MS calc, for 2-methoxyphenyl)-6- 50 C40H41F3N7O6 [M+H]+: m / z fluoro-2-oxo- 1 -((5)- = 772.3; Found: 772.3. tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-4 / 7- benzofe] [ 1,4]diazepin- 4-yl)methyl)-7V,7V- dimethylpicolinamide- 137 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationLC-MS calc, for C40H43FN7O6 [M+H]+: m / z = 736.3; Found: 736.6. 'H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 11.06 (s,6-((8-(3-((5-acetyl-2- 6 11.15 (s, 1H), 11.06 (s, ((15,27?)-2- 1H), 8.87 (s, 1H), 8.03 (t, J= fluorocyclopropane-1- 7.7 Hz, 1H), 7.97 (s, 1H), carb oxami do)py ri din- 7.65 (d, J= 7.8 Hz, 1H), 7.57 4-yl)amino)-2- (d, J = 7.0 Hz, 4H), 7.51 methoxyphenyl)-2- (dd, J= 7.7, 1.7 Hz, 1H), 51oxo- 1 -(( / ?)- 7.31 (t, J= 7.7 Hz, 1H), 7.26 tetrahy drofuran-3 -yl)- (d, J = 7.7 Hz, 1H), 4.41 (s, 1,2, 3, 5 -tetrahy dro-47 / - 4H), 3.99 - 3.93 (m, 2H), benzofe] [ 1,4]diazepin- 3.67 (d, J= 8.3 Hz, 1H), 3.47 4-yl)methyl)-7V,7V- (s, 2H), 3.36 (s, 3H), 3.03 (s, dimethylpicolinamide 3H), 2.94 (s, 3H), 2.66 (s,3H), 2.61 -2.52 (m, 1H), 2.25 (s, 2H), 1.59 - 1.46 (m, 1H), 1.21 (dt, J= 13.0, 6.5 Hz, 1H).6-((8-(3-((5-acetyl-2- ((17?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for methoxyphenyl)- 1 - 52 C38H39F3N7O5 [M+H]+: m / z (2,2-difluoroethyl)-2- = 730.3; Found: 730.5. oxo-1, 2,3,5- tetrahydro-47 / - benzofe] [ 1,4]diazepin- 4-yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((17?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for 53 methoxyphenyl)- 1 -(2- C38H40F2N7O5 [M+H]+: m / z fluoroethyl)-2-oxo- = 712.3; Found: 712.5.1,2, 3, 5 -tetrahy dro-47 / - benzofe] [ 1,4]diazepin- 4-yl)methyl)-7V,7V- dimethylpicolinamide- 138 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- (cyclopropanecarboxa mido)pyridin-4- yl)amino)-6-fluoro-2- LC-MS calc, for methoxyphenyl)- 1 - 54 C38H41FN7O5 [M+H]+: m / z = ethyl-2-oxo-l, 2,3,5- 694.3; Found: 694.4. tetrahydro-47 / - benzofe] [ 1,4]diazepin- 4-yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((15,27?)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for 55 methoxyphenyl)-2- C36H37FN7O5 [M+H]+: m / z = oxo-1, 2,3,5- 666.3; Found: 666.5. tetrahydro-47 / - benzofe] [ 1,4]diazepin- 4-yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((17?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- methoxy-5- LC-MS calc, for (trifluoromethyl)pheny C37H37F4N8O5 [M+H]+: m / z l)-l-methyl-2-oxo- = 749.3; Found: 749.2.1,2, 3, 5 -tetrahydro-4 / f- pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 139 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationLC-MS calc, for C37H36F4N7O5 [M+H]+: m / z = 734.3; Found: 734.2. 'H 6-((8-(3-((5-acetyl-2- NMR (400 MHz, DMSO-tL) ((U?,25)-2- 8 11.15 (s, 2H), 10.12 (s, fluorocyclopropane-1- 1H), 8.90 (s, 1H), 8.34 (s, carb oxami do)py ri din- 1H), 7.99 (s, 1H), 7.92 (t, J = 4-yl)amino)-2- 7.7 Hz, 1H), 7.81 (s, 1H), methoxy-5- 7.55 (d, J = 7.6 Hz, 1H), 7.48 57(trifluoromethyl)pheny (s, 1H), 7.44 (d, J = 7.7 Hz, l)-2-oxo-l, 2,3,5- 1H), 7.31 (d, J= 12.9 Hz, tetrahydro-47 / - 2H), 4.92 (s, 1H), 4.76 (s, benzofe] [ 1,4]diazepin- 1H), 3.87 (d, J= 15.1 Hz, 4-yl)methyl)-7V,7V- 4H), 3.44 (s, 3H), 2.99 (s, dimethylpicolinamide 3H), 2.91 (s, 3H), 2.66 (s,3H), 1.59 - 1.46 (m, 2H), 1.20 (dd, J= 13.4, 6.7 Hz,2H).6-((8-(3-((5-acetyl-2- ((U?,25)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- LC-MS calc, for methoxyphenyl)-2- C39H42FN8O6 [M+H]+: m / z = 58 oxo- 1 -((5)- 737.3; Found: 737.2. tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- ((15,27?)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-2- methoxyphenyl)-2- LC-MS calc, for 59 oxo- 1 -((5)- C39H42FN8O6 [M+H]+: m / z = tetrahy drofuran-3 -yl)- 737.3; Found: 737.2. 1,2, 3, 5 -tetrahy dro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 140 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- ((15,27?)-2- fluorocyclopropane-1- carb oxami do)py ri din- 4-yl)amino)-5 -fluoro- LC-MS calc, for 2-methoxyphenyl)-2- C39H41F2N8O6 [M+H]+: m / z 60 oxo- 1 -((5)- = 755.3; Found: 755.2.tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- (cyclopropanecarboxa mido)pyridin-4- yl)amino)-5 -fluoro-2- methoxyphenyl)- 1 -(2- LC-MS calc, for fluoro-2- C39H43F2N8O5 [M+H]+: m / z methylpropyl)-2-oxo- = 741.3; Found: 741.3.1,2, 3, 5 -tetrahy dro^TZ- pyrido^^- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide6-((8-(3-((5-acetyl-2- (cyclopropanecarboxa mido)pyridin-4- yl)amino)-5 -fluoro-2- methoxyphenyl)- 1 -(2- LC-MS calc, for methoxy-2- C40H46FN8O6[M+H]+: m / z = 62 methylpropyl)-2-oxo- 753.4; Found: 753.4.1,2, 3, 5 -tetrahy dro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamide- 141 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- (cyclopropanecarboxamido)pyridin-4- yl)amino)-5 -fluoro-2- LC-MS calc, for methoxyphenyl)- 1 - C39H44FN8O5 [M+H]+: m / z = 63 isobutyl-2-oxo- 723.3; Found: 723.3.1,2, 3, 5 -tetrahydro-47 / - pyrido[3,2- e][l,4]diazepin-4- yl)methyl)-7V,7V- dimethylpicolinamideExample 64. 3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A^^V-dimethylbenzamide

[0381] Step 1. tert-butyl 8-bromo-l-(2, 2-difluoroethyl)-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2-e ][ 1, 4 ]diazepine-4-carboxylateBr

[0382] The title compound was prepared in accordance with the synthetic protocols set forth in Example 36 Step 1 using the appropriate intermediates. LC-MS calc, for CisHwB^NsCh [M+H]+: m / z = 406.1 / 408.1; Found: 406.1 / 408.1.- 142 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0383] Step 2. tert-butyl 8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2, 2-difluoroethyl)-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2- e] [1,4 ]diazepine-4-carboxylate

[0384] The title compound was prepared in accordance with the synthetic protocols set forth in Example 36 Step 2 using the appropriate intermediates. LC-MS calc, for C33H36F3N6O6 [M+H]+: m / z = 669.3; Found: 669.2.

[0385] Step 3. N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[ 3, 2-e ][ 1, 4 diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl) cyclopropanecarboxamide

[0386] To a stirring solution of tert-butyl 8-(3-((5-acetyl-2- (cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2- difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e][l,4]diazepine-4-carboxylate (1820 mg, 2.73 mmol) in 1,4-dioxane (12 mL) was added HC1 (12 mL, 48 mmol, 4 M in 1,4-dioxane). The suspension was stirred at rt for 3 hours, then directly condensed to afford the title compound- 143 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(1650 mg, 99% yield) as the HC1 salt. LC-MS calc, for C28H28F3N6O4 [M+H]+: m / z = 569.2; Found: 569.2.

[0387] Step 4. 3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2 -methoxyphenyl)-! -(2, 2-difhioroethyl)-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2-e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylbenzamide

[0388] To a stirring solution of 3 -(hydroxymethyl) JV,7V-dimethylbenzamide (6 mg, 0.033 mmol) and triethylamine (21 pL, 0.15 mmol) in DMSO (0.5 mL) at 0 °C was addedSCh pyridine (16 mg, 0.099 mmol) in DMSO (0.5 mL). The resulting solution was allowed to warm to rt and stirred for 2h before another portion of SO3 pyridine (25 mg, 0.16 mmol) in DMSO (100 pL) was added. The reaction was stirred an additional 45 minutes before MeCN (0.5 mL) was added and the reaction was returned to 0 °C. Acetic acid (14 pL, 0.25 mmol) and A-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-U / -pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)-pyridin-2-yl)cyclopropanecarboxamide HC1 (10 mg, 0.0165 mmol) were added sequentially and the reaction was allowed to stir at rt for 30 minutes before STAB (17.5 mg, 0.083 mmol) was added. After stirring at rt overnight, the reaction mixture was diluted in MeCN and purified by prep-LCMS (CSH-C18, 19.2-39.2% MeCN / water with 0.2% TFA over 5 min) to afford the title compound (2.4 mg, 15% yield) as a TFA salt. LC-MS calc, for C38H39F3N7O5 [M+H]+: m / z = 730.3; Found: 730.3.Example 65. 6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4Z7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V-methyl-A-(2,2,2-trifluoroethyl)picolinamideN N IN NO HNN- 144 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0389] Step 1. Methyl 6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)- 5-fhioro-2-methoxyphenyl)-l-(2, 2-difluoroethyl)-2-oxo- 1, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2- e] [1,4 ]diazepin-4-yl)methyl)picolinate

[0390] To a solution of A-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lJT- pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropane- carboxamide; HCl (204 mg, 0.34 mmol) in DMF (3 mL) was added acetic acid (0.19 mL, 3.4 mmol) and methyl 6-formylpicolinate (170 mg, 1.0 mmol). The solution stirred at 35 °C for 20 min then sodium triacetoxyborohydride (360 mg, 1.7 mmol) was added. After 1 hour, the reaction was cooled to rt and quenched with sat. sodium bicarbonate (aq) and extracted with EtOAc (2x). The combined organic layers were dried with sodium sulfate, filtered and condensed. Crude was purified by silica gel column chromatography (0-100% EtOAc / Hexanes then 0-10% MeOHZEtOAc) to elute the product as a yellow-orange solid. LCMS calc, for C36H35F3N7O6 [M+H]+: m / z = 718.3; Found: 718.2.

[0391] Step 2. 6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2, 2-difluoroethyl)-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2- e] [1,4 ]diazepin-4-yl)methyl)picolinic acid- 145 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0392] To a solution of methyl 6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4- yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / - pyrido[3,2-e][l,4]diazepin-4-yl)methyl)picolinate (210 mg, 0.29 mmol) in methanol (10 mL), THF (10 mL) and water (10 mL) was added lithium hydroxide hydrate (1:1:1) (62 mg, 1.5 mmol). The solution was stirred for 30 min. The reaction mixture was quenched with citric acid to adjust the pH to 6~7. The mixture was then extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and condensed to yield the title compound (150 mg, 73% yield). LCMS calc, for C35H33F3N7O6 [M+H]+: m / z = 704.2; Found: 704.1.

[0393] Step 3. 6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2, 2-difluoroethyl)-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2- e ][ l,4]diazepin-4-yl)methyl)-N-methyl-N-(2, 2, 2-trifluoroethyl)picolinamide

[0394] To a solution of 6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2- e][l,4]diazepin-4-yl)methyl)picolinic acid (7.0 mg, 0.01 mmol) in DMF (0.50 mL) was added HATU (4.2 mg, 0.01 mmol) and DIPEA (7.0 pL, 0.04 mmol) followed by 2,2,2-trifluoro-A- methylethanamine;hydrobromide (3.0 mg, 0.01 mmol). After 2 h, the reaction was diluted in acetonitrile and purified by prep-LCMS (CSH-C18, 25.6-45.6% MeCN / water with 0.2% TFA over 5 min). Product fractions were lyophilized to yield the title compound as a TFA salt (3.2 mg, 28% yield). LCMS calc, for Css^FeNsOs [M+H]+: m / z = 799.3; Found: 799.2.Examples 66-70- 146 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0395] Examples 66-70 are shown below in Table 11 and were prepared in accordance with the synthetic protocols set forth in Example 65 using the appropriate intermediates, as well as commercial starting materials. The following compounds are TFA salts unless otherwise noted.Table 11. Examples 66-70Analytical Data Name Structure (LCMS and / or NMR)7V-(5-acetyl-4-((3-(l-(2,2- difluoroethyl)-4-((6-(3 - hydroxypyrrolidine- 1- LCMS calc, for carbonyl)pyridin-2- C39H40F3N8O6 yl)methyl)-2-oxo-2, 3,4,5- [M+H]+: m / z = tetrahydro-IT / -pyrido[3,2- 773.3; Found: e] [ 1,4]diazepin-8-yl)-5- 773.4. fluoro-2-methoxyphenyl)- amino)pyridin-2- yl)cyclopropane- carb oxami deA-(5-acetyl-4-((3-(l-(2,2- difluoroethyl)-2-oxo-4-((6- (pyrrolidine-1- LCMS calc, for carbonyl)pyridin-2- C39H40F3N8O5 yl)methyl)-2, 3,4,5- [M+H]+: m / z = 67 tetrahydro-IT / -pyrido[3,2- 757.3; Found:e] [ 1,4]diazepin-8-yl)-5- 757.2. fluoro-2-methoxyphenyl)- amino)pyridin-2- yl)cyclopropane- carb oxami de- 147 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do)pyridin-4-yl)amino)-5- LCMS calc, for fluoro-2-methoxyphenyl)- C38H38F5N8O5 1 -(2,2-difluoroethyl)-2- [M+H]+: m / z = 68oxo- 1,2, 3, 5 -tetrahy dro-47 / - 781.3; Found: pyrido[3,2-e][l,4]diazepin- 781.2.4-yl)methyl)-7V-(2,2- di fluoroethyl )-7V- methylpicolinamide6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do) LCMS calc, pyridin-4-yl)amino)-5- for fluoro-2-methoxyphenyl)- C38H40F3N8O6 1 -(2,2-difluoroethyl)-2- [M+H]+: m / z = oxo- 1,2, 3, 5 -tetrahy dro-47 / - 761.3; Found: pyrido[3,2-e][l,4]diazepin- 761.4.4-yl)methyl)-7V-(2- hydroxyethyl)-7V- methylpicolinamide6-((8-(3-((5-acetyl-2- (cy cl opropanecarb oxami do) LCMS calc, pyridin-4-yl)amino)-5- for fluoro-2-methoxyphenyl)- C40H44F3N8O5 70 1 -(2,2-difluoroethyl)-2- [M+H]+: m / z = oxo- 1,2, 3, 5 -tetrahy dro-4 / 7- 773.3; Found: pyrido[3,2-e][l,4]diazepin- 773.2. 4-yl)methyl)-7V-(tert-butyl)- 7V-methylpicolinamideExample 71. 6-((8-(3-((5-acetyl-2-((17?,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4Z / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide- 148 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application

[0396] Step 1. 6-((8-Bromo- l-methyl-2 -oxo- 1,2,3, 5-tetrahydro-4H-pyrido [3,2-e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0397] lodomethane (33 pL, 0.53 mmol) was added to a stirring solution of 6-((8-bromo-2-oxo-l,2,3,5-tetrahydro-4 / 7-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-7V,7V-dimethylpicolinamide (Int. 28) (180 mg, 0.45 mmol) and cesium carbonate (290 mg, 0.89 mmol) in DMF (2 mL) at 0 °C. The reaction mixture was warmed to rt and stirred for 2 hours. The product mixture was diluted with brine (30 mL) and was extracted with a 3: 1 CHCl3 / iPrOH mixture (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (0-10% MeOH / DCM) to yield the title compound (163 mg, 87% yield). LC-MS calc, for CisfbiBrNsCL [M+H]+: m / z = 418.1 / 420.1; Found: 418.1 / 420.1.

[0398] Step 2. 6-((8-(3-((5-Acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l, 2, 3, 5-tetrahydro-4H-pyrido[ 3, 2-e] [1,4 ]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide

[0399] The title compound was prepared in accordance with the synthetic protocols set forth in Example 36 Step...

Claims

105807.005059 PCT ApplicationWhat is claimed:

1. A compound of F ormula (I)or a pharmaceutically acceptable salt or solvate orN-oxide thereof, whereineach of Wi, W2, and W3 is independently N or CRs;each Z is independently O, S, SO2, NR4, NR9 or C(Rs)2, wherein at least 3 Z are C(Rs)2 and wherein at least one Z is NR4;each Rs is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb;or any two Rs groups attached to the same carbon form =0;or any two Rs groups attached to the same carbon form a 3-6 membered spirocycloalkyl or spiroheterocycloalkyl ring;or any two Rs groups attached to adjacent carbon atoms form a 3-6 membered cycloalkyl or heterocycloalkyl ring;each R4 is independently -L1-! -!;each R9is independently H, -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl, -C(0)Rb, -C(0)0Rb, -C(0)NRcRd, -S(O)Rb, -S(0)2NRcRd, -S(0)(=NRb)Rb, -SF5, -P(0)RbRb, -P(0)(0Rb)(0Rb), -B(0Rc)(0Rd) or -S(0)2Rb; wherein each of -Ci-Cealkyl, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, spiroheterocycloalkenyl can be optionally substituted by 1-6 Rf groups;- 324 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationeach L1is independently absent, or is independently -(CRcRd)p-, -(CRaRc)pO-, -S(O)-, -S(O)2-, -C(=O)-, -C(=O)O-, -C(=O)NRa-, -S(=O)NRa-, -S(=O)2NRa-, or aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;each L2is independently absent, or is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;each L3is independently absent, or is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb;p is 1, 2, 3 or 4;each Xi, X2, X3, X4, and Xe is independently N or CR10;each Rio is independently H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -ORa, -SRa, -NRcRd, -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) or -S(O)2Rb;Ri is H, D, -Ci-Cealkyl, -Ci-Cehaloalkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, -NHR5;Rs is H, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;Re is H, D, -OH, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl or spiroheterocycloalkenyl;R7 is H, -Ci-Cealkyl, -Ci-Cehaloalkyl, -C2-Cealkenyl, or cycloalkyl;each Rais independently H, -Ci-Cioalkyl, -C2-C10 alkenyl, -C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;each Rb, is independently H, D, -Ci-Ce alkyl, -C2-Ce alkenyl, -C2-Ce alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;each Rcor Rdis independently H, D, -C1-C10 alkyl, -C2-Ce alkenyl, -C2-Ce alkynyl, -OCi-Cealkyl, -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;- 325 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationwherein any of the -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, spirocycloalkyl, spiroheterocycloalkyl and spiroheterocycloalkenyl groups in any of R1-R10 and L1-! is optionally substituted by 1-6 Rfgroups; andeach Rfis independently H, D, oxo, halogen, Ci-Cs alkoxy, Ci-Cs alkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, -OH, -CN, -NO2, -C2-6 alkenyl, -C2-6 alkynyl, Ce-io aryl, C5-12 heteroaryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkyl, C3-8 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, -SF5, -P(O)RbRb, -P(O)RcRd, -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 Ci-C8alkyl is optionally substituted by 1-6 groups selected from D, halogen, -OH, -CN, -ORa, -SRa, -NRaRd, or NRcRd.

2. The compound of claim 1, wherein Wi is N.

3. The compound of claim 1, wherein W2 is N.

4. The compound of claim 1, wherein W3 is N.

5. The compound of claim 1, wherein each Wi, W2, and W3 is CRs.

6. The compound of claim 5, wherein each Rs is independently H, halogen, -ORa, -CN or - Ci-C6alkyl.

7. The compound of any one of the previous claims, wherein one Z is NR4.

8. The compound of any one of the previous claims, wherein the compound is a compound of Formula (II):- 326 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor a pharmaceutically acceptable salt or solvate orN-oxide thereof.

9. The compound of claim 8, wherein the compound is a compound of Formula (III), Formula (IV) or Formula (V):or a pharmaceutically acceptable salt or solvate orN-oxide thereof.

10. The compound of any one of claims 8 or 9, wherein two Rs groups attached to the same carbon join together to form =0.

11. The compound of any one of claims 1-7, wherein the compound is a compound of Formula (VI), Formula (VII), Formula (VIII), Formula (XIX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), or Formula (XV):- 327 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application- 328 - 105807.005059\4925-4900-9536.3105807.005059 PCT Applicationor a pharmaceutically acceptable salt or solvate orN-oxide thereof; whereinL1is absent, -(CRcRd)P-, -S(O)-, -S(O)2-, or-C(=O)-;L2is absent, aryl or heteroaryl; andL3is H, D, halogen, -OH, -CN, -NO2, -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or 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) or -S(O)2Rb; wherein any of the -Ci-Cealkyl, Ci-Cs alkoxide, -C2-Cealkenyl, -C2-Cealkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl groups of L2and L3are optionally substituted by 1-6 Rf groups.

12. The compound of any one of the preceding claims, wherein each of X2, X3, and X4 is CH.

13. The compound of any one of claims 1-11, wherein X2= N.

14. The compound of any one of claims 1-11, wherein X3 = N.

15. The compound of any one of claims 1-11, wherein X4 = N.

16. The compound of any one of claims 1-11, wherein X2= N and X4 = N.

17. The compound of any one of the preceding claims, wherein Xe is CH.

18. The compound of any one of claims 1-16, wherein Xe is N.- 329 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application19. The compound of any one of the preceding claims, wherein Xi is CH.

20. The compound of any one of claims 1-18, wherein Xi is N.

21. The compound of any one of the preceding claims, wherein Reis -Ci-Cealkyl, cycloalkyl or spirocycloalkyl, wherein the -Ci-Cealkyl, cycloalkyl and spirocycloalkyl are optionally substituted by 1-6 Rf groups.

22. The compound of claim 21, wherein Re is cycloalkyl optionally substituted by 1-6 Rf groups.

23. The compound of claim 22, wherein Re is cyclopropyl optionally substituted by 1-6 Rf groups.

24. The compound of claim 22, wherein Re is fluorine substituted cyclopropane.

25. The compound of any one of claims 11-24, wherein L1is -(CRcRd)p-.

26. The compound of any one of claims 11-25, wherein L1is -CH2-.

27. The compound of any one of claims 11-26, wherein L2is phenyl or pyridyl.

28. The compound of any one of claims 11-27, wherein L3is -C(O)NRcRdwherein Rcand Rdare each independently -C1-C10 alkyl;or Rcand Rd, together with the atom to which they are both attached, form a monocyclic or multi cyclic heterocycloalkyl.

29. The compound of claim 22, wherein L3is -C(O)NRcRdand at least one of Rcand Rdis methyl.

30. The compound of any one of the preceding claims, wherein Ri is -NHR5.- 330 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application31. The compound of claim 30, wherein Rs is H, -Ci-Cealkyl, or Ci-Cs alkoxide, wherein the -Ci-Cealkyl and Ci-Cs alkoxide groups are optionally substituted by 1-6 Rf groups.

32. The compound of claim 31, wherein Rs is -Ci-Cealkyl optionally substituted by 1-6 Rf groups.

33. The compound of claim 32, wherein Rs is methyl.

34. The compound of claim 32, wherein Rs is methyl optionally substituted by at least one D atom.

35. The compound of claim 32, wherein Rs is CD3.

36. The compound of any one of claims 1-29, wherein Ri is Ci-Ce alkyl optionally substituted by 1-6 R group selected from H, D or halogen or -Ci-Cehaloalkyl optionally substituted by 1-6 R groups selected from H, D or halogen.

37. The compound of claim 36, wherein Ri is Ci-Ce alkyl optionally substituted by 1-6 R groups selected from H, D or halogen.

38. The compound of claim 36, wherein Ri is methyl.

39. The compound of any one of the preceding claims, wherein R7 is -Ci-Cealkyl.

40. The compound of any one of the preceding claims, wherein R7 is methyl.

41. The compound of any one of the preceding claims that is:6-(Cyclopropanecarboxamido)-4-((3-(l-ethyl-4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-17 / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-isopropyl-2-oxo-2,3,4,5-tetrahydro-17 / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;- 331 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-(Cyclopropanecarboxamido)-4-((3-(4-(3-(dimethylcarbamoyl)-2-fluorobenzyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-17 -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cyclopropanecarboxamido)-4-((3-(l-cyclopropyl-4-((6-(dimethylcarbamoyl)pyridin- 2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-17 -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(2-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-oxo-2, 3,4, 5-tetrahydro-U -benzo[c]azepin-7 -yl)-2-methoxyphenyl)amino)-7V-methylpyridazine- 3 -carboxamide;6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-5-oxo-2, 3,4, 5-tetrahydrobenzo[ / ][l, 4]oxazepin-8-yl)-2 -methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cyclopropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)-6-fluoro-5-oxo-2,3,4,5-tetrahydrobenzo[ / ][l,4]oxazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-methyl-5-oxo-2,3,4,5-tetrahydro-lJ -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-ethyl-5-oxo-2,3,4,5-tetrahydro-lJ -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-isopropyl-5-oxo-2,3,4,5-tetrahydro-lJ / -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-methyl-2,5-dioxo-2,3,4,5-tetrahydro-17 -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-ethyl-2,5-dioxo-2,3,4,5-tetrahydro-lJ -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3 -carboxamide;6-(Cy cl opropanecarboxamido)-4-((3-(4-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)-l-isopropyl-2,5-dioxo-2,3,4,5-tetrahydro-17 -benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-7V-methylpyridazine-3-carboxamide;- 332 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;3-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-2-fluoro-A, A-dimethylbenzamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2-fluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(cyanomethyl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(oxetan-3-yl)-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(tetrahy drofuran-3 -yl)- 1,2, 3, 5 -tetrahy dro-4 / / -benzo[< ] [ 1,4] diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lA,25)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(3-((5-Acetyl-2-(spiro[2.2]pentane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;(A)-6-((8-(3-((5-Acetyl-2-(spiro[2.2]pentane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4JH-benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;- 333 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-Acetyl-2-((15,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lA,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lS,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-cyclopropyl-2-oxo-l,2,3,5-tetrahydro-4J / -benzo[e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 1-40 that is:6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-A, A-dimethylpicolinamide;(5)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4 / 7-pyri do[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2-fluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((15,2A)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l -isopropyl -2-oxo-l, 2,3, 5-tetrahydro-4J / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-isobutyl-2-oxo-l,2,3,5-tetrahydro-4J / -pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-A, A-dimethylpicolinamide;or a pharmaceutically acceptable salt thereof.- 334 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application43. The compound of any one of claims 1-40 that is:6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -cyclobutyl-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -( 1 -fluoropropan-2-yl)-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-2-oxo-l-(thiazol-5-ylmethyl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(cyclopropylmethyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-cyclopentyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -((S)-tetrahy drofuran-3 -yl)- 1,2,3,5 -tetrahy dro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-2-oxo-l-((S)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5 -fluoro-2-methoxyphenyl)- 1 -(2-fluoroethyl)-2-oxo- 1,2,3, 5 -tetrahy dro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4H-pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 335 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-m ethoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4H-pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2R)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 3,5 -tetrahydro-4H-pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2S)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 3,5 -tetrahydro-4H-pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-2-oxo-l-((S)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5 -fluoro-2-methoxyphenyl)- 1 -(2-fluoroethyl)-2-oxo- 1,2,3, 5 -tetrahy dro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-cyclobutyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-6-fluoro-2-oxo-l-((S)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -((R)-tetrahy drofuran-3 -yl)- 1,2,3,5 -tetrahy dro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)- 1 -(2-fluoroethyl)-2-oxo- 1,2, 3, 5 -tetrahy dro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 336 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-6-fluoro-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-m ethoxy-5 -(trifluoromethyl)phenyl)- 1 -methyl -2-oxo- 1,2,3, 5 -tetrahy dro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-m ethoxy-5 -(trifluoromethyl)phenyl)-2-oxo- 1,2,3, 5 -tetrahy dro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -((S)-tetrahy drofuran-3 -yl)- 1,2,3,5 -tetrahy dro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -((S)-tetrahy drofuran-3 -yl)- 1,2,3,5 -tetrahy dro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-2-oxo-l-((S)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2-fluoro-2-methylpropyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2-methoxy-2-methylpropyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-isobutyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylbenzamide;- 337 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N-methyl-N-(2,2,2-trifluoroethyl)picolinamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(3-hydroxypyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-((6-(pyrrolidine-l-carbonyl)pyridin-2-yl)methyl)-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N-(2,2-difluoroethyl)-N-methylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N-(2-hydroxyethyl)-N-methylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N-(tert-butyl)-N-methylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1 -methyl -2-oxo- 1,2,3, 5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-6-fluoro-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 338 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-6-fluoro-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-6-fluoro-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxy-5-methylphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxy-5-(trifluoromethyl)phenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-4-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(R)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 339 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-((ls,3s)-3-cyanocyclobutyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -( 1 -cyanoethyl)-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxy-5-(trifluoromethyl)phenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-ethyl-7-fluoro-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -(2-cyanoethyl)-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[4,3-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2 -methoxy ethyl)-2-oxo-l, 2,3, 5-tetrahydro-4H-pyrido[4, 3-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[4,3-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 340 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[4,3-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[4,3-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(2,2-difluoropropyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(R)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(l-methoxypropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-l-cyclobutyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyri din-2 -yl)-6-fluoro-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3,5 -tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(2,2-difluoroethyl)-6-fluoro-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-ethyl-6-fluoro-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 341 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(2-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-4-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lS,2S)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2R)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-(8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepine-4-carbonyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-2-oxo-l-((S)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(2-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-4-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(2-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-4-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyri din-2 -yl)-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyri din-2 -yl)-l -cyclobutyl -2-oxo-l, 2,3, 5-tetrahydro-4H-pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 342 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyri din-2 -yl)-2-oxo- 1 -(tetrahydrofuran-3 -yl)- 1,2,3, 5 -tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2S)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lR,2R)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 3-methoxypyridin-2-yl)-l -isopropyl -2-oxo-l, 2,3, 5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lR,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((2-(cyclopropanecarboxamido)-5-propionylpyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 343 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-chloro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(R)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(l-methoxypropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;( 1 R, 2 S)-N-(5 -acetyl -4-((5 -fluoro-2 -m ethoxy-3 -(1 -methyl-4-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)-2 -fluorocyclopropane-1 -carboxamide;N-(5-acetyl-4-((3 -(4-((6-(3,3 -difluoropyrrolidine- 1 -carbonyl)pyri din-2 -yl)methyl)- 1 -ethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-4-((l-methyl-lH-pyrazol-4-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-4-((6-((3aR,6aR)-hexahydro-lH-furo[3,4-c]pyrrole-5-carbonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-4-((6-(morpholine-4-carbonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(4-((3-(4-([l,2,4]triazolo[l,5-a]pyridin-5-ylmethyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-5-acetylpyridin-2-yl)cyclopropanecarboxamide;N-(4-((3-(4-([l,2,4]triazolo[l,5-a]pyridin-8-ylmethyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)-5-acetylpyridin-2-yl)cyclopropanecarboxamide;- 344 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationN-(5-acetyl-4-((3-(l-ethyl-4-(imidazo[l,5-a]pyridin-8-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-4-(imidazo[l,2-a]pyridin-8-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-2-oxo-4-(pyrazolo[l,5-a]pyridin-7-ylmethyl)-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-4-(imidazo[l,2-a]pyridin-5-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-4-((6-(methylsulfonyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-ethyl-4-(isoquinolin-l-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyri din-2 -yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(4-((4-cyanopyridin-2-yl)methyl)-l-ethyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyri din-2 -yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-(imidazo[l,5-a]pyridin-8-ylmethyl)-2-oxo- 2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-(imidazo[l,2-a]pyridin-8-ylmethyl)-2-oxo- 2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-(3-(difluoromethyl)-2-fluorobenzyl)-2-oxo- 2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(4-(3-chlorobenzyl)-l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;- 345 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationN-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-((6-oxo-l,6-dihydropyridin-2-yl)methyl)-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(difluoromethyl)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(hydroxymethyl)pyridin-2-yl)methyl)-2-oxo-2, 3,4, 5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-2-oxo-4-(thiazol-4-ylmethyl)-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N-methoxy-N-methylpicolinamide;3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N-methoxy-N-methylbenzamide;N-(5-acetyl-4-((3-(4-((6-aminopyridin-2-yl)methyl)-l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-(3-methylureido)pyridin-2-yl)methyl)-2-oxo-2, 3,4, 5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-acetyl-4-((3-(l-(2,2-difluoroethyl)-4-((6-((N-methylsulfamoyl)amino)pyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepin-8-yl)-5-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;- 346 - 105807.005059\4925-4900-9536.3105807.005059 PCT ApplicationN-(5-Acetyl-4-((2-methoxy-3-(l-methyl-2-oxo-4-((6-(tetrahydrofuran-2-yl)pyridin-2-yl)methyl)-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-Acetyl-4-((2-methoxy-3-(4-((6-(3-methoxyoxetan-3-yl)pyridin-2-yl)methyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;N-(5-Acetyl-4-((3-(4-((6-acetylpyridin-2-yl)methyl)-l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;6-(2-(8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)propan-2-yl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(tert-butyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(l-acetylpyrrolidin-3-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(azetidin-3-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-2-yl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-2-yl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2S)-2-methylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-2-yl)-2-oxo-l-((S)-tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(2-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxy-6-(trifluoromethyl)pyridin-4-yl)-2-oxo-l-(tetrahydrofuran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 347 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(bicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(3-fluorobicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(bicyclo[l.l.l]pentan-l-yl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2-oxabicyclo[2.

1. l]hexan-4-yl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isobutyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-cyclopentyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-((lR,2S)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l-((S)-tetrahydro-2H-pyran-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(sec-butyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(R)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(sec-butyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-((lS,2R)-2-fluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-((R)-sec-butyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;5-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylbicyclo[3.1.1 ]heptane- 1 -carboxamide;- 348 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-cyclopentyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-2-oxo-l-propyl-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-2-oxo-l-(pentan-3-yl)-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-cyclohexyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-cyclohexyl-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo- 1 -(tetrahydro-2H-pyran-4-yl)- 1,2,3, 5 -tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)- 1 -(2 -hydroxy -2 -methylpropyl)-2-oxo- 1,2, 3,5 -tetrahydro-4H-benzofe] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-cyclopropyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;3-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-2-methoxy-N, N-dimethylbenzamide;3-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -ethyl-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N,2-trimethylbenzamide;6-(8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepine-4-carbonyl)-N, N-dimethylpicolinamide;- 349 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application5-(8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-2,3,4,5-tetrahydro-lH-pyrido[3,2-e][l,4]diazepine-4-carbonyl)-N, N-dimethylbicyclo[3.1.1]heptane-l -carboxamide;6-((l-(4-(lH-Pyrazol-l-yl)phenyl)-8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-(( 1 -(6-( 1 H-Pyrazol - 1 -yl)pyri din-3 -y 1 ) - 8 - (3 -((5 -acetyl -2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l-(pyridin-3-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -(6-methoxypyri din-3 -yl)-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2-fluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(3,4-difluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 2-oxo-l-(quinolin-7-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-2-oxo-l-(quinolin-6-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(5-fluoropyridin-2-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(3-fluoropyridin-4-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 350 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(2,4-difluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-1 -(4-cyanophenyl)-2-oxo- 1,2,3, 5-tetrahydro-4H-benzo[e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 2-oxo-l-phenyl-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(3-chlorophenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(3-fluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(6-methylpyridin-3-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-2-oxo-l-(quinolin-3-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(4-fluorophenyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 2-oxo-l-(thiazol-5-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-2-oxo-l-(pyridin-2-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-2-oxo-l-(pyridin-4-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 351 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(5-fluoropyridin-3-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)-l-(2-methoxypyridin-4-yl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;N-(5-acetyl-4-((2-methoxy-3 -(4-((6-(morpholine-4-carbonyl)pyri din-2 -yl)methyl)-2-oxo-l-(pyridin-3-yl)-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;6-((8-(3-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2 -methoxyphenyl)- 1-(methylsulfonyl)-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin- 2-yl)-6-cyano-l -isopropyl -2-oxo-l, 2,3, 5-tetrahydro-4H-benzo[e][l, 4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(4-((5-acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(l,l-difluoropropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(R)-6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-(l,l-difluoropropan-2-yl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-6-(ethylamino)-l-isopropyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l -ethyl -2-oxo-l, 2,3, 5-tetrahydro-4H-pyrido[2,3-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-6-ethoxy-l -ethyl -2-oxo-l, 2,3, 5-tetrahydro-4H-benzo[e][l, 4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-6-ethoxy-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 352 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-l-isopropyl-6-methoxy-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(4-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methoxypyridin-2-yl)-6-chloro-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)sulfonyl)-N, N-dimethylpicolinamide;N-(5-Acetyl-4-((2-methoxy-3-(l -methyl -4-((6-(morpholine-4-carbonyl)pyridin-2-yl)sulfonyl)-2-oxo-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepin-8-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-2-oxo-l-(pyridin-3-yl)-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)sulfonyl)-N, N-dimethylpicolinamide;(R)-6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-3-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-3-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-5-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)-5-(2-fluoroacetyl)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)-5-(2,2-difluoroacetyl)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-Acetyl-2-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;- 353 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application6-((8-(3-((3-Acetyl-6-(cyclopropanecarboxamido)pyridazin-4-yl)amino)-2-methoxyphenyl)-l-methyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((2-(Cyclopropanecarboxamido)-5-oxo-5,6-dihydro-l,6-naphthyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(2-cyclopropylacetamido)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin- 4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-((lR,2R)-2-(trifluoromethyl)cyclopropane-l-carboxamido)pyridin- 4-yl)amino)-5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(S)-6-((8-(3-((5-acetyl-2-(2,2-difluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-l-(2,2-difluoroethyl)-2-oxo-l,2,3,5-tetrahydro-4H-pyrido[3,2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;(R)-6-((8-(3-((5-acetyl-2-(2,2-difluorocyclopropane-l-carboxamido)pyridin-4-yl)amino)-2-methoxyphenyl)-l-ethyl-2-oxo-l,2,3,5-tetrahydro-4H-benzo[e][l,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((8-(3-((5-acetyl-2-(2,2-dimethylcyclopropane-l-carboxamido)pyridin-4-yl)amino)-5-fluoro-2-m ethoxyphenyl)- 1 -(2, 2-difluoroethyl)-2-oxo- 1,2, 5 -tetrahydro-4H-pyrido[3, 2-e] [ 1,4]diazepin-4-yl)methyl)-N, N-dimethylpicolinamide;6-((5-((l-((3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthen]-5-yl)amino)-l-thioxo-5,8,ll-trioxa-2-azatridecan-13-yl)carbamoyl)pyridin-2-yl)amino)-4-((3-(l-(l-((6-(dimethylcarbamoyl)pyri din-2 -yl)methyl)azetidin-3-yl)-lH-pyrazol-4-yl)-2-methoxyphenyl)amino)-N-methylpyridazine-3-carboxamide;or a pharmaceutically acceptable salt thereof.

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

45. 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.- 354 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application46. 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 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

47. The method of claim 46, 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.

48. The method of claim 46, 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.

49. 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 1-44, or a pharmaceutically acceptable salt thereof, or a composition of claim 45.

50. The method of claim 49, wherein the JAK2 -mediated disorder is a disorder mediated by a JAK2 containing a V617F mutation.

51. The method of any one of claim 49 or claim 50, wherein the JAK2 -mediated disorder is a proliferative disease.

52. The method of any one of claims 49-51, wherein the proliferative disease displays overexpression or amplification of JAK2, or somatic mutation of JAK2.

53. The method of any one of claims 49-52, 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).

54. The method of any one of claims 49-54, wherein the method comprises the steps of:- 355 - 105807.005059\4925-4900-9536.3105807.005059 PCT Application(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.- 356 - 105807.005059\4925-4900-9536.3

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