ZER1 binders, pharmaceutical compositions, and uses thereof

Abstract

Pyridazinone derivatives, and pharmaceutically acceptable salts, solvates, or stereoisomer thereof, comprising a structure of formula I: are provided. Also provided are pharmaceutical compositions comprising these compounds and the use of these compounds, intermediates thereof, and compositions in the prevention or treatment of cancers and / or tumors.

Description

ZER1 BINDERS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Patent Application Serial No. 63 / 729,078 filed December 6, 2024, the entire contents of which are incorporated by reference herein.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing (26123-WO-PCT_SL.xml; Size: 6,745 bytes; and Date of Creation: 23 October 2025) are herein incorporated by reference in their entirety.BACKGROUND

[0003] Human papillomavirus (HPV) E7 proteins bind to host cell proteins to facilitate virus replication. ZER1 is an E3 ubiquitin ligase adapter protein. In cells, ZER1 and its homolog ZYGI IB function to promote the ubiquitylation and consequent proteasomal degradation of proteins bearing “N-degrons,” or N-terminal peptide sequences recognized by ZER1 or ZYGI IB. ZER1 and ZYGI IB activity may be involved in the proteostatic regulation of proteins that fail N-myristoylation, as well as of protein fragments generated during caspase cleavage. Richard T. Timms, et al., Science, Vol. 365, NO. 6448, July 2019. ZER1 contributes to HPV carcinogenesis through interaction with viral oncoprotein E7. Thus, molecules targeting ZER1 may find use in the treatment of HPV+ cancers and HPV infection. See Joangela Nouel et al., ASM Journals / mBio / Nol.13, No.6, November 2022 (mBiol3:e02033-22. https: / / doi.org / 10.1128 / mbio.02033-22) and Elizabeth White et al., PNAS Vol. 105, no. 5, E260-E267, (2012).

[0004] Binders to ZER1 and ZYGI IB can be embedded within heterobifunctional molecules to elicit the degradation of proteins of interest through induced proximity. This has been exemplified in the discovery of ZER1 / ZYG1 IB-recruiting heterobifunctional degraders of EML4-LK and mutant EGFR. Jianchao Zhang et al., J. Med. Chem., Vol. 67, Issue 16, (2024). ZER1 / ZYGI IB binders, as well as ZER1 / ZYG1 IB-recruiting heterobifunctional degraders are disclosed in CN118126115. See also Yao Li, et al., Nature Communications, 13, Article No. 7636 (2022) and Yan et al., Molecular Cell 81, 3262-3274, August 2021.

[0005] This disclosure is directed to pyridazinones posessing activity against the E3 ubiquitin ligase ZER1 (zyg-11 related cell cycle regulator) for the treatment of cancers arising frominfection by human papillomavirus (HPV). The compounds exhibit activity in a biochemical assay wherein a fluorescently labeled tracer peptide is displaced by the analyte (fluorescence polarimetry, FP), and in a cellular assay gauging compounds’ effect in blocking the function of ZER1 to mediate the degradation of green fluorescent protein (GFP) fused to an N-terminal degron peptide.SUMMARY

[0006] Provided are substituted derivatives of Formula I:OIand salts, solvates and pharmaceutical compositions thereof, wherein R1, R2, R3, A and B are described below.

[0007] Also described herein are methods of treatment of cancers arising from infection by human papillomavirus (HPV) comprising administering to a subject in need thereof a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also described herein are methods of treatment of treatment of cancers arising from infection by human papillomavirus (HPV) comprising administering to a subject in need thereof a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0008] Therapeutic uses and processes for making such compounds, which may be suitable for the treatment of cancers arising from infection by human papillomavirus (HPV) are also described.

[0009] The summary of the disclosure described herein is non-limiting and other features and advantages will be apparent from the following detailed description, and from the claims.DETAILED DESCRIPTION

[0010] For each of the following embodiments, any variable not explicitly defined in the embodiment is as defined in Formula I. In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted.

[0011] An embodiment, the present disclosure provides pyridazinone derivatives, pharmaceutically acceptable salts, solvates, or stereoisomer thereof, comprising a structure of Formula I:oIwherein:A is a five membered heteroaryl selected from triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadi azolyl;B is a six membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidinyl;R1and R2are independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, -C1-6 alkylOH, heteroaryl, and -OC1-6 alkyl, said alkyl, cycloalkyl, and heteroaryl unsubstituted or substituted with 1 to 3 substituents selected from OH, halogen, C1-6 alkyl, and -OC1-6 alkyl; orR3is selected from -(CH2)nC(O)NHCi-6alkyl, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, (CH2)nC(O)heterocycle, (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra,each Rais independently selected from -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -(CH2)nC(O)NHCi-6 alkyl, -C(O)heterocycle, halogen and Ci-shaloalkyl;R is selected from hydrogen, -C1-6 alkyl, C(O)OH, C(O)OCi-6 alkyl, and hydroxyl; and Each n is an integer independently selected from 0 to 4.

[0012] An embodiment, the present disclosure provides pyridazinone derivatives, pharmaceutically acceptable salts, solvates, or stereoisomer thereof, comprising a structure of Formula IA:oIAwherein:A is a five membered heteroaryl selected from triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadi azolyl;B is a six membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidinyl;R1and R2are independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, -C1-6 alkylOH, (CH2)nheteroaryl, and -(CR)nOCi-6 alkyl, said alkyl, cycloalkyl, and heteroaryl unsubstituted or substituted with 1 to 3 substituents selected from OH, halogen, C1-6 alkyl, and -OC1-6 alkyl; or R1and R2combine to the atom to which they are attached to form a C3-6 cycloalkyl,R3is selected from -(CH2)nC(O)NHCi-6alkyl, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, (CH2)nC(O)heterocycle, (CHR)ncarbocycyle, (CHR)naryl, (CHR)nOaryl, C2-6alkenylaryl, and (CH2)nheteroaryl, said heterocycle, aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra,each Rais independently selected from -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -NHC(0)CI-6 alkyl, -NRC1-6 alkyl, NH2, -C(O)NR(CHR)naryl, -C(O)NRC3-6 cycloalkyl, -C(O)N(CI-6alkyl)2, -C(O)NR(CHR)nheteroaryl, -NHC(O)aryl, -(CH2)nC(O)NRCi-6alkyl, C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -OC3-6 cycloalkyl, (CHR)naryl, (CHR)nheteroaryl, -NRheteroaryl, (CH2)nO(CH2)naryl, -S(O)2NHaryl, -NR(CH2)nC3-6cycloalkyl, heterocycle, -NH(CH2)nheterocycle, -S(O)2heterocycle, (CH2)nC(O)heterocycle, halogen, OH, C(O)OH, CN, (CH2)nO(CH2)nhaloalkyl, and (CH2)nCi-3 haloalkyl, said alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, and heterocycle optionally substituted with 1 to 3 substituents selected from Rb; each Rbis independently selected from C1-6 alkyl, C1-6 alkylOR, OR, -C(O)OR, (CR2)nCN, (CH2)nS(O)2R, oxo, halogen, NHC(O)Ci-6alkyl, (CH2)nC3-6 cycloalkyl, (CHR)nheteroaryl, (CH2)nheterocycle, -S(O)2C3-6cycloalkyl, (CH2)nOCi-3 haloalkyl, and (CH2)nC 1-3 haloalkyl, said alkyl, cycloalkyl, heteroaryl and heterocycle optionally substituted with 1 to 3 substituents selected from Rc;each Rcis selected from C1-6 alkyl, halogen, CN, and OH;R is selected from hydrogen, -C1-6 alkyl, C(O)OH, C(O)OCi-6 alkyl, and hydroxyl; and Each n is an integer independently selected from 0 to 4.

[0013] Another embodiment is realized when A is triazolyl. A subembodiment of this aspect is realized when a nitrogen atom of A is bonded to a carbon atom of B.

[0014] Another embodiment is realized when A is isoxazolyl. A subembodiment of this aspect is realized when a carbon atom of A is bonded to a carbon atom of B.

[0015] Another embodiment is realized when A is thiazolyl. A subembodiment of this aspect is realized when a carbon atom of A is bonded to a carbon atom of B.

[0016] Another embodiment is realized when A is thiadiazolyl. A subembodiment of this aspect is realized when a carbon atom of A is bonded to a carbon atom of B.

[0017] Still another embodiment is realized when A is tetrazolyl.

[0018] Another embodiment is realized when A is oxazolyl. A subembodiment of this aspect is realized when a carbon atom of A is bonded to a carbon atom of B.

[0019] Another embodiment is realized when A is furanyl. A subembodiment of this aspect is realized when a carbon atom of A is bonded to a carbon atom of B.

[0020] Another embodiment is realized when A is thiophenyl. A subembodiment of this aspect is realized when a carbon atom of A is bonded to a carbon atom of B.

[0021] Another embodiment is realized when A is oxadiazolyl. A subembodiment of this aspect is realized when a carbon atom of A is bonded to a carbon atom of B.

[0022] Another embodiment is realized when A in Formula I is triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadiazolyl represented as follows:

[0023] Another embodiment is realized when B is pyridyl. Another embodiment is realized when B is pyridazinyl. Another embodiment is realized when B is pyrmidinyl.

[0024] Another embodiment is realized when B is pyridyl and A is triazolyl. Another embodiment is realized when B is pyridyl and A is isoxazolyl. Another embodiment is realized when B is pyridyl and A is thiazolyl. Another embodiment is realized when B is pyridyl and A is thiadiazolyl. Another embodiment is realized when B is pyridyl and A is oxazolyl. Another embodiment is realized when B is pyridyl and A is furanyl. Another embodiment is realized when B is pyridyl and A is thiophenyl. Another embodiment is realized when B is pyridyl and A is oxadi azolyl.

[0025] Another embodiment is realized when B is pyridazinyl and A is triazolyl. Another embodiment is realized when B is pyridazinyl and A is isoxazolyl. Another embodiment is realized when B is pyridazinyl and A is thiazolyl. Another embodiment is realized when B is pyridazinyl and A is thiadiazolyl. Another embodiment is realized when B is pyridazinyl and A is oxazolyl. Another embodiment is realized when B is pyridazinyl and A is furanyl. Another embodiment is realized when B is pyridazinyl and A is thiophenyl. Another embodiment is realized when B is pyridazinyl and A is oxadiazolyl.

[0026] Another embodiment is realized when B is pyrimidinyl and A is triazolyl. Another embodiment is realized when B is pyrimidinyl and A is isoxazolyl. Another embodiment is realized when B is pyrimidinyl and A is thiazolyl. Another embodiment is realized when B is pyrimidinyl and A is thiadiazolyl. Another embodiment is realized when B is pyrimidinyl and A is oxazolyl. Another embodiment is realized when B is pyrimidinyl and A is furanyl. Another embodiment is realized when B is pyrimidinyl and A is thiophenyl. Another embodiment is realized when B is pyrimidinyl and A is oxadiazolyl.

[0027] Another embodiment of this disclosure is realized when R3is bonded to a nitrogen atom ofB.

[0028] Another embodiment of this disclosure is realized when R1is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and hexyl, said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and hexyl optionally substituted with 1 to 3 substituents selected from OH, and OCi-6 alkyl. An aspect of this embodiment is realized when R1is selected from hydrogen, methyl, CH2OH, CH2OCH3. Another aspect of this embodiment is realized when R1is hydrogen. Another aspect of this embodiment is realized when R1is methyl. Another aspect of this embodiment is realized when R1is CH2OH. Another aspect of this embodiment is realized when R1is CH2OCH3.

[0029] A subembodiment of this aspect is realized when R1is C3-6 cycloalkyl ring. Another embodiment of this disclosure is realized when R1is C3-6 cycloalkyl selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Another embodiment of this disclosure is realized when R1is cyclopropyl. Another embodiment of this disclosure is realized when R1is cyclobutyl. Another embodiment of this disclosure is realized when R1cyclopentyl. Another embodiment of this disclosure is realized when R1is cyclohexyl.

[0030] Another embodiment of this disclosure is realized when R1is optionally substituted heteroaryl. A subembodiment of this aspect is realized when R1is heteroaryl selected from optionally substituted triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadiazolyl. A subembodiment of this aspect is realized when R1is optionally substituted triazolyl. A subembodiment of this aspect is realized when R1is optionally substituted isoxazolyl. A subembodiment of this aspect is realized when R1is optionally substituted thiazolyl. A subembodiment of this aspect is realized when R1is optionally substituted thiadiazolyl. A subembodiment of this aspect is realized when R1is optionally substituted isothiazolyl. A subembodiment of this aspect is realized when R1is optionally substituted pyrazolyl. A subembodiment of this aspect is realized when R1is optionally substituted pyrrolyl. A subembodiment of this aspect is realized when R1is optionallysubstituted tetrazolyl. A subembodiment of this aspect is realized when R1is optionally substituted oxazolyl. A subembodiment of this aspect is realized when R1is optionally substituted furanyl. A subembodiment of this aspect is realized when R1is optionally substituted thiophenyl. A subembodiment of this aspect is realized when R1is optionally substituted oxadi azolyl.

[0031] Another embodiment of this disclosure is realized when R2is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and hexyl, said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and hexyl optionally substituted with 1 to 3 substituents selected from OH, and OCi-6 alkyl. An aspect of this embodiment is realized when R2is selected from hydrogen, methyl, CH2OH, CH2OCH3. Another aspect of this embodiment is realized when R2is hydrogen. Another aspect of this embodiment is realized when R2is methyl. Another aspect of this embodiment is realized when R2is CH2OH. Another aspect of this embodiment is realized when R2is CH2OCH3.

[0032] A subembodiment of this aspect is realized when R2is C3-6 cycloalkyl ring. Another embodiment of this disclosure is realized when R2is C3-6 cycloalkyl ring selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Another embodiment of this disclosure is realized when R2is cyclopropyl. Another embodiment of this disclosure is realized when R2is cyclobutyl. Another embodiment of this disclosure is realized when R2cyclopentyl. Another embodiment of this disclosure is realized when R2is cyclohexyl.

[0033] Another embodiment of this disclosure is realized when R2is optionally substituted heteroaryl. A subembodiment of this aspect is realized when R2is heteroaryl selected from optionally substituted triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadiazolyl. A subembodiment of this aspect is realized when R2is optionally substituted triazolyl. A subembodiment of this aspect is realized when R2is optionally substituted isoxazolyl. A subembodiment of this aspect is realized when R2is optionally substituted thiazolyl. A subembodiment of this aspect is realized when R2is optionally substituted thiadiazolyl. A subembodiment of this aspect is realized when R2is optionally substituted tetrazolyl. A subembodiment of this aspect is realized when R2is optionally substituted oxazolyl. A subembodiment of this aspect is realized when R2is optionally substituted furanyl. A subembodiment of this aspect is realized when R2is optionally substituted thiophenyl. A subembodiment of this aspect is realized when R2is optionally substituted oxadiazolyl.

[0034] Another embodiment of this disclosure is realized when both R1and R2are hydrogen. Another embodiment of this disclosure is realized when both R1and R2are CH3. Another embodiment of this disclosure is realized when one of R1and R2is hydrogen and the other is26123selected from CH3, CH2OH, and CH2OCH3. A subembodiment of this aspect is realized when one of R1and R2is hydrogen and the other is selected from CH3.

[0035] Another embodiment of this disclosure is realized when one of R1and R2is hydrogen and the other is selected from heteroaryl selected from triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, and tetrazolyl. Another embodiment of this disclosure is realized when one of R1and R2is hydrogen and the other is triazolyl. Another embodiment of this disclosure is realized when one of R1and R2is hydrogen and the other isoxazolyl. Another embodiment of this disclosure is realized when one of R1and R2is hydrogen and the other thiazolyl. Another embodiment of this disclosure is realized when one of R1and R2is hydrogen and the other thiadiazolyl. Another embodiment of this disclosure is realized when one of R1and R2is hydrogen and the other tetrazolyl.

[0036] R1and R2combine to the atom to which they are attached to form a C3-6 cycloalkyl. Another embodiment of this disclosure is realized when R3is unsubstituted or substituted (CHR)nphenyl. An aspect of this embodiment is realized when n is 0. Another aspect of this embodiment is realized when n is 1. Another aspect of this embodiment is realized when n is 2. Another aspect of this embodiment is realized when n is 3. An aspect of this embodiment is realized when R3is (CHR)nphenyl optionally substituted with 1 to 3 substituents of Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb.

[0037] Another embodiment of the aspect is realized when Rais selected from C1-6 alkyl, OC1-6 alkyl, (CH2)nC(O)heterocycle, fluorine, chlorine, bromine, idodine, CH2F, CHF2, (CH2)nCF3, (CH2)nOCF3, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -(CH2)nC(O)NHCi-6alkyl, (CH2)nC(O)aryl, pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl, and -C(O)heterocycle, said alkyl, aryl, and pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl optionally substituted with 1 to 3 groups ofRb. Another aspect of this embodiment is realized when the heterocycle is morpholinyl. Another aspect of this embodiment is realized when Rais selected from CH2F, CHF2, and CF3. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NH(CH2)nOCi-6 alkyl. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NHCi-6 alkyl. Another aspect of this embodiment is realized when Rais -C(O)heterocycle, said alkyl being thiazolyl.Another embodiment of this disclosure is realized when R3is unsubstituted or substituted (CHR)npyridyl. An aspect of this embodiment is realized when n is 0. Another aspect of this embodiment is realized when n is 1. Another aspect of this embodiment is realized when n is 2. An aspect of this embodiment is realized when R3is (CHR)npyridyl substituted with 1 to 326123substituents of Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb.

[0038] Another embodiment of the aspect is realized when Rais selected from C1-6 alkyl, OC1-6 alkyl, (CH2)nC(O)heterocycle, fluorine, chlorine, bromine, idodine, CH2F, CHF2, (CH2)nCF3, (CH2)nOCF3, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -(CH2)nC(O)NHCi-6alkyl, (CH2)nC(O)aryl, pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl, and -C(O)heterocycle, said alkyl, aryl, and pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl optionally substituted with 1 to 3 groups ofRb. Another aspect of this embodiment is realized when the heterocycle is morpholinyl. Another aspect of this embodiment is realized when Rais selected from CH2F, CHF2, and CF3. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NH(CH2)nOCi-6 alkyl. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NHCi-6 alkyl. Another aspect of this embodiment is realized when Rais -C(O)heterocycle, said alkyl being thiazolyl.Another embodiment of this disclosure is realized when R3is unsubstituted or substituted (CHR)nthiophenyl. An aspect of this embodiment is realized when n is 0. Another aspect of this embodiment is realized when n is 1. Another aspect of this embodiment is realized when n is 2. An aspect of this embodiment is realized when R3is (CHR)nthiophenyl substituted with 1 to 3 substituents of Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb.

[0039] Another embodiment of the aspect is realized when Rais selected from C1-6 alkyl, OC1-6 alkyl, (CH2)nC(O)heterocycle, fluorine, chlorine, bromine, idodine, CH2F, CHF2, (CH2)nCF3, (CH2)nOCF3, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -(CH2)nC(O)NHCi-6alkyl, (CH2)nC(O)aryl, pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl, and -C(O)heterocycle, said alkyl, aryl, and pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl optionally substituted with 1 to 3 groups ofRb. Another aspect of this embodiment is realized when the heterocycle is morpholinyl. Another aspect of this embodiment is realized when Rais selected from CH2F, CHF2, and CF3. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NH(CH2)nOCi-6 alkyl. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NHCi-6 alkyl. Another aspect of this embodiment is realized when Rais -C(O)heterocycle, said alkyl being thiazolyl.Another embodiment of this disclosure is realized when R3is unsubstituted or substituted (CHR)nthiazolyl. An aspect of this embodiment is realized when n is 0. Another aspect of this embodiment is realized when n is 1. Another aspect of this embodiment is realized when n is 2. An aspect of this embodiment is realized when R3is (CHR)nthiazolyl substituted with 1 to 326123substituents of Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb.

[0040] Another embodiment of the aspect is realized when Rais selected from C1-6 alkyl, OC1-6 alkyl, (CH2)nC(O)heterocycle, fluorine, chlorine, bromine, idodine, CH2F, CHF2, (CH2)nCF3, (CH2)nOCF3, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -(CH2)nC(O)NHCi-6alkyl, (CH2)nC(O)aryl, pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl, and -C(O)heterocycle, said alkyl, aryl, and pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl optionally substituted with 1 to 3 groups ofRb. Another aspect of this embodiment is realized when the heterocycle is morpholinyl. Another aspect of this embodiment is realized when Rais selected from CH2F, CHF2, and CF3. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NH(CH2)nOCi-6 alkyl. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NHCi-6 alkyl. Another aspect of this embodiment is realized when Rais -C(O)heterocycle, said alkyl being thiazolyl.

[0041] Another embodiment of this disclosure is realized when R3is unsubstituted or substituted (CHR)nOphenyl. An aspect of this embodiment is realized when n is 0. An aspect of this embodiment is realized when aryl is phenyl. Another aspect of this embodiment is realized when n is 1. Another aspect of this embodiment is realized when n is 2. An aspect of this embodiment is realized when R3is (CHR)nOphenyl substituted with 1 to 3 substituents of Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb.

[0042] Another embodiment of the aspect is realized when Rais selected from C1-6 alkyl, OC1-6 alkyl, (CH2)nC(O)heterocycle, fluorine, chlorine, bromine, idodine, CH2F, CHF2, (CH2)nCF3, (CH2)nOCF3, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -(CH2)nC(O)NHCi-6alkyl, (CH2)nC(O)aryl, pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl, and -C(O)heterocycle, said alkyl, aryl, and pyrazolopyridinyl, triazolyl, pyrazolyl, oxazolyl optionally substituted with 1 to 3 groups ofRb. Another aspect of this embodiment is realized when the heterocycle is morpholinyl. Another aspect of this embodiment is realized when Rais selected from CH2F, CHF2, and CF3. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NH(CH2)nOCi-6 alkyl. Another aspect of this embodiment is realized when Rais -(CH2)nC(O)NHCi-6 alkyl. Another aspect of this embodiment is realized when Rais -C(O)heterocycle, said alkyl being thiazolyl.

[0043] Another embodiment of this disclosure is realized when R3is unsubstituted or substituted C2-6alkenylaryl, wherein the aryl is phenyl.

[0044] Another embodiment of this disclosure is represented by structural Formula II:IIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0045] Another embodiment of this disclosure is represented by structural Formula III:IIIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0046] Another embodiment of this disclosure is represented by structural Formula IV:IVwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0047] Another embodiment of this disclosure is represented by structural Formula V:Vwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0048] Another embodiment of this disclosure is represented by structural Formula VI:VIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0049] Another embodiment of this disclosure is represented by structural Formula VII:VIIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. An aspect of this embodiment is realized when R3is selected from (CH2)nphenyl, and (CH2)npyridyl, said phenyl and pyridyl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0050] Another embodiment of this disclosure is represented by structural Formula Vila:26123Vilawherein R1, R2and R3are as described herein and X is a bond or -(CH2)n- and n is as described herein. Another embodiment of this aspect is realized when X is a bond. Another embodiment of this aspect is realized when X is -(CH2)n-. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.Another aspect of this embodiment is realized when each Rbis independently selected from C1-6 alkyl, Ci-ealkylOR, OR, halogen, (CH2)nC3-6 cycloalkyl, and (CH2)nCi-3 haloalkyl, said alkyl, and cycloalkyl with 1 to 3 substituents selected from Rc.

[0051] Another embodiment of this disclosure is represented by structural Formula VIII:VIIIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.26123

[0052] Another embodiment of this disclosure is represented by structural Formula IX:wherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0053] Another embodiment of this disclosure is represented by structural Formula X:Xwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0054] Another embodiment of this disclosure is represented by structural Formula XI:26123F< NH9XIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0055] Another embodiment of this disclosure is represented by structural Formula XII:XIIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0056] Another embodiment of this disclosure is represented by structural Formula XIII:26123H2N S^ JL / N 3RI¥X\ J JR2 hH0XIIIwherein R1, R2and R3are as described herein. An aspect of this embodiment is realized when R3is selected from (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra. Another embodiment of this aspect is realized when Rais selected from Ci-6 alkyl, -OCi-6 alkyl, C3-6 cycloalkyl, -C(O)NRC3-6 cycloalkyl, and (CHR)nheteroaryl, said alkyl, cycloalkyl, and heteroaryl optionally substituted with 1 to 3 substituents selected from Rb. Another aspect of this embodiment is realize when R3is substituted with 1 to 3 Raselected from C1-6 alkyl, C1-6 alkylOH, -C(O)NHC3-6 cycloalkyl, C3-6 cycloalkyl, triazolyl, pyrazolyl, pyrazolopyridinyl, and oxazolyl, said alkyl, cycloalkyl, triazolyl, pyrazolyl pyrazolopyridinyl, and oxazolyl optionally substituted with 1 to 3 groups of Rb.

[0057] An aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulae I through XIII or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipients(s).

[0058] Another aspect of the disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulae I through XIII as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipient(s).

[0059] Another aspect of the disclosure relates to a compound of Formulae I through XIII as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof for use as a drug or drug component.

[0060] Another aspect of the disclosure relates to a compound of Formulae I through XIII as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a medicament for treating cancers arising from infection by human papillomavirus (HPV).26123

[0061] In another embodiment, the compounds of the disclosure include those identified herein as Examples in the tables below, and pharmaceutically acceptable salts thereof.

[0062] The compounds of the disclosure may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this disclosure. Unless a specific stereochemistry is indicated, the present disclosure is meant to encompass all such isomeric forms of these compounds.

[0063] The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined, amongst other methods, by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

[0064] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0065] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0066] In the compounds of Formulae I through XIII the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure may include all suitable isotopic variations of the compounds of generic Formulae I through XIII. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H).26123Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. For purposes of this disclosure when a compound is said to be “not deuterated” it means not enriched in deuterium beyond the background state. Isotopically-enriched compounds within generic Formulae I through XIII can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0067] When a compound of the disclosure can form tautomers, all such tautomeric forms are also included within the scope of the present disclosure. For example, compounds including carbonyl -CH2C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both keto and enol forms, where present, are included within the scope of the present disclosure.

[0068] When any variable (e.g., R5, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be bonded to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.

[0069] It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant disclosure in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

[0070] It is understood that substituents and substitution patterns on the compounds of the instant disclosure can be selected by one of ordinary skill in the art to provide compounds that26123are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase “optionally substituted with one or more substituents” should be understood as meaning that the group in question is either unsubstituted or may be substituted with one or more substituents.

[0071] Absolute stereochemistry is illustrated by the use of hashed and solid wedge bonds. As shown in Illus-I and Illus-II. Accordingly, the methyl group of Illus-I is emerging from the page of the paper and the ethyl group in Illus-II is descending into the page, where the cyclohexene ring resides within the plane of the paper. It is assumed that the hydrogen on the same carbon as the methyl group of Illus-I descends into the page and the hydrogen on the same carbon as the ethyl group of Illus-II emerges from the page. The convention is the same where both a hashed and solid rectangle are appended to the same carbon as in Illus-III, the methyl group is emerging from the plane of the paper and the ethyl group is descending into the plane of the paper with the cyclohexene ring in the plane of the paper.

[0072] As is conventional, unless otherwise noted in accompanying text, ordinary "stick" bonds or "wavy" bonds indicate that all possible stereochemistry is represented, including, pure compounds, mixtures of isomers, and racemic mixtures.

[0073] As used herein, unless otherwise specified, the following terms have the following meanings:

[0074] The phrase “at least one” used in reference to the number of components comprising a composition, for example, "at least one pharmaceutical excipient" means that one member of the specified group is present in the composition, and more than one may additionally be present. Components of a composition are typically aliquots of isolated pure material added to the composition, where the purity level of the isolated material added into the composition is the normally accepted purity level for a reagent of the type.

[0075] Whether used in reference to a substituent on a compound or a component of a pharmaceutical composition the phrase "one or more", means the same as "at least one";

[0076] “Effective amount” or “therapeutically effective amount” is meant to describe the provision of an amount of at least one compound of the disclosure or of a composition comprising at least one compound of the disclosure which is effective in treating or inhibiting a26123disease or condition described herein, and thus produce the desired therapeutic, ameliorative, inhibitory or preventative effect. For example, in treating central nervous system diseases or disorders with one or more of the compounds described herein “effective amount” (or “therapeutically effective amount”) means, for example, providing the amount of at least one compound of Formulae I through XIII that results in a therapeutic response in a patient afflicted with a central nervous system disease or disorder ("condition"), including a response suitable to manage, alleviate, ameliorate, or treat the condition or alleviate, ameliorate, reduce, or eradicate one or more symptoms attributed to the condition and / or long-term stabilization of the condition, for example, as may be determined by the analysis of pharmacodynamic markers or clinical evaluation of patients afflicted with the condition;

[0077] “Patient” and "subject" means an animal, such as a mammal (e.g., a human being) and is preferably a human being;

[0078] “Prodrug” means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of Formula I through Formula XIII to a compound of Formula I, through Formula XIII or to a salt thereof; a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987, both of which are incorporated herein by reference; the scope of this disclosure includes prodrugs of the novel compounds of this disclosure.

[0079] The term “substituted” means that one or more of the enumerated substituents can occupy one or more of the bonding positions on the substrate typically occupied by "-H", provided that such substitution does not exceed the normal valency rules for the atom in the bonding configuration presented in the substrate, and that the substitution ultimately provides a stable compound, which is to say that such substitution does not provide compounds with mutually reactive substituents located geminal or vicinal to each other; and wherein the substitution provides a compound sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

[0080] Where optional substitution of a moiety is described (e.g., "optionally substituted") the term means that if substituents are present, one or more of the enumerated substituents for the specified substrate can be present on the substrate in a bonding position normally occupied by the default substituent normally occupying that position. For example, a default substituent on the carbon atoms of an alkyl moiety is a hydrogen atom, an optional substituent can replace the default substituent.

[0081] As used herein, unless otherwise specified, the following terms used to describe moieties, whether comprising the entire definition of a variable portion of a structural representation of a compound of the disclosure or a substituent appended to a variable portion of a structural representation of a group of compounds of the disclosure have the following meanings, and unless otherwise specified, the definitions of each term (i.e., moiety or substituent) apply when that term is used individually or as a component of another term (e.g., the definition of aryl is the same for aryl and for the aryl portion of arylalkyl, alkylaryl, arylalkynyl moieties, and the like); moieties are equivalently described herein by structure, typographical representation or chemical terminology without intending any differentiation in meaning, for example, an "acyl" substituent may be equivalently described herein by the term “acyl”, by typographical representations " R'-(C=O)-" or " R'-C(O)-", or by a structural representation:Oequally, with no differentiation implied using any or all of these representations;

[0082] The term “alkyl” (including the alkyl portions of other moieties, such as trifluoromethyl-alkyl- and alkoxy-) means a straight or branched aliphatic hydrocarbon moiety comprising up to about 20 carbon atoms (for example, a designation of " Ci-20 -alkyl" indicates an aliphatic hydrocarbon moiety of from 1 to 20 carbon atoms). In some embodiments, alkyls preferably comprise up to about 10 carbon atoms, unless the term is modified by an indication that a shorter chain is contemplated, for example, an alkyl moiety of from 1 up to 8 carbon atoms is designated herein " Ci-8-alkyl". Where the term "alkyl" is indicated with two hyphens (i.e., "-alkyl-" it indicates that the alkyl moiety is bonded in a manner that the alkyl moiety connects the substituents on either side of it, for example, "-alkyl-OH" indicates an alkyl moiety connecting a hydroxyl moiety to a substrate.

[0083] As used herein, when the term "alkyl" is modified by "substituted" or "optionally substituted", it means that one or more C-H bonds in the alkyl moiety group is substituted, or optionally may be substituted, by a substituent bonded to the alkyl substrate which is called out in defining the moiety.

[0084] Where a structural formula represents bonding between a moiety and a substrate using a bonding line that terminates in the middle of the structure, for example the followingrepresentations:whether or not numbered the structure indicates that unless otherwise defined the moiety may be bonded to the substrate through any of available ring atom, for example, the numbered atoms of the example moieties.

[0085] The term " Cycloalkyl" means a non-aromatic monocyclic or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of multicyclic cycloalkyls include [1.1. l]-bicyclo pentane, indanyl, 1-decalinyl, norbornyl, adamantyl and the like.

[0086] The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic ring or polycyclic fused ring (i.e., each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) having a conjugated it-electron system, preferably a 6 to 10 membered aryl, for example, phenyl and naphthyl, and preferably phenyl.

[0087] The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms for monocyclic, 1-6 heteroatoms for bicyclic, or 1-9 heteroatoms for tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S for monocyclic, bicyclic, or tricyclic, respectively). Non-limiting examples of heteroaryls are pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, furanyl, oxazolyl, triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, and thiophenyl. The heteroaryl groups herein described may also contain fused rings that share a common carbon-carbon bond.

[0088] “Heterocycloalkyl” (heterocycle or "heterocyclyl") means a non-aromatic, saturated or partially saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system.Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocycloalkyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this disclosure. The heterocycloalkyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S, S-di oxide. “Heterocycloalkyl” also includes rings wherein =0 replaces two available hydrogens on the same carbon atom (i.e., heterocycloalkyl includes rings having a carbonyl group in the ring). Such =0 groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (orpyrrolidone):. As used herein, the term “monocyclic heterocycloalkyl” refers monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(0), and S(0)2. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Anon-limiting example of a monocyclic heterocycloalkyl group includes the moiety:Non-limiting examples of multicyclic heterocycloalkyl groups include, bicyclic heterocycloalkylgroups. Specific examples include, but are not limited to,

[0089] The term "solvate" refers to a pharmaceutically acceptable solvate formed by a compound of the present disclosure with one or more solvent molecule(s). Non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate.

[0090] The term “halogen” means fluorine, chlorine, bromine, or iodine; preferred halogens, unless specified otherwise where the term is used, are fluorine, chlorine and bromine, a substituent which is a halogen atom means -F, -Cl, -Br, or -I, and “halo” means fluoro, chloro, bromo, or iodo substituents bonded to the moiety defined, for example, "haloalkyl” means an alkyl, as defined above, wherein one or more of the bonding positions on the alkyl moiety typically occupied by hydrogen atoms are instead occupied by a halo group, perhaloalkyl (or “fully halogenated” alkyl) means that all bonding positions not participating in bonding the alkyl substituent to a substrate are occupied by a halogen, for example, where the alkyl is selected to be methyl, the term perfluoroalkyl means -CF3;

[0091] The term "hydroxyl" and "hydroxy" means an HO- group, “hydroxyalkyl” means a substituent of the formula: " HO-alkyl-" or equivalently “-alkyl-OH”, wherein the alkyl group is bonded to the substrate and may be substituted or unsubstituted as defined above; preferred hydroxyalkyl moieties comprise a lower alkyl; Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxy ethyl.

[0092] The bonding sequence is indicated by hyphens where moieties are represented in text, for example -alkyl, indicates a single bond between a substrate and an alkyl moiety, -alkyl-X, indicates that an alkyl group bonds an " X" substituent to a substrate, and in structural representation, bonding sequence is indicated by a wavy line terminating a bond representation,for example:, indicates that the methylphenyl moiety is bonded to a substrate through a carbon atom ortho to the methyl substituent, while a bond representation terminated with a wavy line and drawn into a structure without any particular indication of an atom to which it is bonded indicates that the moiety may be bonded to a substrate via any of the atoms in the moiety which are available for bonding as described in the examples above.

[0093] The line —, as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (5)- stereochemical configuration.

[0094] Unwedged-bolded or unwedged-hashed lines are used in structures containing multiple stereocenters in order to depict relative configuration where it is known. For example:means that the fluorine and hydrogenatoms are on the same face of the piperidine ring, but represents a mixture of, F and / or,vF or one of, the possible isomers at rightwhereas:H H H H H

[0095] In all cases, compound name(s) accompany the structure drawn and are intended to capture each of the stereochemical permutations that are possible for a given structural isomer based on the synthetic operations employed in its preparation. Lists of discrete stereoisomers that are conjoined using or indicate that the presented compound (e.g., ‘Example number’) was isolated as a single stereoisomer, and that the identity of that stereoisomer corresponds to one of the possible configurations listed. Lists of discrete stereoisomers that are conjoined using and indicate that the presented compound was isolated as a racemic mixture or diastereomeric mixture.

[0096] A specific absolute configuration is indicated by use of a wedged-bolded or wedged-hashed line. Unless a specific absolute configuration is indicated, the present disclosure is meant to encompass all such stereoisomeric forms of these compounds.

[0097] In this specification, where there are multiple oxygen and / or sulfur atoms in a ring system, there cannot be any adjacent oxygen and / or sulfur present in said ring system.

[0098] As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

[0099] Unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein is assumed to have a hydrogen atom or atoms of sufficient number to satisfy the valences.

[0100] One or more compounds of the disclosure may also exist as, or optionally be converted to, a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, and hemisolvate, including hydrates (where the solvent is water or aqueous-based) and the like are described by E. C. van Tonder et al., AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting, process involvesdissolving the inventive compound in desired amounts of the desired solvent (for example, an organic solvent, an aqueous solvent, water or mixtures of two or more thereof) at a higher than ambient temperature, and cooling the solution, with or without an antisolvent present, at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (including water) in the crystals as a solvate (or hydrate in the case where water is incorporated into the crystalline form).

[0101] This disclosure also includes the compounds of this disclosure in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of Formula I through Formula XIII and of the salts, solvates and prodrugs of the compounds of Formula I through Formula XIII are intended to be included in the present disclosure. Certain compounds of the disclosure may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). The inventive compounds include all isomeric forms thereof, both in pure form and admixtures of two or more, including racemic mixtures.

[0102] In the same manner, unless indicated otherwise, presenting a structural representation of any tautomeric form of a compound which exhibits tautomerism is meant to include all such tautomeric forms of the compound. Accordingly, where compounds of the disclosure, may exist in different tautomeric forms or in equilibrium among such forms, all such forms of the compound are embraced by, and included within the scope of the disclosure. Examples of such tautomers include, but are not limited to, ketone / enol tautomeric forms, imine-enamine tautomeric forms, and for example heteroaromatic forms such as the following moieties:H

[0103] 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.

[0104] As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Salts in the solid form may exist in more than one crystal structure and may also be in the form of hydrates. 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;26123and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as formic, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.

[0105] When the compound of the present disclosure is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. In one aspect of the disclosure the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.

[0106] The terms “treating” or “treatment” (of, e.g., a disease, disorder, or conditions or associated symptoms, which together or individually may be referred to as “indications”) as used herein include: inhibiting the disease, disorder or condition, i.e., arresting or reducing the development of the disease or its biological processes or progression or clinical symptoms thereof; or relieving the disease, i.e., causing regression of the disease or its biological processes or progression and / or clinical symptoms thereof. “Treatment” as used herein also refers to control, amelioration, or reduction of risks to the subject afflicted with a disease, disorder or condition in which a tumor is involved. The terms “preventing” or “prevention” or “prophylaxis” of a disease, disorder or condition as used herein includes: impeding the development or progression of clinical symptoms of the disease, disorder, or condition in a mammal that may be exposed to or predisposed to the disease, disorder or condition but does not yet experience or display symptoms of the disease, and the like.

[0107] As would be evident to those skilled in the art, subjects treated by the methods described herein are generally mammals, including humans and non-human animals (e.g., laboratory animals and companion animals). The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system,26123animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

[0108] The term "composition" as used herein is intended to encompass a product comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, together with one or more additional specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), which include a compound of the disclosure or a pharmaceutically acceptable salt thereof, optionally together with one or more additional active ingredients, and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0109] As noted above, additional embodiments of the present disclosure are each directed to a method for the treatment a disease, disorder, or condition, or one or more symptoms thereof (“indications”) which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or salt thereof.

[0110] In another embodiment, the present disclosure is directed to a method for the manufacture of a medicament for use in a subject comprising combining a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, with a pharmaceutical carrier or diluent.[OHl] One such embodiment provides a method of treating or preventing cancers arising from infection by human papillomavirus (HPV), including cancers selected from cervical cancer, oropharyngeal (head and neck) cancer, rectal cancer, penile cancer, vulval cancer, vaginal cancer, cutaneous squamous cell carcinoma in a subject in need thereof, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a26123pharmaceutical composition comprising said compound, salt or solvate thereof. In one such embodiment, the subject is a human.

[0112] Combinations with additional therapeutic agents are also contemplated in the instant methods. For example, combinations of the compounds of Formula I through XIII with PPAR-y (i.e., PPAR-gamma) agonists and PPAR-6 (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPAR-y and PPAR-6 are the nuclear peroxisome proliferator-activated receptors y and 6. PPAR-y agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice (Arch. Ophthamol. 2001; 119:709-717). Examples of PPAR-y agonists and PPAR- y / oc agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09 / 782,856), and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy) phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in USSN 60 / 235,708 and 60 / 244,697), or a pharmaceutically acceptable salt thereof.

[0113] Another embodiment of the disclosure is a method for treating HPV infections in a subject in need thereof, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising said compound, salt or solvate thereof.

[0114] Another embodiment of the instant disclosure is the use of the compounds of Formula I through XIII in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer see Hall et al., (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe et al., (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U. S. Patent No. 6,069,134, for example), a uPA / uPAR antagonist (" Adenovirus-Mediated Delivery of a uPA / uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998; 5(8): 1105-13), and interferon gamma (J. Immunol. 2000; 164:217-222).26123

[0115] The compounds of Formula I through XIII may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar), or a pharmaceutically acceptable salt thereof.

[0116] The compounds of Formula I through XIII may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin, or a pharmaceutically acceptable salt thereof.

[0117] The compounds of Formula I through XIII may also be useful for treating or preventing cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclob enzaprine, erythromycin, cocaine, furafyline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone and nelfinavir, or a pharmaceutically acceptable salt thereof.

[0118] The compounds of Formula I through XIII may also be useful for treating or preventing cancer in combination with Pgp and / or BCRP inhibitors including: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorgin C, Kol32, Kol34, Iressa, Imatnib mesylate, EKI-785, Cl 1033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A, flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and talinolol, or a pharmaceutically acceptable salt thereof.

[0119] The compounds of Formula I through XIII may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates, including but not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.

[0120] The compounds of Formula I through XIII may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane, or a pharmaceutically acceptable salt thereof.

[0121] The compounds of Formula I through XIII may also be useful for treating or preventing cancer in combination with siRNA therapeutics.26123

[0122] The compounds of Formula I through XIII may also be administered in combination with y-secretase inhibitors and / or inhibitors of NOTCH signaling. Such inhibitors include compounds described in WO 01 / 90084, WO 02 / 30912, WO 01 / 70677, WO 03 / 013506, WO 02 / 36555, WO 03 / 093252, WO 03 / 093264, WO 03 / 093251, WO 03 / 093253, WO 2004 / 039800, WO 2004 / 039370, WO 2005 / 030731, WO 2005 / 014553, USSN 10 / 957,251, WO 2004 / 089911, WO 02 / 081435, WO 02 / 081433, WO 03 / 018543, WO 2004 / 031137, WO 2004 / 031139, WO 2004 / 031138, WO 2004 / 101538, WO 2004 / 101539 and WO 02 / 47671 (including LY-450139), or a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, specific anticancer agents useful in the present combination therapies include, but are not limited to: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone injection®); Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU26123(Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (El oxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®);Tositumomab (Bexxar®); Tositumomab / I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); Olaparib (Lynparza®) vorinostat (Zolinza®) and zoledronate (Zometa®), or a pharmaceutically acceptable salt thereof.

[0124] Thus, the scope of the instant disclosure encompasses the use of the compounds of Formula I through XIII in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an26123HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-y agonists, PPAR-6 agonists, an inhibitor of inherent multidrug resistance, an anti -emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, y-secretase and / or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed above.

[0125] Yet another example of the disclosure is a method of treating cancer that comprises administering a therapeutically effective amount of a compound of Formula I through XIII in combination with paclitaxel or trastuzumab.

[0126] The therapeutic combination disclosed herein may be used in combination with one or more other active agents, including but not limited to, other anti -cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cell-proliferation disorders). In one embodiment, a compound of Formula I through XIII is combined with one or more other anti-cancer agents for use in the prevention, treatment, control amelioration, or reduction of risk of a particular disease or condition for which the compounds of Formula I through XIII are useful. Such other active agents may be administered, by a route and in an amount commonly used therefor, prior to, contemporaneously, or sequentially with a compound of the present disclosure.

[0127] The instant disclosure also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of compounds of Formula I through XIII and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-y agonist, a PPAR-6 agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, y-secretase and / or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed above.

[0128] The disclosure further relates to a method of treating cancer in a human patient comprising administration of a compound of Formula I through Formula XIII and a PD-1 antagonist to the patient. The compound of the disclosure and the PD-1 antagonist may be administered concurrently or sequentially.26123

[0129] In particular embodiments, the PD-1 antagonist is an anti-PD-1 antibody, or antigen binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-Ll antibody, or antigen binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody, independently selected from pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, atezolizumab (MPDL3280A), camrelizumab and toripalimab. In other embodiments, the PD-L1 antagonist is an anti-PD-Ll antibody independently selected from atezolizumab, durvalumab and avelumab.

[0130] In one embodiments, the PD-1 antagonist is pembrolizumab. In particular subembodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.

[0131] In further sub-embodiments, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every three weeks. In particular sub-embodiments, the patient is a pediatric patient.

[0132] In some embodiments, the PD-1 antagonist is nivolumab. In particular subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to the patient about every four weeks.

[0133] In some embodiments, the PD-1 antagonist is cemiplimab. In particular embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.

[0134] In some embodiments, the PD-1 antagonist is atezolizumab. In particular subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every three weeks.

[0135] In some embodiments, the PD-1 antagonist is durvalumab. In particular subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every two weeks.

[0136] In some embodiments, the PD-1 antagonist is avelumab. In particular sub-embodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks.

[0137] When the compounds of Formula I through XIII are administered in combination with an anti-human PD-1 antibody (or antigen-binding fragment thereof), the anti-human PD-1 antibody (or antigen-binding fragment thereof) may be administered either simultaneously with, or before or after, one of the compounds of Formula I through XIII. Either of the anti-human PD-1 antibody (or antigen-binding fragment thereof), and / or a compound of Formula I through XIII, or a pharmaceutically acceptable salt thereof, may be administered separately, by the same or26123different route of administration, or together in the same pharmaceutical composition as the other agent(s). The weight ratio of the anti-human PD-1 antibody (or antigen-binding fragment thereof) to a compound of Formula I through XIII, may be varied and will depend upon the therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each will be used. Combinations including at least one anti-human PD-1 antibody (or antigen-binding fragment thereof), a compound of Formula I through XIII, and optionally other active agents will generally include a therapeutically effective dose of each active agent. In such combinations, the anti-human PD-1 antibody (or antigen -binding fragment thereof), the compounds of Formula I through XIII, and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of other agent(s).

[0138] In one embodiment, this disclosure provides an anti-human PD-1 antibody (or antigenbinding fragment thereof), and / or a compound of Formula I through XIII, and at least one other active agent as a combined preparation for simultaneous, separate or sequential use in treating cancer.

[0139] The disclosure also provides the use of a compound of Formula I through XIII, for treating cancer, where the patient has previously (e.g., within 24-hours) been treated with an antihuman PD-1 antibody (or antigen-binding fragment thereof). The disclosure also provides the use of an anti -human PD-1 antibody (or antigen-binding fragment thereof) for treating a cellular proliferative disorder, where the patient has previously (e.g., within 24-hours) been treated with an antibody -linker-payload compound (ADC)a compound of Formula I through XIII.

[0140] The present disclosure further relates to methods of treating cancer, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) a compound of Formula I through XIII, and (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof); wherein the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 21 days.

[0141] Additionally, the present disclosure relates to methods of treating cancer, said method comprising administering to a subject in need thereof a combination therapy that comprises: (a) a compound of Formula I through XIII, and (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof. In specific embodiments, the cancer occurs as one or more solid tumors or lymphomas. In further specific embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In still further specific embodiments, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, MSI-H cancer, MMR deficient cancer, non-small cell lung cancer, urothelial26123carcinoma, gastric or gastroesophageal junction adenocarcinoma, breast adenocarcinoma, and lymphomas. In additional embodiments, the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma / leukemia, nasal type extranodal NK / T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma / delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma. In particular embodiments, the cellular proliferative disorder is a cancer that has metastasized, for example, a liver metastases from colorectal cancer. In additional embodiments, the cellular proliferative disorder is a cancer is classified as stage III cancer or stage IV cancer. In instances of these embodiments, the cancer is not surgically resectable.

[0142] In embodiments of the methods disclosed herein, the anti-human PD-1 antibody (or antigen binding fragment thereof) is administered by intravenous infusion or subcutaneous injection.

[0143] In one embodiment, the present disclosure provides compositions comprising a compound of Formula I through XIII, a pharmaceutically acceptable carrier, and an anti-human PD-1 antibody (or antigen-binding fragment thereof).

[0144] In another embodiment, the present disclosure provides compositions comprising a compound of Formula I through XIII, a pharmaceutically acceptable carrier, and pembrolizumab.

[0145] In one embodiment, the present disclosure provides compositions comprising a compound of Formula I through XIII, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is an anti-human PD-1 antibody (or antigen-binding fragment thereof), and the other of which is independently selected from the group consisting of anti cancer agents.

[0146] A compound of Formulas I through XIII may be employed in conjunction with antiemetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present disclosure, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present disclosure may be used in conjunction with other anti-emetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron,26123and zatisetron, GAB AB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U. S. Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide, aprepitant, fosaprepitant, or dronabinol. In another example, conjunctive therapy with an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the compounds of Formula I through XIII.

[0147] The compounds of Formula I through XIII may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous erythropoiesis receptor activator (such as epoetin alfa).

[0148] The compounds of Formula I through XIII may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim.

[0149] The compounds of Formula I through XIII may be useful when co-administered with other treatment modalities, including but not limited to, radiation therapy, surgery, and gene therapy. Accordingly, in one embodiment, the methods of treating cancer described herein, unless stated otherwise, can optionally include the administration of an effective amount of radiation therapy. For radiation therapy, y-radiation is preferred.

[0150] The methods of treating cancers described herein can optionally include the administration of an effective amount of radiation (i.e., the methods of treating cancers described herein optionally include the administration of radiation therapy).

[0151] The methods of treating cancer described herein include methods of treating cancer that comprise administering a therapeutically effective amount of a compound of Formula I through XIII in combination with radiation therapy and / or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic / ytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-y agonists, PPAR-6 agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA26123therapeutic, y-secretase and / or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the additional therapeutic agents listed herein.

[0152] Additionally provided are pharmaceutical compositions, combinations, uses and methods set forth in above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.Kits

[0153] In one aspect, provided is a kit comprising a therapeutically effective amount of a compound of Formula I through XIII or a pharmaceutically acceptable salt, solvate or ester of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

[0154] In another aspect provided is a kit comprising an amount of a compound of Formula I through XIII, and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect. In one embodiment, the compound of Formula I through XIII, and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the compound of Formula I through XIII, and the one or more additional therapeutic agents are provided in separate containers.

[0155] The present disclosure includes within its scope prodrugs of the compounds of this disclosure. In general, such prodrugs will be functional derivatives of the compounds of this disclosure which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present disclosure, the terms "administration of or "administering a" compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in " Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this disclosure into the biological milieu.

[0156] The compounds of Formulas I through XIII may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion,26123subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals the compounds of the disclosure are effective for use in humans.

[0157] The pharmaceutical compositions for the administration of the compounds of this disclosure may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0158] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be 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 may be employed. They may also be coated by the techniques described in the U. S. Patents 4,256,108; 4,166,452; and 4,265,874 to form26123osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.

[0159] Formulations for oral use may 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.

[0160] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy -propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0161] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0162] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0163] The pharmaceutical compositions of the disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring26123phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0164] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

[0165] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3 -butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0166] The compounds of the present disclosure may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0167] For topical use, creams, ointments, jellies, solutions or suspensions and the like, containing the compounds of the present disclosure are employed. Similarly, transdermal patches may also be used for topical administration.

[0168] The pharmaceutical composition and method of the present disclosure may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above-mentioned pathological conditions.

[0169] In the treatment, prevention, control, amelioration, or reduction of risk of the conditions disclosed herein an appropriate dosage level of the compounds of this disclosure will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions may be26123provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day or may be administered once or twice per day.

[0170] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0171] Methods for preparing the compounds of this disclosure are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein.Preparative Examples

[0172] The compounds of the present disclosure can be prepared according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. It is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail. The general procedures for making the compounds claimed in this disclosure can be readily understood by one skilled in the art from viewing the following schemes and descriptions. Abbreviations used in the experimentals may include, but are not limited to the following:aq AqueousAcOH Acetic acidCu(OAc)2 Cupric acetateCuSO4 Copper(II) sulfatecv Column volumeDCM DichloromethaneDIBAL-H Diisobutylaluminum hydrideDIPEA / DIEA N, N -Dii sopropy 1 ethyl amineDIC DiisopropylcarbodiimideDMF DimethylformamideDMP Dimethyl phthalateeq. Equivalent(s)DMSO Dimethyl sulfoxideDTT Dithiothreitol261231 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide EDCI hydrochlorideEtOAc Ethyl acetateEDTA Ethylenediaminatetraacetic acidEtOH EthanolEt3N / TEA TriethylamineEt2O Diethyl etherEt2NH DiethylamineEEDQ N-Ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline FA Formic acidFmoc Fluorenylmethyloxy carbonyl(l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- HATU b]pyridinium 3 -oxide hexafluorophosphate AfAfA\ / ' / '-Tetramethyl-(9-(l / / -benzotri azol- 1 -yl)uronium HBTU hexafluorophosphateHOAt 1 -Hydroxy-7-azabenzotri azolehr, h Hour(s)'HAMR Proton nuclear magnetic resonanceHC1 Hydrochloric acidHPLC High performance liquid chromatographyIPA Isopropyl alcoholIPTG Isopropyl (3-D-l-thioglalactopyranosideKHSO4 Potassium bisulfateK2CO3 Potassium carbonateK3PO4 Tripotassium phosphateLCMS Liquid chromatography-mass spectrometryLiOH Lithium hydroxideLiCl Lithium chloridemAb Monoclonal antibodyMBHA 4-methylbenzhydrylamine resinMgSO4Magnesium Sulfatemin Minute(s)MeCN AcetonitrileMeOH MethanolMgBr Magnesium bromideMS Mass spectrometryMTBE Methyl tert-butyl etherm / z Mass to charge ratioNaBH3CN Sodium cyanoborohydrideNaCl Sodium chlorideNaIO4Sodium periodateNaN3Sodium azideNaNO2Sodium nitrateNa2SO4Sodium sulfateNaHCCh Sodium bicarbonateNaBH4Sodium borohydrideNaOTMS Sodium trimethyl silanoateNH4CI Ammonium chlorideNH4OAc Ammonium acetate26123NH4OH Ammonium hydroxideNHS N-hydroxy succinimideNMM N-MethylmorpholinePb(OAc)4Lead(IV) acetatePBS Phosphate-buffered salinePd PalladiumPd / C Palladium on carbonPd(dppf)Cl2Bis(diphenylphosphino)ferrocene palladium(II) dichloride Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)PhB(OH)2Phenylboronic acidbenzotriazol-l-yloxytripyrrolidinophosphoniumPyBOP hexafluorophosphatePyNO Py ri dine-N-oxi deRT Room temperatureRUO2Ruthenium(IV) oxideSFC Supercritical Fluid ChromatographyTBSC1 tert-Butyl dimethyl silyl chlorideTCEP Tris(2-carboxyethyl)phosphineTFA Trifluoroacetic acidTHPTA Tris(3-hydroxypropyltriazolylmethyl)amineTHF TetrahydrofuranTi(Oi-Pr)4Titanium tetra-iso-propoxideTLC Thin Layer ChromatographyTMS T etram ethyl silanetR Retention timeGeneral Experimental Information:

[0173] Unless otherwise noted, all reactions were magnetically stirred. All reagents and solvents were purchased from commercial sources and used as is unless otherwise noted.Reaction progress and synthetic intermediate analysis were assessed by LCMS (UV detection with ESI, APCI, or other mass detection) when applicable using a MeCN / water gradient with either TFA, formic acid, or NH4HCO3 modifier. Silica gel and reverse-phase flash column chromatography were conducted with commercially available pre-packed columns. Reversephase preparative HPLC purification was performed on preparative HPLC instruments with UV and MS detection using a MeCN / water gradient with either TFA, formic acid, or NFUOH modifier.XH NMR spectra were collected at room temperature, and chemical shifts are reported in ppm relative to the residual proteo-solvent signals, and multiplicities, coupling constants (where applicable), and signal integrations are listed parenthetically. Unless otherwise noted, all EC50 data presented in tables refers to the cytotoxicity assays that are described in the Biological Assay section.26123

[0174] The compounds of the disclosure may be prepared by methods known in the art of organic synthesis as set forth in part by the following general synthetic schemes and specific preparative examples. Starting materials are available commercially or may be prepared by known methods. Absolute stereochemistry of separate stereoisomers in the Examples and Intermediates was not determined unless stated otherwise in an Example or Intermediate synthesis.Absolute stereochemistry of separate stereoisomers in the Examples and Intermediates was not determined unless stated otherwise in an Example or Intermediate synthesis.SYNTHESIS OF INTERMEDIATES4-ethynylDyridazin-3(2H)-one (1-1)Et3N, DHP, pTsOH TMS Pd(PPh3)2Cl2 Sfep 1 III Step 2HCI K2CO3, MeOH Sfep 3 Sfep 4O1-1 Step. 4-chloro-2-(tetrahvdro-2H-pyran-2-yl)pyridazin-3(2H)-oneUnder an inert atmosphere, a solution of 4-chloropyridazin-3(2J7)-one (180 g, 1.4 mol) in THF (3.60 L) was treated with / ?-toluenesulfonic acid monohydrate (32 g, 0.17 mol) at 20 °C. 3,4- Dihydro-27 / -pyran (DHP, 580 g, 6.9 mol) was added, and the mixture was heated with stirring to 70 °C for 17 h. The mixture was cooled to RT, and the cooled mixture was diluted with water (3.00 L). Extraction with ethyl acetate (500 mL, three times) was performed, and the combined organic extracts were washed with saturated aqueous NaCl solution. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5% EtOAc / hexanes initially, grading to 50% EtOAc / hexanes) to provide the desired product.1H NMR (400 MHz, CD3CN) 3 7.77 (d, J = 4.4 Hz, 1H), 7.49 (d, J= 4.4 Hz, 1H), 5.94 (dd, J= 2.4, 10.8 Hz, 1H), 4.04 - 3.99 (m, 1H), 3.74 - 3.59 (m, 1H), 2.14 - 2.07 (m, 1H), 2.04 - 1.96 (m, 1H), 1.80 - 1.46 (m, 4H)Step 2 2-(tetrahydro-2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)pyridazin-3(2H)-oneUnder an inert atmosphere, triethylamine (525 mL, 382 g, 3.77 mol) and ethynyltrimethylsilane (349 mL, 247 g, 2.52 mol) were added to a solution of 4-chloro-2-26123(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (270 g, 1.26 mol) in THF (2.70 L) at 20 °C. Next, Pd(PPh3)C12 (44.1 g, 63.0 mmol) was added, and the mixture was heated to 70 °C with stirring for 12 h. The reaction was cooled to RT, and water (2.00 L) was added. The resulting mixture was extracted with ethyl acetate (500 mL, three times). The combined organic extracts were washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5% EtOAc / hexanes initially, grading to 20% EtOAc / hexanes) to provide the desired product. 'H NMR (400 MHz, CD3CN) 67.81 (d, J = 4.0 Hz, 1H), 7.28 (s, 1H), 6.10 (dd, J = 2, 10.8 Hz, 1H), 4.16 - 4.10 (m, 1H), 3.75 (dt, = 2.4, 11.6 Hz, 1H), 2.17 - 2.08 (m, 1H), 2.05 - 1.99 (m, 1H), 1.80 - 1.54 (m, 4H), 0.30 - 0.23 (m, 9H).Step 3 4-((trimethylsilyl)ethvnyl)pyridazin-3(2H)-oneA solution of 2-(tetrahydro-2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)pyridazin-3(2H)-one (313 g, 1.13 mol) in methanol (2.35 L) was treated with cone. HC1 (10M, 738 mL) at 20 °C. The reaction was heated to 50 °C with stirring for 3 hours, cooled to RT, and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water (3.00 L), and extraction with ethyl acetate was performed (500 mL, three times). The combined extracts were washed with sat. aq. NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in MTBE (500 mL), and this suspension was stirred at 25 °C for 30 min. The mixture was then filtered, and the filter cake was dried under reduced pressure to provide the desired product.1H NMR (400 MHz, CDCh) 3 12.53 (s, 1H), 7.80 (d, J= 4 Hz, 1H), 7.36 (d, J= 4 Hz, 1H), 0.27 (s, 9H).Step 4 4-ethynylpyridazin-3(2H)-onePotassium carbonate (262 g, 1.89 mol) was added to a stirred solution of 4-((trimethylsilyl)ethynyl)pyridazin-3(2H)-one (182 g, 0.95 mol) in methanol (1.82 L) at 20 °C. The mixture was stirred for 30 min before it was filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water (3.00 L), and the resulting mixture was acidified with the addition of aq. HC1 to attain pH ~ 3. The acidified mixture was then extracted with 2-methyl-tetrahydrofuran (1.00 L, ten times). The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in MTBE (500 mL), and the resulting suspension was stirred at 25 °C for 30 mn. The mixture was filtered, and the filter cake was dried under reduced pressure to provide the desired product.1H NMR (400 MHz, CDCI3) d 7.90 (d, J= 4.0 Hz, 1H), 7.57 (d, J= 4.4 Hz, 1H), 4.19 (s, 1H).261232-benzyl-2-oxo-l.,2-dihydroDyridine-3-carboxylic acid (1-2)K2CO3PdCI2(PPh3)2Step 1 Step 2Step. 2-benzyl-4-chloropyridazin-3(27 / )-oneIn a glass vial equipped with a magnetic stir bar, 4-chloropyridazin-3-ol (1.0 g, 8.0 mmol) and potassium carbonate (3.0 g, 20.0 mol) were combined under air. The mixture was suspended in DMF (30 mL) at 25 °C, and benzyl bromide (1.0 mL, 9.0 mmol) was added. The reaction mixture was stirred at 25 °C for 18 h. The crude reaction mixture was diluted with EtOAc (50 mL) and water (50 mL). The aqueous mixture was extracted with EtOAc (50 mL, twice).Combined organic mixture was washed with aqueous LiCl solution (0.5% w / v, 50 mL) and brine (50 mL, three times). The organic solution was then dried over Na2SO4 and concentrated. Silica gel flash-column chromatography (eluting with 5% B / hexanes initially, grading to 100% B [B = 25% v / v EtOH / EtOAc]) to afford the desired product. MS: 221 [M+H]+.XH NMR (500 MHz, CDC13) 87.70 (d, J= 4.2 Hz, 1H), 7.48 (d, J= 7.4 Hz, 2H), 7.39 - 7.31 (m, 4H), 5.38 (s, 2H). Step 2 2-benzyl-4-((trimethylsilyl)ethynyl)pyridazin-3(2J7)-oneIn a glass vial equipped with a magnetic stir bar, 2-benzyl-4-chloropyridazin-3(2J7)-one (500. mg, 2.3 mmol), and bis(triphenylphosphine)palladium chloride (79.5 mg, 0.13 mmol) were combined under air. The mixture was placed under nitrogen and suspended in THF (11 mL) at 25 °C. Triethylamine (947 pL, 6.8 mmol) and trimethylsilylacetylene (633 pL, 4.5 mmol) were added. The reaction mixture was stirred under nitrogen at 70 °C for 18 h. The crude reaction mixture was diluted with EtOAc (50 mL) then washed with saturated aqueous NH4CI solution (50 mL) and brine (50 mL). The organic solution was then dried over Na2SO4 and concentrated. Silica gel flash-column chromatography (eluting with 5% B / hexanes initially, grading to 60% B [B = 25% v / v EtOH / EtOAc]) yielded the desired product. MS: 283 [M+H]+. 'H NMR (500 MHz, CDCI3) 67.73 (s, 1H), 7.46 (d, J= 7.0 Hz, 2H), 7.38 - 7.30 (m, 4H), 5.34 (s, 2H), 0.28 (s, 9H).Step 3 2-benzyl-4-ethynylpyridazin-3(2Zf)-one26123In a glass vial equipped with a magnetic stir bar, 2-benzyl-4-((trimethylsilyl)ethynyl)pyridazin-3(27 / )-one (350 mg, 1.2 mmol), and potassium carbonate (68.5 mg, 0.5 mmol) were combined under air. The mixture was suspended in MeOH (6 mL). The reaction mixture was stirred at 25 °C for 5 mins. The crude reaction mixture was diluted with DCM (50 mL) then washed with water (50 mL) and brine (50 mL). The organic solution was then dried over Na2SO4 and concentrated. Silica gel flash-column chromatography (eluting with 5% B / hexanes initially, grading to 60% B [B = 25% v / v EtOH / EtOAc]) yielded the desired product. MS: 211 [M+H]+. 'H NMR (500 MHz, CDC13) 87.76 (d, J= 3.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.34 (m, 4H), 5.36 (s, 2H), 3.60 (s, 1H).Step 4 2-benzyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acidIn a glass vial equipped with a magnetic stir bar, 2-benzyl-4-ethynylpyridazin-3(2rt)-one (60. mg, 0.29 mmol), sodium periodate (0.31 g, 1.4 mmol), acetonitrile (1.1 mL) and water (0.76 mL) were combined in a glass vial equipped with a magnetic stir bar. Ruthenium(IV) oxide monohydrate (2.2 mg, 14 pmol) was added, and the resulting mixture was stirred at 25 °C for 20 min. The mixture was then diluted with IM aq. citric acid solution (10 mL). The acidified mixture was extracted with ethyl acetate (3 ^ 10 mL). The combined extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluting with 10% B / hexanes initially, grading to 60% B / hexanes [B = 25% v / v EtOH / EtOAc]) to provide the desired product. MS: 231 [M+H]+.tert-butyl 6S)-(l-(2-(2-benzyl-3-oxo-2.,3-dihvdroDyridazine-4-carbonyl)hvdrazineyl)-l-oxoDropan-Z-yllcarbamate (1-3)In a glass vial equipped with a magnetic stir bar, 2-benzyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (47 mg, 0.20 mmol), tert-butyl CS')-( I -hydrazineyl- l-oxopropan-2-yl)carbamate (62 mg, 0.31 mmol) and THF (2.0 mL) were combined a glass vial. HATU (97 mg, 0.26 mmol) and triethylamine (85 pL, 0.61 mmol) were added sequentially at 25 °C, and the mixture was stirred for 45 min. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel flash-column chromatography (eluting with hexanes initially, grading26123to 60% B / hexanes [B = 25% v / v EtOH / EtOAc]) to provide the desired product. MS: 438 [M+Na]+.Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-3, substituting appropriate starting materials:Compound 00O O MSIz Structure IUPAC NameNumber [M+H]+>otert-butyl (5)-(l-oxo-l-(2-(2- O IZoxo- 1-phenyl- 1,2- 1-4 dihydropyridine-3- 401 carbonyl)hydrazineyl)propan- 2-yl)carbamatetert-butyl (2-oxo-2-(2-(2-oxo- 1-phenyl- 1.,2-dihvdropyridine-3-carbonyl)hvdrazineyl)ethyl)carbamate (1-5)EDC, HOAt Et3N1-5In a glass vial equipped with a magnetic stir bar, tert-butyl (2-hydrazineyl-2-oxoethyl)carbamate (100 mg, 528 pmol), 2-oxo-l -phenyl- l,2-dihydropyridine-3 -carboxylic acid (114 mg, 528 pmol), l-hydroxy-7-azabenzotriazole (HOAt, 71.9 mg, 528 pmol), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 152 mg, 793 pmol) were combined. The mixture was suspended in THF (2.64 mL) at 25 °C, and triethylamine (184 pL, 1.32 mmol) was added. After 3 h, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash-column chromatography (eluting with 10% B / hexanes initially, grading to 100% B [B = 25% v / v EtOH / EtOAc]) to afford the desired product. MS: 387 [M+H]+.tert-butyl (5l)-2.,2-dimethyl-4-(2-(2-oxo-l-phenyl-l.,2-dihvdropyridine-3-carbonyl)hvdrazine-l-carbonyl)oxazolidine-3-carboxylate (1-6)26123Hydrazine EDC, HOBt, TEAStep t Step 2Step. tert-butyl (5)-4-(hydrazinecarbonyl)-2,2-dimethyloxazolidine-3 -carboxylateA stirred solution of 3 -(tert-butyl) 4-methyl (5)-2, 2-dimethyloxazolidine-3,4-dicarboxylate (2.5 g, 9.6 mmol) in MeOH (15 mL) was treated with hydrazine hydrate (0.70 mL, 14 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 20 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with n-pentane and dried under reduced pressure to yield the desired product. MS: 260 [M+H]+Step 2 tert-butyl (M-2,2-dimethyl-4-(2-(2-oxo-l -phenyl- L2-dihydropyridine-3-carbonyl)hydrazine-l-carbonyl)oxazolidine-3 -carboxylateTo a stirred solution of tert-butyl (< S)-4-(hydrazinecarbonyl)-2,2-di methyl oxazoli di ne-3-carboxylate (900 mg, 3.47 mmol), 2-oxo-l-phenyl-l,2-dihydropyridine-3-carboxylic acid (747 mg, 3.47 mmol), l-hydroxy-7-azabenzotriazole (472 mg, 3.47 mmol) and l-(3-Dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (EDCI) (998 mg, 5.21 mmol) in THF (15 mL) was added TEA (1.21 mL, 8.68 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h before it was concentrated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluting with 100% EtOAc) afforded the desired product. MS: 457 [M+H]+(ty)-4-((5-(3-(l-((terf-butoxycarbonyl)amino)ethyl)isoxazol-5-yl)-6-oxoDyridazin-l(6ZD-yl)methyl)benzoic acid (1-7)26123Step 7: methyl 4-((5-chloro-6-oxopyridazin-l(677)-yl)methyl)benzoateIn a glass vial equipped with a magnetic stir bar, 4-chloropyridazin-3-ol (1.0 g, 8.0 mmol) methyl 4-(bromomethyl)benzoate (2.0 g, 9.0 mmol), and potassium carbonate (3.0 g, 20. mol) were combined under air. The mixture was suspended in DMF (30 mL). The reaction mixture was stirred at 25 °C for 18 h. The crude reaction mixture was diluted with EtOAc (50 mL) and water (50 mL); the mixture was shaken, and the layers were then separated. The aqueous mixture was further extracted with EtOAc (50 mL, twice). The combined organic extracts were washed with aqueous LiCl solution (0.5% w / v, 50 mL) and brine (50 mL, three times). The organic solution was then dried over Na2SO4 and concentrated. Silica gel flash-column chromatography (eluting with 5% B / hexanes initially, grading to 60% B [B = 25% v / v EtOH / EtOAc]) to afford the desired product. MS: 279 [M+H]+. 'H NMR (500 MHz, CDC13) 88.03 (d, J= 7.8 Hz, 2H), 7.72 (d, J= 4.1 Hz, 1H), 7.52 (d, J= 7.8 Hz, 2H), 7.38 (d, J= 4.1 Hz, 1H), 5.42 (s, 2H), 3.93 (s, 3H).Step 2 methyl 4-((6-oxo-5-((trimethylsilyl)ethvnyl)pyridazin-l(677)-yl)methyl)benzoateIn a glass vial equipped with a magnetic stir bar, 4-((5-chloro-6-oxopyridazin- 1(677)-yl)methyl)benzoate (50 mg, 0.18 mmol), and bis(triphenylphosphine)palladium(II) chloride (6.3 mg, 9.0 pmol) were combined under air. The mixture was placed under nitrogen and suspended in THF (0.9 mL) at 25 °C. Triethylamine (75 pL, 0.54 mmol) and trimethylsilylacetylene (50 pL, 0.36 mmol) were added. The reaction mixture was stirred under nitrogen at 70 °C for 18 h. The crude reaction mixture was diluted with EtOAc (50 mL) then washed sequentially with sat. aq.26123NH4CI solution (50 mL) and brine (50 mL). The organic solution was then dried over Na2SC>4 and concentrated. Silica gel flash-column chromatography (eluting with 5% B / hexanes initially, grading to 80% B [B = 25% v / v EtOH / EtOAc]) yielded the desired product. MS: 341 [M+H]+. 'H NMR (500 MHz, CDCI3) 8.01 (d, J= 7.9 Hz, 2H), 7.75 (d, J= 4.1 Hz, 1H), 7.51 (d, J= 8.0 Hz, 2H), 7.31 (d, J= 4.1 Hz, 1H), 5.38 (s, 2H), 3.92 (s, 3H), 0.28 (s, 9H).Step 3 methyl 4-((5-ethynyl-6-oxopyridazin-l(6rt)-yl)methyl)benzoateIn a glass vial equipped with a magnetic stir bar, methyl 4-((6-oxo-5-((trimethylsilyl)ethynyl)pyridazin-l(6rt)-yl)methyl)benzoate (80. mg, 0.23 mmol), and potassium carbonate (13.0 mg, 94 pmol) were combined under air. The mixture was suspended in MeOH (1.2 mL). The reaction mixture was stirred at 25 °C for 5 mins. The crude reaction mixture was diluted with EtOAc (50 mL), then washed sequentially with water (50 mL) and brine (50 mL). The organic solution was then dried over Na2SO4 and concentrated to yield the desired product, which was used in the next step without further purification. MS: 269 [M+H]+.Step 4 methyl (M-4-((5-(3-(l-((tert-butoxycarbonyl)amino)ethyl)isoxazol-5-yl)-6-oxopyridazin-1 (AT / j-yl (methyl (benzoateIn a glass vial equipped with a magnetic stir bar, methyl 4-((5-ethynyl-6-oxopyridazin-l(6rt)-yl)methyl)benzoate (50 mg, 0.19 mmol) was added under air. A solution of tert-butyl (5)-(1 -chloro- 1 -(hydroxyimino)propan -2 -yl)carbamate (120 mg, 0.56 mmol) in DMF (2.0 mL) was added, followed by tri ethylamine (100 pL, 0.75 mmol). The reaction mixture was stirred at 25 °C for 18 h. The crude reaction mixture was diluted with EtOAc (50 mL) and water (50 mL); the layers were shaken, then separated. The aqueous mixture was extracted with EtOAc (50 mL, twice). The combined organic extracts were washed sequentially with aqueous LiCl solution (0.5% w / v, 50 mL) and brine (50 mL, three times). The organic solution was then dried over Na2SO4 and concentrated. Silica gel flash-column chromatography (eluting with hexanes, grading to 30% B / hexanes [B = 25% v / v EtOH / EtOAc]) to afford the desired product. MS: 477 [M+Na]+.XH NMR (500 MHz, CD3CN) 88.03 (d, J= 4.1 Hz, 1H), 7.99 (d, J= 7.8 Hz, 2H), 7.88 (d, J= 4.3 Hz, 1H), 7.48 (d, J= 8.4 Hz, 2H), 7.31 (s, 1H), 5.82 (s, 1H), 5.48 (s, 2H), 4.91 (s, 1H), 3.88 (s, 3H), 1.48 (d, J= 7.0 Hz, 3H), 1.42 (s, 9H).Step 5 (M-4-((5-(3-(l-((tert-butoxycarbonyl)amino)ethyl)isoxazol-5-yl)-6-oxopyridazin-l(6rt)-yl)methyl)benzoic acidIn a glass vial equipped with a magnetic stir bar, methyl (5)-4-((5-(3-(l-((tert-butoxycarbonyl)amino)ethyl)isoxazol-5-yl)-6-oxopyridazin-l(6rt)-yl)methyl)benzoate (50 mg, 0.11 mmol) and lithium hydroxide (7.9 mg, 0.33 mmol) were added under air. The mixture was suspended in 1 / 1 THF / H2O mixture (2.2 mL). The reaction mixture was stirred at 25 °C for 4 h.26123THF was removed under reduced pressure. The remaining aqueous mixture was acidified to pH ~5 with IM aq. HC1. This mixture was then freeze-dried to yield desired product, which was used in the next step without further purification. MS: 463 [M+Na]+.Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-7, substituting appropriate starting materials:Intermediate MS Structure IUPAC NameNumber [M+Na]+O^OH (5)-3-((5-(3-(l-((tert- butoxycarbonyl)amino)ethyl)is1-8 463Io oxazol-5-yl)-6-oxopyridazin- Mfi N'° 0 l(6J7)-yl)methyl)benzoic acidzz- ^o=(5)-2-(5-(3-(l-((tert- C ' u butoxycarbonyl)amino)ethyl)is1-9 Yz387 oxazol-5-yl)-6-oxopyridazin- M ze N*° °O TO l(6J7)-yl)acetic acidCD(7?)-2-(5 -(3 -(1 -((tertbutoxy carbonyl)amino)-2- 1-10 methoxyethyl)isoxazol-5-yl)-6- 417 oxopyridazin- 1 (6J7)-yl)aceticacid(5l)-4-((5-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-lH-l.,2.,3-triazol-l-yl)-6-oxoDyridazin-l(6 / n-yl)methyl)benzoic acid (1-11)26123Step. methyl 4-((5-azido-6-oxopyridazin-l(6 / 7)-yl)methyl)benzoateIn a glass vial, methyl 4-((5-chloro-6-oxopyridazin-l(6 / 7)-yl)methyl)benzoate (3.172 g, 11.38 mmol), sodium azide (1.529 g, 23.53 mmol), and 7V,7V-dimethylformamide (12.0 mL) were combined. The reaction mixture was heated with stirring to 80 °C for 3 hours before it was cooled to ambient temperature and poured into aqueous lithium chloride (5 % w / v, 100 mL). The resulting mixture was extracted with ethyl acetate (50 mL, three times), and the combined organic extracts were washed with brine (50 mL, two times). The organic solution was then dried over anhydrous sodium sulfate. The solids were removed via vacuum filtration and the volatiles were removed in vacuo. The resultant residue was purified via column chromatography (eluting with 5% B / hexanes initially, grading to 60% B [B = 25% v / v EtOH / EtOAc]) to afford the desired product. MS: 286 [M+H]+. 'H NMR (500 MHz, CD3OD) 88.00 (d, J= 8.3 Hz, 2H), 7.82 (d, J = 4.6 Hz, 1H), 7.48 (d, J= 8.2 Hz, 2H), 6.86 (d, J= 4.6 Hz, 1H), 5.40 (s, 2H), 3.91 (s, 3H).Step 2 methyl (M-4-((5-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-U / -L2,3-triazol-l-yl)-6-oxopyridazin-lfOT / l-yl (methyl (benzoateIn a glass flask equipped with a magnetic stir bar, methyl 4-((5-azido-6-oxopyridazin-l(6J7)-yl)methyl)benzoate (1.7 g, 5.9 mmol), / <? / 7-butyl (5)-but-3-yn-2-ylcarbamate (998 mg, 5.90 mmol), aqueous buffered sodium ascorbate solution (55 mL; see below), and dimethyl sulfoxide (50 mL) were combined. To this mixture, aqueous copper (II) sulfate solution (20.0 mM,15.0 mL, 300 pmol) and aqueous tris(3-hydroxypropyltriazolylmethyl)amine (20.0 mM, 15.0 mL, 300 pmol) were added. The resulting mixture was stirred at ambient temperature for 20 hours whereupon it was treated with aqueous citric acid (I M, 100 mL, 100 mmol). The mixture was then extracted with ethyl acetate (50 mL, three times), and the combined organic extracts were dried over anhydrous sodium sulfate. The solids were removed via vacuum filtration and26123the volatiles were removed in vacuo. The resultant residue was purified via column chromatography (eluting with hexanes initially, grading to 60% B / hexanes [B = 25% v / v EtOH / EtOAc]) to provide the desired product. MS: 455 [M+H]+.XH NMR (500 MHz, CD3OD) 6 8.88 (s, 1H), 8.14 (d, J= 4.1 Hz, 2H), 8.01 (d, J= 7.7 Hz, 2H), 7.54 (d, J= 7.7 Hz, 2H), 5.55 (s, 2H), 4.96 (s, 1H), 3.91 (s, 3H), 1.55 (d, J= 6.9 Hz, 3H), 1.46 (s, 9H).Stock aqueous buffer was created by combining the following: Sodium ascorbate (5.0 g, 25mmol), sodium phosphate dibasic (14.2 g, 100 mmol), citric acid (9.6 g, 50 mmol), and water (200 mL).Step 3 (M-4-((5-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-17 / -L2,3-triazol-l-yl)-6-oxopyridazin-l(677)-yl)methyl)benzoic acidA solution of methyl (5)-4-((5-(4-(l-((te / 7-butoxycarbonyl)amino)ethyl)-17 / -l,2,3-triazol-l-yl)-6-oxopyridazin-l(677)-yl)methyl)benzoate (1.27 g, 2.79 mmol) in tetrahydrofuran (30.0 mL) was prepared in a glass flask equipped with a magnetic stir bar. To this, a solution containing lithium hydroxide hydrate (351 mg, 8.37 mmol) in water (30.0 mL) was added. The reaction was stirred at ambient temperature for 3 hours before it was partially concentrated under reduced pressure. The resultant suspension was treated with hydrochloric acid (1 M, 8.5 mL) and acetonitrile (30 mL), and freeze-dried to afford the desired product, which was used in later steps without further purification MS: 441 [M+H]+. 'H NMR (500 MHz, CD3OD) 88.89 (s, 1H), 8.18 - 8.13 (m, 2H), 8.04 - 7.99 (m, 2H), 7.53 (d, J= 8.4 Hz, 2H), 5.55 (s, 2H), 4.96 (d, J= 6.4 Hz, 1H), 1.55 (d, J = 7.0 Hz, 3H), 1.46 (s, 9H), 1.17 (d, J= 6.2 Hz, 2H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-11, substituting appropriate starting materials:Intermediate MS Structure IUPAC NameNumber [M+H]+(5)-3-((5-(4-(l-((tert- O^OHbutoxycarbonyl)amino)ethyl)- 1-12 17 / -l,2,3-triazol-l-yl)-6- 441BOCHNX^N^"^Joxopyridazin- 1 (677)- Me' N*N 0yl)methyl)benzoic acid26123(5)-2-(5 -(4-( 1 -((tert- butoxycarbonyl)amino)ethyl)- U / -l,2,3-triazol-l-yl)-6- 365 oxopyridazin- 1 (6J7)-yl)aceticacidtert-butyl (l-methoxybut-3-vn-2-yl)carbamate (1-14)NHBoc K2CO3NHBocMeO1-14To a stirred solution of tert-butyl (A')-(l-m ethoxy-3 -oxopropan-2-yl)carbamate (8.00 g, 39.4 mmol) and dimethyl (l-diazo-2-oxopropyl)phosphonate (11.3 g, 59.0 mmol) in MeOH (100 mL) was added K2CO3 (10.9 g, 78.7 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 20% EtOAc in hexane) yielded the desired product. 'H NMR (400 MHz, CDCI3): 84.98 (br s, 1H), 4.59 (br s, 1H), 3.47-3.60 (m, 2H), 3.43 (s, 3H), 2.29 (d, J= 2.4 Hz, 1H), 1.46 (s, 9H).( / ?)- \-(l-iiietli()xy-2-iiietliylbut-3-vii-2-yl)-2-iiietliyli)r()i):iiie-2-suiriiiainide (1-15)tBu tBu TMS^^ Ti(OEt)4, S< nBuLi, Me3AI O NH TBAF O NStep 1 Step 2 Step 3TMS1-15Step. (A)-7V-(l-methoxypropan-2-ylidene)-2-methylpropane-2-sulfinamide26123To a stirred mixture of l-methoxypropan-2-one (5.0 g, 57 mmol) and (R)-2-methylpropane-2-sulfmamide (6.9 g, 57mmol) in THF (50 mL) was added titanium ethoxide (40. mL, 57mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was then quenched with saturated aqueous NaHCCh (200 mL). The precipitated solid was filtered and the filtrate was extracted with DCM (3 ^ 35 mL). The organic layer was washed with brine (35 mL) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with 40% EtOAc in hexane) to afford the desired product. 'HNMR (400 MHz, CDC13): 64.03 (s, 2H), 3.40 (s, 3H), 2.34 (s, 3H), 1.26 (s, 9H).Step 2 (A)-A-(l-methoxy-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfmamideTo a mixture of ethynyltrimethylsilane (3.594 g, 36.59 mmol) in THF (1 mL) was added n-butyl lithium (2.5 M in hexanes, 9.2 mL, 23 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. A pre-stirred mixture of (A)-A-(l-methoxypropan-2-ylidene)-2-methylpropane-2-sulfmamide (2.0 g, 10. mmol), trimethylaluminum (2 M in hexanes, 6.3 mL, 13 mmol) and THF (1 mL) was added to the reaction mixture at -78 °C. The mixture was allowed to slowly warm to 25 °C for 16 hours. The reaction mixture was then quenched with aqueous sodium sulfate solution (15 mL). The mixture was filtered, and then aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 40% EtOAc in hexane) to afford the desired product. 'HNMR (400 MHz, CDCI3): 83.64 (s, 1H), 3.56 (d, J= 9.6 Hz, 1H), 3.40-3.48 (m, 4H), 1.44 (s, 2H), 1.20 (s, 9H), 0.17 (t, J = 3.4 Hz, 9H).Step 3 (A)-A-(l-methoxy-2-methylbut-3-vn-2-yl)-2-methylpropane-2-sulfinamideTo a stirred mixture of (A)-A-(l-methoxy-2-methyl-4-(trimethylsilyl)but-3-yn-2-yl)-2-methylpropane-2-sulfmamide (820 mg, 2.83 mmol) in THF (5 mL) was added TBAF (1.0 M in THF, 1.48 g, 5.66 mmol) at 0 °C. The reaction mixture was allowed to warm to 25 °C for 2 hours. The mixture was diluted with ice cold water (5 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product. 'HNMR (400 MHz, CDCI3): 63.75 (br s, 1H), 3.56 (d, J= 8.8 Hz, 1H), 3.45 (s, 3H), 3.42 (s, 1H), 2.50 (s, 1H), 1.48 (s, 3H), 1.21 (s, 9H).te -butyl 6S)-(l-(5-(tributylstannyl)isoxazol-3-yl)ethyl)carbamate (1-16)26123— — SnBu3OH NCS, then K2CO3BOCHN / - / SnBu3j N _ >.NHBoc / ^ N'O1-16To a stirred solution of tert-butyl (5 -(l-(hydroxyimino)propan-2-yl)carbamate (5.00 g, 26.6 mmol) in DMF (50 mL) was added NCS (3.90 g, 29.2 mmol) at 25 °C. The reaction mixture was astirred at 40 °C for 1 h. Then the reaction mixture was allowed to 25 °C. Then tributyl(ethynyl)stannane (9.21 mL, 31.9 mmol) and K2CO3 (4.41 g, 31.9 mmol) were added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 20% ethyl acetate in hexane) yielded the desired product. MS: 503 [M+H]+.Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-16, substituting appropriate starting materials:Intermediate MS Structure IUPAC NameNumber [M+H]+ / c / 7-butyl (R)-(2-methoxy-l-(5- BocHN z^ / SnBu31-17 (tributyl stannyl)i soxazol-3 - 533MeoJ^N'Oyl)ethyl)carbamatefSl-fV-fCSl-l-lS-bromothiazol-Z-yllethyll-Z-methylDroDane-Z-sulfinamide (1-18)Me Me fs; ll Ti(O / -Pr)4DIBAL-HMe S *'NH2Me Step 1 Step 2MeMe Me1-18Step. (M- f-(l-(5-bromothiazol-2-yl)ethylidene)-2-methylpropane-2-sulfinamideA solution of l-(5-bromothiazol-2-yl)ethan-l-one (1 g, 5 mmol) in THF (20 mL) was treated with (5)-2-methylpropane-2-sulfinamide (0.6 g, 5 mmol) and titatium tetra-Ao-propoxide (3 g, 0.01 mmol) at room temperature. The mixture was heated with stirring to 70 °C for 16 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluting with 30% EtOAc / hexane) to provide the desired product. MS: 309 & 311 [M+H]+.!H NMR (400 MHz, CDC13): 87.81 (s, 1H), 2.81 (s, 3H), 1.32 (s, 9H).Step 2\ ( )-A-(( )-l-(5-bromothiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamideA solution of (5)-A-(l-(5-bromothiazol-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (700 mg, 2.26 mmol) in THF (20 mL) was cooled to -75 °C, whereupon diisobutylaluminum hydride solution (DIBAL-H, 4M solution in toluene, 1.70 mL, 6.79 mmol) was added. The mixture was stirred for 1 h before saturated aqueous ammonium chloride solution (2 mL) was added. The mixture was diluted with water and extracted with EtOAc (30 mL, two times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluting with 30% EtOAc / hexanes) to provide the desired product. MS: 311 & 313 [M+H]+.1H NMR (400 MHz, CDCI3): 67.60 (s, 1H), 4.74-4.85 (m, 1H), 4.15 (d, J= 4.8 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.26 (s, 9H).ferf-butyl (l-(5-bromothiazol-2-yl)cycloDroDyl)carbamate (1-19)(BOC)2O, NH4HCO3!Pyridine Lawesson's reagentStep 1 Step 2DBDMHStep 3 Step 41-19Step. terLbutyl (l-carbamoylcvclopropyl)carbamafeTo a stirred solution of I -(( / c / 7-butoxycarbonyl)amino)cyclopropane- l -carboxylic acid (10 g, 50 mmol) in ACN (100 mL) were added di-terAbutyl decarbonate (17 mL, 75 mmol), ammonium bicarbonate (5.1 g, 65 mmol) and pyridine (2.4 mL, 30 mmol) at 25 °C. The reactionmixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to yield the desired product. MS: 201 [M+H]+.Step 2\ tert-butyl (l-carbamothioylcvclopropyl)carbamateTo a stirred solution of tert-butyl (l-carbamoylcyclopropyl)carbamate (10 g, 50 mmol) in THF (20 mL) was added Lawesson’s reagent (14 g, 35 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then treated with sat. aq. sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 10% EtOAc in petroleum ether) yielded the desired product. MS: 161 [M+H-C4H8]+.Step 3 tert-butyl (l-(thiazol-2-yl)cyclopropyl)carbamateTo a stirred solution of tert-butyl (l-carbamothioylcyclopropyl)carbamate (5 g, 0.02 mol) in THF (50 mL) was added chloroacetaldehyde (50% w / w aq. solution, 6 mL, 0.05 mol) at 0 °C. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 20% EtOAc in petroleum ether) yielded the desired product. MS: 241 [M+H]+.Step 4 tert-butyl (l-(5-bromothiazol-2-yl)cvclopropyl)carbamateTo a stirred solution of tert-butyl (l-(thiazol-2-yl)cyclopropyl)carbamate (1.2 g, 5.0 mmol) in ACN (10 mL) was added l,3-dibromo-5,5-dimethylhydantoin (DBDMH, 1.4 g, 5.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 30% EtOAc in petroleum ether) yielded the desired product. MS: 263, 265 [M+H-C4H8]+.Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-19, substituting appropriate starting materials:Intermediate MS Structure IUPAC NameNumber [M+H]+1-21 Step. l-(5-chlorothiazol-2-yl)ethan-l-amineTo a stirred solution of l-(5-chlorothiazol-2-yl)ethan-l-one (10.0 g, 61.9 mmol) in MeOH (40 mL) and THF (40 mL) was added ammonium acetate (47.7 g, 619 mmol) at 25 °C. The reaction mixture was stirred at 60 °C for 1 h. Then, sodium cyanoborohydride (9.72 g, 155 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 60 °C for 3 h before it was concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 50% EtOAc in petroleum ether) yielded the desired product. MS: 163 [M+H]+. Step 2\ benzyl (l-(5-chlorothiazol-2-yl)ethyl)carbamateTo a stirred solution of l-(5-chlorothiazol-2-yl)ethan-l-amine (5.0 g, 31 mmol) in THF (30 mL) and water (30 mL) were added sodium bicarbonate (3.9 g, 46 mmol) and benzyl chloroformate (9.4 mL, 61 mmol) at 0 °C. The reaction was warmed to 25 °C and stirred at that temperature for 4 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 * 200 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 20% EtOAc in petroleum ether) yielded the desired product. MS: 297 [M+H]+.benzyl (l-(5-chlorothiazol-2-yl -2-methoxyethyl carbamate (1-22)26123o KOH, Phl(OAc)2Ag2O, Mel TFA Step 1 Step 2 Step 3NH4OAc, 4A MS; „Cbz NaH3BCN I2Cbz-CI, NaHCO3UN - ’ - - n. - ' zA / V VN >-CI Step 4 Step 5N~^1-22 Step. 2-(5-chlorothiazol-2-yl)-2,2-dimethoxyethan-l-olTo a stirred solution of l-(5-chlorothiazol-2-yl)ethan-l-one (15 g, 93 mmol) in MeOH (150 mL) was added KOH (16 g, 0.28 mol) and (Di acetoxy iodo)benzene (60 g, 0.19 mol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with 30% EtOAc in hexane) to afford the desired product.1H NMR (400 MHz, CDC13) 87.64 (s, 1H), 4.00 (s, 2H), 3.32 (s, 6H).Step 2 5-chloro-2-(LL2-trimethoxyethyl)thiazoleTo a stirred solution of 2-(5-chlorothiazol-2-yl)-2,2-dimethoxyethan-l-ol (6.0 g, 27 mmol) in THF (50 mL) was added silver oxide (31 g, 0.13 mol) and Mel (8.4 mL, 0.13 mol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with 30% EtOAc in hexane) to afford the desired product. 'HNMR (400 MHz, CDCI3) 67.64 (s, 1H), 3.83 (s, 2H), 3.29 (s, 9H).Step 3 l-(5-chlorothiazol-2-yl)-2-methoxyethan-l-oneTo a stirred solution of 5-chloro-2-(l,l,2-trimethoxyethyl)thiazole (2 g, 8.4 mmol) in DCM (15 mL) was added TFA (6.5 mL, 84 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was then concentrated and dried under reduced pressure to afford the desired product. MS: 192 [M+H]+.Step 4: l-(5-chlorothiazol-2-yl)-2-methoxyethan-l -amineTo a stirred solution of l-(5-chlorothiazol-2-yl)-2-methoxyethan-l-one (2.0 g, 10 mmol) in MeOH (1.0 mL) and THF (1.0 mL) was added 4A Molecular Sieves (10 mmol) and ammonium acetate (12 g, 0.16 mol) at 25 °C. The reaction mixture was heated to 60 °C for 1 hour. After 1 hour, the mixture was allowed to cool to room temperature. Sodium cyanoborohydride (3.3 g, 52 mmol) was added and the mixture was heated to 60 °C for 2 hours. After 2 hours, the mixture was allowed to cool to room temperature and then purified by reverse26123phase C18 Silica gel flash-column chromatography (eluting with 30% ACN in H2O) to afford the desired product. MS: 193 [M+H]+.Step 5 benzyl (1 -(5 -chlorothiazol-2-yl)-2-m ethoxy ethyl)carbamateTo a stirred solution of l-(5-chlorothiazol-2-yl)-2-methoxyethan-l -amine (1.5 g, 7.8 mmol) in THF (5.0 mL) and H2O (5.0 mL) were added Cbz-Cl (1.7 mL, 12 mmol) and sodium bicarbonate (2.0 g, 23 mmol) at 0 °C. The reaction mixture was then stirred at 25 °C for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with 30% EtOAc in pet ether) to afford the desired product. MS: 327 [M+H]+.3-azido-l-DhenylDyridin-2(lH)-one (1-23)Fe, NH4CI Step 2Step. 3-nitro-l-phenylpyridin-2(lJ7)-oneTo a stirred solution of 3-nitropyridin-2( IT / )-one (1.00 g, 7.14 mmol) in 1,4-dioxane (30.0 mL) were added phenylboronic acid (1.31 g, 10.7 mmol), pyridine (8.66 mL, 107 mmol) and copper(II) acetate (1.94 g, 10.7 mmol) at room temperature. The solution was saturated with oxygen gas at room temperature for 5 min. The reaction mixture was stirred under oxygen atmosphere at 80 °C for 16 h, then filtered through a celite pad. The filtrate was diluted with EtOAc (150 mL), washed with water (80 mL, two times), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash-column chromatography (eluting with 30% EtOAc in petroleum ether) to afford the desired product. MS: 217 [M+H]+.Step 2 3-amino-l-phenylpyridin-2(177)-oneTo a stirred solution of 3-nitro-l-phenylpyridin-2(177)-one (600 mg, 2.78 mmol) in ethanol (10 mL) and water (10 mL) was added ammonium chloride (742 mg, 13.9 mmol) at room temperature. Then iron (775 mg, 13.9 mmol) was added to the reaction mixture at 80 °C. The26123reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, the filtrate was diluted with water (20 mL) and the diluted mixture was extracted with EtOAc (50 mL, two times). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford the desired product. MS: 187 [M+H]+.Step 3 3-azido-l-phenylpyridin-2(177)-oneTo a stirred solution of 3-amino-l-phenylpyridin-2(177)-one (220 mg, 1.18 mmol) in water (3.50 mL) and cone. HC1 (3.5 mL) was added a solution of sodium nitrite (163 mg, 2.36 mmol) in water (3.00 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then sodium azide (154 mg, 2.36 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with water (20 mL) and dried under reduced pressure to afford the desired product. MS: 213 [M+H]+.3-azido-l-(3.,5-bis(trifluoromethyl)Dhenyl)Dyridin-2(lH)-one (1-24)Pyridine, Cu(OAc)2PyNO, MS Pd / C, H2Step 1 Step 2NaNO2then NaN3Step 3CF3Step. l-(3,5-bis(trifluoromethyl)phenyl)-3-nitropyridin-2(lJ7)-oneTo a stirred solution of 3-nitropyridin-2(IT / )-one (5.00 g, 35.7 mmol) in DCM (60 mL) were added (3,5-bis(trifluoromethyl)phenyl)boronic acid (18.4 g, 71.4 mmol), pyridine (28.9 mL, 357 mmol), pyridine 1-oxide (10.2 g, 107 mmol), copper(II) acetate (19.4 g, 107 mmol) and 4A molecular sieve powder at room temperature. The reaction mixture was stirred under oxygen atmosphere at 25 °C for 16 h. The reaction mixture was filtered through a celite pad. The filtrate was diluted with water (50 mL) and extracted with DCM (100 mL, three times). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluting with 30% EtOAc in petroleum ether) to provide the desired product. MS: 353 [M+H]+.Step 2 3-amino-l-(3,5-bis(trifluoromethyl)phenyl)pyridin-2(lJ7)-one26123To a stirred solution of l-(3,5-bis(trifluoromethyl)phenyl)-3-nitropyridin-2(lJ7)-one (1.0 g, 2.8 mmol) in MeOH (50 mL) was added 10% Pd / C (60 mg, 0.57 mmol) at room temperature. The reaction mixture was stirred under H2 (40 psi) at 25 °C for 2 h. The reaction mixture was filtered through a celite pad, and the filter cake was rinsed with EtOAc (100 mL, three times). The filtrate was concentrated under reduced pressure to afford the desired product. MS: 323 [M+H]+.Step 3 3-azido-l-(3,5-bis(trifluoromethyl)phenyl)pyridin-2(lH)-oneTo a stirred solution of 3-amino-l-(3,5-bis(trifluoromethyl)phenyl)pyridin-2(U7)-one (400 mg, 1.24 mmol) in water (8 mL) and cone HC1 (8 mL) was added sodium nitrite (171 mg, 2.48 mmol) in water (8 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. Then sodium azide (161 mg, 2.48 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was filtered. The solid thus obtained was washed with water (10 mL) and dried under vacuum. The crude residue was purified by silica gel flash-column chromatography (eluting with 20% ethyl acetate in hexane) to provide the desired product. MS: 349 [M+H]+.4-azido-2-(3.,5-bis(trifluoromethyl)Dhenyl)Dyridazin-3(2ZD-one (1-25)H HCI Hydrazine Step 1 Step 2NaNO2then NaN3Step 3I-25 CF3Step. 2-(3,5-bis(trifluoromethyl)phenyl)-4,5-dichloropyridazin-3(2J7)-oneTo a stirred solution of (3,5-bis(trifluoromethyl)phenyl)hydrazine (10 g, 41 mmol) in 4M HCI in 1,4-dioxane (100 mL, 400 mmol) was added (Z)-2,3-dichloro-4-oxobut-2-enoic acid (6.9 g, 41 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was filtered, washed with water (200 mL, two times), and dried under reduced pressure to afford the desired product. 'H NMR (400 MHz, CDCI3): 88.21 (s, 2H), 8.00 (s, 1H), 7.93 (s, 1H).Step 2 4-amino-2-(3,5-bis(trifluoromethyl)phenyl)pyridazin-3(2J7)-one26123To a stirred solution of 2-(3,5-bis(trifluoromethyl)phenyl)-4,5-dichloropyridazin-3(2J7)-one (3.0 g, 8.0 mmol) in EtOH (20 mL) was added hydrazine hydrate (4.0 mL, 0.080 mol) at room temperature. The reaction mixture was heated in a microwave reactor at 85 °C for 20 min. The reaction mixture was concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 30% ethyl acetate in pet ether) yielded the desired product. MS: 324 [M+H]+.Step 3 4-azido-2-(3,5-bis(trifluoromethyl)phenyl)pyridazin-3(2J7)-oneTo a stirred solution of 4-amino-2-(3,5-bis(trifluoromethyl)phenyl)pyridazin-3(2J7)-one (400. mg, 1.24 mmol) in EtOAc (5 mL) were added 6M HC1 (2.5 mL, 15 mmol) and sodium nitrite (171 mg, 2.48 mmol) at 0 °C and stirred at 0 °C for 30 min. To this reaction mixture was added sodium azide (161 mg, 2.48 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with ice cold water (50 mL) and extracted with EtOAc (100 mL, two times). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 30% ethyl acetate in pet ether) yielded the desired product. MS: 350 [M+H]+.4-azido-2-benzylDyridazin-3(2H)-one (1-26)OF3C-S-N3OHydrazine CuSO4Step 1 Step 21-26Step. 4-amino-2-benzylpyridazin-3(2J7)-oneTo a stirred solution of 2-benzyl-4, 5-dichloropyridazin-3(2J7)-one (5.10 g, 20 mmol) in EtOH (45 mL) was added hydrazine hydrate (6.28 mL, 200 mmol) at room temperature. The reaction mixture was heated in a microwave reactor at 85 °C for 18 min. The reaction mixture was concentrated and dried under reduced pressure. Silica gel flash-column chromatography (eluting with 40% EtOAc in hexane) yielded the desired product. MS: 202 [M+H]+.Step 2 4-azido-2-benzylpyridazin-3(2H)-oneTo a stirred solution of sodium azide (3.231 g, 49.69 mmol) in DCM (10 mL) and H2O (7 mL) was added triflic anhydride (3.36 mL, 19.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The aqueous layer was extracted with DCM (7 mL, two times). The26123combined organic extracts were washed with aqueous saturated Na2COs, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford triflyl azide.To a stirred solution of 4-amino-2-benzylpyridazin-3(2J7)-one (1.0 g, 5.0mmol) in MeOH (10 mL) and H2O (7 mL) were added K2CO3 (1.37 g, 9.94 mmol) and copper(II) sulfate (79 mg, 500 pmol). The triflyl azide solution described above was then added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then diluted with water (15 mL) and extracted with DCM (25 mL, three times). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Neutral alumina flash-column chromatography (eluting with 40% EtOAc in hexane) yielded the desired product. MS: 228 [M+H]+.4-azido-2-DhenylDyridazin-3(2H)-one (1-27)Hydrazine hydrate NaNO2, NaN3Step 1 Step 2Step. 4-amino-2-phenylpyridazin-3(2J7)-oneTo a stirred solution of 4,5-dichloro-2-phenylpyridazin-3(2J7)-one (3.0 g, 0.01 mol) in EtOH (20 mL) was added hydrazine hydrate (6.0 mL, 0.1 mol) at room temperature. The reaction mixture was heated in microwave reactor at 85 °C for 20 min. The reaction mixture was concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 30% EtOAc in pet ether) yielded the desired product. MS: 188 [M+H]+.Step 2 4-azido-2-phenylpyridazin-3(2J7)-oneTo a stirred mixture of 4-amino-2-phenylpyridazin-3(2J7)-one (700 mg, 3.74 mmol) in 6M aq. HC1 (3 mL) and EtOAc (5 mL) was added sodium nitrite (516 mg, 7.48 mmol) in H2O (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. Then sodium azide (486 mg, 7.48 mmol) was added to this reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for another 30 min. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL, two times). The combined organic extracts were concentrated under reduced pressure and then purified by silica gel flash-column chromatography (eluting with 30% EtOAc in pet ether) to yield the desired product. MS: 214 [M+H]+.2-(tetrahydro-2H-Dyran-2-yl)-4-(4.,4.,5.,5-tetramethyl-l.,3.,2-dioxaborolan-2-yl)Dyridazin- 3(2H)-one (1-28)26123B2Pin2, KOAc DHP, p-TSA XPhos Pd G2 Step 1 Step 2Step. 4-chloro-2-(tetrahydro-2J / -pyran-2-yl)pyridazin-3(2J7)-oneTo a stirred solution of 4-chloropyridazin-3(2J7)-one (20.0 g, 153 mmol) in THF (200 mL) was added / ?-toluenesulfonic acid monohydrate (2.91 g, 15.3 mmol) and 3,4-dihydro-2JT-pyran (55.9 mL, 613 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 30% EtOAc in petroleum ether) yielded the desired product. MS: 215 [M+H]+.Step 2 2-(tetrahydro-2J / -pyran-2-yl)-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridazin-3(2J7)-oneIn a nitrogen-filled glovebox, a solution comprising 4-chloro-2-(tetrahydro-27 / -pyran-2-yl)pyridazin-3(2J7)-one (5 g, 0.02 mol) in THF (150 mL) was treated with bis(pinacolato)diborane (0.01 kg, 0.06 mol), potassium acetate (7 g, 0.07 mol), and XPhos Pd G2 precatalyst (0.9 g, 1 mmol). The reaction mixture was stirred under an inert atmosphere at 50 °C for 16 h. The reaction mixture was then filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to yield the desired product, which was used without purification.1HNMR(400 MHz, CDC13): 87.81 (d, J= 3.6 Hz, 1H), 7.54 (d, J= 3.6 Hz, 1H), 6.09 (dd, J= 10.6 Hz, 1.8 Hz, 1H), 4.17-4.09 (m, 1H), 3.82-3.66 (m, 1H), 1.88-1.50 (m, 6H), 1.34 (s, 12H).(2-benzyl-3-oxo-2.,3-dihydroDyridazin-4-yl)boronic acid (1-29)B2(Pin)2, KOAc XPhos Pd G2In a nitrogen-filled glovebox, a stirred solution of 2-benzyl-4-chloropyridazin-3(2H)-one (2.0 g, 9.1 mmol) in 1,4-di oxane (20 mL) was treated with potassium acetate (1.8 g, 18 mmol), bis(pinacolato)diborane (4.6 g, 18 mmol), and XPhos Pd G2 precatalyst (0.36 g, 0.45 mmol) at RT. The mixture was heated under an inert atmosphere to 60 °C for 16 hours. The mixture was then filtered, and the filter cake was rinsed with THF (50 mL). The filtrate was concentrated to26123provide (2-benzyl-3-oxo-2,3-dihydropyridazin-4-yl)boronic acid, which was used without purification. MS: 231 [M-pinacol+H]+.2-(2-methoxyDyridin-4-yl)-4-(4.,4.,5.,5-tetramethyl-l.,3.,2-dioxaborolan-2-yl)Dyridazin-3(2H)-one (1-30)Step. 4-chloro-2-(2-methoxypyridin-4-yl)pyridazin-3(2J7)-oneTo a stirred solution of 4-chloropyridazin-3(2J7)-one (1.5 g, 11 mmol) and (2-methoxypyridin-4-yl)boronic acid (1.8 g, 11 mmol) in DCM (50 mL) were added pyridine (9.3 mL, 0.11 mol), pyridine 1 -oxide (3.3 g, 34 mmol), and 4A molecular sieves at 25 °C. The mixture then sparged with, O2 at 25 °C for 5 min. Then copper (II) acetate (4.2 g, 23 mmol) was added to the reaction mixture. The reaction mixture was stirred under an atmosphere of oxygen gas at 25 °C for 16 h. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 100% EtOAc) yielded the desired product. MS: 238 [M+H]+.Step 2 2-(2-methoxypyridin-4-yl)-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridazin-3(2J7)-oneIn a nitrogen-filled glovebox, a stirred solution of 4-chloro-2-(2-methoxypyridin-4-yl)pyridazin-3(2J7)-one (700 mg, 2.95 mmol) in THF (30 mL) was treated with added bis(pinacolato)diboron (2.24 g, 8.84 mmol), potassium acetate (867 mg, 8.84 mmol) and XPhos Pd G2 precatalyst (232 mg, 295 pmol) at 25 °C. The reaction mixture was stirred under an inert atmosphere at 45 °C for 16 h. The reaction mixture was filtered through a Celite pad and the filter cake was washed with THF (150 mL). The filtrate was concentrated under reduced pressure to yield the desired product, which was used without purification. MS: 248 [M-pinacol+2(OH)+H]+.26123Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-30, substituting appropriate starting materials:MS[M- IntermediateStructure IUPAC Name pinacol+2 Number(OH)+H] +2-phenyl-4-(4,4, 5, 5- tetramethyl-1,3,2- 1-31 ' n if | 217 V-o 0 dioxaborolan-2-yl)pyridazin- 3(2H)-onebenzyl (7?)-(l-(5-(3-oxo-2.,3-dihvdroDyridazin-4-yl)thiazol-2-yl)ethyl)carbaniate and benzyl 6S)-(l-(5-(3-oxo-2.,3-dihvdropyridazin-4-yl)thiazol-2-yl)ethyl)carbaniate (1-32)K2CO3, Pd(dppf)CI2*CH2CI2Step 1HCI, then SFC Step 2I-32BStep. benzyl (l-(5-(3-oxo-2-(tetrahydro-2J / -pyran-2-yl)-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamateTo a stirred and deoxygenated solution of benzyl (l-(5-chlorothiazol-2-yl)ethyl)carbamate (4.8 g, 16 mmol) in 1,4-dioxane (60 mL) and water (30 mL) were added 2-(tetrahydro-2J / -pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazin-3(2J7)-one (7.2 g, 32 mmol), Pd(dppf)C12*CH2C12 (1.3 g, 1.6 mmol) and K2CO3 (4.5 g, 32 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 50% EtOAc in petroleum ether) yielded the desired product. MS: 441 [M+H]+.26123Step 2\ benzyl (l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamate llnt-XI and benzyl (l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamateTo a stirred solution of benzyl (l-(5-(3-oxo-2-(tetrahydro-2J / -pyran-2-yl)-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamate (5.2 g, 12 mmol) in DCM (30 mL) was added 4M HC1 in 1,4-dioxane (30 mL, 0.12 mol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude compound was triturated with / / -pentane (50 mL) and diethyl ether (50 mL). The triturated residue was subjected to chiral SFC separation ((7?,7?)-Whelk-01, 60:40 CO2:modifier, modifier = MeOH) to afford the following:I-32A (faster eluting isomer): MS: 357 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 6 13.50 (br s, 1H), 8.60 (s, 1H), 8.24 (d, J= 7.6 Hz, 1H), 7.96-8.04 (m, 2H), 7.12-7.50 (m, 5H), 5.08 (s, 2H), 4.97 (qt, J= 7.4 Hz, 1H), 1.50 (d, J= 7.2 Hz, 3H).I-32B (slower eluting isomer): MS: 357 [M+H]+. 'HNMR (400 MHz, DMSO-tL) VT at 90 °C: 8 13.21 (br s, 1H), 8.51 (s, 1H), 7.93 (d, J= 4.4 Hz, 1H), 7.77-7.89 (m, 2H), 7.24-7.40 (m, 5H), 5.08 (s, 2H), 4.99 (qt, J= 7.4 Hz, 1H), 1.53 (dd, J= 6.8 Hz, 1.6 Hz, 3H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-32, substituting appropriate starting materials:Intermediate MS Structure IUPAC NameNumber [M+H]+benzyl (2 -methoxy- 1 -(5 -(3- CbzHNsJI |^IH1-33 oxo-2,3-dihydropyridazin-4- 387 oyl)thiazol-2-yl)ethyl)carbamatete -butyl ((17?.,2tS)-2-methoxy-l-(5-(3-oxo-2.,3-dihvdroDyridazin-4-yl)isoxazol-3-yl)proDyl)carbamate (1-34)26123Step 1: methyl A-ftertebutoxycarbonyD-O-methyl-Z-allothreoninateTo a stirred solution of (tertebutoxycarbonyl)-Z-allothreonine (7 g, 0.03 mol) in ACN (100 mL) were added silver oxide (0.04 kg, 0.2 mol) and iodomethane (0.02 L, 0.3 mol) at 25 °C. The reaction mixture was stirred at 25 °C for 3 d. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 30% EtOAc in petroleum ether) yielded the desired product.XH NMR (400 MHz, CDC13): 8 5.28 (d, J= 7.2 Hz, 1H), 4.43 (dd, J= 8.6 Hz, 3.8 Hz, 1H), 3.76 (s, 3H), 3.70-3.58 (m, 1H), 3.36 (s, 3H), 1.45 (s, 9H), 1.20 (d, J= 6.4 Hz, 3H).Step 2: tert-butyl ((2A M-1 -hydroxy-3 -methoxybutan-2-yl)carbamateTo a stirred solution of methyl A-(tertebutoxycarbonyl)-O-methyl-Z-allothreoninate (6 g, 0.02 mol) in THF (100 mL) was added IM DIBAL-H in THF (0.06 L, 0.06 mol) dropwise over a period of 10 min at -78 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with saturated aqueous sodium potassium tartrate (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 30% EtOAc in petroleum ether) yielded the desired product. 'HNMR (400 MHz, CDCI3): 65.35 (br s, 1H), 3.96 (d, J= 11.2 Hz, 1H), 3.68-3.49 (m, 3H), 3.35 (s, 3H), 2.91 (d, J= 8.8 Hz, 1H), 1.46 (s, 9H), 1.22 (d, J= 6.4 Hz, 3H).Step 3: of tert-butyl ((2&3M-3 -methoxy- l-oxobutan-2-yl)carbamateTo a stirred solution of tert-butyl ((2 / 3A')-l -hydroxy-3 -methoxybutan-2-yl)carbam ate (3.5 g, 16 mmol) in EtOAc (60 mL) was added IBX (8.9 g, 32 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to 25 °C. Then the reaction mixture was filtered and the filtrate was washed with sat. aq. NaHCO? solution (2 x 20 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the desired product. 'HNMR (400 MHz, CDCI3): 69.72 (s, 1H), 5.68-4.82 (m, 1H), 4.26 (s, 1H), 3.85-3.57 (m, 1H), 3.49-3.26 (m, 3H), 1.46 (s, 9H), 1.35 (d, J= 6.4 Hz, 3H).26123Step 4: tert-butyl ((2A,35,£)-l-(hydroxyimino)-3-methoxybutan-2-yl icarbamateTo a stirred solution of tert-butyl ((25, 35)-3 -methoxy- l-oxobutan-2-yl)carbamate (3 g, 0.01 mol) in ethanol (30 mL) and water (30 mL) were added hydroxylamine hydrochloride (2 g, 0.03 mol) and sodium acetate (2 g, 0.03 mol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 * 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to yield the desired product. MS: 233 [M+H]+.Step 5: tert-butyl ((25,35,2)- 1 -chloro- l-(hydroxyimino)-3-methoxybutan-2-yl)carbamateTo a stirred solution of tert-butyl ((2A,35,£)-l-(hydroxyimino)-3-methoxybutan-2-yl)carbamate (1.5 g, 6.5 mmol) in DMF (15 mL) was added NCS (0.95 g, 7.1 mmol) at 25 °C. The reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was quenched with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to yield the desired product. MS: 267 [M+H]+.Step 6: tert-butyl ((lA,25)-2-methoxy-l-(5-(3-oxo-2,3-dihvdropyridazin-4-yl)isoxazol-3-yDpropyDcarbamateTo a stirred solution of tert-butyl ((25,35,2)-l-chloro-l-(hydroxyimino)-3-methoxybutan-2-yl)carbamate (1.47 g, 5.49 mmol) in DMF (10 mL) were added 4-ethynylpyridazin-3(2J7)-one (300 mg, 2.50 mmol) and TEA (1.04 mL, 7.49 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was diluted with ice water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 50% EtOAc in petroleum ether) yielded the desired product. MS: 351 [M+H]+.Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-34, substituting appropriate starting materials:MSIntermediateStructure IUPAC Name [M+H- NumberC4H8]+26123tert-butyl (5)-(l-(5-(3-oxo-2,3- <^NBocHN NH dihydropyridazin-4- 1-35 251 yl)isoxazol-3-ZN'O 0yl)ethyl)carbamatetert-butyl (7?)-(2-methoxy-l-(5- [f^N(3-oxo-2,3-dihydropyridazin-4- 1-36 BocHN NH281 yl)isoxazol-3- MeO — ' N" O 0yl)ethyl)carbamate / m-biityl (7?)-2,2-dimethyl-4- i (5 -(3 -oxo-2, 3- 1-37 — L-NBOCdihydropyridazin-4- 307 °^' Vo 0 yl)isoxazol-3-yl)oxazolidine-3- carb oxy latetert-butyl (l-(5-(3-oxo-2,3- [f^Ndihydropyridazin-4- 1-38 BocHN NH263 yl)isoxazol-3- <n^o oyl)cyclopropyl)carbamaterf^N 4-(3-(l- 1-39H2Naminocyclobutyl)isoxazol-5- 277 u l'O 0 yl)pyridazin-3(2J7)-onetert-butyl ((lR,2S)-2- [f^N (benzyloxy)- 1 -(5 -(3 -oxo-2, 3 - BocHN 7^ / X. NH1-40 dihydropyridazin-4- 3710yl)isoxazol-3- OBnyl)propyl)carbamatetert-butyl (2-iiietli()xy-l-(l-(3-()x()-2.3-dilivdr()pyridaziii-4-yl)-l / / -1.2.3-triazol-4-yl)ethyl)carbamate (1-41)261231-41 Step. 4-azidopyridazin-3(2J7)-oneTo a stirred solution of 4-chloropyridazin-3(2J7)-one (9 g, 0.07 mol) in DMF (50 mL) was added sodium azide (9 g, 0.1 mol) at room temperature. The reaction mixture was stirred under argon atmosphere at 80 °C for 16 h. Reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 ^ 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 30% EtOAc in hexane) to provide the desired product. MS: 138 [M+H]+.Step 2 tert-butyl (A)-(2-methoxy-l-(l-(3-oxo-2,3-dihvdropyridazin-4-yl)-U / -L2,3-triazol-4-yPethyDcarbamateSodium ascorbate buffer solution was prepared by combining sodium ascorbate (24.8g, 125 mmol), Na2HPO4 (70.0 g, 493 mmol), citric acid (48.7 g, 254 mmol) and water (to make a total volume of 1000 mL) with pH ~5. A separate aqueous CuSO THPTA solution was prepared by combining anhydrous Q1SO4 (948 mg, 6.00 mmol), tris((l-benzyl-4-triazolyl)methyl)amine (THPTA, 2.61 g, 6.00 mmol), and H2O (300 mL). A stirred solution of 4-azidopyridazin-3(2Z / )-one (1.0 g, 7.0 mmol) in DMSO (30 mL) was diluted with sodium ascorbate buffer solution. The resulting mixture was stirred at 30 °C for 15 min before it was added to a mixture comprising tert-butyl (l-methoxybut-3-yn-2-yl)carbamate (2.0 g, 9.0 mmol), DMSO (20 mL), and CUSO4 / THPTA solution (20 mL). The resulting reaction mixture was heated with stirring to 40 °C for 20 min before it was cooled to RT. Ice-cold water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL, twice). The combined organic extracts were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting with 70% THF / petroleum ether) to provide the desired product as a scalemic mixture. Chiral purity was upgraded by SFC (IC, 70:30 CO2:modifier, modifier = 0.1% cone. aq. NH4OH in MeOH), affording the desired product as the slower-eluting isomer. MS: 281 [M+H-C4H8]+. 'HNMR (400 MHz, DMSO-t / 6): 6 13.84 (br s, 1H), 8.91 (s, 1H), 8.12 (d, J= 4.4 Hz, 1H), 8.09 (d, J= 4.4 Hz, 1H), 7.45 (d, J= 8.8 Hz, 1H), 4.99 (q, J= 7.2 Hz, 1H), 3.54-3.66 (m, 2H), 3.27 (s, 3H), 1.39 (s, 9H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-41, substituting appropriate starting materials:26123MSIntermediateStructure IUPAC Name [M+H- NumberC4H8]+tert-butyl (S)-(l-(l-(3-oxo-2,3- dihydropyridazin-4-yl)-lH- 1-42 BocHN JI NH 251 l,2,3-triazol-4-ZN^N oyl)ethyl)carbamatetert-butyl (R)-2,2-dimethyl-4-. Boc (l-(3-oxo-2,3- 1-43 dihydropyridazin-4-yl)-lH- 307 N=N 0 l,2,3-triazol-4-yl)oxazolidine- 3-carboxylate / ‘crt-butyl (ty)-(l-(5-(2-(3-bromo-5-chloroDhenyl)-3-oxo-2,3-dihydroDyridazin-4-yl)isoxazol- 3-yl)ethyl)carbamate (1-44)CU(OAC)2, PyNO Pyridine, O2ciA solution of tert-butyl (S)-(l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (7.00 g, 22.9 mmol) in DCM (100 mL) was treated with (3-bromo-5-chlorophenyl)boronic acid (8.07 g, 34.3 mmol), pyridine 1 -oxide (PyNO, 1.09 g, 11.4 mmol), pyridine (5.54 mL, 5.42 g, 68.6 mmol), and copper(II) acetate (2.08 g, 11.4 mmol) atRT. The reaction was stirred at RT for 16 h under an atmosphere of oxygen gas. The mixture was then diluted with water (50 mL) and extracted with DCM (50 mL, twice). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 20% EtOAc / petroleum ether) to provide the desired product. MS: 439, 441 [M+H-C4H8]+.XH NMR (500 MHz, DMSO-t / r,): 88.24 (d, J= 4.3 Hz, 1H), 8.03 (d, J= 4.3 Hz, 1H), 7.90 (t, J= 1.7 Hz, 1H), 7.88 (t, J= 1.8 Hz, 1H), 7.82 (t, J= 1.8 Hz, 1H), 7.56 (d, J= 9.5 Hz, 1H), 7.31 (s, 1H), 4.85-4.80 (m, 1H), 1.39 (d, J= 6.3 Hz, 3H), 1.38 (s, 9H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-44, substituting appropriate starting materials:26123MSIntermediateStructure IUPAC Name [M+H- NumberC4H8]+tert-butyl (S)-(l-(5-(2-(3- bromo-5-fluorophenyl)-3-oxo- 1-45 2,3-dihydropyridazin-4- 423, 425 yl)isoxazol-3- yl)ethyl)carbamatetert-butyl (S)-(l-(5-(2-(2- cobromopyridin-4-yl)-3 -oxo-2, 3 - rf^N1-46 BocHN A N / x Br dihydropyridazin-4- 406, 408''' N'°0zz- Y>Nyl)isoxazol-3- ^o= yl)ethyl)carbamatetert-butyl (S)-(l-(5-(6'-chloro- [f^NJ? C / VBocHN I N _ ci 6-oxo-6H-[l,4'-bipyridazin]-5- 1-47NY^Y 363Io yl)isoxazol-3- o '' N-0 0 ll^N00 yl)ethyl)carbamatetert-butyl (S)-(l-(5-(2-(2- fj^N chloro-6-methoxypyridin-4- BocHN^^_A __CI yl)-3-oxo-2,3- 1-48 392'N'°0YNdihydropyridazin-4- yl)isoxazol-3- °\yl)ethyl)carbamatetert-butyl (S)-(l-(5-(2-(3- bromo-5-chloro-4- YNfluorophenyl)-3 -oxo-2, 3 -B0CHN\SL / ^Y^V^YBr1-49 457, 459ZN'O o LAFdihydropyridazin-4- CI yl)isoxazol-3- yl)ethyl)carbamate26123rC^N 0 methyl (S)-3-(5-(3-(l-((tert- butoxycarbonyl)amino)ethyl)is1-50 ^ L / YYYVV 419'''' N-0 O oxazol-5-yl)-6-oxopyridazin- Cl 1 (6H)-yl)-5 -chlorob enzoatetert-butyl (S)-(l-(5-(2-(3-chloro-5-(4.,4.,5.,5-tetramethyl-l.,3.,2-dioxaborolan-2-yl)Dhenyl)-3-oxo-2.,3-dihydroDyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (1-51)KOAc Pd(dppf)Cl2«CH2Cl2ciA solution of tert-butyl (S)-(l-(5-(2-(3-bromo-5-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (100 mg, 202 pmol) in 1,4-dioxane (2.02 mL) was treated with bis(pinacolato)diborane (76.8 mg, 303 pmol), Pd(dppf)C12*CH2C12 (16.5 mg, 20.2 pmol), and potassium acetate (59.4 mg, 605 pmol). The mixture was sparged with argon for 5 min, then heated to 100 °C for 5 h. The mixture was cooled to RT, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with hexanes initially, grading to 50% EtOAc / hexanes) to provide the desired product. MS: 565 [M+Na]+. 'HNMR (500 MHz, CD3OD): 88.16 (d, J= 3.8 Hz, 1H), 7.97 (d, J= 3.8 Hz, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.32 (s, 1H), 4.95-4.88 (m, 1H), 1.50 (d, J= 7.0 Hz, 3H), 1.43 (s, 9H), 1.36 (s, 12H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-51, substituting appropriate starting materials:Intermediate MS Structure IUPAC NameNumber [M+Na]+tert-butyl (S)-(l-(5-(2-(3- chloro-5-(4,4,5,5-tetraethyl- V([ 'NO" \ Et l,3,2-dioxaborolan-2- BocHN A N zx R A1-52 ysLXy Tf'0 Etyl)phenyl)-3 -oxo-2, 3 - 621ZN'O O Odihydropyridazin-4- Clyl)isoxazol-3- yl)ethyl)carbamate26123(S -3-(5-(3-(l-((tert-butoxycarbonyl amino ethyl)isoxazol-5-yl -6-oxopyridazin-l(6H)-yl -5-chlorobenzoic acid (1-53)NBocHN i NO o1-53 A stirred solution of methyl CS')-3-(5-(3-(l-(( / c / 7-butoxycarbonyl)amino)ethyl)isoxazol-5-yl)-6-oxopyridazin-l(6J7)-yl)-5-chlorobenzoate (0.85 g, 1.8 mmol) in THF (10 mL) and water (10 mL) was treated with lithium hydroxide (0.43 g, 18 mmol) at 0 °C. The mixture was allowed to warm to RT, and was stirred at that temperature for 6 h. The mixture was then partially concentrated under reduced pressure, and the concentrated mixture was acidified by the addition of IN aq. HC1. The solid was collected by filtration and dried under reduced pressure to afford the desired product. MS: 405 [M+H-C4H8]+. 'H NMR (400 MHz, DMSO-t / e): 68.23 (d, J= 4.4 Hz, 1H), 8.01 (d, J= 4.4 Hz, 1H), 7.95 (dd, J= 2.0 Hz, 1.2 Hz, 1H), 7.87 (dd, J= 2.0 Hz, 1.2 Hz, 1H), 7.63 (t, J= 2.0 Hz, 1H), 7.57 (d, J= 8.4 Hz, 1H), 7.33 (s, 1H), 4.83 (t, J= 7.6 Hz, 1H), 1.42-1.30 (m, 12H)4-(3-bromoDhenyl)-2-methyl-2H-l.,2.,3-triazole (I-54A) and 4-(3-bromoDhenyl)-l-methyl- lH-L2,3-triazole (I-54B)TMSN3, Cui CS2CO3, Mel N Me BrStep 1 Step 2 Step. 4-(3-bromophenyl)-U / -l,2,3-triazoleTo a stirred solution of l-bromo-3-ethynylbenzene (3.00 mg, 16.6 mmol) in DMF (20.0 mL) and methanol (2.20 mL) were added azido(trimethyl)silane (3.29 mL, 24.9 mmol) and copper(I) iodide (158 mg, 829 pmol) at 25 °C. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 25 mL). The combined organic extracts were washed with brine (2 x 25 mL), then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 40% EtOAc in hexane) yielded the desired product. MS: 224, 226 [M+H]+.Step 2\ 4-(3 -bromophenyl)- 1 -methyl- ITT- 1,2,3 -triazole (I-54A) and 4-(3-bromophenyl)-2-methyl-277-1,2,3-triazole (I-54B)26123To a stirred solution of 4-(3-bromophenyl)-U / -l,2,3-triazole (2.0 g, 8.9 mmol) in DMF (20 mL) was added CS2CO3 (5.8 g, 18 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Next, methyl iodide (0.67 mL, 11 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for an additional 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 40% EtOAc in hexane) yielded the following, in order of elution from the column:I-54A (faster-eluting isomer): MS: 238, 240 [M+H]+.I-54B (slower eluting isomer): MS: 238, 240 [M+H]+.4-(3-bromo-5-chlorophenyl)-2-methyl-2H-l.,2.,3-triazole (I-55A) and 4-(3-bromo-5-chlorophenyl)-l-methyl-lH-l.,2.,3-triazole (I-55B)Cl ClBr BrI-55A I-55BUsing methods similar to those outlined for 1-54, and employing silica gel column chromatograpy (eluting with 15% EtOAc / hexane initially, grading to 60% EtOAc / hexane) in Step 2, the following were obtained:I-55A (faster eluting isomer, 4-(3-bromo-5-chlorophenyl)-2-methyl-2H-l,2,3-triazole): MS: 272, 274 M+H]+. 'H NMR (400 MHz, DMSO-tfc): 68.39 (s, 1H), 8.00 (t, J= 1.6 Hz, 1H), 7.91 (t, J= 1.6 Hz, 1H), 7.71 (t, J= 1.8 Hz, 1H), 4.22 (s, 3H).I-55B (slower eluting isomer, 4-(3-bromo-5-chlorophenyl)-l-methyl-lH-l,2,3-triazole): MS: 272, 274 M+H]+. 'HNMR (400 MHz, DMSO-tfc): 68.70 (s, 1H), 8.02 (t, J= 1.6 Hz, 1H), 7.92 (t, J= 1.6 Hz, 1H), 7.67 (t, J= 2.0 Hz, 1H), 4.11 (s, 3H).l-(4-bromo-2H-l.,2.,3-triazol-2-yl)-2-niethylpropan-2-ol (I-56A) and l-(4-bronio-llI-1.2.3-triazol-l-yl)-2-methylpropan-2-ol (I-56B)OHI-56A I-56B26123To a stirred solution of 4-bromo-lH-l,2,3-triazole (2.0 g, 14 mmol) in NMP (10.0 mL) were added cesium carbonate (0.88 g, 2.7 mmol) and 2,2-dimethyloxirane (1.5 g, 20 mmol) at RT. The reaction was stirred at 60 °C for 16 hour under air before it was cooled again to RT. Water (50 mL) was added, and the mixture was extracted with DCM (50 mL, two times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 20% EtOAc / petroleum ether) to provide:I-56A (faster eluting isomer). MS: 220, 222 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 68.21 (s, 1H), 4.89 (s, 1H), 4.29 (s, 2H), 1.08 (s, 6H).I-56B (slower eluting isomer): MS: 220, 222 [M+Hf.'HNMR (400 MHz, DMSO-tfc): 67.96 (s, 1H), 4.78 (s, 1H), 4.32 (s, 2H), 1.11 (s, 6H).l-(4-(3-bromo-5-chloroDhenyl)-lH-Dyrazol-l-yl)-2-methylDroDan-2-ol (1-57)1-57 Under an inert atmosphere, 1,4-dioxane (18.2 mL) and water (1.82 mL), both deoxygenated by sparging with nitrogen gas, were added to a mixture of l,3-dibromo-5-chlorobenzene (1.08 g, 4.00 mmol), 2-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-U / -pyrazol-l-yl)propan-2-ol (532 mg, 2.00 mmol), potassium carbonate (829 mg, 6.00 mmol), and Pd(dppf)C12*CH2C12 (163 mg, 0.200 mmol). The mixture was stirred at 90 °C for 3 h. The mixture was then cooled to RT, diluted with EtOAc (50 mL), and washed sequentially with sat. aq. NH4CI solution (50 mL) and sat. aq. NaCl solution (50 mL). The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 5% B / hexanes initially, grading to 60% B / hexanes [B = 25% v / v EtOHZEtOAc]) to provide the desired product. MS: 329, 331 [M+H]+. 'HNMR (500 MHz, DMSO-t / 6): 88.27 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.48 (s, 1H), 4.74 (s, 1H), 4.02 (s, 2H), 1.08 (s, 6H).2-(l-(3-bromo-5-chloroDhenyl)-lH-l.,2.,3-triazol-4-yl)DroDan-2-ol (1-58)26123Step. l-azido-3-bromo-5-chlorobenzeneTo a stirred solution of 3-bromo-5-chloroaniline (5000 mg, 24.22 mmol) in EtOAc (35 mL) were added 6MHC1 (16.14 mL, 96.87 mmol), sodium nitrite (3.341 g, 48.43 mmol) and sodium azide (3.149 g, 48.43 mmol) portion wise at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. The organic layer was separated and washed with water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Silica gel column chromatography (eluting with 10% EtOAc in hexane) yielded the desired product.XH NMR (400 MHz, DMSO-tfc): 6 (ppm) 7.28 (t, J= 1.6 Hz, 1H), 7.07 (t, J= 1.8 Hz, 1H), 6.96 (t, J= 2.0 Hz, 1H).Step 2 2-(l-(3-bromo-5-chlorophenyl)-U / -L2,3-triazol-4-yl)propan-2-olTo a stirred solution of l-azido-3-bromo-5-chlorobenzene (2.9 g, 12 mmol) in t-BuOH (30 mL) and water (30 mL) were added 2-methylbut-3-yn-2-ol (3.1 g, 37 mmol), sodium ascorbate (0.99 g, 5.0 mmol) and copper(II)sulfate pentahydrate (0.62 g, 2.5 mmol) in water (5 mL) dropwise at 0 °C. The reaction mixture was stirred vigorously at 25 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The precipitated solid was filtered and dried under reduced pressure. Silica gel column chromatography (eluting with 60% EtOAc in hexane) yielded the desired product. MS: 316 [M+H]+.4-bromo-6-chloro-l-(2.,2-difluoroethyl)-lH-indazole (1-59)To a vial containing 4-bromo-6-chloro-lH-indazole (600 mg, 2.59 mmol) was added a mixture of 2,2-Difluoroethyl trifluoromethanesulphonate (414 pL, 3.11 mmol) and DMF (13 mL). Potassium carbonate (716 mg, 5.18 mmol) was added and the mixture was heated to 60 °C. Upon completion, the mixture was allowed to cool to room temperature and then diluted with26123ethyl acetate and brine. The organic layer was separated, dried over magnesium sulfate, filtered and then concentrated reduced pressure. The resulting mixture was purified by column chromatography (eluting with a 0-70% (3:1 ethyl acetate: ethanol) gradient in hexanes) to afford the desired product. 'HNMR (500 MHz, DMSO) 88.19 (d, J= 1.0 Hz, 1H), 8.05 (s, 1H), 7.54 (d, J= 1.5 Hz, 1H), 6.60 - 6.30 (m, 1H), 4.99 (td, J= 15.3, 3.6 Hz, 2H).(lS,2R)-2-(4-bromo-lH-Dyrazol-l-yl)cyclobutan-l-ol., (! S.,2S)-2-(4-bromo-lH-Dyrazol-l-vDcyclobutan-l-ol., (! R.,2R)-2-(4-bromo-lH-Dyrazol-l-yl)cvclobutan-l-ol., and (lR,2S)-2-(4-bromo-lH-Dyrazol-l-yl)cvclobutan-l-ol (1-60)2-(4-bromo-lH-pyrazol-l-yl)cyclobutan-l-ol was prepared according to a procedure in the literature (WO 2025 / 137507). The stereoisomeric mixture thus obtained was subjected to chiral SFC (IG, 21 x 250 mm, 5 pm, 75:25 CO2:modifier, modifier = 0.1% v / v cone. aq. NH4OH in methanol) to afford a mixture of I-60A and I-60B (fastest eluting peak), I-60C (eluted second, single isomer), and I-60D (slowest eluting peak, single isomer). The mixture comprising I-60A and I-60B was resubjected to chiral SFC (IG, 21 x 250mm, 5 pm, 85:15 CO2:modifier, modifier = 0.1% v / v cone. aq. NH4OH in methanol) to afford I-60A as the faster eluting isomer and I-60B as the slower eluting isomer. MS: 217, 219 [M+H]+.(3-clil()r()-5-(l-iiietliyl-l / / -1.2.3-tri:iz()l-4-yl)i)lieiiyl)boronic acid (1-61)triisopropyl borate2.5M n-BuLi THF, -78 °C-rt, 4 h(HO)2Blnt-61To a stirred mixture of 4-(3-bromo-5-chlorophenyl)-l-methyl-U / -l,2,3-triazole (700 mg, 2.57 mmol) in THF (10 mL) under inert atmosphere was added triisopropyl borate (4.74 mL, 20.5 mmol) at -78 °C. Then, w-butyllithium (2.5 M in hexanes, 4.11 mL, 10.3 mmol) was added dropwise to the reaction mixture at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. Then the reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with DCM (3 x 25 mL). The26123combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired product. MS: 238 [M+H]+.Compounds in the table below were prepared using methods similar to those outlined in the synthesis of 1-61, substituting appropriate starting materials:Intermediate MS Structure IUPAC NameNumber [M+Na]+Cl (3-chloro-5-(2-methyl-2H- 1-62 l,2,3-triazol-4- 238V / v / — ' N'N\(HO)2Bxyl)phenyl)boronic acidEXAMPLESExample 1: 3-(5-(aminomethyl)-l.,3.,4-thiadiazol-2-yl)-l-DhenylDyridin-2(LH)-oneLawesson’s Reagent;then TFAExample 1In a glass vial equipped with a magnetic stir bar, tert-butyl (2-oxo-2-(2-(2-oxo-l-phenyl- l,2-dihydropyridine-3-carbonyl)hydrazineyl)ethyl)carbamate (50 mg, 0.13 mmol) and Lawesson’s reagent (58 mg, 0.14 mmol) were combined with THF (0.65 mL). The resulting suspension was heated to 60 °C with stirring. After 5 h, the mixture was cooled to RT and concentrated under reduced pressure. The residue was redissolved in TFA (1.0 mL). The resulting solution was aged at room temperature for 15 min before it was concentrated under reduced pressure. The residue was purified by HPLC (MeCN / water containing 0.1% v / v TFA modifier) to afford the desired product as the TFA salt. MS: 285 [M+H]+.XH NMR (500 MHz, CD3OD): 88.87 (d, J= 7.3 Hz, 1H), 7.98 (d, J= 6.7 Hz, 1H), 7.62-7.49 (m, 3H), 7.50 (d, J= 7.8 Hz, 2H), 6.78 (t, J= 6.9 Hz, 1H), 4.67 (s, 2H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 1, substituting appropriate starting materials:Example Starting MS Structure IUPAC NameNumber material [M+H]+26123(S)-4-(5-( 1 -aminoethyl)- 1,3,4- Example 2 thiadiazol-2-yl)-2- 1-3 314 benzylpyridazin-3(2J7)-one2A zn\ / z\ (S)-3 -(5 -( 1 -aminoethyl)- 1,3,4- Example 3 H2N... thiadiazol-2-yl)-l- 1-4 299 W T n zz- If nMe N phenylpyridin-2(177)-oneExample 4: (tS)-3-(5-(l-amino-2-hvdroxyethyl)-l.,3.,4-thiadiazol-2-yl)-l-phenylpyridin-2(lH)-oneLawesson's ReagentStep 1HCIStep 2Example 4Step. Tert-butyl (y)-2,2-dimethyl-4-(5-(2-oxo-l-phenyl-L2-dihydropyridin-3-yl)-L3,4- thiadiazol-2-yl)oxazolidine-3-carboxylateTo a stirred solution of tert-butyl (5)-2,2-dimethyl-4-(2-(2-oxo-l -phenyl- 1,2- dihydropyridine-3-carbonyl)hydrazine-l-carbonyl)oxazolidine-3 -carboxylate (850 mg, 1.86 mmol) in THF (15 mL) was added Lawesson's reagent (1.13 g, 2.79 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for 6 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 70-100% EtOAc in pet ether) yielded the desired product. MS (ESI) [M+H]+m / z: 455Step 2\ (M-3-(5-(l-amino-2-hydroxyethyl)-L3,4-thiadiazol-2-yl)-l-phenylpyridin-2(lJ7)-one To a stirred solution of tert-butyl (5)-2,2-dimethyl-4-(5-(2-oxo-l-phenyl-l,2- dihydropyridin-3-yl)-l,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate (100 mg, 220 pmol) in26123DCM (2 mL) was added 4M HC1 in 1,4-dioxane (165 pL, 660 pmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Crude compound was triturated with diethyl ether (2 mL), n-pentane (2 mL) and dried under reduced pressure. Prep HPLC purification (MeCN / water containing 10 mM ammonium bicarbonate modifier) yielded the desired product. MS (ESI) [M+H]+m / z 315.XH NMR (400 MHz, DMSO-tfc): 88.68 (dd, J= 7.2 Hz, 2.0 Hz, 1H), 8.02 (dd, J= 6.8 Hz, 2.0 Hz, 1H), 7.49-7.60 (m, 5H), 6.66 (t, J= 7.0 Hz, 1H), 5.05 (t, J= 5.8 Hz, 1H), 4.31 (t, J= 5.4 Hz, 1H), 3.65-3.74 (m, 1H), 3.52-3.60 (m, 1H), 2.27-2.40 (m, 2H).Example 5: Tert-butyl 6S)-(l-(5-(2-benzyl-3-oxo-2.,3-dihvdropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamateNEt3, then TFAExample 5In a glass vial equipped with a magnetic stir bar, 2-benzyl-4-ethynylpyridazin-3(2rt)-one (140 mg, 0.67 mmol), and sodium bicarbonate (57 mg, 0.67 mmol) were combined under air. The mixture was suspended in EtOAc (2 mL) then tert-butyl (5, Z)-(l-chloro-l-(hydroxyimino)propan-2-yl)carbamate (50 mg, 0.22 mmol) was added. The reaction mixture was stirred at 25 °C for 18 h. The crude reaction mixture was filtered, concentrated then dissolved in DCM (2 mL). Trifluoroacetic acid (170 pL, 2.2 mmol) was added. The reaction mixture was stirred at 25 °C for 18 h. The resulting solution was concentrated under reduced pressure. The residue was then purified by HPLC (MeCN / water containing 0.1% v / v cone. aq. NH4OH as modifier), followed by another round of HPLC (MeCN / water containing 0.1% v / v cone. aq. TFA as modifier) to afford the desired product as the TFA salt. MS (ESI) [M+H]+m / z: 297.1.1H NMR (500 MHz, DMSO-d6) 68.55 (s, 3H), 8.18 (d, J= 3.6 Hz, 1H), 8.04 (d, J= 3.5 Hz, 1H), 7.61 (s, 1H), 7.35 (s, 3H), 7.32 (s, 1H), 5.40 (s, 2H), 4.72 (s, 1H), 1.56 (d, J= 6.7 Hz, 3H).Example 6: 4-(4-(l-:imiiiocvclopropyl)-l / / -1.2.3-triazol-l-yl)-2-plieiiylpyridazin-3(2 / / )-one Na-ascorbate CuSO4, THPTA HCI Step 1 Step 2Example 626123Step. Tert-butyl (l-(l-(3-oxo-2-phenyl-2,3-dihydropyridazin-4-yl)-U / -L2,3-triazol-4- yl)cyclopropyl)carbamateTo a flask was added sodium ascorbate (24.8 g, 125 mmol), Na2HPC>4 (70 g, 492 mmol) citric acid (48.7 g, 254 mmol) and water (to make a total volume of 1000 mL). This sodium ascorbate / Na2HPC>4 / citric acid buffer was stored for this and future reactions.To a flask was added Q1SO4 (960 mg, 6.0 mmol), THPTA (2.61 g, 6.0 mmol) and water (300 mL). This CuSCh / THPTA solution was stored for this and future reactions.To a stirred mixture of 4-azido-2-phenylpyridazin-3(2rt)-one (200 mg, 938pmol) in DMSO (10 mL) was added sodium ascorbate / citric acid / Na2HPC>4(Buffer-pH-5) (10 mL). The resulting mixture was heated to 30 °C for 30 min. After 30 minutes, the mixture was cooled to 25 °C. Then a mixture of tert-butyl (l-ethynylcyclopropyl)carbamate (170 mg, 938 pmol) and DMSO (10 mL) was added followed by the aqueous CUSO4 / THPTA solution (3 mL). The mixture was then heated to 40 °C for 6 hours. After 6 hours, the reaction mixture was allowed to cool to 25 °C. The precipitated solid was filtered and dried under reduced pressure.The solid was then purified by column chromatography (eluting with 30% EtOAc in hexane) to afford the desired product. MS (ESI) [M+H]+m / z 395Step 2 4-(4-(l -aminocyclopropyl)- ITT- L2,3-triazol-l-yl)-2-phenylpyridazin-3(2J7)-oneTo a mixture of tert-butyl (l-(l-(3-oxo-2-phenyl-2,3-dihydropyridazin-4-yl)- 177-1,2,3- triazol-4-yl)cyclopropyl)carbamate (100 mg, 254 pmol) in 1,4-di oxane (2 mL) was added HC1 (4 M in 1,4-dioxane, 317 pL, 1.27 mmol) at 0 °C. The mixture was then allowed to warm 25 °C for 3 hours. After 3 hours, the reaction mixture was concentrated under reduced pressure. The resulting crude compound was triturated with diethyl ether (3 x 15 mL). The white solid was lyophilized to afford the desired product as an HC1 salt. MS (ESI) [(M-HC1)+H]+. m / z MS: 295.1HNMR(400 MHz, DMSO-tL): 68.80-9.26 (m, 4H), 8.31 (d, J= 4.4 Hz, 1H), 8.19 (d, J= 4.4 Hz, 1H), 7.60-7.66 (m, 2H), 7.53-7.60 (m, 2H), 7.46-7.54 (m, 1H), 1.45-1.54 (m, 2H), 1.31-1.40 (m, 2H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 6, substituting appropriate starting materials, and employing either HC1 in 1,4-dioxane or TFA in DCM for A-Boc removal in Step 2\Example Starting MS Structure IUPAC NameNumber material [M+H]+261234-(4-(2-amino-l- methoxypropan-2-yl)- \H- Example 7 327: < 1,2,3 -tri azol- 1 -yl)-2- 1-15+ CI-zCD,Z / I ra M phenylpyridazin-3(2J7)-one 27! J °^p z)S < / wzz- z z— (S)-4-(4-(l -aminoethyl)- 1H- Example 8 1,2,3 -tri azol- 1 -yl)-2- 1-26 297 z z—benzylpyridazin-3(2H)-oneb(S)-3-(4-(l-aminoethyl)-lH- Example 9 H2N p pr z zz—- 1,2,3 -tri azol- 1 -yl)- 1 - (1-27 282 WTN ^ To>= r nM / VN\ )0o=phenylpyridin-2( 1 H)-oneMzzz z-- (R)-3 -(4-( 1 -amino-2- hy droxy ethyl)- 1H- 1,2,3- Example 10xr % XO - 1 (1-27 298 I triazol- 1 -yl)- 1 -phenylpyridin- 2(lH)-one(5)-3 -(4-( 1 -aminoethyl)- 1H- l,2,3-triazol-l-yl)-l-(3,5- Example 11 M / 1-25 418V" ° Y bis(trifluoromethyl)phenyl)pyriCF3din-2(177)-one(7?)-4-(4-(l -amino-2- hy droxy ethyl)- 1H- 1,2,3- Example 12 1-26 313 triazol-l-yl)-2- benzylpyridazin-3(2J7)-oneExample 13: (7?)-3-(4-(l-amino-2-methoxyethyl)-lH-l.,2.,3-triazol-l-yl)-l-phenylpyridin- 2(LH)-one26123MeOCuSO4Sodium Ascorbatethen SFC chiralseparationStep 1HCIStep 2Example 13Step. Tert-butyl (A)-(2-methoxy- l-(l-(2-oxo-l -phenyl- 1,2-dihydropyri din-3 -yl)- ITT- 1,2,3 -triazol-4-yl)ethyl)carbamateTo a stirred solution of 3-azido-l-phenylpyridin-2(IT / )-one (100 mg, 471 pmol) and tertbutyl (l-methoxybut-3-yn-2-yl)carbamate (141 mg, 707 pmol) in THF (3 mL) and H2O (3 mL) were added ascorbate (93.4 mg, 471 pmol) and anhydrous copper(II)sulfate (75.2 mg, 471 pmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was treated with water (10 mL) and extracted with EtOAc (30 mL, three times). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 20% EtOAc in hexane) yielded the desired product as a stereoisomeric mixture. This material was subjected to chiral SFC (Cellulose-SC, 70:30 CO2:modifier, modifier = MeOH) to afford tertbutyl (A)-(2-methoxy-l-(l-(2-oxo-l-phenyl-l,2-dihydropyridin-3-yl)-U / -l,2,3-triazol-4-yl)ethyl)carbamate as the slower-eluting isomer. MS (ESI) [M+H]+m / z: 412Step 2'. (A)-3-(4-(l-amino-2-methoxy ethyl)- ITT- 1,2,3 -triazol- l-yl)-l-phenylpyridin-2(lrt)-one To a stirred solution of tert-butyl (A)-(2-methoxy- l-(l-(2-oxo-l -phenyl- 1,2-dihydropyridin-3-yl)-U / -l,2,3-triazol-4-yl)ethyl)carbamate (40 mg, 97 pmol) in DCM (5 mL) was added 4M HCI in 1,4-dioxane (0.12 mL, 0.49 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. Reaction mixture was concentrated under reduced pressure. The crude compound was triturated with diethyl ether (5 mL), dried under reduced pressure, and lyophilized to afford the desired product as an HCI salt. MS (ESI) [M+H]+m / z: 3121H NMR (400 MHz, DMSO-t / e): 68.86 (s, 1H), 8.58 (br s, 3H), 8.24 (dd, J= 7.6 Hz, 2.0 Hz, 1H), 7.95 (dd, J= 6.8 Hz, 2.0 Hz, 1H), 7.47-7.62 (m, 5H), 6.60 (t, J= 7.2 Hz, 1H), 4.81 (br t, J= 5.6 Hz, 1H), 3.73-3.83 (m, 2H), 3.38 (s, 3H).26123Example 14: (S)-4-((5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)methyl)benzoic acid hydrochlorideExample 14To a mixture of (5)-4-((5-(3-(l-((terLbutoxycarbonyl)amino)ethyl)isoxazol-5-yl)-6-oxopyridazin-l(6J7)-yl)methyl)benzoic acid (30 mg, 68 pmol) in DCM (1 mL) was added HC1 (4 M in 1,4-dioxane, 85 pL, 0.34 mmol) at 0 °C. The reaction mixture was allowed to warm to 25 °C for 1 hour. After 1 hour, the mixture was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (20 mL) to afford the desired product as an HC1 salt. MS (ESI) [M+H]+m / z: 341. 'H NMR (400 MHz, DMSO-tfc): 69.15 (br s, 1H), 8.19 (d, J= 4.4 Hz, 1H), 8.05 (d, J= 4.4 Hz, 1H), 7.92 (d, J= 8.0 Hz, 2H), 7.59 (s, 1H), 7.44 (d, J= 8.4 Hz, 2H), 5.47 (s, 2H), 4.65 (q, J= 6.6 Hz, 1H), 1.54 (d, J= 6.8 Hz, 3H).Example 15: (S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(4-(morpholine-4-carbonyl)benzyl)pyridazin-3(2H)-oneExample 15In a glass vial equipped with a magnetic stir bar, (5)-4-((5-(3-(l-((tert-butoxycarbonyl)amino)ethyl)isoxazol-5-yl)-6-oxopyridazin-l(6J7)-yl)methyl)benzoic acid (50 mg, 0.11 mmol) and HATU (130 mg, 0.34 mmol) were combined under air. Next, DMF (4 mL), DIPEA (59 pL, 0.34 mmol), and morpholine (30 pL, 0.34 mmol) were added sequentially. The reaction mixture was stirred at 25 °C for 1 h. The crude reaction mixture was filtered, the filtrate was concentrated, and the residue was then dissolved in DCM (1 mL). Trifluoroacetic acid (430 pL, 5.7 mmol) was added. The resulting mixture was stirred at 25 °C for 18 h, then concentrated under reduced pressure. The residue was purified by prep-HPLC (MeCN / water containing 0.1% v / v cone. aq. TFA as modifier) to afford the desired product as the TFA salt. MS (ESI) [M+H]+m / z: 410. 'H NMR (500 MHz, DMSO-d6) 88.53 (s, 3H), 8.20 (d, J= 4.2 Hz, 1H), 8.05 (d, J =261234.3 Hz, 1H), 7.60 (s, 1H), 7.40 (s, 4H), 5.44 (s, 2H), 4.72 (s, 1H), 3.65-3.55 (m, 8H), 1.56 (d, J = 6.7 Hz, 3H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 15, substituting appropriate starting materials, and employing either HC1 in 1,4-di oxane or TFA in DCM for A-Boc removal:Example Starting MS Structure IUPAC NameNumber material [M+H]+(5)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 16 (3-(morpholine-4- 1-12 410 carb ony l)b enzy l)py ri dazi n- Me N3(277)-one0(5)-4-(3-(l- 0zz- aminoethyl)isoxazol-5-yl)-2- Example 17 (2-morpholino-2- 1-13 334 oxoethyl)pyridazin-3 (27 / )- ol c VZDC''^'* one£2(5)-4-((5-(4-(l-aminoethyl)- o1H- 1,2,3 -tri azol- 1 -y l)-6 - Example 18 oxopyridazin- 1(677)- 1-11 398 Me N*N 0yl)methyl)-A-(2- methoxyethyl)benzamide(5)-4-((5-(4-(l-aminoethyl)- 177- 1,2,3 -tri azol- 1 -y l)-6 - Example 19 oxopyridazin- 1(677)- 1-11 354 Me N*N° yl)methyl)-A- methylbenzamide(S)-4-(4-( 1 -aminoethyl)- 177- 01,2,3 -tri azol- 1 -yl)-2-(4- Example 20 (morpholine-4- 1-11 410 Me N*N° carb ony l)b enzy l)py ri dazi n- 3(277)-one26123(5)-2-(5-(4-(l-aminoethyl)- \H- 1,2,3 -tri azol- 1 -y l)-6 - Example 21 1-13 278 oxopyridazin- 1 (6J7)-yl)-N- methylacetamide(5)-2-(5-(4-(l-aminoethyl)- \H- 1,2,3 -tri azol- 1 -y l)-6 - Example 22 1-13 322i II H 1 oxopyridazin- 1 (6J7)-yl)-N- Me e \ N,*N O OMe(2-methoxyethyl)acetamide(5)-4-(4-( 1 -aminoethyl)- \H- 1,2,3 -tri azol- 1 -yl)-2-(3 - ZIExample 23 (morpholine-4- 1-12 410H! N^ A "~'A rN^. M.e N 0 0zz- carb ony l)b enzy l)py ri dazi n- ^ ^_o=3(2J7)-onezz- (5)-3-((5-(4-(l-aminoethyl)-! l / / -l,2,3-triazol-l-yl)-6- Z® ' C i A H?M<Example 24 £2H2Noxopyridazin- 1 (6J7)- 1-12 398 ^ ^N^^ YN^M / V0 0yl)methyl)-7V-(2- methoxyethyl)benzamide(S)-2-(5-(3-(l- IAN 0aminoethyl)isoxazol-5-yl)-6- Example 25 H2N / A AA'■ / n N / \ / CK 1-13 322 oxopyridazin- 1 (6H)-yl)-N- / ®Vo 0H(2-methoxyethyl)acetamide(S)-2-methoxy-l-(5-(2-(2- ((R)-3 -methoxypy rrolidin- 1 - [AN° yl)-2-oxoethyl)-3 -oxo-2, 3 - H2N JL NExample 26 \ N \ dihydropyridazin-4- 1-13 378(^ N'O 0 UR)O- b- yl)isoxazol-3-yl)ethan-l- aminium 2,2,2- trifluoroacetate26123(R)-2-(5-(3-(l-amino-2- methoxyethyl)isoxazol-5-yl)- IExample 27 6-oxopyridazin- 1 (6H)-yl)-N- 1-13 352 z (2-methoxyethyl)acetamidez z (R)-4-(3 -( 1 -amino-2- methoxyethyl)isoxazol-5-yl)- Example 28 2-(4-(morpholine-4- 1-11 440^ 0 carb ony l)b enzy l)py ri dazi n- 3(2H)-onenZI 0Example 29: (. S)-3-(3-(l-:imiiioetliyl)isox:izol-5-yl)-l-pheiiylpyridiii-2(l / / )-onezz- ^0=1zCM IMex^OMe N H HATU, DIPEA MeMgBr Step 3 Step 4NH4OAC NaBH3CN then chiral SFCStep 5 Example 29 Step. ethyl 5-(2-oxo-l-phenyl-l,2-dihydropyridin-3-yl)isoxazole-3-carboxylateA stirred solution of 3-bromo-l-phenylpyridin-2(l / / )-one (5.00 g, 19.99 mmol) and ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (8.60 g, 19.99 mmol) in toluene (40 mL) was sparged with N2 at room temperature for 5 min. Then tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2.0 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 100 °C for 16 h. Reaction mixture was cooled to room temperature, diluted with cold26123water (30 mL), and extracted with EtOAc (30 mL, two times). The combined organic extracts were dried over Na2SC>4, filtered, and concentrated under reduced pressure. Crude compound was purified by silica gel flash-column chromatography (eluting with 25% EtOAc in hexane) to provide the desired product. MS: 311 [M+H]+.Step 2\ 5-(2-oxo-l-phenyl-E2-dihydropyridin-3-yl)isoxazole-3-carboxylic acidTo a stirred solution of ethyl 5-(2-oxo-l-phenyl-l,2-dihydropyridin-3-yl)isoxazole-3-carboxylate (1.00 g, 3.22 mmol) in THF (10 mL) was added sodium trimethylsilanoate (723 mg, 6.45 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with cold water (5 mL) and acidified with saturated KHSO4 solution to obtain pH~2-4. Solids were collected by filtration, dried under reduced pressure, triturated with n-pentane (10 mL) and dried once again under reduced pressure to afford the desired product. MS: 283 [M+H]+.Step 3: A-m ethoxy -A-methyl-5-(2-oxo- 1 -phenyl- 1,2-dihydropyri din-3 -yl)isoxazole-3 -carboxamideTo a stirred solution of 5-(2-oxo-l-phenyl-l,2-dihydropyridin-3-yl)isoxazole-3-carboxylic acid (600 mg, 2.13 mmol) and A, -dimethylhydroxylamine hydrochloride (415 mg, 4.25 mmol) in DMF (6 mL) was added DIPEA (1.1 mL, 6.38 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. Then HATU (1.21 g, 3.19 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with cold water (40 mL) and extracted with EtOAc (50 mL, two times). The combined organic extracts were washed with ice-cold water (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Crude compound was purified by silica gel flashcolumn chromatography (eluting with 30% ethyl acetate in hexane) to provide the desired product. MS: 326 [M+H]+.Step 4 3-(3-acetylisoxazol-5-yl)-l-phenylpyridin-2(lA)-oneTo a stirred solution of A-methoxy-A-methyl-5-(2-oxo-l-phenyl-l,2-dihydropyridin-3-yl)isoxazole-3-carboxamide (400 mg, 1.23 mmol) in THF (8 mL) was added 3M methylmagnesium bromide in diethyl ether (1.0 mL, 3.07 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours before it was cooled to 0 °C, treated with saturated aqueous NH4CI solution (10 mL) and extracted with EtOAc (20 mL, two times). The combined organic extracts were washed with ice cold water (30 mL, two times), dried over Na2SO4, filtered, and concentrated under reduced pressure. Crude compound was purified by silica gel flash-column chromatography (eluting with 30% EtOAc in petroleum ether) to provide the desired product. MS: 281 [M+H]+.26123Step 5 (M-3-(3-(l-aminoethyl)isoxazol-5-yl)-l-phenylpyridin-2(U7)-oneTo a stirred solution of 3-(3-acetylisoxazol-5-yl)-l-phenylpyridin-2(U7)-one (300 mg, 1.07 mmol) and ammonium acetate (825. mg, 10.70 mmol) was added MeOH (5 mL) at room temperature. The reaction mixture was stirred at 0 °C for 1 hour. Then sodium cyanoborohydride (134.5 mg, 2.14 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours before it was cooled to 0 °C, treated with ice-cold water (1 mL) and extracted with 10% MeOH in DCM (10 mL, two times). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase Cl 8 column chromatography (eluting with 50% MeCN in water). The product was further purified by HPLC (MeCN / water containing 10 mM ammonium bicarbonate modifier). The resulting material was finally subjected to chiral SFC separation (Chiralcel OX-H column, 60:40 CO2:modifier, modifier = 0.5 / 44.5 / 44.5 / 10 NINININ methanolic ammonia / MeCN / IPA / MeOH) to afford (5)-3-(3-(l-aminoethyl)isoxazol-5-yl)-l-phenylpyridin-2(U7)-one as the faster-eluting isomer. MS: 282 [M+H]+. 'H NMR (400 MHz, DMSO-tL) VT at 90 °C: 88.12 (dd, J= 7.2 Hz, 2.0 Hz, 1H), 7.79 (dd, J= 6.8 Hz, 2.0 Hz, 1H), 7.41-7.59 (m, 5H), 7.06 (s, 1H), 6.51 (t, J= 7.0 Hz, 1H), 4.04-4.15 (m, 1H), 1.80 (br s, 2H), 1.35 (d, J= 8.4 Hz, 3H).Example 30: ( / )-3-(4-(l-:iiiiiii()-2-livdioxyetliyl)-l / / -1.2.3-tiiazol-l-yl)-2 / / -| 1.2'-bipyiidin|-2-oneCuSO4NaNO2, NaN3Sodium AscorbateO Step 1 Step 2B(OH)2CU(OAC)2, pyridine HCI Step 3 Step 4Example 30 Step. 3-azidopyridin-2(lH)-oneTo a stirred solution of 3-aminopyridin-2(U7)-one (2 g, 18.2 mmol) in H2O (35 mL) and concentrated HCI (35 mL) was added sodium nitrite (2.51 g, 36.3 mmol) in H2O (35 mL) at 0 °C.26123The reaction mixture was stirred at 0 °C for 30 min. Then to this reaction mixture was added sodium azide (2.36 g, 36.3 mmol) at 0 °C. The reaction mixture was stirred for 30 min. The final reaction mixture was quenched with water (50 mL), extracted with EtOAc (100 mL, three times), and washed with saturated NaHCCh and brine (50 mL). Combined organic layer was dried under reduced pressure to afford the desired product. MS: 137 [M+H]+.Step 2'. tert-butyl (A)-2,2-dimethyl-4-(l-(2-oxo-l,2-dihydropyri din-3 -yl)- ITT- 1, 2,3 -triazol-4-yl)oxazolidine-3-carboxylateTo a stirred solution of 3-azidopyridin-2(IT / )-one (500 mg, 3.67 mmol), tert-butyl (A)-4-ethynyl-2,2-dimethyloxazolidine-3-carboxylate (1.24 g, 5.51 mmol) in a mixture of THF (5 mL) and H2O (5 mL) were added sodium 2-(l,2-dihydroxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-3-olate (728 mg, 3.67 mmol) and copper(II)sulfate anhydrous (586 mg, 3.67 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 50 mL). Combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 20% EtOAc in hexane) yielded the desired product. MS: 362 [M+H]tStep 3 tert-butyl (A)-2,2-dimethyl-4-(l-(2-oxo-2J / -ri,2'-bipyridin]-3-yl)-lJ / -l,2,3-triazol-4-yl)oxazolidine-3-carboxylateTo a stirred solution of tert-butyl (R)-2,2-dimethyl-4-(l-(2-oxo-l,2-dihydropyridin-3-yl)-17 / -l,2,3-triazol-4-yl)oxazolidine-3-carboxylate (200 mg, 553 pmol) in DMF (10 mL) were added pyridin-2-ylboronic acid (116 mg, 941 pmol), pyridine (134 pL, 1.66 mmol) and copper (II) acetate (151 mg, 830 pmol) at room temperature. The reaction mixture was stirred at 65 °C for 16 h under oxygen atmosphere. The reaction mixture was filtered through celite pad, then the filtrate was diluted with water (20 mL) and extracted with EtOAc (3 x 100 mL). Combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 50% EtOAc in hexane) yielded the desired product. MS:439 [M+H]+.Step 4 (A)-3-(4-(l-amino-2-hvdroxyethyl)-lJ / -l,2,3-triazol-l-yl)-2J / -ll,2'-bipyridin1-2-one To a stirred solution of tert-butyl (A)-2,2-dimethyl-4-(l-(2-oxo-2J / -[l,2'-bipyridin]-3-yl)-17 / -l,2,3-triazol-4-yl)oxazolidine-3-carboxylate(100 mg, 228 pmol) in DCM (3 mL) was added 4M HC1 in 1,4-dioxane (285 pL, 1.14 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. Reaction mixture was concentrated under reduced pressure. Prep HPLC purification (MeCN / water containing 10 mM ammonium bicarbonate modifier) yielded the desired product. MS: 299 [M+H]+ 1HNMR (400 MHz, DMSO-tfc): 68.61-8.69 (m, 1H), 8.51 (s, 1H), 8.17 (dd, J26123= 7.2 Hz, 2.0 Hz, 1H), 8.01-8.12 (m, 2H), 7.84 (d, J= 8.0 Hz, 1H), 7.57 (dd, J= 6.8 Hz, 5.2 Hz, 1H), 6.62 (t, J= 7.2 Hz, 1H), 4.81 (br s, 1H), 4.03 (dd, J= 6.8 Hz, 4.8 Hz, 1H), 3.57-3.71 (m, 1H), 3.39-3.49 (m, 1H), 1.60-2.19 (m, 2H).Example 31: (7?)-4-(4-(l-amino-2-methoxyethyl)-lH-l.,2.,3-triazol-l-yl)-2-DhenylDyridazin-3(2H)-onepyridine PyNO, O2MeOExample 31 Step. (A)-tert-butyl (2-methoxy-l-(l-(3-oxo-2-phenyl-2,3-dihvdropyridazin-4-yl)-U / -l,2,3-triazol-4-yl)ethyl)carbamateTo a stirred solution of tert-butyl (2-methoxy-l-(l-(3-oxo-2,3-dihydropyridazin-4-yl)-UT-l,2,3-triazol-4-yl)ethyl)carbamate (150 mg, 446 pmol) in DCM (10 mL) were added pyridine 1-oxide (127 mg, 1.34 mmol), copper(II) acetate (243 mg, 1.34 mmol), pyridine (361 pL, 4.46 mmol) and phenylboronic acid (81.6 mg, 669 pmol) at 25 °C. The reaction mixture was degassed and purged with oxygen gas for 15 min. The reaction mixture was stirred at 25 °C for 16 h under oxygen atmosphere. The reaction mixture was filtered through celite pad and washed with EtOAc (50 mL). The filtrate was quenched with water (50 mL) and extracted with EtOAc (100 mL, two times). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash-column chromatography (eluting with 30% EtOAc in hexane) to provide the desired product MS: 413 [M+H]+.Step 2: (A)-4-(4-( 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl)-2-phenylpyridazin-3 (27 / )-oneTo a stirred solution of (A)-tertebutyl (2-methoxy-l-(l-(3-oxo-2-phenyl-2,3-dihydropyridazin-4-yl)-U / -l,2,3-triazol-4-yl)ethyl)carbamate (50 mg, 0.12 mmol) in DCM (5 mL) was added 4M HC1 in 1,4-dioxane (0.15 mL, 0.61 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h under argon atmosphere. Reaction mixture was concentrated under reduced pressure. Crude compound was triturated with n-pentane and dried under reduced pressure to afford the desired product as the HC1 salt. MS: 313 [M+H]+ 1H NMR (400 MHz, DMSO-t / e): 69.13 (s, 1H), 8.65 (br s, 3H), 8.32 (d, J= 4.4 Hz, 1H), 8.22 (d, J= 4.4 Hz, 1H), 7.60-7.66 (m, 2H), 7.53-7.59 (m, 2H), 7.47-7.53 (m, 1H), 4.87 (br s, 1H), 3.73-3.87 (m, 2H), 3.36 (s, 3H).26123Compounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 31, substituting appropriate starting materials, and employing either HC1 in 1,4-di oxane or TFA in DCM for A-Boc removal.Example Starting MS Structure IUPAC NameNumber material [M+H]+8 (R)-4-(4-(l-amino-2- zz- ^o>= methoxy ethyl)- 1 H- 1,2, 3 - Example 32 Z I-n tri azol- 1 -yl)-2-(8- 1-41 397JS AZZ'Z chl oronaphthal en- 1 - o1 yl)pyridazin-3(2H)-one\ / 0(A)-4-(4-(l -amino-2- NJ^NHmethoxy ethyl)- 1 H- 1,2, 3 - K " > w2Example 33 N o \z z- tri azol- l-yl)-2-(l - 1-41 353 ^ o=(difluoromethyl)- IH-pyrazol- 8r°F, _ CM4-yl)pyridazin-3 (2H)-one**N F; ZO'" (A)-4-[4-(l -amino-2- / KI H2N methoxy ethyl)- 1H-1,2,3- / =*!triazol-l-yl]-2- 1-41 354 Example 34L I X N\ "N([l,2,4]triazolo[l,5-a]pyridin- uN6-yl)pyridazin-3 (2H)-one(A)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - 1-41 364 Example 35tri azol- 1 -yl]-2-(quinolin-7- yl)pyridazin-3(2H)-one(A)-4-[4-(l -amino-2- -0 NH2methoxy ethyl)- 1H-1,2,3- '" {wtri azol - 1 -y 1 ] -2 -(3 -tert- 1-41 369 Example 36N", N X XX / butylphenyl)pyridazin-3(2H)-None26123N=N -OZ(7?)-4-[4-(l -amino-2- || tR NH2 methoxy ethyl)- 1 H- 1,2, 3 -N'NA>Example 37 tri azol - 1 -yl]-2-(l -phenyl - 1H- 1-41 379AN-N pyrazol-4-yl)pyridazin-3(2H)- d one\ / ° (7?)-4-[4-(l -amino-2-Z"0 ’,NJ^NOC0=H2methoxy ethyl)- 1 H- 1,2, 3 - N, >Example 38 N tri azol- 1 -yl]-2-(4- 1-41 333QL. N q methylthi ophen-2 -yl)pyridazin-N' I^ 3(2H)-oneo^(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - zz- Example 39 \ o3=tri azol- 1 -yl]-2-(5- 1-41 358^>z < ethoxypyri din-3 -yl)pyridazin- iz■ '3(2H)-oneo''1 N=N. 0 (7?)-4-[4-(l -amino-2- [| J ‘RJNH2methoxy ethyl)- 1 H- 1,2, 3 - Example 40 % A) triazol-l-yl]-2-[4-fluoro-3- 1-41 399(1,F(trifluoromethyl)phenyl]pyridaI TFzin-3 (2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 41 triazol- 1 -yl]-2-[4-(morpholine- 1-41 4624-sulfonyl)phenyl]pyridazin- 3(2H)-one26123(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 42 triazol-l-yl]-2-[4-(2- 1-41 385 methylpropoxy)phenyl]pyridazZ'Z z z y—00 in-3(2H)-oneO z nz- 00 °K (7?)-4-[4-(l -amino-2- 0 >methoxy ethyl)- 1 H- 1,2, 3 - Example 43 tri azol- l-yl]-2-(5- 1-41 332 fluoropyri din-3 -yl)pyridazin- 3(2H)-oneo—0 V (7?)-4-[4-(l -amino-2- oz z °- £ methoxy ethyl)- 1H-1,2,3- Example 44 Q tOX^ triazol-l-yl]-2-{6-[(propan-2- 1-41 372 yl)oxy]pyridin-3-yl}pyridazin- 3(2H)-oneN=N -OZ(7?)-4-[4-(l -amino-2- fl H(R)NH2methoxy ethyl)- 1 H- 1,2, 3 - Example 45NA tri azol- l-yl]-2-(2- 1-41 344 methoxypyridin-4- 001 yl)pyridazin-3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 46 triazol- 1 -yl]-2-[6-(morpholin- 1-41 3994-yl)pyri din-3 -yl]pyridazin- 3(2H)-one26123\0(R)- 1 -(4-{ 5 - [4-( 1 -amino-2- / ^, NH2N -R(R) methoxy ethyl)- 1H-1,2,3- N_ >N tri azol - 1 -y 1 ] -6 -oxopy ri dazin- Example 47 1-41 3781(6H)- yl }phenyl)cyclopropane- 1 - carbonitrileN(4)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 48 triazol-l-yl]-2-(4-{[3- 1-41 487o 4u-—(trifluoromethyl)phenoxy]methyl }phenyl)pyridazin-3 (2H)-one0zz- ^_? O oZ Zo—-=^zJ Oi (7?)-4-[4-(l -amino-2- f z' 'O'" methoxy ethyl)- 1 H- 1,2, 3 - 1Example 49 tri azol- l-yl]-2-[3-m ethoxy-5- 1-41 411(trifluoromethyl)phenyl]pyridazin-3 (2H)-one(7?)-4-[4-(l -amino-2- Q >F methoxy ethyl)- 1H-1,2,3- Example 50 °YN'N triazol-l-yl]-2-[2- 1-41 397H2N,,(tri fluorom ethoxy )pheny 1 ] py ri d / O"'' N=Nazin-3 (2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1H-1,2,3- Example 51 triazol-l-yl]-2-[3- 1-41 397(tri fluorom ethoxy )phenyl ] py ri dazin-3 (2H)-one26123(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 52 tri azol - 1 -y 1 ] -2 -(3, 4- 1-41 373 dimethoxyphenyl)pyridazin- q 3(2H)-oneoZ^Vq z (7?)-4-[4-(l -amino-2- O z -nz- methoxy ethyl)- 1 H- 1,2, 3 - ° iExample 53 \Ks / triazol- 1 -yl]-2-(2,3 -dihydro- 1-41 371K 1,4-benzodioxin-6- i;yl)pyridazin-3(2H)-one(7?)-4-[4-(l -amino-2- 1 methoxy ethyl)- 1 H- 1,2, 3 - exExample 54 tri azol- l-yl]-2-(2- 1-41 405 phenoxyphenyl)pyridazin- <^> °=4., o £zz- O Oz z- 3(2H)-oneMZz^(7?)-4-[4-(l -amino-2- C0methoxy ethyl)- 1 H- 1,2, 3 - tri azol- l-yl]-2-(4- 1-41 341 Example 55ethylphenyl)pyridazin-3(2H)- one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - tri azol - 1 -y 1 ] -2 -(3, 5 - 1-41 349 Example 56difluorophenyl)pyridazin- 3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - tri azol- l-yl]-2-(3, 4,5- 1-41 367 Example 57trifluorophenyl)pyridazin- 3(2H)-one26123H2N O~ (7?)-4-[4-(l -amino-2- ft 1 wWmethoxy ethyl)- 1 H- 1,2, 3 - Example 58 1-41 364A y,- tri azol- 1 -yl]-2-(quinolin-3 - 1 yl)pyridazin-3(2H)-oneZ^J OZ?—ZE\ (7?)-4-[4-(l -amino-2- ' Z w - 5 c methoxy ethyl)- 1 H- 1,2, 3 - S ° C~ °=Example 59 zz- tri azol- l-yl]-2-(2- 1-41 347* °\ chlorophenyl)pyridazin-3 (2H)- one(7?)-4-[4-(l -amino-2- o—^ methoxy ethyl)- 1H-1,2,3- Example 60 triazol-l-yl]-2-[5- 1-41 382 u zz- d (trifluoromethyl)pyri din-3 - z O z- \ o3=oz z- yl]pyridazin-3(2H)-one^> Z <j igzT'; Z (7?)-4-[4-(l -amino-2- O'"1 methoxy ethyl)- 1H-1,2,3- Example 61 1-41 319 tri azol - 1 -y 1 ] -2 -(thi ophen-3 - yl)pyridazin-3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 62 triazol-l-yl]-2-(3- 1-41 357 ethoxyphenyl)pyridazin-3(2H)- one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 63 tri azol- l-yl]-2-(4- 1-41 405 phenoxyphenyl)pyridazin- 3(2H)-one26123(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 64 triazol-l-yl]-2-{3-[(propan-2- 1-41 371 i yl)oxy]phenyl}pyridazin- 3(2H)-one' z M —N=N...'—O'7(7?)-4-[4-(l -amino-2- $~ c°=z z- methoxy ethyl)- 1 H- 1,2, 3 - Example 65N'NA> tri azol- l-yl]-2-[2- 1-41 382 fto O —— \ (trifluoromethyl)pyridin-4- X;yl]pyridazin-3(2H)-one\ 0oVZ^NH2(7?)-4-[4-(l -amino-2- N- / (R>N". > methoxy ethyl)- 1 H- 1,2, 3 - N Qzz- Example 66 Ar° triazol- 1 -yl]-2-[4-(2,2,2- 1-41 411\ o3=N'N^Zz Fz ri trifluoroethoxy)phenyl]pyridazin-3(2H)-onek, FO'"1 TF(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 67 triazol-l-yl]-2-[4-(benzyloxy)- 1-41 4493-methoxyphenyl]pyridazin- 3(2H)-one\ / ° (7?)-4-[4-(l -amino-2- NJ^NH2N ". > w methoxy ethyl)- 1 H- 1,2, 3 - NExample 68 triazol- 1 -yl]-2-(2,2-difluoro- 1-41 393 rr°2H- 1, 3 -b enzodi oxol - 5 - Lly o yl)pyridazin-3(2H)-oneoy~FF26123\ / ° (7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - N. >Example 69 N tri azol- l-yl]-2-(2- 1-41 345 methoxypyrimidin-5- VyNyl)pyridazin-3(2H)-oneVo1(7?)-4-[4-(l -amino-2-Mcomethoxy ethyl)- 1 H- 1,2, 3 - Example 70 tri azol- 1 -yl]-2-(2- 1-41 333 methylthi ophen-3 -yl)pyridazin- 3(2H)-oneN=N. O— O ' (7?)-4-[4-(l -amino-2- f yoz z- 'RJNH2methoxy ethyl)- 1 H- 1,2, 3 - Example 71N'NA> triazol- 1 -yl]-2-[3- 1-41 363 j7 t<(difluoromethyl)phenyl]pyrida;> ■ F zin-3 (2H)-one\7°(R)-4-{ 5 - [4-( 1 -amino-2- NJT2N"3 methoxy ethyl)- 1H-1,2,3- NExample 72 tri azol - 1 -y 1 ] -6 -oxopy ri dazin- 1-41 439Or"1 (6H)-yl } -N-( 1,3 -thiazol -2- T 1yl)benzamideHN SxI?(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 73 triazol- 1 -yl]-2-[2-(morpholin- 1-41 3994-yl)pyridin-4-yl]pyridazin- 3(2H)-one26123N=N. Q (7?)-N-[4-{5-[4-(l-amino-2- fl 7 'JNH2methoxy ethyl)- 1H-1,2,3-N'NA) tri azol - 1 -y 1 ] -6 -oxopy ri dazin- Example 74 1-41 438 l(6H)-yl}-2- (trifluoromethyl)phenyl]acetam\0HF F40 0 ide(R)-4-[4-(l -amino-2- N=N, 00= X— Q6' zi methoxy ethyl)- 1H-1,2,3- f| V( R'NH25^H Q tri azol - 1 -y 1 ] -2 - [2-m ethy 1 -5 - Example 75 1-41 460(pyrrolidine- 1- 4 sulfonyl)phenyl]pyridazin- ° o° 3(2H)-one(R)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - NOLN-N N-N triazol-l-yl]-2-[l-(3,3,4,4,4- Example 76 1-41 500 a0Y pentafluorobutyl)-lH- XF H=Nk pyrazolo[3,4-b]pyri din-3 - Fyl]pyridazin-3(2H)-one(R)-4-{ 5 - [4-( 1 -amino-2- methoxy ethyl)- 1H-1,2,3- tri azol - 1 -y 1 ] -6 -oxopy ri dazin- Example 77 1-41 502 l(6H)-yl}-N-(3- chlorophenyl)benzene- 1 - sulfonamide\ / ° (R)-4-[4-(l -amino-2- NJ^NH2methoxy ethyl)- 1 H- 1,2, 3 - N, >N triazol-l-yl]-2-{3-ethoxy-4- Example 78 0° 1-41 415[(propan-2-N'NX1 A yl)oxy]phenyl}pyridazin- r° 3(2H)-one26123(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 79 tri azol- 1 -y 1 ] -2 -(3,4-dimethoxy- 1-41 3872-methylphenyl)pyridazin-zFA * - I z z y— 3(2H)-one / z—° / a / b ■n _A^ X -n / \ / M / / z (R)-4-{ 5 - [4-( 1 -amino-2- methoxy ethyl)- 1H-1,2,3- Example 80 tri azol - 1 -y 1 ] -6 -oxopy ri dazin- 1-41 406 l(6H)-yl}-2- (trifluoromethyl)benzonitrile\o\p oZ. Z--?- ~(7?)-4-[4-(l -amino-2-zNJ^NH2methoxy ethyl)- 1 H- 1,2, 3 - N' >NExample 81 triazol- 1 -y 1 ] -2 - [ 1 -(propan-2- 1-41 345X°yl)-lH-pyrazol-3-yl]pyridazin- VNY^>3(2H)-one(7?)-4-[4-(l -amino-2- CK.or methoxy ethyl)- 1 H- 1,2, 3 - triazol-l-yl]-2-{4-[(2- Example 82 1-41 481 chlorophenyl)methoxy]-3,5- V'N dimethylphenyljpyridazin- H2N X J / °-E' N=N 3(2H)-one(R)-4-{ 5 - [4-( 1 -amino-2- methoxy ethyl)- 1H-1,2,3- Example 83 tri azol - 1 -y 1 ] -6 -oxopy ri dazin- 1-41 368 l(6H)-yl}-2- methoxybenzonitrile26123(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 84 tri azol- 1 -yl]-2-(4- 1-41 333 methylthi ophen-3 -yl)pyridazin- 3(2H)-one(7?)-4-[4-(l -amino-2- NH2oz\ / methoxy ethyl)- 1H-1,2,3- Example 85 / ===] 0 fl Nztriazol-l-yl]-2- 1-41 354N*, N A A J([l,2,4]triazolo[l,5-a]pyridin- 7-yl)pyridazin-3(2H)-one(7?)-4-[4-(l -amino-2- T CM / \ methoxy ethyl)- 1 H- 1,2, 3 - Example 86 K V oZtriazol- 1 -yl]-2-[4-(l -methyl- 1-41 393XAJHZlH-pyrazol-4- yl)phenyl]pyridazin-3(2H)-one\o (7?)-4-[4-(l -amino-2- Z)NH2 methoxy ethyl)- 1 H- 1,2, 3 - NAExample 87 N tri azol- 1 -yl]-2-(6- 1-41 328 methylpyri din-3 -yl)pyridazin-CvNn 3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1H-1,2,3- Example 88 triazol-l-yl]-2-[6- 1-41 382(trifluoromethyl)pyri din-3 - yl]pyridazin-3(2H)-one26123N=N. Q (7?)-3-{5-[4-(l-amino-2- [| 'RJNH2methoxy ethyl)- 1H-1,2,3- Example 89N-N^0 1-41 338 tri azol - 1 -y 1 ] -6 -oxopy ri dazin- 1 (6H)-yl Jbenzonitrile / zy-T- \0(7?)-4-[4-(l -amino-2- NJ o =^Z\ / M'zNH2methoxy ethyl)- 1H-1,2,3- N"„ >Example 90 N6 O -n tri azol - 1 -y 1 ] -2 -( 1 -m ethyl - 1 H- 1-41 317 If¥ pyrazol-4-yl)pyridazin-3(2H)-kvYU- N one\(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1H-1,2,3- Example 91 \ zz= O z- tri azol - 1 -y 1 ] -2 -(5 -m ethyl - 1 - 1-41 393 phenyl - 1 H-py razol -4- yl)pyridazin-3(2H)-one<£(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - triazol- 1 -yl]-2-[4-(2,2,2- Example 92 1-41 411 tri fluoro- 1- hydroxyethyl)phenyl]pyridazin-3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 93 triazol-l-yl]-2-[2-fluoro-5-(5- 1-41 413 methyl- 1,3,4-oxadiazol-2- yl)phenyl]pyridazin-3(2H)-one26123\O(R)-4-[4-(l -amino-2- Y. NH2N^< (R> methoxy ethyl)- 1 H- 1,2, 3 - N, >Example 94 N triazol-l-yl]-2-[l-(3,3,3- 1-41 399 trifluoropropyl)- 1 H-pyrazol-4- Y ' — \Fyl]pyridazin-3(2H)-oneF> (R)-4-[4-(l -amino-2- NJ^NH2methoxy ethyl)- 1 H- 1,2, 3 - Example 95 N( >N triazol-l-yl]-2-[l- 1-41 371(tri fluoromethyl)- IH-pyrazol-NY NYTF4-yl]pyridazin-3 (2H)-oneFExample 96: (ty)-4-(4-(amino(thiazol-4-yl)methyl)-lH-l.,2.,3-triazol-l-yl)-2-phenylpyridazin- 3(2ED-oneStep. l-(thiazol-4-yl)prop-2-yn-l-olTo a stirred solution of thiazole-4-carbaldehyde (1.0 g, 8.9 mmol) in THF (10 mL) was added 0.5 M ethynyl magnesium bromide in THF (0.03 L, 0.01 mol) at -78 °C. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was treated with water (100 mL) and extracted with EtOAc (100 mL, two times). The combined organic extracts were dried over26123anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 50% EtOAc in pet ether) yielded the desired product. MS: 140 [M+H]+.Step 2\ 4-(4-(hvdroxy(thiazol-4-yl)methyl)-lJ / -L2,3-triazol-l-yl)-2-phenylpyridazin-3(2J7)-oneStock aqueous buffer was prepared by combining sodium ascorbate (2.48 g, 12.5 mmol), Na2HPC>4 (7.00 g, 49.3 mmol), citric acid (4.87 g, 25.4 mmol), and H2O (100 mL). Stock aqueous CuSCh / THPTA solution was prepared by combining anhydrous Q1SO4 (16 mg, 100 pmol), tris((l-benzyl-4-triazolyl)methyl)amine (THPTA, 43.5 mg, 100 pmol), and H2O (5 mL). To a stirred solution of 4-azido-2-phenylpyridazin-3(2J7)-one (400 mg, 1.88 mmol) in DMSO (10 mL) was added aqueous buffered sodium ascorbate solution (15 mL) at room temperature and stirred for 30 min. Then to this reaction mixture was added l-(thiazol-4-yl)prop-2-yn-l-ol (313 mg, 2.25 mmol) in DMSO (1.0 mL) and aqueous CUSO4 / THPTA solution (5.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL, two times). The combined organic extracts were concentrated under reduced pressure, followed by silica gel flash-column chromatography (eluting with 50% EtOAc in pet ether) to yielde the desired product. MS: 353 [M+H]+.Step 3 2-phenyl-4-(4-(thiazole-4-carbonyl)-lJ / -L2,3-triazol-l-yl)pyridazin-3(2J7)-oneTo a stirred solution of 4-(4-(hydroxy(thiazol-4-yl)methyl)- 1H- 1,2, 3 -triazol- 1 -yl)-2-phenylpyridazin-3(2J7)-one (240 mg, 681 pmol) in DCM (5 mL) was added DMP (318 mg, 749 pmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with DCM (80 mL, two times). The combined organic extracts were concentrated under reduced pressure. Silica gel flash-column chromatography (eluting with 50% EtOAc in pet ether) yielded the desired product. MS: 351 [M+H]+.Step 4 rac-4-(4-(amino(thiazol-4-yl)methyl)-lJ / -L2,3-triazol-l-yl)-2-phenylpyridazin-3(2Z / )-oneTo a stirred solution of 2-phenyl-4-(4-(thiazole-4-carbonyl)-17 / -l,2,3-triazol-l-yl)pyridazin-3(2J7)-one (180 mg, 514 pmol) in MeOH (2 mL), DCM (5 mL) wereadded ammonium acetate (119 mg, 1.54 mmol) and sodium cyanoborohydride (64.6 mg, 1.03 mmol) at 0 °C. The reaction mixture was stirred at 40 °C for 48 h. The reaction mixture was diluted with water (80 mL) and extracted with 20% MeOH in DCM (80 mL, two times).Combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC (MeCN / water containing 10 mM26123ammonium bicarbonate modifier) to afford the desired product. MS: 352 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 69.04 (d, J= 2.0 Hz, 1H), 8.76 (s, 1H), 8.27 (d, J= 4.8 Hz, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.52-7.64 (m, 5H), 7.45-7.52 (m, 1H), 5.44 (s, 1H).Example 97: (. S)-4-(3-(l-:iiiiiii()-2-(l / / -pyi:iz()l-l-yl)etliyl)isox:izol-5-yl)-2-(3.5-dichloroDhenyl)Dyridazin-3(2ZD-oneStep. tert-butyl (A)-4-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)-2,2-dimethyloxazolidine-3-carboxylateTo a stirred degassed solution of tert-butyl (R)-2,2-dimethyl-4-(5-(3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)oxazolidine-3-carboxylate (1.50 g, 4.14 mmol) in DCM (25 mL) was added (3,5-dichlorophenyl)boronic acid (1.19 g, 6.21 mmol) and pyridine (1.0 mL, 12 mmol), pyridine 1-oxide (197 mg, 2.07 mmol) and copper(II) acetate (376 mg, 2.07 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours under oxygen atmosphere. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with 30% EtOAc in petroleum ether) to afford the desired product. MS: 507 [M+H]+.Step 2 (7?)-4-(3-(l-amino-2-hvdroxyethyl)isoxazol-5-yl)-2-(3,5-dichlorophenyl)pyridazin-3(2J7)-oneTo a stirred solution of tert-butyl (R)-4-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)-2,2-dimethyloxazolidine-3-carboxylate (500 mg, 985 pmol) in DCM (5.0 mL) was added HC1 (4 M in 1, 4-dioxane, 1.23 mL, 4.93 mmol) at 0 °C. The26123reaction was then stirred at 25 °C for 3 hours. After 3 hours, the reaction mixture was concentrated under reduced pressure to afford the desired product. MS: 367 [M+H]+.Step 3 tert-butyl (A)-(l-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihvdropyridazin-4-yl)isoxazol-3-yl)-2-hvdroxyethyl (carbamateTo a stirred solution of (A)-4-(3-(l-amino-2-hydroxyethyl)isoxazol-5-yl)-2-(3,5-dichlorophenyl)pyridazin-3(2J7)-one (800 mg, 2.18 mmol) in 1,4-dioxane (5.0 mL) and water (5.0 mL) was added sodium bicarbonate (366 mg, 4.36 mmol) and di -tert-butyl dicarbonate (584 pL, 2.61 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 hour. After 1 hour, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 30% EtOAc in pet ether) to afford the desired product. MS: 411 [M+H-C4H8]+.Step 4 tert-butyl (A)-4-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)-L2,3-oxathiazolidine-3-carboxylate 2,2-dioxideTo a stirred solution of SOCI2 (34.4 pL, 471 pmol), TEA (131 pL, 942 pmol) and imidazole (117 mg, 1.71 mmol) in DCM (1 mL) was added tert-butyl (A)-(l-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)-2-hydroxyethyl)carbamate (200 mg, 428 pmol) in DCM (4.0 mL) at -60 °C. The reaction mixture was stirred at -60 °C for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 80 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was diluted with acetonitrile (3.0 mL) and then sodium periodate (101 mg, 471 pmol), Ruthenium(III)chloride trihydrate (11.2 mg, 42.8 pmol) and water (3 mL) were added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. After 16 hours, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the desired product. MS: 473 [M+H-C4H8]+.Step 5 tert-butyl (M-(l-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihvdropyridazin-4-yl)isoxazol-3-yl)-2-(l JT-pyrazol- 1 -yl)ethyl)carbamateTo a stirred solution of tert-butyl (A)-4-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (200 mg, 378 pmol) in DMF (4.0 mL) was added UT-pyrazole (257 mg, 3.78 mmol) and CS2CO3 (246 mg, 756 pmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with citric acid (1 N in water, 10 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered26123and concentrated under reduced pressure. The crude compound was triturated with n-pentane (2 x 25 mL) and dried under reduced pressure to afford the desired product. MS: 517 [M+H]+. Step 6 (M-4-(3-(l-amino-2-(U / -pyrazol-l-yl)ethyl)isoxazol-5-yl)-2-(3,5-dichlorophenyl)pyridazin-3(2J7)-oneTo a stirred solution of tert-butyl (5)-(l-(5-(2-(3,5-dichlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)-2-(U / -pyrazol-l-yl)ethyl)carbamate (200 mg, 387 pmol) in DCM (3.0 mL) was added TFA (149 pL, 1.93 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure and the resulting mixture was purified by prep-HPLC purification (ACN / water with a 0.1% formic acid modifier). The resulting residue was then purified by prep-HPLC (ACN / water with lOmM ammonium bicarbonate) to afford the desired product. MS: 417 [M+H]+. 'H NMR (400 MHz, DMSO-tL) VT at 90 °C: 88.20 (d, J= 4.4 Hz, 1H), 7.96 (d, J= 7.6 Hz, 1H), 7.76 (d, J= 2.0 Hz, 2H), 7.66 (t, J= 2.0 Hz, 1H), 7.61 (d, J= 1.80 Hz, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 6.17 (t, J= 2.0 Hz, 1H), 4.50-4.30 (m, 3H), 2.20-1.90 (m, 2H).Example 98: tyi-S-fZ-d-aminoethvDthiazol-S-vD-l-Dhenylpyridin-ZdHl-oneMe Me Me Me,ePd(dppf)CI A2Na2CO3Me— \. S-NHS^ JBrStep 1 Me NT Me' NPhB(OH)2CU(OAC)2, PyNO Me Me Me- \ / zHCI S-NH S Step 2 Step 3Me N Example 98 Step. (M-2-methyl-A-((M-l-(5-(2-oxo-L2-dihydropyridin-3-yl)thiazol-2-yl)ethyl)propane-2-sulfmamideA mixture of (5)-A-((5)-l-(5-bromothiazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (300 mg, 0.964 mmol), 1,4-dioxane (20 mL), (2-oxo-l,2-dihydropyri din-3 -yl)boronic acid (201 mg, 1.45 mmol), and sodium carbonate (204 mg, 1.93 mmol) was sparged with argon gas for 15 min. Next, [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (78.7 mg, 0.096 mmol) was added, and the mixture was heated to 100 °C with stirring under an argon atmosphere for 2 hours. The mixture was then cooled to room temperature and filtered through a pad of Celite. The filter cake was rinsed with EtOAc (50 mL). The combined26123filtrate was diluted with water (50 mL) and the layers were shaken and separated. The aqueous layer was further extracted with EtOAc (20 mL, two times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash-column chromatography (eluting with 30% EtOAc / hexanes) to provide the desired product. MS: 326 [M+H]+.Step 2 (M-2-methyl-A-((M-l-(5-(2-oxo-l-phenyl-L2-dihydropyridin-3-yl)thiazol-2-yl)ethyl)propane-2-sulfinamideA stirred solution of (5)-2-methyl-A-((5)-l-(5-(2-oxo-l,2-dihydropyridin-3-yl)thiazol-2-yl)ethyl)propane-2-sulfinamide (250 mg, 0.768 mmol) in DCM (15 mL) was treated with phenylboronic acid (140 mg, 1.15 mmol), copper(II) acetate (419 mg, 2.30 mmol), pyridine (621 pL, 7.68 mmol), and pyridine 1-oxide (219 mg, 2.30 mmol) at room temperature. The mixture was stirred under an atmosphere of oxygen gas at room temperature for 48 h. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel flash-column chromatography (eluting with 30% EtOAc / hexanes) to provide the desired product. MS: 402 [M+H]+.Step 3 (M-3-(2-(l-aminoethyl)thiazol-5-yl)-l-phenylpyridin-2(lJ7)-oneA stirred solution of (5)-2-m ethyl - / ' -(fS')-l -(5 -(2-oxo-l -phenyl- 1,2-dihydropyri din-3 -yl)thiazol-2-yl)ethyl)propane-2-sulfinamide (200 mg, 0.498 mmol) in DCM (5.0 mL) was treated with hydrogen chloride solution (4M in 1,4-dioxane, 0.62 mL, 2.49 mmol) at room temperature. The resulting mixture was stirred under an atmosphere of argon gas for 2 h. The mixture was then concentrated under reduced pressure, and the residue was purified by prep-HPLC (MeCN / water containing 0.1% v / v formic acid modifier) to provide the desired product. MS: 298 [M+H]+. 'H NMR (400 MHz, DMSO-tL) VT at 90 °C: 88.29 (br s, 1H), 8.03 (dd, J= 7.2 Hz, 2.0 Hz, 1H), 7.62 (dd, J= 6.8 Hz, 2.0 Hz, 1H), 7.50-7.56 (m, 2H), 7.41-7.50 (m, 3H), 6.45 (t, J= 7.0 Hz, 1H), 4.26 (br s, 1H), 1.42 (d, J= 6.0 Hz, 3H).Example 99: 4-(3-(CS)-l-aminoethyl)isoxazol-5-yl)-2-((l?)-3-methyl-l-Dhenylbutyl)Dyridazin-3(2ED-one and 4-(3-((tS)-l-aminoethyl)isoxazol-5-yl)-2-(CS)-3-methyl-l- Dhenylbutyl)Dyridazin-3(2ZD-one26123Step. tert-butyl ((lM-l-(5-(2-(3-methyl-l-phenylbutyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamateTo a stirred solution of tert-butyl (5)-(l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (130 mg, 424 pmol) and rac-3 -methyl- 1-phenylbutan-l-ol (69.7 mg, 424 pmol) in THF (3 mL) were added triphenylphosphine (223 mg, 849 pmol) and DIAD (165 pL, 849 pmol) at 25 °C. The reaction mixture was stirred at 100 °C for 1 hour in a microwave reactor. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic extracts were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 50% EtOAc in pet ether) yielded the desired product. MS: 453 [M+H]+.Step: 4-(3 -(( )- 1 -aminoethvDi soxazol-5 -yl)-2-(3 -methyl- 1 -phenylbutyl)pyridazin-3 (2rt)-one To a stirred solution of tert-butyl ((15)-l-(5-(2-(3-methyl-l-phenylbutyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (100 mg, 221 pmol) in DCM (3 mL) was added 4M HC1 in 1,4-di oxane (276 pL, 1.10 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (MeCN / water, containing 10 mM ammonium bicarbonate modifier) to give the product as a mixture of stereoisomers, which was subjected to chiral SFC separation (Chiralpak AD-H, 80:20 CO2:modifier, modifier = 0.035 M methanolic ammonia), providing: Example 99A (faster eluting isomer): MS: 353 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 6 8.19 (d, J= 4.4 Hz, 1H), 7.90 (d, J= 4.4 Hz, 1H), 7.45 (s, 1H), 7.38-7.43 (m, 2H), 7.31-7.37 (m, 2H), 7.26-7.31 (m, 1H), 6.32 (dd, J= 9.8 Hz, 6.2 Hz, 1H), 4.03-4.11 (m, 1H), 2.27-2.30 (m, 1H), 1.85-1.94 (m, 1H), 1.32 (d, J= 6.8 Hz, 4H), 0.92 (t, J= 6.6 Hz, 6H).Example 99B (slower eluting isomer): MS: 353 [M+H]+. 'HNMR (400 MHz, DMSO-tfc): 68.20 (d, J= 4.4 Hz, 1H), 7.91 (d, J= 4.4 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J= 8.8 Hz, 2H), 7.34 (t, J= 7.426123Hz, 2H), 7.25-7.31 (m, 1H), 6.32 (dd, J= 9.6 Hz, 6.0 Hz, 1H), 4.15 (q, J= 6.6 Hz, 1H), 2.23-2.31 (m, 1H), 1.86-1.95 (m, 1H), 1.35 (d, J= 6.8 Hz, 4H), 0.91 (t, J= 6.6 Hz, 6H).Using methods similar to those outlined in the synthesis of Example 99; substituting appropriate starting materials; and employing HC1 in 1,4-dioxane or TFA in DCM for TV-Boc removal or TMSBr in TFA for A-Cbz removal, the following examples were prepared. In each case, Isomer A was the faster-eluting isomer (and Isomer B the slower-eluting isomer) obtained from SFC separation:Example Starting MS Structure and IUPAC name SFC ConditionsNumber material [M+H]+H2N JI N. A JJ'' N-0 O Chiralpak AD-H4-(3-((5)-l-aminoethyl)isoxazol-5- 60:40 CCUmodifier Example 100 1-35 325 yl)-2-((A)-l-phenylpropyl)pyridazin- Modifier = 0.035 M3(27 / )-one and 4-(3-((S)- 1 - methanolic ammonia aminoethyl)isoxazol-5-yl)-2-((5)-l- phenylpropyl)pyridazin-3(2J7)-oneH2N A N * A JN'O O4-(3-((S)-l-aminoethyl)isoxazol-5- (A, A)-Wh elk-01 Example 101 yl)-2-((R)-2-m ethyl- 1 - 1-35 85:15 CO2:modifier 339 phenylpropyl)pyridazin-3(2H)-one Modifier = MeOH and 4-(3-((S)-l -aminoethyl)i soxazol- 5-yl)-2-((S)-2-m ethyl- 1 - phenylpropyl)pyridazin-3(2H)-oneH2N A N * A. JJZN'O O Chiralpak AD-H70:30 CO2:modifier Example 102 4-(3-((S)-l-aminoethyl)isoxazol-5- 1-35 353Modifier = 30 mMyl)-2-((R)-2,2-dimethyl- 1 - methanolic ammonia phenylpropyl)pyridazin-3(2H)-oneand 4-(3-((S)-l -aminoethyl)i soxazol-261235-yl)-2-((S)-2,2-dimethyl-l- phenylpropyl)pyridazin-3(2H)-oneCompounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 99, substituting appropriate starting materials, and without performing chiral SFC separation in Step 2\Example Starting MS Structure IUPAC NameNumber material [M+H]+N=NXNH24-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 103 N„ A. \N^O 1-41 342 triazol- 1 -yl]-2-[ 1 -(pyridin-2- yl)ethyl]pyridazin-3(2H)-oneN=N. NH24-[4-((7?)-l-amino-2- fl T °v methoxy ethyl)- 1 H- 1,2, 3 - N. As \N^OExample 104 triazol-l-yl]-2-[l-(3- 1-41 371 methoxyphenyl)ethyl]pyridazin-3(2H)-oneXX (7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 105 yA triazol-l-yl]-2-[2-(3- 1-41 359N. J fluorophenyl)ethyl]pyridazin- 3(2H)-oneH2N4-[4-((7?)-l-amino-2- N=N. NH2methoxy ethyl)- 1 H- 1,2, 3 - N \\. / 1U. °x \ triazol- 1 -yl]-2-[(2-bromo-4- Example 106 N^O 1-41 461, 463 tert- butylphenyl)methyl]pyridazin- 3(2H)-one26123\o / (7?)-4-[4-(l -amino-2- ZR)NH2N- / <" w methoxy ethyl)- 1 H- 1,2, 3 - N. >NExample 107 triazol-l-yl]-2-[(5- 1-41 3621 Ar°chl oropyri din-3 - yl)methyl]pyridazin-3(2H)-one' Z to —\~ c°= zz- -0 NH2(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - oExample 108 triazol-l-yl]-2-{[4- 1-41 393(difluoromethoxy)phenyl]methF^F yl } pyridazin-3 (2H)-oneCl (7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 109 triazol-l-yl]-2-[l-(3- 1-41 375N'NY°II NH2chl oropheny l)ethy 1 ] py ri dazin- 3(2H)-oneF (7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 110 triazol-l-yl]-2-[l-(3- 1-41 359 N'NY°|l X NH2fluorophenyl)ethyl]pyridazin- 3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 111 triazol-l-yl]-2-[l-(4- 1-41 359 fluorophenyl)ethyl]pyridazin- 3(2H)-oneN'N. oz(7?)-4-[4-(l -amino-2- fl 1 NH2methoxy ethyl)- 1 H- 1,2, 3 -N'rAoExample 112 triazol-l-yl]-2-[3-(2- 1-41 369 methylphenyl)propyl]pyridazin-3(2H)-one26123(7?)-4-[4-(l -amino-2- -o NH2methoxy ethyl)- 1 H- 1,2, 3 - / =n o IExample 113 triazol-l-yl]-2-[l-(4- 1-41 375X chl oropheny l)ethy 1 ] py ri dazin- z3(2H)-oneJz— (7?)-4-[4-(l -amino-2- ^ C°= methoxy ethyl)- 1 H- 1,2, 3 - zz- Example 114 triazol-l-yl]-2-[l-(4- 1-41 356 aminophenyl)ethyl]pyridazin- zT 3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 115 triazol-l-yl]-2-[l-(2- 1-41 359N |i'NJYL °NH2fluorophenyl)ethyl]pyridazin- N=N ^<\3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - ^Cl^FExample 116 triazol-l-yl]-2-{ l-[3,5- 1-41 477 Y'Nf FH2N _ Ju JJ bis(trifluoromethyl)phenyl]ethN=N yl } pyridazin-3 (2H)-oneN'NX (7?)-4-[4-(l -amino-2- \\ T NH2methoxy ethyl)- 1 H- 1,2, 3 - Example 117N'NA> tri azol- 1 -y 1 ] -2 - [(3 -fluoro-2- 1-41 359 methylphenyl)methyl]pyridaziF n-3(2H)-one(7?)-4-[4-(l -amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 118 triazol-l-yl]-2-[l-(4- 1-41 369U u-L NH2methylphenyl)propyl]pyridazin-3(2H)-one / o(7?)-4-[4-(l -amino-2- H2N—methoxy ethyl)- 1 H- 1,2, 3 - nNExample 119 triazol-l-yl]-2-[2-(2- 1-41 355°YS methylphenyl)ethyl]pyridazin- 3(2H)-oneOkN(7?)-3-({5-[4-(l-amino-2- methoxy ethyl)- 1H-1,2,3- AExample 120 tri azol - 1 -y 1 ] -6 -oxopy ri dazin- 1-41 386V'NH2N _ Jk JJ l(6H)-yl}methyl)-5- o~-' \=N chl orob enzonitril e4-[4-((7?)-l-amino-2- x JO(methoxy ethyl)- 1 H- 1,2, 3 - O ZZ- LA^ciFExample 121 triazol-l-yl]-2-{[3-chloro-4- 1-41 429°YN'NH2N Jk JI (trifluoromethyl)phenyl]methyl / O A-'-’ N=N } pyridazin-3 (2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1H-1,2,3- Example 122 tri azol - 1 -y 1 ] -2 -(2-m ethyl - 1 - 1-41 369AL NH2phenylpropyl)pyridazin-3(2H)- one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - 0k / \Example 123 triazol-l-yl]-2-{l-[3- 1-41 423N'NY°L A. NH2(trifluoromethyl)phenyl]propylNYY } pyridazin-3 (2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 124 1-41 342 triazol- 1 -y 1 ] -2 - [ 1 -(pyridin-4- yl)ethyl]pyridazin-3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 125 triazol-l-yl]-2-{l-[2,4- 1-41 477 bis(trifluoromethyl)phenyl]eth1o ^yl } pyridazin-3 (2H)-one' Z N> - 4-[4-((7?)-l-amino-2- ' O zz- methoxy ethyl)- 1H-1,2,3- S~ C°=zz- Example 126 triazol-l-yl]-2-[l-(2- 1-41 385X m ethoxy pheny l)propy 1 ] py ri dazM°xin-3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 127 triazol-l-yl]-2-[(4-fluoro-3,5- 1-41 373zz- dimethylphenyl)methyl]pyrida^ o= O Zz- zin-3 (2H)-onefZ ^^ F^, F 4-[4-((7?)-l-amino-2- Y co'' methoxy ethyl)- 1 H- 1,2, 3 - 1 Y 1Example 128 tri azol - 1 -y 1 ] -2 - { 1 - [5 -chi oro-2- 1-41 459V'NH2N Jk JJ (trifluoromethoxy)phenyl]ethylO~'' \=N } pyridazin-3 (2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 129 1-41 342 tri azol- 1 -yl]-2-[ 1 -(pyri din-3 - yl)ethyl]pyridazin-3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 130 triazol-l-yl]-2-[l-(2- 1-41 389N'NY°U JL _ NH2chlorophenyl)propyl]pyridazin- IYNY^OX3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 131 N'V triazol-l-yl]-2-[l-(4- 1-41 373 |l J. NH2fluorophenyl)propyl]pyridazin- 3(2H)-oneF^F4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 132 triazol-l-yl]-2-{l-[2- 1-41 407N'NY°U NH2(difluoromethoxy)phenyl]ethyl} pyridazin-3 (2H)-one4-[4-((7?)-l-amino-2- mmethoxy ethyl)- 1 H- 1,2, 3 - oExample 133 \ CM tri azol- 1 -y 1 ] -2 - [(5 -bromo- 1 - 1-41 461, 463 z wl I5 / \> °1— b enzothi ophen-3 - VX Z '- '="5°Z / QO- "' yl)methyl]pyridazin-3(2H)-onezz=4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 134,i< triazol-l-yl]-2-[2-(3- 1-41 355NN4 methylphenyl)ethyl]pyridazin- (Rb-NH23(2H)-oneO / 4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 135 triazol-l-yl]-2-[(l-methyl-5- 1-41 407 pheny 1 - 1 H-py razol -4- yl)methyl]pyridazin-3(2H)-one261234-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - N-N triazol-l-yl]-2-[(5- Example 136 o^\ 1-41 381 methylimidazo[l,2-a]pyridin- H2N / RL< rN,> N 2-yl)methyl]pyridazin-3(2H)- T N'o"' one14-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 137 triazol-l-yl]-2-{[3-(pyridin-2- 1-41 395 yl)-l,2-oxazol-4- yl]methyl}pyridazin-3(2H)-oneM " 4-[4-((7?)-l-amino-2- H2N r iioz z- methoxy ethyl)- 1 H- 1,2, 3 - CT " N'NExample 138 tri azol- l-yl]-2-{2-[3- 1-41 409(trifluoromethyl)phenyl]ethyl }oULFpyridazin-3(2H)-oneTF4-[4-((7?)-l-amino-2- OLmethoxy ethyl)- 1 H- 1,2, 3 - Example 139 triazol-l-yl]-2-(l- 1-41 371 N'YIL ^JL NH2phenoxypropan-2-yl)pyridazin- N=N / ^^OX3(2H)-one4-[4-((7?)-l-amino-2- V" NL if methoxy ethyl)- 1 H- 1,2, 3 - Example 140 N y'NJYL° triazol-l-yl]-2-[l-(5- 1-41 374NH2fluoropyridin-2- yl)propyl]pyridazin-3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 141 V'N triazol-l-yl]-2-[(3- 1-41 361H2N Jk JIchl oropheny l)m ethyl ] py ri dazin-3(2H)-one261233-({5-[4-((7?)-l-amino-2- methoxy ethyl)- 1H-1,2,3- Example 142 1-41 352 tri azol - 1 -y 1 ] -6 -oxopy ri dazin- 1 (6H)-yl }methyl)benzonitrile7 ~~ \ i — ) \ Mz \o zz4-[4-((7?)-l-amino-2- (W ”NH2methoxy ethyl)- 1 H- 1,2, 3 - Nx>Ntri azol- l-yl]-2-(2- 1-41 369 Example 143phenylbutyl)pyridazin-3(2H)- oneCM zzW YJ>z <'> X / r wJ_ "zz' 4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - triazol- 1 -yl]-2-[2-(2,3 - 1-41 377 Example 144difluorophenyl)ethyl]pyridazin-3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1H-1,2,3- triazol-l-yl]-2-{[5-(2-methyl- 1-41 430 Example 145l,3-thiazol-4-yl)thiophen-2- yl]methyl}pyridazin-3(2H)-one26123\, N,N-[3-({5-[4-((7?)-l-amino-2- jrj methoxy ethyl)- 1H-1,2,3- tri azol - 1 -y 1 ] -6 -oxopy ri dazin- Example 146 1-41 509 i l(6H)-yl}methyl)-5-chloro-2- O- z§r 7. N.,methylphenyl]-6- o IN'H2N" (m) methylpyridine-3 -carboxamide6'-.l p 0\4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 147 tri azol- 1 -y 1 ] -2 - [(5 -methyl- 1 - 1-41 397 b enzothi ophen-2- yl)methyl]pyridazin-3(2H)-one\(R) <)° " NH24-[4-((7?)-l-amino-2-N'? methoxy ethyl)- 1 H- 1,2, 3 - Example 148 / r° triazol-l-yl]-2-[(l-methyl-3- 1-41 407 pheny 1 - 1 H-py razol - 5 - 0 N'"yl)methyl]pyridazin-3(2H)-oneo~o NH24-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - 7=n 0triazol-l-yl]-2-({4-[l-(2,2,2- Example 149 ■■tax, 1-41 492 trifluoroethyl)piperidin-4- 71, yl]phenyl}methyl)pyridazin- 3(2H)-one261234-[4-((7?)-l-amino-2- H iNH2 methoxy ethyl)- 1H-1,2,3-N'rAExample 150 tri azol - 1 -y 1 ] -2 - [(2 -phenyl -2H- 1-41 394NYT^N'N l,2,3-triazol-4- yl)methyl]pyridazin-3(2H)-one 6zY"hzz4-[4-((7?)-l-amino-2- r i \ / \ I= / wmethoxy ethyl)- 1 H- 1,2, 3 - Example 151 N'Y triazol-l-yl]-2-[l-(2,5- 1-41 409IL ^JL NH2di chi oropheny l)ethy 1 ] py ri dazinN=N (RJ^O-3(2H)-one4-[4-((7?)-l-amino-2- ~°\XNH2 methoxy ethyl)- 1 H- 1,2, 3 - Example 152 o i triazol-l-yl]-2-[l-(4- 1-41 355 methylphenyl)ethyl]pyridazin- 3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 153 triazol-l-yl]-2-{l-[3- 1-41 409(trifluoromethyl)phenyl]ethyl }pyridazin-3(2H)-one4-[4-((7?)-l-amino-2- ~°\ NH2methoxy ethyl)- 1 H- 1,2, 3 - 0,Example 154 triazol-l-yl]-2-{l-[4- 1-41 409(trifluoromethyl)phenyl]ethyl }■■-likvrpyridazin-3(2H)-one4-[4-((7?)-l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 155 tri azol- 1 -y 1 ] -2- [(2, 3 -dihydro- 1-41 367U _JL NH2lH-inden-5- N~NZyl)methyl]pyridazin-3(2H)-one26123Example 156: 4-(3-((ty)-l-aminoethyDisoxazol-5-yl)-2-(3-hydroxy-2.,3-dihydro-LH-inden-4-yl)Dyridazin-3(2ZD-one and 4-(3-((l)-l-aminoethyl)isoxazol-5-yl)-2-(3-hvdroxy-2.,3-dihvdro-1 / / -iiideii-4-yl)pyridazin-3(2 / / )-oneTIPS acetylene 4 PdCI2(PPh3)2, Cui, trans- N, N-dimethylcyclohexane- TEA TFA 1,2-diamine, Cui, K2CO3 DCE, O ’C-rt, 16 h DCM, 0 ”C-rt, 2 h ACN, 100 °C, 16 h Step-1 Step-2 Step-3Et3N TFA DMF, 0 °C-60 °C, 1 h DCM, 0 “C-rt, 1 h Step-5 Step-6Chiral SFCExample 156A Example 156B Step J: 24tetrahydro-2J / -pyran-2-yl)-4-((triisopropylsilyl)ethynyl)pyridazin-3(2 / 7)-oneTo a stirred degassed solution of 4-chloro-2-(tetrahydro-27 / -pyran-2-yl)pyridazin-3(2H)-one (2.0 g, 9.3 mmol) in DCE (20 mL) were added triethylamine (3.9 mL, 28 mmol), bis-(triphenylphosphino)-palladous chloride (1.3 g, 1.9 mmol), [tris(isopropyl)silyl]acetylene (6.3 mL, 28 mmol) and Cui (0.89 g, 4.7 mmol) at 0 °C. The reaction mixture was then allowed to warm to 25 °C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 30% EtOAc in petroleum ether) to afford the desired product MS: 361 [M+H]+.Step 2 4-((triisopropylsilyl)ethynyl)pyridazin-3(2H)-oneTo a stirred solution of 2-(tetrahydro-27 / -pyran-2-yl)-4-((triisopropylsilyl)ethynyl)pyridazin-3(2J7)-one (500 mg, 1.39 mmol) in DCM (10 mL) was added TFA (534 pL, 6.93 mmol) at 0 °C. The reaction mixture was allowed to warm to 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and then triturated with n-pentane (20 mL) to afford the desired. MS: 277 [M+H]+.Step 3 2-(3-hydroxy-2,3-dihydro-lJ / -inden-4-yl)-4-((triisopropylsilyl)ethynyl)pyridazin-3(2J7)-one26123To a stirred and degassed solution of 4-((triisopropylsilyl)ethynyl)pyridazin-3(2J7)-one (NB-08997-1019-001) (200 mg, 723 pmol) in acetontirle (4.0 mL) were added 7-bromo-2,3-dihydro-U / -inden-l-ol (154 mg, 723 pmol), / ra / 7.s-(l / ',2 / - / 7, / 7'-bismethyl-l,2-cyclohexanediamine (57.0 pL, 362 pmol), potassium carbonate (200 mg, 1.45 mmol) and cuprous iodide (68.9 mg, 362 pmol) at 25 °C in a sealed tube. The reaction mixture was heated to 100 °C for 16 hours. After 16 hours, the mixture was allowed to cool to room temperature and then diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 50% EtOAc in petroleum ether) to afford the desired product. MS: 409 [M+H]+.Step 4 4-ethvnyl-2-(3-hvdroxy-2,3-dihydro-lJ / -inden-4-yl)pyridazin-3(2J7)-oneTo a stirred and degassed solution of 2-(3 -hydroxy-2, 3 -dihydro- 17 / -inden-4-yl)-4-((triisopropylsilyl)ethynyl)pyridazin-3(2J7)-one (70 mg, 0.17 mmol) in ACN (1 mL) was added cesium fluoride (52 mg, 0.34 mmol) at 0 °C. The reaction mixture was allowed to warm to 25 °C for 4 hours. The reaction mixture was then diluted with water (5 mL) and extracted with DCM (2 x 5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude compound was triturated with n-pentane (10 mL) to afford the desired product. MS: 235 [M+H-LLO].Step 5 tert-butyl ((lM-l-(5-(2-(3-hvdroxy-2,3-dihydro-lJ / -inden-4-yl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamateTo a stirred solution of tert-butyl fS', Z)-( l-chloro- l-(hydroxyimino)propan-2-yl)carbamate (100 mg, 449 pmol) in DMF (1.0 mL) were added 4-ethynyl-2-(3-hydroxy-2,3-dihydro-17 / -inden-4-yl)pyridazin-3(2J7)-one (45.3 mg, 179.6 pmol) and TEA (188 pL, 1.35 mmol) at 0 °C. The reaction mixture was then heated to 60 °C for 1 hour. The reaction mixture was then allowed to cool to room temperature, diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 50% EtOAc in petroleum ether) to afford the desired product. MS: 421 [M+H-H20]+.Step 6 4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-hydroxy-2,3-dihydro-lH-inden-4-yl)pyridazin-3 (2H)-one and 4-(3 -((S)- 1 -aminoethyl)i soxazol-5 -yl)-2-(3 -hydroxy -2, 3 -dihydro- 1 H-inden-4-yl)pyridazin-3 (2H)-oneTo a stirred solution of tert-butyl ((15)-l-(5-(2-(3-hydroxy-2,3-dihydro-U / -inden-4-yl)-3-oxo-2, 3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (40 mg, 91 pmol) in DCM (1.026123mL) was added TFA (14 pL, 0.18 mmol) at 0 °C. The reaction mixture was then allowed to warm to 25 °C for 1 hour. The reaction mixture was then concentrated under reduced pressure. The resulting crude compound was purified by prep HPLC (MeCN / water, containing 10 mM ammonium bicarbonate modifier) to provide the desired product as a stereoisomeric mixture. MS: 339 [M+H]+. This mixture was separated by chiral SFC (CHIRAL ART Amylose-C Neo, 60:40 CO2: modifier, modifier = 0.035 M methanolic ammonia) to provide the following:Example 156A (faster eluting isomer): MS: 339 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 8 8.18 (d, J= 4.4 Hz, 1H), 7.99 (d, J= 4.4 Hz, 1H), 7.42-7.33 (m, 3H), 7.26 (dd, J= 7.0 Hz, 1.4 Hz, 1H), 5.12 (q, J= 7.2 Hz, 1H), 4.85 (d, J= 7.2 Hz, 1H), 4.11 (d, J= 6.6 Hz, 1H), 3.08-2.94 (m, 1H), 2.79 (qt, J= 8.0 Hz, 1H), 2.40-2.10 (m, 3H), 1.86-1.72 (m, 1H), 1.33 (d, J= 6.8 Hz, 3H).Example 156B (slower eluting isomer): MS: 339 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 6 8.17 (d, J= 4.0 Hz, 1H), 7.99 (d, J= 4.0 Hz, 1H), 7.43-7.33 (m, 3H), 7.26 (dd, J= 7.2 Hz, 1.6 Hz, 1H), 5.12 (q, J= 6.9 Hz, 1H), 4.85 (d, J= 6.8 Hz, 1H), 4.10 (q, J= 6.6 Hz, 1H), 3.08-2.93 (m, 1H), 2.79 (qt, J= 8.0 Hz, 1H), 2.40-2.30 (m, 1H), 2.20 (br s, 2H), 1.96-1.70 (m, 1H), 1.34 (d, J= 6.8 Hz, 3H).Example 157: 4-(2-(l-aminoethyl)thiazol-5-yl)-2-Dhenylpyridazin-3(2H)-one n U o c m Uk / Tjs Cbz. NHcbz~. NH H II Lawesson's reagent H u i Dibromantin i x-N / , ► x-N / , ► xL g - ► 1 3 Cbz NH2Toulene, 100 °C, 40 mincbzps;NH2 THF, 85 °C, 16 h S ACN, 25 °C, 20 min / BrStep-1 Step-2 N^Zstgp-3nJ / K2CO3, PdCI2(dppf)DCM 1. TMS-Br 1,4 dioxane, H2O, 100 °C, 2 h TFA, 0 °C-rt, 2 h Step-4 2. Chiral SFC Step-5Example 157A Example 157BStep 1: Benzyl (S)-(l -amino- l-thioxopropan-2-yl)carbamateTo a mixture ofbenzyl (S)-(l -amino- l-oxopropan-2-yl)carbamate (10 g, 45 mmol) in toluene (100 mL) was added Lawesson's reagent (18.2 g, 45 mmol) at 25 °C. The reaction was heated to 100 °C for 40 minutes. After 40 minutes, the mixture was quenched with water (100 mL) and was extracted with DCM (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with 20% EtOAc in pet ether) to afford the26123desired product. MS: 239 [M+H]+.Step 2: Benzyl (l-(thiazol-2-yl)ethyl)carbamateTo a mixture of benzyl (S)-(l-amino-l-thioxopropan-2-yl)carbamate (8 g, 0.03 mol) in THF (80 mL) was added 2-chloroacetaldehyde (5 g, 0.07 mol) at 25 °C. The reaction mixture was heated to 85 °C for 16 hours. After 16 hours, the mixture was allowed to cool to 25 °C, quenched with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 30% EtOAc in pet ether) to afford the desired product. MS: 263 [M+H]+.Step 3: Benzyl (l-(5-bromothiazol-2-yl)ethyl)carbamateTo a mixture of benzyl (S)-(l-(thiazol-2-yl)ethyl)carbamate (4 g, 0.02 mol) in MeCN (40 mL) was added dibromantin (4 g, 0.02 mol) at 25 °C. After 20 minutes, the mixture was quenched with water (100 mL) and was extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 20% EtOAc in pet ether) to afford the desired product. MS: 341, 343 [M+H]+.Step 4 Benzyl (l-(5-(2-cyclohexyl-3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamateTo a mixture of benzyl (l-(5-bromothiazol-2-yl)ethyl)carbamate (400 mg, 1.17 mmol) and (3-oxo-2-phenyl-2,3-dihydropyridazin-4-yl)boronic acid (304 mg, 1.41 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was added K2CO3 (324 mg, 2.34 mmol) at 25 °C. The reaction mixture was degassed with argon gas for 5 min. Then, PdC12(dppf)-CH2C12 adduct (95.7 mg, 117 pmol) was added and the mixture was heated to 100 °C for 2 hours. After 2 hours, the mixture was allowed to cool to room temperature, quenched with water (80 mL) and extracted with EtOAc (2 x 80 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 70% EtOAc in pet ether) to afford the desired product. MS: 433 [M+H]+.Step 5 4-(2-(l -aminoethyl)thiazol-5-yl)-2-phenylpyridazin-3(2H)-oneTo a mixture of benzyl (l-(5-(3-oxo-2-phenyl-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamate (100 mg, 231 pmol) in TFA (3 mL) was added trimethyl silyl bromide (600 pL, 4.62 mmol) at 0 °C. The mixture was allowed to warm to 25 °C for 2 hours. After 2 hours, the mixture was concentrated under reduced pressure. The crude compound was purified by prep-HPLC purification (ACN / water with 10 mM Ammonium Bicarbonate modifier) to afford the26123desired product. The product was then subjected to chiral SFC (Cellulose SC, 55:45 CO2:modifier, modifier = 45%(0.5 / 49.75 / 49.75 N / N / N isopropylamine / MeCN / IP A) to afford the following:Example 157A (faster eluting isomer): MS: 299 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 6 8.62 (s, 1H), 8.16 (d, J= 4.4 Hz, 1H), 8.03 (d, J= 4.4 Hz, 1H), 7.56-7.61 (m, 2H), 7.50-7.56 (m, 2H), 7.43-7.49 (m, 1H), 4.25 (q, J= 6.8 Hz, 1H), 2.37-2.50 (m, 2H), 1.40 (d, J= 6.8 Hz, 3H). Example 157B (slower eluting isomer): MS: 299 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 6 8.63 (s, 1H), 8.16 (d, J= 4.4 Hz, 1H), 8.04 (d, J= 4.4 Hz, 1H), 7.56-7.61 (m, 2H), 7.50-7.57 (m, 2H), 7.43-7.50 (m, 1H), 4.26 (q, J= 6.8 Hz, 1H), 2.55-2.70 (m, 2H), 1.40 (d, J= 6.8 Hz, 3H).Example 158: (7?)-4-(2-(l-aminoethyl)thiazol-5-yl)-2-benzylDyridazin-3(2ED-one and ( )-4-(2-(l-aminoethyl)thiazol-5-yl)-2-benzylpyridazin-3(2Z / )-onePd(dppf)CI2«CH2CI2TMSBr, K2CO3then chiral SFC Sfep 1 Sfep 2Example 158A Example 158BStep 1 rac-benzyl (l-(5-(2-benzyl-3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamate A solution comprising 2-benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one (400 mg, 1.28 mmol), rac-benzyl (l-(5-bromothiazol-2-yl)ethyl)carbamate (500 mg, 1.47 mmol), 1,4-dioxane (4.00 mL), and water (1.00 mL) was deoxygenated by sparging it with nitrogen gas for 5 min. Potassium carbonate (405 mg, 2.93 mmol) and Pd(dppf)»C12CH2C12 (120 mg, 0.147 mmol) were added, and the mixture was stirred under an inert atmosphere at 100 °C for 2 hours. The mixture was then cooled, diluted with water (80 mL), and extracted with EtOAc (2 x 100 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 50% EtOAc in petroleum ether) to provide the desired product. MS: 447 [M+H]+.Step 2: 4-(2-(l-aminoethyl)thiazol-5-yl)-2-benzylpyridazin-3(2J7)-oneA stirred solution of rac-benzyl (l-(5-(2-benzyl-3-oxo-2,3-dihydropyridazin-4-yl)thiazol- 2-yl)ethyl)carbamate (200 mg, 0.448 mmol) in TFA (3.00 mL) was treated with26123bromotrimethylsilane (1.16 mL, 1.37 g, 8.96 mmol) at 0 °C. The mixture was warmed to RT, and was stirred at that temperature for 3 h. The mixture was then concentrated under reduced pressure. The residue was purified by HPLC (MeCN / water, containing 10 mM ammonium bicarbonate modifier) to provide racemic product. This mixture was then subjected to chiral SFC separation (Chiralpak-IG, 70:30 CO2:modifier, modifier = 0.035 M methanolic ammonia in 2-propanol), affording:Example 158A (faster eluting isomer): MS: 313 [M+H]+.[HNMR (400 MHz, DMSO-tfc): 68.60 (s, 1H), 8.06 (d, J= 4.4 Hz, 1H), 7.99 (d, J= 4.4 Hz, 1H), 7.26-7.37 (m, 5H), 5.37 (s, 2H), 4.31 (q, J= 6.8 Hz, 1H), 3.30-3.60 (m, 2H), 1.41 (d, J= 6.8 Hz, 3H).Example 158B (slower eluting isomer): MS: 313 [M+H]+. 'HNMR (400 MHz, DMSO-tfc): 68.61 (s, 1H), 8.06 (d, J= 4.4 Hz, 1H), 7.99 (d, J= 4.4 Hz, 1H), 7.25-7.37 (m, 5H), 5.37 (s, 2H), 4.31 (q, J= 6.8 Hz, 1H), 3.30-3.70 (m, 2H), 1.41 (d, J= 6.4 Hz, 3H).Example 159: (7?)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-Dhenylpyridazin-3(2ZD-oneand (ty)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-DhenylDyridazin-3(2ED-onePhl(OAc)2, KOH Step 1TFA NH4OAc, NaCNBH4Step 4 Step 5Chiral SFCExample 159A Example 159BStep. l-(5-bromothiazol-2-yl)-l,2-dimethoxyethan-l-olTo a mixture of l-(5-bromothiazol-2-yl)ethan-l-one (2 g, 9.7 mmol) and MeOH (20 mL) were added potassium hydroxide (0.54 g, 9.7 mmol) and (acetyloxy)(phenyl)-lamda3-iodanyl acetate (3.4 g, 11 mmol) at 0 °C. The reaction mixture was then allowed to warm to 27 °C for 16 hours. The reaction mixture was then quenched with water (50 mL) and extracted with26123DCM (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (0-30% EtOAc gradient in hexanes) to afford the desired product. MS: 268 [M+H]+.Step 2 4-(2-(2 -hydroxy- 1,1 -dimethoxy ethyl)thiazol-5-yl)-2-phenylpyridazin-3(2H)-oneTo a vial containing l-(5-bromothiazol-2-yl)-l,2-dimethoxyethan-l-ol (400 mg, 1.49 mmol) was added DCE (40 mL) and H2O (20 mL). The mixture was deoxygenated by sparging with nitrogen for 5 min, then (3-oxo-2-phenyl-2,3-dihydropyridazin-4-yl)boronic acid (967 mg, 4.48 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with di chloromethane (122 mg, 149 pmol), and K3PO4 (390 mg, 2.24 mmol) were added. The mixture was then heated to 80 °C for 16 hours. After 16 hours, the mixture was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 50% EtOAc in pet ether) to afford the desired product. MS: 360 [M+H]+.Step 3 2-phenyl-4-(2-(l, L2-trimethoxyethyl)thiazol-5-yl)pyridazin-3(2H)-oneTo a mixture of 4-(2-(2-hydroxy-l,l-dimethoxyethyl)thiazol-5-yl)-2-phenylpyridazin-3(2H)-one (300 mg, 835 pmol) in THF (1 mL) were added silver oxide (193 mg, 835 pmol) and Methyl iodide (540 pL, 8.35 mmol) at 0 °C. The mixture was then allowed to warm to 27 °C for 16 hours. After 16 hours, the reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 40% EtOAc in pet ether) to afford the desired product. MS: 374 [M+H]+.Step 4 4-(2-(2-methoxyacetyl)thiazol-5-yl)-2-phenylpyridazin-3(2H)-oneTo a mixture of 2-phenyl-4-(2-(l,l,2-trimethoxyethyl)thiazol-5-yl)pyridazin-3(2H)-one (250 mg, 669 pmol) in ACN (2 mL) and H2O (2 mL) was added TFA (103 pL, 1.34 mmol) at 0 °C. The reaction was then allowed to warm to 27 °C for 16 hours. After 16 hours, the reaction mixture was concentrated under reduced pressure. The crude compound was triturated with n-pentane (20 mL) and dried under reduced pressure to afford the desired product. MS: 328 [M+H]+.Step 5: 4-(2-(l -amino-2-methoxyethyl)thiazol-5-yl)-2-phenylpyridazin-3(2H)-oneTo a mixture of 4-(2-(2-methoxyacetyl)thiazol-5-yl)-2-phenylpyridazin-3(2H)-one (200 mg, 611 pmol) in MeOH (5 mL) and THF (5 mL) was added ammonium acetate (471 mg, 6.1126123mmol) at 25 °C. The reaction mixture was then heated to 60 °C for 1 hour. After 1 hour, the mixture was cooled to 25 °C and then sodium cyanoborohydride (96 mg, 1.53 mmol) was added. The mixture was then heated 60 °C for 3 hours. After 3 hours, the mixture was allowed to cool to 25 °C, quenched with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by HPLC (ACN / water with 0.1% formic acid modifier) to afford the desired product. The resulting product was subjected to chiral SFC separation (Chiralcel OD-H, 60:40 CO2:modifier, modifier = 0.035 M methanolic ammonia) to provide the following:Example 159A (faster eluting isomer): MS: 329 [M+H]+.[HNMR (400 MHz, DMSO-tfc): 88.67 (s, 1H), 8.18 (d, J= 4.4 Hz, 1H), 8.08 (d, J= 4.4 Hz, 1H), 7.56-7.61 (m, 2H), 7.50-7.56 (m, 2H), 7.43-7.50 (m, 1H), 4.41 (br s, 1H), 3.66 (dd, J= 9.6 Hz, 4.4 Hz, 1H), 3.56 (dd, J= 9.4 Hz, 6.6 Hz, 1H), 3.29 (s, 3H).Example 159B (slower eluting isomer): MS: 329 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 6 8.70 (s, 1H), 8.19 (d, J= 4.4 Hz, 1H), 8.10 (d, J= 4.4 Hz, 1H), 7.57-7.61 (m, 2H), 7.50-7.56 (m, 2H), 7.44-7.50 (m, 1H), 4.47-4.54 (m, 1H), 3.68 (dd, J= 9.8 Hz, 4.6 Hz, 1H), 3.60 (dd, J= 9.6 Hz, 6.4 Hz, 1H), 3.30 (s, 3H).Example 160: (7?)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-benzylpyridazin-3(2ZD-oneand (5l)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-benzylpyridazin-3(2ZD-oneExample 160A Example 160BUsing methods similar to those outlined in Example 159, substituting 1-51 in Step 2, Example 160 was prepared. The stereoisomeric mixture was separated by chiral SFC (Chiralcel OD-H, 60:40 CO2:modifier, modifier = 0.035 M methanolic ammonia) to provide:Example 160A (faster eluting isomer): MS: 343 [M+H]+. 'H NMR (400 MHz, DMSO-t / e): 6 (ppm) 8.62 (s, 1H), 8.07 (d, J= 4.4 Hz, 1H), 8.0 (d, J= 4.4 Hz, 1H), 7.38-7.26 (m, 5H), 5.37 (s, 2H), 4.35 (t, J= 5.4 Hz, 1H), 3.64 (dd, J= 9.6 Hz, 4.4 Hz, 1H), 3.53 (dd, J= 9.4 Hz, 7.0 Hz, 1H), 3.28 (s, 3H), 3.20-2.70(m. 2H)Example 160B (slower eluting isomer): MS: 343 [M+H]+. 'H NMR (400 MHz, DMSO-t / e): 6 (ppm) 8.62 (s, 1H), 8.07 (d, J= 4.4 Hz, 1H), 8.01 (d, J= 4.4 Hz, 1H), 7.40-7.25 (m, 5H), 5.37 (s,261232H), 4.39 (t, J= 5.2 Hz, 1H), 3.65 (dd, J= 9.6 Hz, 4.4 Hz, 1H), 3.55 (dd, J= 9.2 Hz, 6.8 Hz, 1H), 3.29 (s, 3H).Example 161: (l?)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-(3-chloro-5- (trifluoromethoxy)Dhenyl)Dyridazin-3(2H)-one and (SI- 4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-(3-chloro-5-(trifluoromethoxy)phenyl)Dyridazin-3(2H)-oneExample 161A Example 161B Step. benzyl (l-(5-(2-(3-chloro-5-(trifluoromethoxy)phenyl)-3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)-2-methoxyethyl (carbamateTo a stirred solution of benzyl (2-methoxy-l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)ethyl)carbamate (400 mg, 1.04 mmol) in DCM (15 mL) was added (3-chloro-5-(trifluoromethoxy)phenyl)boronic acid (373 mg, 1.55 mmol), pyridine- 1 -oxide (49.2 mg, 518 pmol), pyridine (251 pL, 3.11 mmol) and copper (II) acetate (94 mg, 518 pmol) at 25 °C. The reaction mixture was degassed with oxygen gas at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours under oxygen atmosphere. Then, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with 50% EtOAc in pet ether) to afford the desired product. MS: 581 [M+H]+.Step 2:4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-(3-chloro-5-(trifluoromethoxy)phenyl)pyridazin-3(2J7)-oneTo a stirred solution of benzyl (l-(5-(2-(3-chloro-5-(trifluoromethoxy)phenyl)-3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)-2-methoxyethyl)carbamate (150 mg, 258 pmol) in TFA (1.0 mL) was added Bromotrimethylsilane (677 pL, 5.16 mmol) at 0 °C. The reaction was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by HPLC (ACN / water containing 10 mM ammonium bicarbonate26123modifier) to provide racemic product. This was subjected to chiral SFC purification (Chiralpak AS-H, 0:100 CO2:modifier, modifier = 0.035 M methanolic ammonia) to provide the following:Example 161A (faster eluting isomer): MS: 447 [M+H]+.XH NMR (400 MHz, DMSO-t / e): 6 8.67 (s, 1H), 8.21 (d, J= 4.4 Hz, 1H), 8.07 (d, J= 4.4 Hz, 1H), 7.88 (t, J= 1.6 Hz, 1H), 7.74 (d, J = 9.6 Hz, 2H), 4.39 (s, 1H), 3.70-3.50 (m, 2H), 3.29 (s, 3H).Example 161B (slower eluting isomer): MS: 447 [M+H]+'HNMR (400 MHz, DMSO-t / e): 6 8.67 (s, 1H), 8.21 (d, J= 4.4 Hz, 1H), 8.07 (d, J= 4.4 Hz, 1H), 7.88 (t, J= 1.6 Hz, 1H), 7.74 (d, J = 9.6 Hz, 2H), 4.39 (s, 1H), 3.70-3.50 (m, 2H), 3.29 (s, 3H).Example 162: 4-(2-(l-aminocvcloDroDyl)thiazol-5-yl)-2-(2-methoxyDyridin-4-yl)Dyridazin- 3(2ED-one K2CO3Pd(dppf)CI2«CH2CI2, Step 1TFAStep 2Example 162Step. tert-butyl (l-(5-(2-(2-methoxypyridin-4-yl)-3-oxo-2,3-dihvdropyridazin-4-yl)thiazol-2-yl)cyclopropyl)carbamateIn a glass vial, 2-(2-methoxypyridin-4-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazin-3(2J7)-one (619 mg, 1.88 mmol) and K2CO3 (260 mg, 1.88 mmol) were added at 25 °C to a stirred solution of tert-butyl (l-(5-bromothiazol-2-yl)cyclopropyl)carbamate (200 mg, 627 pmol) in DMF (5.00 mL) and water (1.00 mL). The vial was sealed, and the reaction mixture was sparged with nitrogen gas at 25 °C for 5 min. Then Pd(dppf)C12*CH2C12 (51.2 mg, 62.7 pmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 50% EtOAc in hexane) yielded the desired product. MS: 442 [M+H]+.Step 2\ 4-(2-(l -aminocyclopropyl)thiazol-5-yl)-2-(2-methoxypyridin-4-yl)pyridazin-3(2Zf)-one To a stirred solution of tert-butyl (l-(5-(2-(2-methoxypyridin-4-yl)-3-oxo-2,3-dihydropyridazin-4-yl)thiazol-2-yl)cyclopropyl)carbamate (75 mg, 0.17 mmol) in DCM (2 mL) was added TFA (65 pL, 0.85 mmol) at 0 °C. The reaction mixture was warmed to 25 °C and was26123stirred at that temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by HPLC (MeCN / water, containing 10 mM ammonium bicarbonate modifier) to provide the desired product. MS: 342 [M+H]+.XH NMR (400 MHz, DMSO-t / e): 8 (ppm) 8.54 (s, 1H), 8.31 (d, J= 5.6 Hz, 1H), 8.18 (d, J= 4.4 Hz, 1H), 7.98 (d, J= 4.4 Hz, 1H), 7.34 (dd, J= 5.6 Hz, 1.6 Hz, 1H), 7.18 (d, J= 1.2 Hz, 1H), 3.92 (s, 3H), 2.84 (br s, 2H), 1.36-1.32 (m, 2H), 1.22-1.19 (m, 2H).Example 163: 4-(3-(l-aminocycloDroDyl)isoxazol-5-yl)-2-(2-methoxyDyridin-4-yl)Dyridazin-3(2H)-oneStep. tert-butyl (l-(5-(2-(2-methoxypyridin-4-yl)-3-oxo-2,3-dihvdropyridazin-4-yl)isoxazol-3-vDcyclopropyDcarbamateTo a vial was added 4-bromo-2-methoxypyridine (150 mg, 800 pmol), tert-butyl (l-(5-(3-oxo-2, 3-dihydropyridazin-4-yl)isoxazol-3-yl)cyclopropyl)carbamate (127 mg, 0.400 mmol), and then AlPhos Pd G6 OTf (48.6 mg, 40.0 pmol). The vial was moved into a glove box and then potassium phosphate, tribasic (170 mg, 800 pmol) and toluene (6 mL) were added. The mixture was then heated to 90.0 °C for 18 hours. After 18 hours, the mixture was allowed to cool to room temperature and then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (5-10% (3:1 ethyl acetate: ethanol) gradient in hexanes) to afford the desired product. MS: 426 [M+H]+.Step 2\ 4-(3-(l -aminocvclopropyl)isoxazol-5-yl)-2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one To a vial containing tert-butyl (l-(5-(2-(2-methoxypyridin-4-yl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)cyclopropyl)carbamate (670 mg, 1.57 mmol) was added DCM (3.15 mL) and then trifluoroacetic acid (2.43 mL, 31.5 mmol). After 1 hour, the mixture was diluted with chloroform / IPA (3 / 1). The mixture was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and then concentrated under reduced26123pressure. The resulting mixture was purified via amino-functionalized silica gel column chromatography (5-80% (3:1 ethyl acetate: ethanol) gradient in hexanes to afford the desired product. MS: 426 [M+H]+. 1H NMR (500 MHz, DMSO) 68.33 (d, J= 5.6 Hz, 1H), 8.27 (d, J = 4.3 Hz, 1H), 7.99 (d, = 4.3 Hz, 1H), 7.36 (s, 1H), 7.34 (dd, J= 5.6, 1.8 Hz, 1H), 7.19 (d, J= 1.8 Hz, 1H), 3.93 (s, 3H), 2.61 (s, 2H), 1.05 (t, J= 3.0 Hz, 2H), 1.01 (t, J= 3.0 Hz, 2H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 163, substituting appropriate starting materials, and employing either HC1 in 1,4-dioxane or TFA in DCM for N-Boc removal:Example Starting MS Structure IUPAC NameNumber material [M+H]+ / (S)-4-(3-(l- / oo oaminoethyl)isoxazol-5-yl)-2- Example 164 < ¥ ¥ I pzz- T 1-35 314(2-methoxypyridin-4- tsy2^o ¥H ^o- = zz- N = zz\O= yl)pyridazin-3(2H)-one) (? V)o c (R)-4-[3 -( 1 -amino-2-, CM zP zXM C ^X1 J " methoxyethyl)-l,2-oxazol-5- Example 165 X 1-36 344 yl]-2-(2-methoxypyridin-4- yl)pyridazin-3(2H)-one(R)-4-[3 -( 1 -amino-2- hydroxy ethyl)- 1,2-oxazol-5- Example 166 1-37 330 yl]-2-(2-methoxypyridin-4- yl)pyridazin-3(2H)-one(S)-4-(3-(l- Example 167 aminoethyl)isoxazol-5-yl)-2- 1-35 283 phenylpyridazin-3(2H)-one26123(S)-4- [3 -( 1 -aminoethyl)- 1,2- oxazol-5-yl]-2-(3,5- Example 168 s u 1-35 351 di chi oropheny l)py ri dazin-H2N\ Cl3(2H)-one(S)-5 - [3 -( 1 -aminoethyl)- 1,2- Example 169 oxazol-5-yl]-6'-methoxy-6H- 1-35 315[l,4'-bipyridazin]-6-oneVs? NH2NZ\^ / ° (S)-4-[3-(l -aminoethyl)- 1,2- / o oxazol-5-yl]-2-(2- Example 170 00 * 1-35 315N-N methoxypyrimidin-4- xN0zz- 0 yl)pyridazin-3(2H)-oneN^7C\tS) NxH2N / \1_? (S)-4-[3-(l -aminoethyl)- 1,2- M C zzI 00 oxazol-5-yl]-2-(5- Example 171 N-N 1-35 314 methoxypyri din-3 - yl)pyridazin-3(2H)-oneo / Usj NH2N / ^ \_ / ° (S)-4-[3-(l -aminoethyl)- 1,2- oxazol-5-yl]-2-(6- Example 172 00 # 1-35 315 N-N methoxypyrazin-2- yl)pyridazin-3(2H)-one\=NVSbN.H2N^ \_ / °(S)-N-(3 -{ 5 - [3 -( 1 -aminoethyl)- 00 *N-N l,2-oxazol-5-yl]-6- Example 173 1-35 340 oxopyridazin-l(6H)- NH yl}phenyl)acetamide26123(S)-4- [3 -( 1 -aminoethyl)- 1,2- oxazol-5-yl]-2-[3- Example 174 N-N 1-35 349(difluorom ethoxy )pheny 1 ] py ri d o azin-3 (2H)-oneF— (F\(SJ NH2N^ \_ / °(S)-4-[3-(l -aminoethyl)- 1,2- o=\ V oxazol-5-yl]-2-[2- Example 175 N-N 1-35 350(difluoromethoxy)pyridin-4- oN=\o yl]pyridazin-3(2H)-oneF^(FH2NZ^\ P (S)-4-[3-(l -aminoethyl)- 1,2- oxazol-5-yl]-2-[2- Example 176 O=\ N-N V 1-35 340(cyclopropyloxy)pyridin-4- yl]pyridazin-3(2H)-oneVs? NH2NZ\^ / ° (S)-4-[3-(l -aminoethyl)- 1,2- oxazol-5 -yl] -2-(5 -fluoro-2- Example 177 0=( N-N V 1-35 332 methoxypyridin-4- yl)pyridazin-3(2H)-one / O4 N^^FVs; NH2N^ \_ / °(S)-4-[3-(l -aminoethyl)- 1,2- 0=( V oxazol-5-yl]-2-[2- Example 178 N-N 1-35 368(tri fluoromethoxy )pyridin-4- Qo yl]pyridazin-3(2H)-oneF-XF F26123Vs? NH2NZ\^ / ° (S)-4-[3-(l -aminoethyl)- 1,2- o=\ * oxazol-5-yl]-2-(6- Example 179 N-N 1-35 314 methoxypyridin-2- 4 Nyl)pyridazin-3(2H)-one0 / NH2N*' \_P (S)-4-[3-(l -aminoethyl)- 1,2- 0=( * oxazol-5-yl]-2-(6- Example 180 N-N 1-35 315 N=( methoxypyrimidin-4- Q N-\ yl)pyridazin-3(2H)-oneO / / zoQHO (S)-5 - [3 -( 1 -aminoethyl)- 1,2- 0Example 181 zz zz-- oxazol-5-yl]-5'-methoxy-6H- 1-35 315^o=?o=[l,3'-bipyridazin]-6-oneso A.gVzM C z zzI CM (R)-4-[3 -( 1 -amino-2- Xrf"^N hydroxy ethyl)- 1,2-oxazol-5-H2N\W / V ¥ NExample 182 yl]-2-(3,5- 1-37 367 HO— '' 'N-O 0 LJCl di chi oropheny l)py ri dazin- 3(2H)-one(S)-3-{5-[3-(l -aminoethyl)- l,2-oxazol-5-yl]-6- Example 183 1-35 342 oxopyridazin- 1 (6H)-yl }-5- chl orob enzonitril e(S)-4-[3-(l -aminoethyl)- 1,2- 0^ / XzN. ^ z oxazol-5-yl]-2-(3-chloro-5- Example 184NA 'M T' o n II Y T 1-35 331 rsy y methylphenyl)pyridazin-3(2H)- H2N^ i|one26123(S)-4-[3-(l -aminoethyl)- 1,2- jpF4-Foxazol-5-yl]-2-[3-chloro-5- Example 185NA T n II I 1-35 401(trifluorom ethoxy )pheny 1 ] py ri dH2H ClX azin-3 (2H)-onetoz_'o(S)-4-[3-(l -aminoethyl)- 1,2- oxazol-5-yl]-2-[3-chloro-5- Example 186 zz- 1-35 385(trifluoromethyl)phenyl]pyridazin-3 (2H)-one(S)-4-[3-(l -aminoethyl)- 1,2- JpFyFoxazol-5-yl]-2-[3-chloro-5- Example 187 V I u 1-35 383(difluorom ethoxy )pheny 1 ] py ri d2tSt / H H ( 1ZZ- L|azin-3 (2H)-one^O=_%O Ax' (S)-4-[3-(l -aminoethyl)- 1,2-zX CM z oxazol-5-yl]-2-(3-chloro-5- Example 188 1-35 335 fluorophenyl)pyridazin-3 (2H)- one(S)-4-[3-(l -aminoethyl)- 1,2- P' 1 oxazol-5-yl]-2-(3-chloro-5- Example 189 < T n T T 1-35 347tsy Y methoxyphenyl)pyridazin- H2N^ ii3(2H)-one(S)-4-[3-(l-aminocyclopropyl)- O^Y Ck.N' l,2-oxazol-5-yl]-2-(3,5- Example 190 1-38 363H2N M Y 5 ° I J di chi oropheny l)py ri dazin- ACl3(2H)-one26123(S)-4-[3-(l -aminoethyl)- 1,2- Example 1912(S MH N )T I WMNoxazol - 5 -y 1 ] -2-( 1 H-indazol - 5 - 1-35 323 yl)pyridazin-3(2H)-one(S)-5-{5-[3-(l-aminoethyl)- Xl,2-oxazol-5-yl]-6- Example 192NA T n || | 1-35 341(s)T N y oxopyridazin- 1 (6H)-yl }-N-H2N\ / NHmethylpyridine-2-carboxamide(S)-4-[3-(l -aminoethyl)- 1,2- N Br oxazol-5-yl]-2-(3-bromo-5- Example 193 < T n if T 1-35- 395 chlorophenyl)pyridazin-3 (2H)- H2N<, ilone(R)-5-{5-[3-(l-amino-2- P 'methoxyethyl)-l,2-oxazol-5-NA T n J |Example 194 'M o(R) / NT yl]-6-oxopyridazin- 1 (6H)-yl } - 1-36 371H2N\, NH / N-methylpyri diner°\carb oxami de(S)-4-[3-(l -aminoethyl)- 1,2- oxazol-5-yl]-2-[4- Example 195 V o ULFV 1-35 367(tri fluorom ethoxy )pheny 1 ] py ri dH2°Fazin-3 (2H)-one(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 196 (3 -chi oro-4 - 1-35 401Np o UL XFH2NP 1 °F(trifluoromethoxy)phenyl)pyrid2'•> Clazin-3 (2H)-one26123(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 197 N. T ¥ I | 1-35 351(3,4-dichlorophenyl)pyridazin- - fsy ci¥ H z0z\2-N^.2-■> C 1¥z l 3(2H)-oneA z.J T "^ 6- (S)-4-(2-(l-aminoethyl)thiazol- ^ 00zz- 5-yl)-2-(4- Example 198 ZZ- 1-35 383(trifluoromethoxy)phenyl)pyrid¥ )> o - azin-3 (2H)-one 0 o \ozo eo (S)-4-(5-(3-(l- ¥^no o ° aminoethyl)isoxaz H, N JL N J0 / ol-5-yl)-6- Example 199 1-35 341 oxopyridazin- 1 (6H)-yl)-N- 0 0 'N'O0 H0 zz- zz- methylpicolinamide ^o= ^o=(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- VV(4-chl oro-3 - 1-35 401 Example 200\(trifluoromethoxy)phenyl)pyridazin-3 (2H)-one(S)-5-(3-(l- aminoethyl)isoxazol-5-yl)-6'- 1-35 353 Example 201(trifluoromethyl)-6H-[ 1,4'- bipyridazin]-6-one3-(5-(3-(l- aminocyclobutyl)isoxazol-5- 1-39 368 Example 202yl)-6-oxopyridazin-l(6H)-yl)- 5 -chi orob enzonitril e26123(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 203 z 1-35 318 z (6-chl oropyri din-3 - Ira IJXA z yl)pyridazin-3(2H)-oneA z^ 6- (S)-5-(3-(l- ^ 00zz- aminoethyl)isoxazol-5-yl)-6'- Example 204 ^ 00 1-35 319 zz- chloro-6H-[l,4'-bipyridazin]-6- 0 oneo0o(S)-4-(3-(l- [ANu aminoethyl)isoxazol-5-yl)-2- Example 205 1-35 318(2-chl oropyri din-4- ' IM'0° \^Nzz- yl)pyridazin-3(2H)-one)o=(S)-4-(3-(l- r° aminoethyl)isoxazol-5-yl)-2- Example 206 JO C 1-35 318(5-chl oropyri din-3- N C, ZY^Iyl)pyridazin-3(2H)-one(R)-4-(3 -( 1 -amino-2- \ OHrf^N VL hydroxyethyl)isoxazol-5-yl)-2- H2N _ JI N 0 N—71-37 + 1- Example 207 \ffiy%Y0f 0AA^ / (3-chloro-5-(l-(2-hydroxy-2- 471HO—' N'° ° YfY 57methylpropyl)-lH-pyrazol-4- Clyl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l- 10^ N / =N aminoethyl)isoxazol-5-yl)-2- O^ A^NX^O^Example 208 " J I U Y' (6-chloro-l-(2,2- 1-35 421I difluoroethyl)-lH-indazol-4- yl)pyridazin-3(2H)-one26123(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 209 (6-chloro- 1 -methyl- 1H- 1-35 371 indazol-4-yl)pyridazin-3(2H)- one(R)-4-(3 -( 1 -amino-2- methoxyethyl)isoxazol-5-yl)-2- N Y I I TCF3Example 210 AJJ o2(R) / (3- 1-36 396 H N / (trifluoromethoxy)phenyl)pyrid0 azin-3 (2H)-one / \ Z'Example 211: (S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloro-2-(2-hydroxy-2- methylpropyl)-2H-indazol-4-yl zz)-pyridazin-3(2H)-one and (S)-4-(3-(l-aminoethyl)isoxazol-5- ^o=yl)-2-(6-chloro-l-(2-hvdroxy-2-methylpropyl)-lH-indazol-4-yl)pyridazin-3(2H)-one. Xs - ' °''M C zIAlPhos Pd G6 OTf, K3PO4, CS2CO3 then TFA Step 1 Step 2OHCl Cl Example 211A Example 211 BStep. l-(4-bromo-6-chloro-2H-indazol-2-yl)-2-methylpropan-2-ol and l-(4-bromo-6-chloro- 1 H-indazol- 1 -yl)-2-methylpropan-2-olA solution of 4-bromo-6-chloro-l / Z-indazole (175 mg, 756 pmol) and 1,2-epoxy- isobutane (169 pL, 136 mg, 1.89 mmol) in acetonitrile (2.00 mL) was treated with cesium carbonate (372 mg, 1.14 mmol). The mixture was heated to 90 °C for 2.5 h, then cooled back to RT. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts26123were washed with sat. aq. NaCl solutoin, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with hexanes initially, grading to 25% B / hexanes [B = 25% v / v EtOH / EtOAc]) to provide the desired product as a mixture of A-alkylated regioisomers. MS: 303, 305 [M+H]+.Step 2: (S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloro-2-(2-hydroxy-2-methylpropyl)-2H-indazol-4-yl)pyridazin-3(2H)-one (Example 211A) and (S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloro-l-(2-hvdroxy-2-methylpropyl)-lH-indazol-4-yl)pyridazin-3(2H)-one (Example 21 IB)In a nitrogen-filled glovebox, tert-butyl (S)-(l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (44.0 mg, 144 pmol), l-(4-bromo-6-chloro-indazol-l-yl)-2-methylpropan-2-ol (mixture of regioisomers, 87.2 mg, 287 pmol), AlPhos Pd G6 OTf precatalyst (17.5 mg, 14.4 pmol), tripotassium phosphate (61.0 mg, 287 pmol), and toluene (1.00 mL) were combined. The mixture was heated to 100 °C for 16 h, then the reaction was cooled to RT. The mixture was concentrated, and the residue was filtered through a plug of silica gel, eluting with 30% MeOH / DCM. The filtrate was concentrated, and the residue was redissolved in DCM (1.00 mL). TFA (166 pL) was added, and the resulting solution was aged at RT overnight. The mixture was then concentrated, and the residue was purified by HPLC (MeCN / water, containing 0.1% NH4OH modifier) to provide:Example 211A (faster-eluting isomer): MS: 429 [M+H]+. 'H NMR (500 MHz, DMSO-tfc): 8 8.29 (d, J= 4.3 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J= 4.4 Hz, 1H), 7.89 (s, 1H), 7.42 (s, 1H), 7.41 (s, 1H), 4.82 (s, 1H), 4.34 (s, 2H), 4.12 (q, J= 6.4 Hz, 1H), 1.34 (d, J= 6.7 Hz, 3H), 1.10 (s, 6H). Example 211B (slower-eluting isomer): MS: 429 [M+H]+.XH NMR (500 MHz, DMSO-tfc): 6 8.29 (d, J= 4.3 Hz, 1H), 8.06 (d, J= 4.3 Hz, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 4.72 (s, 1H), 4.36 (s, 2H), 4.11 (q, J = 6.7 Hz, 1H), 1.33 (d, J = 6.7 Hz, 3H), 1.14 (s, 6H).Example 212: 4-[3-(l-aminoethyl)-l.,2-oxazol-5-yl]-2-[3- (trifluoromethoxy)phenyl] pyridazin-3(2H)-one andExample 213: 4-[3-(l-aminoethyl)-l.,2-oxazol-5-yl]-2-[4-(trifluoromethyl)phenyl]pyridazin- 3(2H)-oneExample 212 Example 21326123Step 1: tert-butyl (S)-(l-(5-(3-oxo-2-(3-(trifluoromethoxy)phenyl)-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate and tert-butyl (S)-(l-(5-(3-oxo-2-(4-(trifluoromethyl)phenyl)-2,3-dihvdropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamateTo a vial was added l-bromo-3-(trifluorom ethoxy )benzene (24.1 mg, 100 pmol), tertbutyl (5)-(l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (15.3 mg, 50.0 pmol) and AlPhos Pd G6 OTf (6.08 mg, 5.00 mol). The vial was moved into a glove box and then potassium phosphate, tribasic (21.2 mg, 100 pmol) and toluene (1.0 mL) were added. The mixture was then heated to 90.0 °C for 18 hours. After 18 hours, the mixture was allowed to cool to room temperature, diluted with DCM, filtered and concentrated. The resulting mixture dissolved in DCM (1 mL) and then trifluoroacetic acid (77.0 pL, 1.00 mmol) was added. The reaction was stirred at 25 °C for 18 hours. After 18 hours, the mixture was concentrated, dissolved in DMSO, filtered, and purified via mass-directed reverse phase HPLC (ACN / water with 0.1% TFA modifier). The resulting mixture was then subjected to SFC purification (AD-H, 21X250mm, 5um, 70:30 CO2:modifier, modifier = 0.1% NFLOH) to afford the following:Example 212: MS: 367 [M+H]+. 1HNMR (500 MHz, DMSO) 88.26 (d, J= 4.3 Hz, 1H), 8.02 (d, J= 4.3 Hz, 1H), 7.73 (s, 1H), 7.71 - 7.68 (m, 2H), 7.54 - 7.49 (m, 1H), 7.43 (s, 1H), 4.11 (q, J= 6.7 Hz, 1H), 2.11 (s, 2H), 1.34 (d, J = 6.7 Hz, 3H).Example 213: MS: 351 [M+H]+. 1HNMR (500 MHz, DMSO) 68.32 (d, J = 4.3 Hz, 1H), 8.13 (d, J= 4.3 Hz, 1H), 7.98 - 7.94 (m, 2H), 7.92 - 7.89 (m, 2H), 7.57 (s, 1H), 4.71 (q, J= 6.9 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H).Example 214: ( / ?)-4-(4-(l-:iiiiiii()-2-iiietlioxyetliyl)-l / / -1.2.3-tiiazol-l-yl)-2-(3-(l-iiietliyl-l / / -l,2.,3-triazol-4-yl)Dhenyl)Dyridazin-3(2ZD-oneExample 214 Step. tert-butyl (A)-(2-methoxy-l-(l-(2-(3-(l -methyl- ITT- L2,3-triazol-4-yl)phenyl)-3-oxo-2,3-dihydropyridazin-4-yl)- 1H- 1,2,3-triazol-4-yl)ethyl)carbamate26123To a stirred solution of tert-butyl (R)-(2-methoxy-l-(l-(3-oxo-2,3-dihydropyridazin-4- yl)-U / -l,2,3-triazol-4-yl)ethyl)carbamate (120 mg, 357 pmol) in acetonitrile (5.00 mL) were added 4-(3-bromophenyl)-l-methyl-U / -l,2,3-triazole (127 mg, 535 pmol), potassium carbonate (98.6 mg, 714 pmol) and teaw -A, A'-dimethylcyclohexane-l,2-diamine (113 pL, 714 pmol) at 25 °C and sparged with nitrogen gas at 25 °C for 2 min. Then copper(I) iodide (34.0 mg, 178 pmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 100 °C under an inert atmosphere for 16 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 10% MeOH in DCM) yielded the desired product. MS: 494 [M+H]+.Step 2 (A)-4-(4-(l -amino-2-methoxy ethyl)- ITT- 1,2,3-triazol- l-yl)-2-(3-(l -methyl- 177-1,2,3- triazol-4-yl)phenyl)pyridazin-3(2Zf)-oneoA stirred solution comprising tert-butyl (2-methoxy-l-(l-(2-(3-(l-methyl-U / -l,2,3- triazol-4-yl)phenyl)-3-oxo-2,3-dihydropyridazin-4-yl)-17 / -l,2,3-triazol-4-yl)ethyl)carbamate (80 zz- mg, 0.16 mmol) in DCM (1.0 ^ mLo=) was treated with TFA (0.12 mL, 1.6 mmol) at 0 °C. The reaction mixture was then wza Z-rmed to 25 °C and stirred at that temperature for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by HPLC (MeCN / water, conta Kining 10 mM ammonium bicarbonate modifier) to yield the title compound. MS: 394 [M+H]+.1HNMR(400 MHz, DMSO-tfc): 68.84 (d, J= 0.4 Hz, 1H), 8.60 (s, 1H), 8.31 (d, J= 4.8 Hz, 1H), 8.18 (d, J= 4.8 Hz, 1H), 8.13 (t, J= 1.4 Hz, 1H), 7.93 (dt, J= 7.2 Hz, 1.6 Hz, 1H), 7.67-7.57 (m, 2H), 4.24 (t, J= 6.0 Hz, 1H), 4.11 (s, 3H), 3.59 (dd, J= 9.2 Hz, 5.2 Hz, 1H), 3.54-3.45 (m, 1H), 3.28 (s, 3H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 214, substituting appropriate starting materials, and employing either HC1 in 1,4-dioxane or TFA in DCM to achieve N-Boc removal, or TMS-Br in TFA to achieve A-Cbz removal in Step 2, the following examples were prepared:Example Starting MS Structure IUPAC NameNumber material [M+H]+(R)-4-[4-(l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - Example 215 tri azol - 1 -y 1 ] -2 -(3, 5 - 1-41 381 di chi oropheny l)py ri dazin- 3(2H)-one26123Cl (R)-4-(4-(l-amino-2- methoxy ethyl)- 1 H- 1,2, 3 - 1-41 Example 216N=N triazol-l-yl)-2-(3-chloro-5-(l- 428\QI^A / N+ I-55B ~\_^NZ methyl- 1H- 1,2,3 -triazol-4- NH2yl)phenyl)pyridazin-3(2H)-oneV (S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 217 A2^ O zz- 1-35 289(thiophen-2-yl)pyridazin- ( z=3(2H)-oneVo(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- 1-35 324 Example 218zz- }o= (5-chlorothiazol-2- yl)pyridazin-3(2H)-oner° (S)-4-(3-(l-HA CNExample 2 T Z^A A / NN S aminoethyl)isoxazol-5-yl)-2- 19 A V n Y / Vci 1-35 357(4, 5 -di chi orothi ophen-2- - Vo oCl yl)pyridazin-3(2H)-one(S)-4-(3-(l- ANaminoethyl)isoxazol-5-yl)-2- Z^A / N SX(5-chloro-4- 1-35 391 Example 220 A ' n ¥ / VciVo 0(trifluoromethyl)thiophen-2- CF3yl)pyridazin-3(2H)-one(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- ANH2N JL N F ( 1 -(difluoromethyl)- 1 H- 1-35 323 Example 221 \® / Y Y AN^ / / \\ I H,N\ N'° 0 V F pyrazol-4-yl)pyridazin-3(2H)- one26123(S)-4-(3-(l- rY'N aminoethyl)isoxazol-5-yl)-2- Example 222 H2N _ JI N _ (l-(2,2,2-trifluoroethyl)-lH- 1-35 355Z \\ 1 II N \N-0 0 CF3pyrazol-4-yl)pyridazin-3(2H)- one(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- YYH2N JI N ^OH ( 1-(1 -hydroxy -2- Example 223 WV Y 1-35 345 methylpropan-2-yl)- 1 H- N'°0Y1pyrazol-4-yl)pyridazin-3(2H)- oneYY o (S)-3-(5-(3-(l- aminoethyl)isoxazol-5-yl)-6- Example 224H! N®AJYWN^ 1-35 374Y -o oHoxopyridazin-l(6H)-yl)-5- Cl chl oro-N -methy lb enzami deY^N (S)-4-(2-(l-aminoethyl)thiazol-H2N S Y Y'" N WCI5-yl)-2-(3,5- Example 225 n lJ I 1 J I-32A 367\Y0Y-Y di chi oropheny l)py ri dazin- Cl 3(2H)-one4-(3-((lR,2S)-l-amino-2- YY methoxypropyl)isoxazol-5-yl)- H2N N ^_CIExample 226 2-(3,5- 1-40 395S JJdi chi oropheny 1 )py ri dazin- Cl3(2H)-one(R)-4-(4-(l-amino-2- H2N J iJCNN ci hy droxy ethyl)- 1H- 1,2,3- Example 227 YY triazol-l-yl)-2-(3,5- 1-43 366HO—'N=N O YYdi chi oropheny 1 )py ri dazin- Cl3(2H)-one26123[T^N (R)-4-(3 -( 1 -amino-2- methoxyethyl)isoxazol-5-yl)-2- Example 228 1-36 3810-"'' N'O 0 O (3,5-dichlorophenyl)pyridazin- Cl 3(2H)-one(R)-4-(4-(l-amino-2- \ OH methoxy ethyl)- 1 H- 1,2, 3 - rf^N VLH2N 1 N / x A / triazol-l-yl)-2-(3-chloro-5-(l- 1-41 + 1- Example 229 485 o-' 0 (2-hydroxy-2-methylpropyl)- 57Cl lH-pyrazol-4- X.o / yl)phenyl)pyridazin-3(2H)-one4-(3-(l- aminocyclopropyl)isoxazol-5- yl)-2-(3 -chi oro-5 -( 1 -(2- 1-38 + 1- Example 230 467 zz- hy droxy-2-m ethylpropyl)- 1H- 57C )o=pyrazol-4-yl)phenyl)pyridazin- 3(2H)-oneE (R)-4-(4-(l-amino-2- X cix V\ z7"methoxy ethyl)- 1 H- 1,2, 3 - Example 231 tri azol- 1 -yl)-2-(3 -chloro-5- 1-41 4310-' > N 0 O(trifluoromethoxy)phenyl)pyridClazin-3 (2H)-one(S)-4-(2-(l-aminoethyl)thiazol-H2*l5-yl)-2-(3-chloro-5-(l-(2- Example 232 hy droxy-2-m ethylpropyl)- 1H- I-32A 471 / N-N pyrazol-4-yl)phenyl)pyridazin- ^OH 3(2H)-oneExample 233: (7?)-4-(4-(l-amino-2-methoxyethyl)-lH-l.,2.,3-triazol-l-yl)-2-(8- bromonaphthalen-l-yl)pyridazin-3(2ED-one26123Boc 8-hydroxy quinoline. K2CO3, Cui HCI Step 1 Step 2Example 233 Step. tert-butyl (A)-(l-(l-(2-(8-bromonaphthalen-l-yl)-3-oxo-2,3-dihydropyridazin-4-yl)-U / -1,2,3 -tri azol-4-yl)-2-m ethoxy ethyDcarbamateTo a vial containing tert-butyl (R)-(2-methoxy-l-(l-(3-oxo-2,3-dihydropyridazin-4-yl)-U / -l,2,3-triazol-4-yl)ethyl)carbamate (200 mg, 595 pmol) and 1,8-dibromonaphthalene (510 mg, 1.78 mmol) was added DMSO (5 mL). The mixture was degassed via subsurface bubbling with nitrogen for five minutes. Potassium carbonate (247 mg, 1.78 mmol), 8-hydroxyquinoline (43.2 mg, 297 pmol) and copper(I) iodide (56.6 mg, 297 pmol) were then added to the vial in a glove box. The reaction mixture was heated to 100 °C for 16 hours. After 16 hours, the mixture was diluted with water (80 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography (eluting with 40% EtOAc in petroleum ether) to afford the desired product. MS: 541 [M+H]+.Step 2: (A)-4-(4-( 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl)-2-(8-bromonaphthalen- 1 -yl)pyridazin-3(2rt)-oneTo a mixture of tert-butyl (l-(l-(2-(8-bromonaphthalen-l-yl)-3-oxo-2,3-dihydropyridazin-4-yl)-U / -l,2,3-triazol-4-yl)-2-methoxyethyl)carbamate (120 mg, 222 pmol) in DCM (5 mL) was added HCI (4.0 M in 1,4-dioxane, 277 pL, 1.11 mmol) at 0 °C. The reaction mixture was then allowed to warm to 25 °C for 3 hours. After 3 hours, the mixture was concentrated under reduced pressure. The resulting crude compound was purified by prep HPLC (ACN / water with 0.1% formic acid modifier) to afford the desired product. MS: 441 [M+H]+. 'H NMR (400 MHz, DMSO-tfc): 68.84 (d, J= 2.0 Hz, 1H), 8.36 (d, J= 4.8 Hz, 1H), 8.32-8.25 (m, 2H), 8.19 (dd, J= 8.4 Hz, 0.8 Hz, 2H), 7.93 (dd, J= 7.4 Hz, 1.0 Hz, 1H), 7.82-7.75 (m, 2H), 7.51 (t, J= 7.8 Hz, 1H), 5.78 (br s, 1H), 4.28 (br s, 1H), 3.57-3.53 (m, 1H), 3.53-3.50 (m, 1H), 3.27-3.26 (m, 3H).Example 234: (ty)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(4-(2-hvdroxyDropan-2-yl)-l / / -l.2.3-tri:iz()l-l-yl)i)lieiiyl)i)yridazin-3(2 / / )-one26123ClCl Example 234Step 1 tert-butyl (M-(l-(5-(2-(3-chloro-5-(4-(2-hvdroxypropan-2-yl)-U / -L2,3-triazol-l-yl)phenyl)-3-oxo-2,3-dihvdropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamateIn a nitrogen-filled glovebox, a stirred solution of tert-butyl (5)-(l-(5-(3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (300 mg, 979 pmol) in DMSO (9.79 mL) was treated with cuprous iodide (37.3 mg, 196 pmol) and potassium phosphate, tribasic (624 mg, 2.94 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 min. Then, 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (75.7 mg, 392 pmol) and 2-(l-(3-bromo-5-chlorophenyl)-U / -l,2,3-triazol-4-yl)propan-2-ol (465 mg, 1.47 mmol) were added to the reaction mixture at 25 °C. The reaction mixture was stirred at 90 °C for 16 h under an inert atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Silica gel column chromatography (eluting with 60% EtOAc in hexane) yielded the desired product. MS: 542 [M+H]+.Step 2 (M-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(4-(2-hydroxypropan-2-yl)-lJ / -L2,3-triazol-l-yl)phenyl)pyridazin-3(2Zf)-oneTo a stirred solution of tert-butyl (5)-(l-(5-(2-(3-chloro-5-(4-(2-hydroxypropan-2-yl)-UT-l,2,3-triazol-l-yl)phenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (140 mg, 258 pmol) in DCM (5 mL) was added TFA (398 pL, 5.17 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (MeCN / water containing 10 mM ammonium bicarbonate modifier) to yield the desired product. MS: 442 [M+H]+.XH NMR (400 MHz, DMSO-tL) VT at 90 °C: 8 (ppm) 8.62 (d, J= 0.4 Hz, 1H), 8.28-8.22 (m, 2H), 8.12-8.09 (m, 1H),261237.97 (d, J= 4.4 Hz, 1H), 7.88-7.84 (m, 1H), 7.37 (s, 1H), 4.88 (s, 1H), 4.14 (q, J= 6.8 Hz, 1H), 1.56 (d, J= 0.8 Hz, 6H), 1.37 (dd, J= 6.8 Hz, 0.8 Hz, 3H).Example 235: (ty)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxy-2-methylDroDyl)-lH-Dyrazol-4-yl)Dhenyl)Dyridazin-3(2ZD-oneOHPd(dppf)CI2-CH2CI2K2CO3, dioxane-water then TFA ciExample 235A glass vial equipped with a magnetic stir bar was charged with tert-butyl (5)-(l-(5-(2-(3- bromo-5-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate (100 mg, 0.202 mmol), 2-m ethyl- 1 -(4-(4, 4, 5,5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)- I rt-pyrazol - 1 - yl)propan-2-ol (80.5 mg, 0.303 mmol), potassium carbonate (83.6 mg, 0.605 mmol), and Pd(dppf)C12*CH2C12 (16.5 mg, 20.2 pmol). The vial was sealed, flushed with nitrogen, and 1,4- dioxane (3.67 mL) and water (367 pL) were then added by syringe. The mixture was sparged with nitrogen for 5 min, then heated to 100 °C with stirring. After 1 h, the mixture was concentrated under reduced pressure. The residue was redissolved in TFA (6.00 mL), and the resulting solution was aged at RT for 30 min. The mixture was then concentrated under reduced pressure. The residue was purified by HPLC (MeCN / water containing 0.1% v / v NH4OH modifier) to provide (5)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxy-2- methylpropyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3(2rt)-one. MS: 455 [M+H]+.1HNMR (500 MHz, CD3OD): 88.13 (d, J= 4.3 Hz, 1H), 8.05 (s, 1H), 7.94 (d, J= 4.3 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 4.19 (q, J= 6.8 Hz, 1H), 4.08 (s, 2H), 1.43 (d, J= 6.8 Hz, 3H), 1.16 (s, 6H).Compounds in the table below were prepared using methods similar to those outlined in the synthesis of Example 235, substituting appropriate starting materials, and employing either HC1 in 1,4-dioxane or TFA in DCM for N-Boc removal:Example Starting MS Structure IUPAC NameNumber material [M+H]+26123(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 236 I I NJ (3-chloro-5-(l-cyclopropyl- 1-44 423A Z zlH-pyrazol-4- \^ z> / / ' yl)phenyl)pyridazin-3(2H)-one° \(S)-4-(3-(l- A? A °zz- zz- aminoethyl)isoxazol-5-yl)-2- H2N _ A N A. / N"Example 237 (3-chloro-5-(l-methyl-lH- 1-44 397ZN'O 0 O( \ < o—pyrazol-4-yl)phenyl)pyridazin- Cl Pz' z Z r — 3(2H)-oneY \ / o= (S)-4-(3-(5-(3-(l- A aminoethyl)isoxazol-5-yl)-6- Example 238 \ / — oxopyridazin-l(6H)-yl)-5- 1-44 474 zz- chlorophenyl)-2- ^ ^O=o= zz- methyli soquinolin- 1 (2H)-one(S)-4-(3-(l- r°aminoV J^zfl N ] H ethyl)isoxazol-5-yl)-2- H2NjJ C / A N A JExample 239 (3-chloro-5-(l,M CN C 4-dimethyl-2- 1-44 438 I T' N'O O kJ1oxo- 1,2-dihydropyri din-3 - Cl yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 240 (3-chloro-5-(6,7-dihydro-5H- 1-44 423 pyrrolof 1,2-a]imidazol-3 - yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- (3 -chi oro-5 -(1- Example 241 1-44 487(cy clopropyl sulfonyl)- 1 H- pyrazol-4-yl)phenyl)pyridazin- 3(2H)-one26123(S)-4-(3-(l- H2N. JI N Jl — \ aminoethyl)isoxazol-5-yl)-2- Example 242 I KJ rYr Y r (3-chloro-5-(5,6-dihydro-8H- 1-44 439< Z■' Vo OnvJ<-■ / Cl imidazo[2, 1 -c] [ 1,4]oxazin-3 - yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l- zz- aminoethyl)isoxazol-5-yl)-2- Example 243 J C Q— (3-chloro-5-(l-cyclopropyl-5- 1-44 437 methyl-lH-pyrazol-4- yl)phenyl)pyridazin-3(2H)-oneY 1r O 0 ° \YA ZI °Z(S)-4-(3-(l- Az= / / / aminoethyl)isoxazol-5-yl)-2- N JflN\ \\ (3 -(2-(azetidin- 1 -yl)pyrimidin- Example 244 / Y NV^o \ JV- Vf 1-44 450 o XfX 5-yl)-5- zz zz-- zz- Cl chlorophenyl)pyridazin-3 (2H)- r r c r° A°3*one? \> A ° (S)-N-(4-(3-(5-(3-(l- Vz2J & <aminoethyl)isoxazol-5-yl)-6- I CMN C T TExample 245 oxopyridazin-l(6H)-yl)-5- 1-44 451 chlorophenyl)pyridin-2- yl)acetamide(S)-5-(3-(5-(3-(l- aminoethyl)isoxazol-5-yl)-6- Example 246 oxopyridazin-l(6H)-yl)-5- 1-44 462 chlorophenyl)-2- methylisoindolin- 1 -one(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 247 (3-chloro-5-(2,3-dihydro- 1-44 452[l,4]dioxino[2,3-b]pyridin-7- yl)phenyl)pyridazin-3(2H)-one26123(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2-H2N / x JL N JL Xx / NExample 248 (3-chloro-5-(2-methyl-2H- 1-44 448ZN'O 0 Opyrazolo[4,3-b]pyridin-6- Clyl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l- rf^N r\ aminoethyl)isoxazol-5-yl)-2-H2NJL N JL — <3Example 249 (3 -chi oro-5 -(2- 1-44 424ZN'O O Ocy cl opropy 1 oxazol - 5 - Clyl)phenyl)pyridazin-3(2H)-one(S)-8-(3-(5-(3-(l- [f^N AA aminoethyl)isoxazol-5-yl)-6- H2N x. A N / x. Ax A / Example 250 'VY l AY I oxopyridazin-l(6H)-yl)-5- 1-44 478<■ Vo o O <\ANOchlorophenyl)-4-methyl-2H- Clbenzofb] [ 1,4]oxazin-3 (4H)-one(S)-4-(3-(l- A^N r*N aminoethyl)isoxazol-5-yl)-2- H2N J-L N / -x Ax / N~\Example 251 A (3-chloro-5-(l-(2,2- 1-44 447N'° ° AAFdifluoroethyl)- lH-pyrazol-4- Clyl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- / < N N A r H '"(3 -chi oro-5 -(2-(2- Example 252 1-44 453N'O 0 O hydroxypropan-2-yl)pyrimidin- Cl 5 -yl)phenyl)pyridazin-3 (2H)- one(S)-4-(3-(l- CNAaminoethyl)isoxazol-5-yl)-2- Example 253 1-44 412ZN'O o O (3-chloro-5-(5-fluoropyridin-3- Cl yl)phenyl)pyridazin-3(2H)-one26123(S)-4-(3-(l- aminoethyl)isoxazol-5-yl)-2- Example 254 (3 -chi oro-5 -(2-(2- 1-44 455'' N'O o LJfluoropropan-2-yl)pyrimidin-5- I ClNJ yl)phenyl)pyridazin-3(2H)-one\ oNAA...

Claims

WHAT IS CLAIMED:

1. A compound of structural Formula I:Ior a pharmaceutically acceptable salt or solvate thereof,wherein:A is a five membered heteroaryl selected from triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadi azolyl;B is a six membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidinyl;R1and R2are independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, -C1-6 alkylOH, heteroaryl, and -OC1-6 alkyl, said alkyl, cycloalkyl, and heteroaryl unsubstituted or substituted with 1 to 3 substituents selected from OH, halogen, C1-6 alkyl, and -OC1-6 alkyl; orR3is selected from -(CH2)nC(O)NHCi-6alkyl, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, (CH2)nC(O)heterocycle, (CHR)naryl, and (CH2)nheteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra,each Rais independently selected from -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -(CH2)nC(O)NHCi-6 alkyl, -C(O)heterocycle, halogen and Ci-shaloalkyl;R is selected from hydrogen, -C1-6 alkyl, C(O)OH, C(O)OCi-6 alkyl, and hydroxyl; and each n is an integer independently selected from 0 to 4.

2. A compound of structural Formula IA:OIAor a pharmaceutically acceptable salt or solvate thereof, wherein:A is a five membered heteroaryl selected from triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadi azolyl;B is a six membered heteroaryl selected from pyridyl, pyridazinyl, and pyrimidinyl;R1and R2are independently selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, -C1-6 alkylOH, (CH2)nheteroaryl, and -(CR)nOCi-6 alkyl, said alkyl, cycloalkyl, and heteroaryl unsubstituted or substituted with 1 to 3 substituents selected from OH, halogen, C1-6 alkyl, and -OC1-6 alkyl; or R1and R2combine to the atom to which they are attached to form a C3-6 cycloalkyl,R3is selected from -(CH2)nC(O)NHCi-6alkyl, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, (CH2)nC(O)heterocycle, (CHR)ncarbocycyle, (CHR)naryl, (CHR)nOaryl, C2-6alkenylaryl, and (CH2)nheteroaryl, said heterocycle, aryl and heteroaryl optionally substituted with 1 to 3 substituents selected from Ra,each Rais independently selected from -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, -NHC(0)CI-6 alkyl, -NRC1-6 alkyl, NH2, -C(O)NR(CHR)naryl, -C(O)NRC3-6 cycloalkyl, -C(O)N(CI-6alkyl)2, -C(O)NR(CHR)nheteroaryl, -NHC(O)aryl, -(CH2)nC(O)NRCi-6alkyl, C1-6 alkyl, -OC1-6 alkyl, C3-6 cycloalkyl, -OC3-6 cycloalkyl, (CHR)naryl, (CHR)nheteroaryl, -NRheteroaryl, (CH2)nO(CH2)naryl, -S(O)2NHaryl, -NR(CH2)nC3-6cycloalkyl, heterocycle, -NH(CH2)nheterocycle, -S(O)2heterocycle, (CH2)nC(O)heterocycle, halogen, OH, C(O)OH, CN, (CH2)nO(CH2)nhaloalkyl, and (CH2)nCi-3 haloalkyl, said alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, and heterocycle optionally substituted with 1 to 3 substituents selected from Rb; each Rbis independently selected from C1-6 alkyl, C1-6 alkylOR, OR, -C(O)OR, (CR2)nCN, (CH2)nS(O)2R, oxo, halogen, NHC(O)Ci-6alkyl, (CH2)nC3-6 cycloalkyl, (CHR)nheteroaryl, (CH2)nheterocycle, -S(O)2C3-6cycloalkyl, (CH2)nOCi-3 haloalkyl, and (CH2)nC 1-3 haloalkyl, said alkyl, cycloalkyl, heteroaryl and heterocycle optionally substituted with 1 to 3 substituents selected from Rc;each Rcis selected from C1-6 alkyl, halogen, CN, and OH;R is selected from hydrogen, -C1-6 alkyl, C(O)OH, C(O)OCi-6 alkyl, and hydroxyl; and each n is an integer independently selected from 0 to 4.

3. The compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt or solvate thereof, wherein A is a five membered heteroaryl selected from triazolyl, thiazolyl, isoxazolyl, thiadiazolyl, and tetrazolyl.

4. The compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt or solvate thereof, wherein B is a six -membered nitrogen containing heteroaryl selected from pyridyl and pyridazinyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridyl and A is selected from triazolyl, isoxazolyl, thiazolyl, thiadi azolyl, and tetrazolyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridyl and A is triazolyl.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridyl and A is isoxazolyl.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridyl and A is thiazolyl.

9. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof wherein, B is pyridyl and A is thiadiazolyl.

10. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridazinyl and A is triazolyl.

11. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridazinyl and A is isoxazolyl.

12. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridazinyl and A is thiazolyl.

13. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein B is pyridazinyl and A is thiadiazolyl.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof wherein R3is bonded to a nitrogen atom of B.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, triazolyl,isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadiazolyl, said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadiazolyl optionally substituted with 1 to 3 substituents selected from OH, halogen, Ci-6 alkyl, and -OCi-6 alkyl.

16. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadiazolyl, said methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, triazolyl, isoxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, furanyl, thiophenyl, and oxadiazolyl optionally substituted with 1 to 3 substituents selected from OH, halogen, Ci-6 alkyl, and -OCi-6 alkyl.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is unsubstituted or substituted (CH2)nphenyl.

18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is unsubstituted or substituted (CH2)npyridyl.

19. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt of solvate thereof, wherein R3is selected from -(CH2)nC(O)NHCi-6 alkyl, -(CH2)nC(O)NH(CH2)nOCi-6 alkyl, and (CH2)nC(O)heterocycle, said heterocycle optionally substituted with 1 to 3 substituents selected from Ra.

20. The compound according to any one of claims 1 to 19, of Formulae II through XIII:II III IV26123or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2and R3are as described herein.

21. A compound according to claims 1-5, 7, 11, and 14-20, or a pharmaceutically acceptable salt or solvate thereof, represented by structural Formula VII:VII22. A compound according to claims 1-5, 7, 11, and 14-20, or a pharmaceutically acceptable salt or solvate thereof, represented by structural Formula Vila:Vilawherein X is a bond or -(C h23. A compound selected from:3 -(5 -(aminomethyl)- 1,3,4-thiadiazol-2-yl)- 1 -phenylpyridin-2( 1 H)-one(5)-4-(5-( 1 -aminoethyl)- 1,3, 4-thiadiazol-2-yl)-2-benzylpyridazin-3(2TT)-one(. S') -3 -(5 -( 1 -aminoethyl)- 1,3, 4-thiadiazol-2-yl)- 1 -phenylpyridin-2( 1 TT)-onc(. S') -3 -(5 -( 1 -amino-2 -hydroxy ethyl)- 1,3,4-thiadiazol-2-yl)- 1 -phenylpyridin-2( 1 TT)-oneTert-butyl (S)-(l-(5-(2-benzyl-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethyl)carbamate4-(4-( 1 -aminocyclopropyl)- ITT- 1,2,3 -triazol- 1 -yl)-2-phenylpyridazin-3 (2TT)-one4-(4-(2 -amino- 1 -methoxypropan-2-yl)- ITT- 1,2,3 -triazol- 1 -yl)-2-phenylpyridazin-3 (2TT)-one(S)-4-(4-( 1 -aminoethyl)- 1H- 1,2,3-triazol- 1 -yl)-2-benzylpyridazin-3(2H)-one(S)-3-(4-(l-aminoethyl)-lH-l,2,3-triazol-l-yl)-l-phenylpyridin-2(lH)-one(R)-3-(4-( 1 -amino-2 -hydroxyethyl)- 1H- 1,2,3-triazol- 1-yl)- 1 -phenylpyridin-2( lH)-one(. S') -3 -(4-( 1 -aminoethyl)- ITT- 1,2,3-triazol- 1 -yl)- 1 -(3,5 -bis(trifluoromethyl)phenyl)pyridin-2( lTT)-one( / ?)-4-(4-( 1 -amino-2 -hydroxyethyl)- ITT- 1,2,3-triazol- 1 -yl)-2-benzylpyridazin-3(2TT)-one(R)-3 -(4-( 1 -amino-2 -methoxyethyl)- ITT- 1,2,3-triazol- 1 -yl)- 1 -phenylpyridin-2( lTT)-one(S)-4-((5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)methyl)benzoic acid hydrochloride(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(4-(morpholine-4-carbonyl)benzyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-(morpholine-4-carbonyl)benzyl)pyridazin-3(2TT)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(2-morpholino-2-oxoethyl)pyridazin-3(2TT)-one(5)-4-((5 -(4-( 1 -aminoethyl)- ITT- 1,2,3-triazol- 1 -yl)-6-oxopyridazin- 1 (6TT)-yl)methyl)-JV-(2-methoxyethyl)benzamide(5)-4-((5-(4-( 1 -aminoethyl)- 1H- 1,2,3-triazol- 1 -yl)-6-oxopyridazin- 1 (6 / 7)-y 1 )mcthy 1 )-A'-mcthy Ibcnzamidc(5)-4-(4-( 1 -aminoethyl)- 1H- 1,2,3-triazol- 1 -yl)-2-(4-(morpholine-4-carbonyl)benzyl)pyridazin-3 (277) -one(. S)-2-(5-(4-( 1 -aminoethyl)- 1H- 1,2,3-triazol- 1 -yl)-6-oxopyridazin- 1 (6 / 7)-y 1 )-N-mcthy lacctam ide(5)-2-(5-(4-( 1 -aminoethyl)- 1H- 1,2,3-triazol- 1 -yl)-6-oxopyridazin- 1 (6 / 7)-y 1 )-N-(2-methoxyethyl)acetamide(5)-4-(4-( 1 -aminoethyl)- 1H- 1,2,3-triazol- 1 -yl)-2-(3 -(morpholine-4-carbonyl)benzyl)pyridazin-3 (277) -one(. S') -3 -((5 -(4-( 1 -aminoethyl)- 177- 1,2,3-triazol- 1 -yl)-6-oxopyridazin- 1 (677)-yl)methyl)-JV-(2-methoxyethyl)benzamide(S)-2-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-N-(2-methoxyethyl)acetamide(S)-2-methoxy-l-(5-(2-(2-((R)-3-methoxypyrrolidin-l-yl)-2-oxoethyl)-3-oxo-2,3-dihydropyridazin-4-yl)isoxazol-3-yl)ethan-l-aminium 2,2,2-trifluoroacetate(R)-2-(5-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-N-(2-methoxyethyl)acetamide(R)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-(4-(morpholine-4-carbonyl)benzyl)pyridazin-3(2H)-one(. S') -3 -(3 -( 1 -aminoethyl)isoxazol-5 -yl)- 1 -phenylpyridin-2( 177)-one(7?)-3 -(4-( 1 -amino-2 -hydroxy ethyl)- 177- 1,2,3-triazol- 1 -yl)-277-[ 1,2'-bipyridin] -2 -one( / ?)-4-(4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- l-yl)-2-phenylpyridazin-3(2H) -one(R)-4-(4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl)-2-(8-chloronaphthalen-l -yl)pyridazin-3(2H)-one26123(7?)-4-(4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2,3-triazol- 1 -yl) -2-( 1 -(difluoromethyl)- IH-pyrazol -4-yl)pyridazin-3 (2H)-one( / ?)-4-|4-(l-ammo-2-mcthoxycthyl)-IH-l.2.3-triazol-l-yl|-2-(| l.2.4|triazolo| l.5-a|pyridin-6-yl)pyridazin-3(2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl] -2-(quinolin-7 -yl)pyridazin-3 (2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl] -2-(3 -tert-butylphenyl)pyridazin-3 (2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1-yl] -2-( 1 -phenyl- IH-pyrazol -4-yl)pyridazin-3(2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1-yl] -2-(4-methylthiophen-2-yl)pyridazin-3(2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl] -2-(5 -ethoxypyridin-3 -yl)pyridazin-3 (2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl] -2-[4-fluoro-3 -(trifluoromethyl)phenyl] pyridazin-3 (2H) -one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl] -2-[4-(morpholine-4-sulfonyl)phenyl] pyridazin-3 (2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1-yl] -2-[4-(2-methylpropoxy)phenyl]pyridazin-3(2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl] -2-(5 -fluoropyridin-3 -yl)pyridazin-3 (2H)-one(J?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{6-[(propan-2-yl)oxy]pyridin-3-yl}pyridazin-3(2H)-one( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1-yl] -2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one26123(7?)-4-| 4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-[6-(morpholin-4-yl)pyridin-3 -yl]pyridazin-3(2H)-one(J?)-l-(4-{5-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-6-oxopyridazin-l(6H)-yl}phenyl)cyclopropane- 1 -carbonitrile(7?)-4-[4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(4- { [3 - (trifluoromethyl)phenoxy]methyl}phenyl)pyridazin-3(2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-[3 -methoxy-5 -(trifluoromethyl)phenyl] pyridazin-3 (2H) -one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-[2-(trifluoromethoxy)phenyl]pyridazin-3(2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-[3-(trifluoromethoxy)phenyl]pyridazin-3(2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(3,4-dimethoxyphenyl)pyridazin-3 (2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(2, 3 -dihydro- 1,4-benzodioxin-6-yl)pyridazin-3 (2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-(2-phenoxyphenyl)pyridazin-3(2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(4-ethylphenyl)pyridazin-3 (2H)-one( / ?)-4-|4-( l-ammo-2-mcthoxycthyl)-l H- 1.2.3-tri azol- l-yl |-2-(3.5-difliiorophcnyl)pyridazin-3(2H)-onc(J?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-(3,4,5-trifluorophenyl)pyridazin-3(2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(quinolin-3 -yl)pyridazin-3 (2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-(2-chlorophenyl)pyridazin-3(2H)-one26123(7?)-4-| 4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-[5 -(trifluoromethyl)pyridin-3 -yl]pyridazin-3(2H)-one( / ? ) -4 - 14 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(thiophen-3 -yl)pyridazin-3 (2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-(3-ethoxyphenyl)pyridazin-3(2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-(4-phenoxyphenyl)pyridazin-3(2H)-one(J?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{3-[(propan-2-yl)oxy]phenyl}pyridazin- 3(2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-[2-(trifluoromethyl)pyridin-4-yl]pyridazin-3(2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-[4-(2,2,2-trifluoroethoxy)phenyl]pyridazin-3(2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-[4-(benzyloxy)-3-methoxyphenyl]pyridazin-3(2H)-one( / ? ) -4 - 14 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(2,2-difluoro-2H- 1,3 -benzodioxol-5 -yl)pyridazin-3 (2H)-one( / ? ) -4 - 14 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(2-methoxypyrimidin-5 -yl)pyridazin-3 (2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-(2-methylthiophen-3-yl)pyridazin-3(2H)-one( / ? ) -4 - 14 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-[3 -(difluoromethyl)phenyl]pyridazin-3 (2H)-one(7?)-4-{5-|4-( l-amino-2-mcthoxycthyl)-l H-l.2.3-triazol-l-yl |-6-oxopyridazin-l(6H)-yl [-N-( 1.3-thiazol-2-yl)benzamide26123(7?)-4-| 4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-[2-(morpholin-4-yl)pyridin-4-yl]pyridazin-3(2H)-one(7?)-N-|4-{5-|4-( l-amino-2-mcthoxycthyl)-l H-l.2.3-triazol-l-yl |-6-oxopyridazin-l(6H)-yl [-2-(trifluoromethyl)phenyl] acetamide(7?)-4-|4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2,3-triazol- 1-yl] -2-[2-methyl-5-(pyrrolidine- 1 -sulfonyl)phenyl] pyridazin-3 (2H)-one(7?)-4-[4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2,3-triazol- 1-yl] -2-[ 1 -(3, 3,4,4, 4-pentafluorobutyl)- 1H-pyrazolo [3,4 -b]pyridin-3 -yl] pyridazin-3 (2H) -one(7?)-4-{5-|4-( l-amino-2-mcthoxycthyl)-l H- 1.2.3-tri azol- l-yl |-6-oxopyridazin-l(6H)-yl [-N-(3-chlorophenyl)benzene- 1 -sulfonamide(J?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{3-ethoxy-4-[(propan-2-yl)oxy]phenyl}pyridazin-3(2H)-one(7?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- 1 -yl] -2-(3,4-dimethoxy-2-methylphenyl)pyridazin-3(2H)-one(7?)-4-{5-|4-( l-amino-2-mcthoxycthyl)-l H- 1.2.3-tri azol- l-yl |-6-oxopyridazin-l(6H)-yl [-2-(trifluoromethyl)benzonitrile( / ?)-4-|4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2,3-triazol- l-yl] -2-[ 1 -(propan-2 -yl)- lH-pyrazol-3-yl]pyridazin-3(2H)-one(J?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{4-[(2-chlorophenyl)methoxy]-3,5-dimethylphenyl }pyridazin-3 (2H)-one(J?)-4-{5-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-6-oxopyridazin-l(6H)-yl}-2-methoxybenzonitrile( / ?)-4-| 4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3-triazol- l-yl] -2-(4-methylthiophen-3-yl)pyridazin-3(2H)-one(J?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-([l,2,4]triazolo[l,5-a]pyridin-7-yl)pyridazin- 3(2H)-one(7?)-4-|4-( 1 -amino-2 -methoxy ethyl)- 1H- 1,2, 3-triazol- 1-yl] -2-[4-( 1 -methyl- lH-pyrazol-4-yl)phenyl]pyridazin-3(2H)-one( / ? ) -4 - 14 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(6-methylpyridin-3 -yl)pyridazin-3 (2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-[6-(trifluoromethyl)pyridin-3-yl]pyridazin-3(2H)-one(R)-3 - { 5 -[4-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -6-oxopyridazin- 1 (6H)-yl }benzonitrile( / ? ) -4 - 14 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-( 1 -methyl- lH-pyrazol-4-yl)pyridazin-3 (2H)-one( / ? ) -4 - 14 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-(5 -methyl- 1 -phenyl- IH-pyrazol -4-yl)pyridazin-3 (2H)-one(7?) -4 - [4 -( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1 -yl] -2-[4-(2,2,2-trifluoro- 1 -hydroxyethyl)phenyl]pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[2-fluoro-5-(5-methyl-l,3,4-oxadiazol-2-yl)phenyl]pyridazin-3(2H)-one( / ?)-4-|4-( l-ammo-2-mcthoxycthyl)-l H-l.2.3-triazol-l-yl |-2-| l-(3.3.3-trifhioropropyl)-l H-pyrazol-4-yl]pyridazin-3(2H)-one( / ?)-4- 14-( 1 -amino-2 -methoxyethyl)- 1H- 1,2,3 -triazol- 1-yl] -2-[ 1 -(trifluoromethyl)- IH-pyrazol -4-yl]pyridazin-3(2H)-one(. S)-4-(4-(amino(thiazol-4-yl)mcthyl)- 1H- 1,2, 3-triazol- 1 -yl)-2-phenylpyridazin-3(2H) -one(S)-4-(3 -( 1 -amino-2-( IH-pyrazol- 1 -yl)ethyl)isoxazol-5 -yl)-2-(3,5 -dichlorophenyl)pyridazin-3 (2H)-one(5)-3-(2-(l-aminoethyl)thiazol-5-yl)-l-phenylpyridin-2(l / / )-one4-(3-((5)-l-aminoethyl)isoxazol-5-yl)-2-((7?)-3-methyl-l-phenylbutyl)pyridazin-3(2J7)-one and 4-(3-((5)-l-aminoethyl)isoxazol-5-yl)-2-((5)-3-methyl-l-phenylbutyl)pyridazin-3(2J7)-one4-(3 -((5)- 1 -aminoethyl)i soxazol-5 -y 1 ) -2 -((7?) - 1 -phenylpropyl)pyridazin-3 (2J7)-one and 4-(3 -((5)- l-aminoethyl)isoxazol-5-yl)-2-((5)-l-phenylpropyl)pyridazin-3(2J7)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-((R)-2-methyl-l-phenylpropyl)pyridazin-3(2H)-one and 4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-((S)-2-methyl-l-phenylpropyl)pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-((R)-2,2-dimethyl-l-phenylpropyl)pyridazin-3(2H)-one and 4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-((S)-2,2-dimethyl-l-phenylpropyl)pyridazin-3(2H)-one4-[4-((7?)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl]-2-[ 1 -(pyridin-2-yl)ethyl]pyridazin-3(2H)-one4-[4-((7?)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl]-2-[ 1 -(3 -methoxyphenyl)ethyl]pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[2-(3-fluorophenyl)ethyl]pyridazin- 3(2H)-one4-[4-((7?)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[(2-bromo-4-tert-butylphenyl)methyl]pyridazin-3(2H)-one(7?)-4-[4-(l -amino-2-methoxyethyl)-lH- 1,2, 3-triazol-l-yl]-2-[(5-chloropyri din-3-yl)methyl]pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{[4- (difluoromethoxy)phenyl]methyl}pyridazin-3(2H)-one26123(7?)-4-[4-(l -ami no-2-methoxyethyl )-l H-l, 2, 3-tri azol-1 -yl]-2-[l -(3 -chlorophenyl )ethyl]pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(3-fluorophenyl)ethyl]pyridazin- 3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(4-fluorophenyl)ethyl]pyridazin- 3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[3-(2-methylphenyl)propyl]pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(4-chlorophenyl)ethyl]pyridazin- 3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(4-aminophenyl)ethyl]pyridazin- 3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(2-fluorophenyl)ethyl]pyridazin- 3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{l-[3,5-bis(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[(3-fluoro-2-methylphenyl)methyl]pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(4-methylphenyl)propyl]pyridazin-3(2H)-one(7?)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[2-(2-methylphenyl)ethyl]pyridazin-3(2H)-one26123(7?)-3-({5-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-6-oxopyridazin-l(6H)-yl}methyl)-5-chlorobenzonitrile4-[4-((7?)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{[3-chloro-4- (trifluoromethyl)phenyl]methyl}pyridazin-3(2H)-one4-[4-((7?)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl]-2-(2-methyl- 1 -phenylpropyl)pyridazin-3(2H)-one4-[4-((7?)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -y 1 ] -2- { 1 - [3 -(trifluoromethyl)phenyl]propyl}pyridazin-3(2H)-one4-[4-((7?)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl]-2-[ 1 -(pyridin-4-yl)ethyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{l-[2,4-bi s(trifluoromethyl)phenyl] ethyl } pyridazin-3 (2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl]-2-[ 1 -(2-methoxyphenyl)propyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[(4-fluoro-3,5-dimethylphenyl)methyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{l-[5-chloro-2- (trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(pyridin-3-yl)ethyl]pyridazin- 3(2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl]-2-[ 1 -(2-chlorophenyl)propyl]pyridazin-3(2H)-one261234-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl]-2-[ 1 -(4-fluorophenyl)propyl]pyridazin-3(2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -y 1 ] -2- { 1 -[2-(difluoromethoxy)phenyl]ethyl }pyridazin-3 (2H)-one4-[4-((R)-l-amino-2-methoxy ethyl)-lH- 1,2, 3-triazol-l-yl]-2-[(5-bromo-l-benzothi ophen-3-yl)methyl]pyridazin-3(2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -y 1 ] -2- [2-(3 -methylphenyl)ethyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[(l-methyl-5-phenyl-lH-pyrazol-4-yl)methyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[(5-methylimidazo[l,2-a]pyridin-2-yl)methyl]pyridazin-3(2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -y 1 ] -2- { [3 -(pyridin-2-yl)- 1,2-oxazol-4-yl]methyl }pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-{2-[3- (trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -y 1 ] -2-( 1 -phenoxypropan-2-yl)pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(5-fluoropyridin-2-yl)propyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[(3-chlorophenyl)methyl]pyridazin- 3(2H)-one261233-({ 5-[4-((R)-l-amino-2-methoxy ethyl)-lH- 1,2, 3-tri azol- 1 -yl]-6-oxopyridazin- 1(6H)-yl}methyl)benzonitrile4-[4-((R)-l-amino-2-rnethoxyethyl)-lH-l,2,3-triazol-l-yl]-2-(2-phenylbutyl)pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[2-(2,3-difluorophenyl)ethyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxy ethyl)-lH- 1,2, 3-tri azol-l-yl]-2-{[5-(2-methyl-l,3-thiazol-4-yl)thiophen-2-yl]methyl}pyridazin-3(2H)-oneN-[3 -({ 5 -[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -tri azol- 1 -yl]-6-oxopyridazin- 1 (6H)-yl}methyl)-5-chloro-2-methylphenyl]-6-methylpyridine-3-carboxamide4-[4-((R)-l-amino-2-methoxy ethyl)-lH- 1,2, 3-tri azol-l-yl]-2-[(5-methyl-l-benzothi ophen-2-yl)methyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxy ethyl)-lH- 1,2, 3-tri azol-l-yl]-2-[(l-methyl-3-phenyl-lH-pyrazol-5-yl)methyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxy ethyl)-lH-l, 2, 3-tri azol-l-yl]-2-({4-[l -(2,2,2-trifluoroethyl)piperidin-4-yl]phenyl}methyl)pyridazin-3(2H)-one4-[4-((R)- l-amino-2-methoxyethyl)-lH- 1,2, 3-tri azol-l-yl]-2-[(2-phenyl-2H-l, 2, 3-tri azol -4-yl)methyl]pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[l-(2,5-di chi oropheny l)ethy 1 ] py ri dazin-3 (2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -tri azol- 1 -yl]-2-[ 1 -(4-methylphenyl)ethyl]pyridazin-3(2H)-one261234-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -y 1 ] -2- { 1 - [3 -(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one4-[4-((R)- 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -y 1 ] -2- { 1 -[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one4-[4-((R)-l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-[(2,3-dihydro-lH-inden-5-yl)methyl]pyridazin-3(2H)-one4-(3-((5)-l-aminoethyl)isoxazol-5-yl)-2-(3-hydroxy-2,3-dihydro-lJ / -inden-4-yl)pyridazin- 3(2J7)-one and 4-(3-((5)-l-aminoethyl)isoxazol-5-yl)-2-(3-hydroxy-2,3-dihydro-lJ / -inden-4-yl)pyridazin-3(2J7)-one4-(2-(l-aminoethyl)thiazol-5-yl)-2-phenylpyridazin-3(2H)-one(7?)-4-(2-(l-aminoethyl)thiazol-5-yl)-2-benzylpyridazin-3(2J7)-one and (5)-4-(2-(l-aminoethyl)thiazol-5-yl)-2-benzylpyridazin-3(2J7)-one(7?)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-phenylpyridazin-3(2J7)-one and (5)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-phenylpyridazin-3(2J7)-one(7?)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-benzylpyridazin-3(2J7)-one and (5)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-benzylpyridazin-3(2J7)-one(7?)-4-(2-(l-amino-2-methoxyethyl)thiazol-5-yl)-2-(3-chloro-5- (trifluoromethoxy)phenyl)pyridazin-3(2H)-one and (S)- 4-(2-(l-amino-2 -methoxy ethyl)thiazol- 5-yl)-2-(3-chloro-5-(trifluoromethoxy)phenyl)pyridazin-3(2H)-one4-(2-(l-aminocyclopropyl)thiazol-5-yl)-2-(2-methoxypyridin-4-yl)pyridazin-3(2J7)-one4-(3-(l-aminocyclopropyl)isoxazol-5-yl)-2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one26123(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one(R)-4-[3-(l-amino-2-methoxyethyl)-l,2-oxazol-5-yl]-2-(2-methoxypyridin-4-yl)pyridazin- 3(2H)-one(R)-4-[3-(l-amino-2-hydroxy ethyl)- l,2-oxazol-5-yl]-2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-phenylpyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(3,5-dichlorophenyl)pyridazin-3(2H)-one(S)-5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6'-methoxy-6H-[l,4'-bipyridazin]-6-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(2-methoxypyrimidin-4-yl)pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(5-methoxypyridin-3-yl)pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(6-methoxypyrazin-2-yl)pyridazin-3(2H)-one(S)-N-(3 - { 5 - [3 -(1 -aminoethyl)- 1,2-oxazol-5-yl]-6-oxopyridazin- 1 (6H)-yl }phenyl)acetamide(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-(difluoromethoxy)phenyl]pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[2-(difluoromethoxy)pyridin-4-yl]pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[2-(cyclopropyloxy)pyridin-4-yl]pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)pyridazin-3(2H)-one26123(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[2-(trifluoromethoxy)pyridin-4-yl]pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(6-methoxypyridin-2-yl)pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(6-methoxypyrimidin-4-yl)pyridazin-3(2H)-one(S)-5-[3-(l -aminoethyl)- l,2-oxazol-5-yl]-5'-methoxy-6H-[l,3'-bipyridazin]-6-one(R)-4-[3-(l-amino-2-hydroxyethyl)-l,2-oxazol-5-yl]-2-(3,5-dichlorophenyl)pyridazin-3(2H)-one(S)-3-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-5-chlorobenzonitrile(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(3-chloro-5-methylphenyl)pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-chloro-5-(trifluoromethoxy)phenyl]pyridazin- 3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-chloro-5-(trifluoromethyl)phenyl]pyridazin- 3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-chloro-5-(difluoromethoxy)phenyl]pyridazin- 3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(3-chloro-5-fluorophenyl)pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(3-chloro-5-methoxyphenyl)pyridazin-3(2H)-one(S)-4-[3-(l-aminocyclopropyl)-l,2-oxazol-5-yl]-2-(3,5-dichlorophenyl)pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(lH-indazol-5-yl)pyridazin-3(2H)-one26123(S)-5-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-N-methylpyridine-2-carb oxami de(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-(3-bromo-5-chlorophenyl)pyridazin-3(2H)-one(R)-5-{ 5-[3-(l-amino-2-methoxy ethyl)- l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-N-methylpyridine-2-carboxamide(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[4-(trifluoromethoxy)phenyl]pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-4-(trifluoromethoxy)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3,4-dichlorophenyl)pyridazin-3(2H)-one(S)-4-(2-(l-aminoethyl)thiazol-5-yl)-2-(4-(trifluoromethoxy)phenyl)pyridazin-3(2H)-one(S)-4-(5 -(3 -( 1 -aminoethyl)i soxazol -5 -yl)-6-oxopyridazin- 1 (6H)-yl)-N -methylpicolinamide(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(4-chloro-3-(tri fluoromethoxy )phenyl)pyridazin-3(2H)-one(S)-5-(3-(l-aminoethyl)isoxazol-5-yl)-6'-(trifluoromethyl)-6H-[l,4'-bipyridazin]-6-one3-(5-(3-(l-aminocyclobutyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorobenzonitrile(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloropyridin-3-yl)pyridazin-3(2H)-one(S)-5-(3-(l-aminoethyl)isoxazol-5-yl)-6'-chloro-6H-[l,4'-bipyridazin]-6-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(2-chloropyridin-4-yl)pyridazin-3(2H)-one26123(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(5-chloropyridin-3-yl)pyridazin-3(2H)-one(R)-4-(3-(l-amino-2-hydroxyethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxy-2-methylpropyl)- lH-pyrazol-4-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloro-l-(2,2-difluoroethyl)-lH-indazol-4-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloro-l-methyl-lH-indazol-4-yl)pyridazin-3(2H)-one(R)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-(3-(trifluoromethoxy)phenyl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloro-2-(2-hydroxy-2-methylpropyl)-2H-indazol-4-yl)pyridazin-3(2H)-one and (S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(6-chloro-l-(2 -hydroxy -2-methylpropyl)-lH-indazol-4-yl)pyridazin-3(2H)-one4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-(trifluoromethoxy)phenyl]pyridazin-3(2H)-one4-[3-(l -aminoethyl)-!, 2-oxazol-5-yl]-2-[4-(trifluoromethyl)phenyl]pyridazin-3(2H)-one(7?)-4-(4-(l -amino-2-methoxy ethyl)- 1J7- 1,2, 3-tri azol-l-yl)-2-(3-(l -methyl- \H- 1,2, 3-triazol-4-yl)phenyl)pyridazin-3 (2J7)-one(R)-4-[4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl]-2-(3,5-dichlorophenyl)pyridazin- 3(2H)-one(R)-4-(4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl)-2-(3-chloro-5-(l-methyl-lH-l,2,3-triazol-4-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(thiophen-2-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(5-chlorothiazol-2-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(4,5-dichlorothiophen-2-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(5-chloro-4-(trifluoromethyl)thiophen-2-yl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(l-(difluoromethyl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(l-(l-hydroxy-2-methylpropan-2-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-methylbenzamide(S)-4-(2-(l-aminoethyl)thiazol-5-yl)-2-(3,5-dichlorophenyl)pyridazin-3(2H)-one4-(3-((lR,2S)-l-amino-2-methoxypropyl)isoxazol-5-yl)-2-(3,5-dichlorophenyl)pyridazin-3(2H)-one(R)-4-(4-( 1 -amino-2-hy droxy ethyl)- 1H- 1,2,3 -tri azol- 1 -yl)-2-(3, 5-dichlorophenyl)pyridazin-3(2H)-one(R)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-(3,5-dichlorophenyl)pyridazin-3(2H)-one(R)-4-(4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl)-2-(3-chloro-5-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3(2H)-one4-(3-(l-aminocyclopropyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3(2H)-one(R)-4-(4-(l-amino-2-methoxyethyl)-lH-l,2,3-triazol-l-yl)-2-(3-chloro-5- (trifluoromethoxy)phenyl)pyridazin-3(2H)-one(S)-4-(2-(l-aminoethyl)thiazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol- 4-yl)phenyl)pyridazin-3 (2H)-one(7?)-4-(4-( 1 -amino-2-methoxy ethyl)- 1H- 1,2,3 -triazol- 1 -yl)-2-(8-bromonaphthalen- 1 -yl)pyridazin-3(2J7)-one(5)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(4-(2-hydroxypropan-2-yl)-lJH-l,2,3-triazol-l-yl)phenyl)pyridazin-3(2J7)-one(5)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol- 4-yl)phenyl)pyridazin-3 (2J7)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-cyclopropyl-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-methyl-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-2-methyli soquinolin- 1 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l,4-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3-yl)phenyl)pyridazin-3 (2H)-one26123(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(cyclopropylsulfonyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(5,6-dihydro-8H-imidazo[2,l-c][l,4]oxazin- 3 -yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-cyclopropyl-5-methyl-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-(2-(azetidin-l-yl)pyrimidin-5-yl)-5-chlorophenyl)pyridazin-3(2H)-one(S)-N-(4-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)pyridin-2-yl)acetamide(S)-5-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-2-methyli soindolin- 1 -one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-7-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-cyclopropyloxazol-5-yl)phenyl)pyridazin-3 (2H)-one(S)-8-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-4-methyl-2H-benzo[b][l,4]oxazin-3(4H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(5-fluoropyridin-3-yl)phenyl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-(2-fluoropropan-2-yl)pyrimidin-5-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(pyridazin-4-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(imidazo[l,2-a]pyrimi din-6-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-methylthiazol-5-yl)phenyl)pyridazin- 3(2H)-one(S)-2-(3-(2-(lH-pyrazol-l-yl)pyrimidin-5-yl)-5-chlorophenyl)-4-(3-(l-aminoethyl)isoxazol-5-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-[3-(l -aminoethyl)- 1, 2-oxazol-5-yl]-2-[3-chl oro-5-(3-methoxy-l -methyl- lH-pyrazol-4-yl)phenyl]pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-chloro-5-(3-cyclopropyl-l-methyl-lH-pyrazol-4-yl)phenyl]pyridazin-3(2H)-one(S)-4-[3-(l -aminoethyl)- 1, 2-oxazol-5-yl]-2-{3-chl oro-5 -[3 -(difluoromethyl)- 1 -methyl-lH-pyrazol-4-yl]phenyl}pyridazin-3(2H)-one(S)-4-[3-(l -aminoethyl)- 1, 2-oxazol-5-yl]-2-{3-chl oro-5-[l -(2 -methoxy ethyl)-3,5-dimethyl-lH-pyrazol-4-yl]phenyl}pyridazin-3(2H)-one(S)-4-[3-(l -aminoethyl)- 1, 2-oxazol-5-yl]-2-[3-chl oro-5-(2-methyl-l, 3-oxazol-5-yl)phenyl]pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-chloro-5-(6-methyl-2,3-dihydropyrazolo[5,l-b][l,3]oxazol-7-yl)phenyl]pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2,2-difluorocyclopropyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-{3-chloro-5-[2-(l,l-difluoroethyl)pyrimidin-5-yl]phenyl}pyridazin-3(2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-{3-chloro-5-[l-(l-hydroxy-2-methylpropan-2-yl)- lH-pyrazol-4-yl]phenyl}pyridazin-3(2H)-one(R)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxy-2-methylpropyl)- lH-pyrazol-4-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(4-methoxypyrimidin-5-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2,4-dimethyloxazol-5-yl)phenyl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(3-methoxyisothiazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-l-((4-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-lH-pyrazol- 1 -yl)methyl)cyclopropane- 1 -carbonitrile26123(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-methyl-lH-indazol-5-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(difluoromethyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-methoxypyrimidin-5-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-cyclopropyl-lH-pyrazol-5-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(pyrazolo[l,5-a]pyrimidin-6-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-cyclobutyl-2H-l,2,3-triazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2 -hydroxy -2-methylpropyl)-3, 5-dimethyl-lH-pyrazol-4-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-l-methyl - 1 H-py razol e- 5 -carb onitril e(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-fluoro-5-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol- 4-yl)phenyl)pyridazin-3 (2H)-one26123(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(2-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)pyridin-4-yl)pyridazin-3(2H)-one(S)-5-(3-(l-aminoethyl)isoxazol-5-yl)-6'-(l-cyclopropyl-lH-pyrazol-4-yl)-6H-[l,4'-bipyridazin]- 6-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(2-(l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)-6-methoxypyridin-4-yl)pyridazin-3(2H)-one(S)-2-(4-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-lH-pyrazol-l-yl)acetonitrile2-(4-(3-(5-(3-((S)-l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-lH-pyrazol-l-yl)propanenitrile(S)-2-(4-(3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-lH-pyrazol-l-yl)-2-methylpropanenitrile(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-((methylsulfonyl)methyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-4-fluoro-5-(l-(2-hydroxy-2-methylpropyl)- lH-pyrazol-4-yl)phenyl)pyridazin-3(2H)-one(R)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)pyridazin-3(2H)-one(R)-4-(3-(l-amino-2-hydroxyethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-methyl-2H-pyrazolo[4,3-b]pyridin-6-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-4-fluoro-5-(l-(2-hydroxy-2-methylpropyl)- lH-pyrazol-4-yl)phenyl)pyridazin-3(2H)-one26123(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2 -hydroxy -2-methylpropyl)-lH-l, 2,3-triazol-4-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-(2-hydroxy-2-methylpropyl)-2H-l,2,3-triazol-4-yl)phenyl)pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxycyclobutyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxycyclobutyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxycyclobutyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-(2-hydroxycyclobutyl)-lH-pyrazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-chloro-5-(2-cyclopropyl-2H-l,2,3-triazol-4-yl)phenyl]pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(7-chloro-lH-indazol-5-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-(trifluoromethyl)-lH-indazol-5-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(l-methyl-3-(trifluoromethyl)-lH-indazol-5-yl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(7-chloro-lH-indazol-5-yl)pyridazin-3(2H)-one4-[2-(l -aminoethyl)-!, 3-thiazol-5-yl]-2-(5-fluoropyridin-3-yl)pyridazin-3(2H)-one261234-[2-(l -aminoethyl)-!, 3-thiazol-5-yl]-2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one4-[2-(l-aminoethyl)-l,3-thiazol-5-yl]-2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one4-[2-(l -aminoethyl)-!, 3-thiazol-5-yl]-2-(2-methoxypyrimidin-5-yl)pyridazin-3(2H)-one(E)-4-(2-(l-aminoethyl)thiazol-5-yl)-2-styrylpyridazin-3(2H)-one(R, E)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-styrylpyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(l-methyl-lH-l,2,3-triazol-4-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-methyl-2H-l,2,3-triazol-4-yl)phenyl)pyridazin-3 (2H)-one(R)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-(6-fluoropyridin-2-yl)pyridazin-3(2H)-one(R)-5-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-6'-methoxy-6H-[l,4'-bipyridazin]-6-one(R)-4-(3-(l-amino-2-methoxyethyl)isoxazol-5-yl)-2-(2-methoxypyridin-4-yl)pyridazin-3(2H)-one4-(3-((lR,2S)-l-amino-2-hydroxypropyl)isoxazol-5-yl)-2-(3,5-dichlorophenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-oxopyrrolidin-l-yl)phenyl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-morpholinophenyl)pyridazin-3(2H)-one26123(5)- 1 -(3 -(5-(3 -((5)- 1 -aminoethyl)isoxazol-5-yl)-6-oxopyridazin- 1 (6J7)-yl)-5-chlorophenyl)pyrrolidine-3-carbonitrile(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(((l- (trifluoromethyl)cyclopropyl)methyl)amino)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(4,4-difluoropiperidin-l-yl)phenyl)pyridazin-3 (2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2,2-dimethylmorpholino)phenyl)pyridazin- 3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-((3,3,3-trifluoro-2-methylpropyl)amino)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(ethyl(3,3,3-trifluoropropyl)amino)phenyl)pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(3-oxaspiro[bicyclo[3.1.0]hexane-2,4'-piperidin]-r-yl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(methyl(2-(trifluoromethyl)pyrimidin-5-yl)amino)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(methyl(l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-yl)amino)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)phenyl)pyridazin-3(2H)-oneethyl (lR,5R)-3-(3-(5-(3-((S)-l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chlorophenyl)-3 -azabicyclo[3.1,0]hexane- 1 -carboxylate261234-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-((S)-2-isopropylmorpholino)phenyl)pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-((((lR,5S,6r)-6-methyl-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(3-(l,l-difluoroethoxy)azetidin-l-yl)phenyl)pyridazin-3 (2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(((S)-2,2-dimethyl-l,l-dioxidothietan-3-yl)amino)phenyl)pyridazin-3(2H)-one2-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-chlorophenyl)-4-(3-((S)-l-aminoethyl)isoxazol-5-yl)pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2,6-dimethylmorpholino)phenyl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-((3,3-difluorocyclobutyl)(methyl)amino)phenyl)pyridazin-3(2H)-one(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(3,5-dimethylisoxazol-4-yl)benzamide4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(3-hydroxy-3-methylpyrrolidine-l-carbonyl)phenyl)pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-((2R,3S)-3-hydroxy-2-methylazetidine-l-carbonyl)phenyl)pyridazin-3(2H)-one(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(2,2,2-trifluoroethy 1 )b enzami de26123(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(l-methyl-lH-py razol -3 -y l)b enzami de(S)-3-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-5-chloro-N, N-dimethylbenzamide(S)-3-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-5-chloro-N- (cyclopropylmethyl)benzamide(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-chloro-5-(3,3-difluoroazetidine-l-carbonyl)phenyl]pyridazin-3(2H)-one(S)-3-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-5-chloro-N-methyl-N-phenylbenzamide(S)-3-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-5-chloro-N-cyclobutyl- N -methy lb enzami de(S)-3-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-5-chloro-N-(3-cyanophenyl)benzamide(S)-4-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-2-[3-(5-azaspiro[2.3]hexane-5-carbonyl)-5-chlorophenyl]pyridazin-3(2H)-one(S)-3-{5-[3-(l-aminoethyl)-l,2-oxazol-5-yl]-6-oxopyridazin-l(6H)-yl}-5-chloro-N-(2 -methyl- 2H- 1,2,3 -triazol-4-yl)benzamide3-(5-(3-((S)-l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-((ls,3R)-3-hydroxycyclobutyl)-N-methylbenzamide(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(morpholine-4-carbonyl)phenyl)pyridazin- 3(2H)-one26123(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(4-methylpiperazine-l-carbonyl)phenyl)pyridazin-3(2H)-one(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-cy cl opropy lb enzami de(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(pyrrolidine-l-carbonyl)phenyl)pyridazin- 3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(6-fluoro-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-carbonyl)phenyl)pyridazin-3(2H)-one3-(5-(3-((S)-l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(l-(5-fluoropyridin-2-yl)ethyl)benzamide3-(5-(3-((S)-l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-((S)-l-(5-fluoropyridin-2-yl)ethyl)benzamide4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(3-methyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-carbonyl)phenyl)pyridazin-3(2H)-one(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(3-(difluoromethoxy)-3-methylazetidine-l-carbonyl)phenyl)pyridazin-3(2H)-one3 -(5 -(3 -((S)- 1 -aminoethyl)i soxazol -5 -yl)-6-oxopyridazin- 1 (6H)-yl)-5 -chloro-N-( 1 -(3 -fluoropyridin-2-yl)ethyl)benzamide(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(2-methylpyri din-3 -yl)benzamide(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(4-chloro-2,3-difluorophenyl)benzamide261234-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(4,4-difluoro-2-methylpyrrolidine-l-carbonyl)phenyl)pyridazin-3(2H)-one(S)-3 -(5 -(3 -( 1 -aminoethyl)i soxazol -5 -yl)-6-oxopyridazin- 1 (6H)-yl)-5 -chloro-N-((5 -(trifluoromethyl)pyrimidin-2-yl)methyl)benzamide(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(2,4,5-trifluorobenzyl)benzamide4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2-methyl-6-(2,2,2-trifluoroethyl)morpholine-4-carbonyl)phenyl)pyridazin-3(2H)-one4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(2,2-difluoro-5-methylmorpholine-4-carbonyl)phenyl)pyridazin-3(2H)-one3-(5-(3-((S)-l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(l-(5- (trifluoromethyl)pyrimidin-2-yl)ethyl)benzamide(S)-4-(3-(l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-(3,3-dimethylazetidine-l-carbonyl)phenyl)pyridazin-3(2H)-one(S)-3-(5-(3-(l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-(2-isopropylpyridin-3-yl)benzamide4-(3-((S)-l-aminoethyl)isoxazol-5-yl)-2-(3-chloro-5-((R)-4,4-difluoro-2-methylpyrrolidine-l-carbonyl)phenyl)pyridazin-3(2H)-one3-(5-(3-((S)-l-aminoethyl)isoxazol-5-yl)-6-oxopyridazin-l(6H)-yl)-5-chloro-N-methyl-N-((S)- 1,1,1 -trifluoropropan-2-yl)benzamideor a pharmaceutically acceptable salt or solvate thereof.2612324. A pharmaceutical composition comprising a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

25. Use of a compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, or of the pharmaceutical composition of claim 24, for the manufacture of a medicament for the treatment or prevention of cancers or tumors arising from infection by human papillomavirus (HPV).

26. A method of treating or preventing a cancer selected from cervical cancer, oropharyngeal (head and neck) cancer, rectal cancer, penile cancer, vulval cancer, vaginal cancer and cutaneous squamous cell carcinoma in a subject in need thereof, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of anv.on.. claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising said compound, salt or solvate thereof.

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