TW202204333A - Menin inhibitors and methods of use for treating cancer - Google Patents

Abstract

The present disclosure provides compounds represented by Formula I: or a pharmaceutically acceptable salt thereof, wherein R<SP>a</SP>, R<SP>b</SP>, R<SP>c</SP>, R<SP>d</SP>, V, Q, T, n, p, q, r and s are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat cancer or any other disease, condition, or disorder that is responsive to inhibition of menin.

Description

MENIN inhibitors and methods of use for treating cancer

The present invention provides compounds that are menin inhibitors and methods of treatment of conditions and diseases in which inhibition of menin provides benefits.

Mixed lineage leukemia (MLL) is a proto-oncogene at a chromosomal translocation site originally discovered in human leukemia. Due to chromosomal translocations, MLL is fused to more than 40 different partner proteins to generate a diverse collection of chimeric fusion proteins. The MLL protein is a histone methyltransferase that covalently modifies chromosomes and is mutated in certain subsets of acute leukemia. Many fusion partners constitutively activate novel transcriptional effector properties of MLL that are often associated with their oncogenic potential in animal models of acute leukemia. MLL typically binds to a set of highly conserved cofactors to form macromolecular complexes including menin, the product of the MEN1 tumor suppressor gene. The MEN1 gene is mutated in hereditary and sporadic endocrine tumors.

Menin is involved in diverse protein-protein interaction networks. Cierpicki and Grembecka, Future Med. Chem. 6 :447-462 (2014). Overexpression of menin results in inhibition of Ras-transformed cells. Menin interacts with transcription factors JunD and NF-κB and inhibits the activation of their gene transcription. Studies of these interacting proteins suggest that menin exerts its effects primarily through repressive effects on transcription. An alternative possibility, however, is that menin mediates its effects through transcriptional activation of target genes. Additionally, menin interacts with RPA2, a component of single-stranded DNA-binding proteins involved in DNA repair and replication. Menin also interacts with FANCD2, a nuclear protein that plays an important role in maintaining the stability of the genome with the product of the breast cancer 1 gene (Brca1).

The mechanisms by which menins, which do not share significant homology with other proteins, act as tumor suppressors are not fully understood. Menin plays a role in regulating cell proliferation as MEN1 knockout mice show increased proliferation in neuroendocrine tissues, menin downregulation in epithelial cells increases proliferation, and MEN1 knockout as analyzed by tritiated thymidine incorporation Fibroblasts proliferate more rapidly than wild-type cells. MEN1 cells also have increased sensitivity to DNA damaging agents. Menin interacts with the promoter of the HOX gene.

Certain oncogenic MLL fusion proteins stably bind menin via high-affinity interactions required to initiate MLL-mediated leukemogenesis. Menin is required for the maintenance of MLL-associated but not other oncogene-induced myeloid transformation. Acute gene ablation of menin reverses HOX gene expression mediated by the ML-menin promoter-associated complex, and specifically abrogates the differentiation arresting and oncogenic properties of MLL-transformed leukemic blasts.

MLL fusion proteins (the result of acquired genetic aberrations) transform hematopoietic cells through two alternative mechanisms, either by constitutive transcriptional effector activity or by induction of forced MLL dimerization and oligomerization. Both mechanisms lead to the inappropriate expression of a subset of HOX genes (specifically HOXA9), which are consistently characteristic of human MLL leukemia.

Abnormal expression of HOX gene is also seen in AML patients with NPM1 mutation. NPM1 is primarily located in the nucleus and functions in different cellular processes, including ribosome assembly, nucleosome assembly, and cell proliferation. NPM1 mutations produce abnormal cytoplasmic localization and constitute one of the second most frequent mutations in AML, accounting for almost 30% of all AML patients. Menin has recently been shown to contribute to the regulation of HOX genes and cell proliferation in NPM1 mutant AML cells in vitro and in vivo, but the mechanism remains largely unknown.

Menin interacts with: transcriptional activators such as sc-Myb, MLL1, SMAD 1,3,5, Pem, Runx2, Hlbx9, ER, PPARγ, vitamin D receptors; transcriptional repressors such as JunD, Sin3A, HDAC, EZH2, PRMT5, NFκB, Sirt1, CHES1; cell signaling proteins such as AKT, SOS1/GEF, β-catenin, SMAD 1,3,5, NFκB, ER, PPARγ, vitamin D receptors; and other proteins such as Cell cycle: RPA2, ASK; DNA repair: FANCD2; Cell structure: GFAP, vimenten, NMMHCIIA, IQGAP1; Others: HSP70, CHIP ("menin interacting proteins") involved in regulating gene transcription and cell signaling. Matkar, Trends in Biochemical Sciences 38 : 394-402 (2013). Targeting the interaction of menin with small molecules, such as the menin-MLL interaction, presents an attractive strategy to develop new anticancer agents. See , eg, Cierpicki and Grembecka, Future Med. Chem. 6 :447-462 (2014); He et al, J. Med. Chem. 57 :1543-1556 (2014); and Borkin et al, Cancer Cell 27 :589- 602 (2015); Krivtsov et al, Cancer Cell 36 : 660-673 (2019); Klossowski et al, J. Clin. Invest. 130 : 981-997 (2020); Uckelmann et al, Science 367 : 586-590 ( 2020).

Small molecules that disrupt the interaction of MLL with menin are disclosed in: US Patent Nos. 9,212,180 and 9,216,993; US Patent Application Publication Nos. 2011/0065690, 2014/0275070, 2016/0045504, and 2016 /0046647; and International Publication Nos. WO 2017/192543 and WO 2018/183857; WO 2019/191526; WO 2020/072391 and PCT/US2020/053186. Peptides that disrupt the interaction of MLL with menin are disclosed in US Patent Application Publication No. 2009/0298772.

There is a continuing need for new small molecule drugs for the treatment of cancer and other diseases responsive to menin inhibition.

In one aspect, the present invention provides compounds represented by Formulas I - XLV and pharmaceutically acceptable salts thereof, which are collectively referred to herein as "compounds of the present invention." The compounds of the present invention are menin inhibitors and are therefore useful in the treatment of diseases or conditions in which inhibition of menin provides a therapeutic benefit to the patient.

In another aspect, the present invention provides a method of treating a condition or disease by administering to an individual, eg, a human, in need thereof a therapeutically effective amount of a compound of the present invention. A disease or condition, such as cancer (eg, leukemia), chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections, can be treated by inhibiting menin. Also provided are methods of preventing the proliferation of undesired proliferative cells, such as cancer, in an individual comprising administering to an individual at risk of developing a condition characterized by undesired proliferative cells a therapeutically effective amount of one of the present invention compound. In some embodiments, the compounds of the present invention reduce the proliferation of unwanted cells by inducing apoptosis and/or differentiation in those cells.

In another aspect, the present invention provides a method of inhibiting menin in a subject comprising administering to the subject an effective amount of at least one compound of the present invention.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and an excipient and/or a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a composition comprising a compound of the present invention and an excipient and/or a pharmaceutically acceptable carrier for use in the treatment of a disease or condition in which inhibition of menin provides benefit (eg cancer).

In another aspect, the present invention provides a composition comprising: (a) a compound of the present invention; (b) a second therapeutically active agent; and (c) optional excipients and/or pharmaceuticals acceptable carrier.

In another aspect, the present invention provides a compound of the present invention for use in the treatment of a disease or condition of interest (eg, cancer).

In another aspect, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of a disease or condition of interest, such as cancer.

In another aspect, the present invention provides a kit comprising a compound of the present invention, and optionally an encapsulated composition comprising a second therapeutic agent suitable for the treatment of a disease or condition of interest, and a A package insert with instructions for treating a disease or condition (eg, cancer).

Additional embodiments and advantages of the invention will be set forth, in part, in the description that follows and will be learned from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that the foregoing summary and the following embodiments are exemplary and explanatory only and do not limit the invention as claimed.

Cross-references to related applications

This application claims the benefit of PCT Application No. PCT/CN2020/083752, filed April 8, 2020, the disclosure of which is incorporated by reference in its entirety. U.S. Government Licensing Rights

This invention was made with US Government support under Grant No. CA208267 awarded by the National Institutes of Health. The US Government has certain rights in this invention. I. Compounds of the Invention

The compounds of the present invention are menin inhibitors.

， 或其醫藥學上可接受之鹽，其中： 各R^a 獨立地選自由氫及C₁ -C₄ 烷基組成之群； 各R^b 獨立地選自由氫及C₁ -C₄ 烷基組成之群； R^c 選自由氫及鹵基組成之群； 各R^d 獨立地選自由鹵基組成之群； p、q、r及s獨立地為1或2； 各n獨立地為0、1或2； Q選自由以下組成之群：-N(H)C(=O)OR、-N(R)C(=O)OR、-N(H)C(=O)R、-N(H)C(O)NHR、-N(H)C(O)NR₂ 、-OC(=O)NR₂ 、

； V選自由以下組成之群：-CH₂ OH、-CH₂ OMe、-CH₂ OEt、-CH₂ NH₂ 、-CH₂ NHMe、-CH₂ NMe₂ 、氰基、-(C=O)H、-CO₂ Me、-CO₂ Et、-CH₂ NR¹ CO₂ Me、-CH₂ NR¹ CO₂ CD₃ 、-CH₂ NR¹ CO₂ Et、-CH₂ NR¹ CO₂ iPr、-CH₂ NR¹ CONH₂ 、-CO₂ H、-CONH₂ 、-CONHMe、-CONMe₂ 、-CONHEt、-CONEt₂ 、-CON(Me)(Et)、-CON(CD₃ )₂ 、-CON(Me)(CD₃ )、-CON(Et)(CD₃ )、-CON(i-Pr)(CD₃ )、-CH₂ NHCONHCH₂ CF₃ 、-CH₂ NHCONHiPr、-CH₂ NHCONHMe、-CH₂ NHCONHEt、

； 各R^f 獨立地選自由以下組成之群：氫、C₁ -C₄ 烷基、羥基、C₁ -C₄ 烷氧基及鹵基； 各R^g 獨立地選自由以下組成之群：氫、C₁ -C₄ 烷基及NH₂ ； 各R獨立地為C₁ -C₄ 烷基、C₁ -C₄ 鹵烷基或CD₃ ； 各R¹ 獨立地為氫或C₁ -C₄ 烷基； 各R² 獨立地為C₁ -C₄ 烷基或C₃ -C₆ 環烷基； 各k獨立地為0、1、2、3或4； T選自由以下組成之群：-C₁ -C₄ 烷基、C₁ -C₄ 烷基磺醯基、環烷基磺醯基、-C₁ -C₄ 烷基羰基、芳基羰基、

其中 R⁴ 為氫、C₁ -C₄ 烷基、C₁ -C₄ 烷基羰基、雜環基及鹵烷基； 各m獨立地為1或2； J為氫、氰基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、芳基磺醯基、雜芳基磺醯基、雜環磺醯基、雜環烷基磺醯基及甲醯胺基； v為0或1； R⁶ 為氫、鹵烷基、-C₁ -C₄ 烷基、-C₁ -C₄ 烷基羰基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、芳基磺醯基、雜芳基磺醯基、雜環磺醯基、雜環烷基磺醯基、甲醯胺基、甲磺酸酯基或三級丁氧基羰基； 各R⁷ 獨立地選自由以下組成之群：氫、氰基、鹵基、鹵烷基、-C₁ -C₄ 烷基、-C₁ -C₄ 烷基羰基、羥基、磺醯胺基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、芳基磺醯基、雜芳基磺醯基、雜環磺醯基、雜環烷基磺醯基或甲醯胺基； R^8a 、R^8b 、R^8c 及R^8d 獨立地選自由以下組成之群：氫、鹵基、羧基、羥基、-C₁ -C₄ 烷氧基羰基、-C₁ -C₄ 烷基、-C₁ -C₄ 烷氧基、鹵烷基、鹵基烷氧基、-CH₂ SO₂ C₁ -C₄ 烷基、磺醯胺基及R^a1 ； Z為氫、C₁ -C₄ 烷基、-C₁ -C₄ 烷基羰基、羥基、氰基、鹵烷基、-NO₂ 、鹵基、-NR¹ SO₂ (C₁ -C₄ 烷基)、-NR¹ SO₂ (C₂ -C₆ 烯基)、-NR¹ CO(C₁ -C₄ 烷基)、-CONH₂ 、-CONH(C₁ -C₄ 烷基)、-CON(C₁ -C₄ 烷基)₂ 、-S(=O)(=NR¹ )CF₃ 、S(=O)(=NR¹ )(C₁ -C₄ 烷基)、胺基、磺醯胺基、烷基磺醯基、鹵烷基磺醯基及環烷基磺醯基； R^a1 為氰基、烷氧基烷基、芳烷氧基、烷基磺醯基、(胺基)烷基、甲醯胺基、硫醯胺、視情況經取代之雜芳基、(雜芳基)烷基、-NR¹³ C(O)C₁ -C₄ 烷基、-OCH₂ CH=CH-烷基磺醯基、-O(C₁ -C₄ 烷基)O(C₁ -C₄ 烷基)、-C₂ -C₆ 烯基、雜環氧基、胺基羰氧基及(雜環基)烷基； X選自由以下組成之群：-C₁ -C₄ 烷基、-C₂ -C₄ 烯基、-NH₂ 、-NHC₁ -C₄ 烷基、-N(C₁ -C₄ 烷基)₂ 、(胺基)烷基及-CH₂ CH₂ NR¹ Y-Z² ；

，其中 t及u獨立地為0、1、2或3； Y為不存在或為-C(=O)-、-SO₂ -、-C(=O)NH-、-C(=O)N(Me)-； Z² 選自由以下組成之群：-C(R^14a )=C(R^14b )(R^14c )、-C≡CR^14d 、烷基、烷氧基、鹵烷基及R^a2 R^9a 及R^9b 各自獨立地選自由以下組成之群：烯基、炔基、氰基、-C₁ -C₄ 烷基、鹵基、(胺基)烷基及-C(R^14a )=C(R^14b )(R^14c )； 各Q¹ 獨立地選自由-CH₂ -及-C(=O)-組成之群 R¹⁰ 選自由以下組成之群：氫、-C₁ -C₄ 烷基、-NR¹³ CO(C₁ -C₄ 烷基)、-NR¹³ SO₂ (C₁ -C₄ 烷基)、氰基、鹵基、-OCH₂ CH=CH-R^a3 、-CH₂ CH₂ CH=CH-R^a3 ； R¹¹ 為鹵基、-NR¹³ COC(R^14a )=C(R^14b )(R^14c )、甲醯胺基、-C(O)NR¹³ CH₂ R^a5 、-C(O)NR¹³ CH₂ CH=CH-R^a3 、-C(O)NR¹³ CH₂ C≡CR^a6 或-CH₂ CH₂ CH=CH-R^a3 ； R¹² 選自由以下組成之群：烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基及甲醯胺基； R¹³ 為氫或C₁ -C₄ 烷基； R^14a 、R^14b 、R^14c 及R^14d 各自獨立地選自由以下組成之群：氫、鹵基、C₁ -C₄ 烷基、(胺基)烷基及R^a3 ； R^a2 為-N(R¹⁵ )CH₂ CH=CH-R^a3 或-CH=CHCH₂ R^a4 ； R^a3 選自由以下組成之群：烷氧基羰基、烷基磺醯基、環烷基磺醯基及甲醯胺基； R^a4 為視情況經取代之雜環基； R^a5 選自由氰基及(胺基)烷基組成之群； R^a6 為氫或甲醯胺基； R¹⁵ 為氫或C₁ -C₄ 烷基；且 各W獨立地選自由-CH-或-N-組成之群。In one embodiment, the compound of the present invention is a compound represented by formula I ,

, or a pharmaceutically acceptable salt thereof, wherein: each R ^a is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; each R ^b is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl R ^c is selected from the group consisting of hydrogen and halo; each R ^d is independently selected from the group consisting of halo; p, q, r and s are independently 1 or 2; each n is independently 0, 1 or 2; Q is selected from the group consisting of: -N(H)C(=O)OR, -N(R)C(=O)OR, -N(H)C(=O)R, -N( H)C(O)NHR, -N(H)C(O)NR ₂ , -OC(=O)NR ₂ ,

; V is selected from the group consisting of: _-CH2OH , _-CH2OMe , _-CH2OEt , _-CH2NH2 , _-CH2NHMe , _-CH2NMe2 , cyano, _{- (} C=O) H, -CO ₂ Me, -CO ₂ Et, -CH ₂ NR ¹ CO ₂ Me, -CH ₂ NR ¹ CO ₂ CD ₃ , -CH ₂ NR ¹ CO ₂ Et, -CH ₂ NR ¹ CO ₂ iPr, - CH ₂ NR ¹ CONH ₂ , -CO ₂ H, -CONH ₂ , -CONHMe, -CONMe ₂ , -CONHEt, -CONEt ₂ , -CON(Me)(Et), -CON(CD ₃ ) ₂ , -CON( Me)( _CD3 ), -CON(Et)( _CD3 ), -CON ₍ i-Pr)( _{CD3 )} , _{-CH2NHCONHCH2CF3} , _{-CH2NHCONHiPr} , _-CH2NHCONHMe , _-CH2 NHCONHEt,

; each R ^{f is} independently selected from the group consisting of: hydrogen, C ₁ -C ₄ alkyl, hydroxy, C ₁ -C ₄ alkoxy, and halo; each R ^g is independently selected from the group consisting of: hydrogen , C ₁ -C ₄ alkyl and NH ₂ ; each R is independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or CD ₃ ; each R ¹ is independently hydrogen or C ₁ -C ₄ alkyl; each R2 is independently _C1 ^- _C4 alkyl or C3 _{- C6} cycloalkyl; each k is independently 0, 1, 2, 3 or 4; T is selected from the group consisting of:- C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylsulfonyl, cycloalkylsulfonyl, -C ₁ -C ₄ alkylcarbonyl, arylcarbonyl,

wherein R ⁴ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylcarbonyl, heterocyclyl and haloalkyl; each m is independently 1 or 2; J is hydrogen, cyano, alkylsulfonyl Sulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocycloalkylsulfonyl and carboxamido; v is 0 or 1; R ⁶ is hydrogen, haloalkyl, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate, or tertiary butoxycarbonyl; each R ⁷ is independently selected from the group consisting of hydrogen, cyano, halo, haloalkyl, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkylcarbonyl, hydroxy, sulfonamido, alkyl sulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclicsulfonyl, heterocycloalkylsulfonyl, or carboxamido; R ^8a , R ^8b , R ^8c and R ^8d are independently selected from the group consisting of hydrogen, halo, carboxyl, hydroxyl, -C ₁ -C ₄ alkoxycarbonyl, -C ₁ -C ₄ alkyl, - C ₁ -C ₄ alkoxy, haloalkyl, haloalkoxy, -CH ₂ SO ₂ C ₁ -C ₄ alkyl, sulfonamido and R ^a1 ; Z is hydrogen, C ₁ -C ₄ alkane group, -C ₁ -C ₄ alkylcarbonyl, hydroxyl, cyano, haloalkyl, -NO ₂ , halo, -NR ¹ SO ₂ (C ₁ -C ₄ alkyl), -NR ¹ SO ₂ (C ₂ -C ₆ alkenyl), -NR ¹ CO(C ₁ -C ₄ alkyl), -CONH ₂ , -CONH(C ₁ -C ₄ alkyl), -CON(C ₁ -C ₄ alkyl) ₂ , -S(=O)(=NR ¹ )CF ₃ , S(=O)(=NR ¹ )(C ₁ -C ₄ alkyl), amino, sulfonamido, alkylsulfonamido, halogen Alkylsulfonyl group and cycloalkylsulfonyl group; R ^a1 is cyano group, alkoxyalkyl group, aralkoxy group, alkylsulfonyl group, (amino)alkyl group, carboxamido group, thionyl group Amines, optionally substituted heteroaryl, (heteroaryl)alkyl, -NR13C(O) _{C1 -} C4alkyl, ^-OCH2CH = _CH -alkylsulfonyl, -O( C ₁ -C ₄ alkyl)O(C ₁ -C ₄ alkyl), -C ₂ -C ₆ alkenyl, heterocyclyloxy, aminocarbonyloxy and (heterocyclyl)alkyl; X is selected from The group consisting of: -C ₁ -C ₄ alkyl, -C ₂ -C ₄ alkenyl, -NH ₂ , -NHC ₁ -C ₄ alkyl, -N(C ₁ -C ₄ alkyl) ₂ , ( amino) alkyl and -CH ₂ CH ₂ NR ¹ YZ ² ;

, where t and u are independently 0, 1, 2, or 3; Y is absent or is -C(=O)-, -SO ₂ -, -C(=O)NH-, -C(=O) N(Me)-; Z ² is selected from the group consisting of -C(R ^14a )=C(R ^14b )(R ^14c ), -C≡CR ^14d , alkyl, alkoxy, haloalkyl and R ^a2 R ^9a and R ^9b are each independently selected from the group consisting of alkenyl, alkynyl, cyano, -C ₁ -C ₄ alkyl, halo, (amino)alkyl and -C(R ^14a ) =C(R ^14b )(R ^14c ); each Q ¹ is independently selected from the group consisting of -CH ₂ - and -C(=O)- R ¹⁰ is selected from the group consisting of: hydrogen, -C ₁ -C ₄ Alkyl, -NR ¹³ CO (C ₁ -C ₄ alkyl), -NR ¹³ SO ₂ (C ₁ -C ₄ alkyl), cyano, halo, -OCH ₂ CH=CH-R ^a3 , -CH ₂ CH ₂ CH=CH-R ^a3 ; R ¹¹ is halogen, -NR ¹³ COC(R ^14a )=C(R ^14b )(R ^14c ), formamide, -C(O)NR ¹³ CH ₂ R ^a5 , -C(O)NR ¹³ CH ₂ CH=CH-R ^a3 , -C(O)NR ¹³ CH ₂ C≡CR ^a6 or -CH ₂ CH ₂ CH=CH-R ^a3 ; R ¹² is selected from the following compositions The group: alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl and carboxamido; R ¹³ is hydrogen or C ₁ -C ₄ alkyl; R ^14a , R ^14b , R ^14c and R ^14d are each independently selected from the group consisting of hydrogen, halo, C ₁ -C ₄ alkyl, (amino)alkyl and R ^a3 ; R ^a2 is -N(R ¹⁵ )CH ₂ CH=CH- R ^a3 or -CH=CHCH ₂ R ^a4 ; R ^a3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl and carboxamido; R ^a4 is optionally substituted R ^a5 is selected from the group consisting of cyano and (amino) alkyl; R ^a6 is hydrogen or carboxamido; R ¹⁵ is hydrogen or C ₁ -C ₄ alkyl; and each W is independently Selected from the group consisting of -CH- or -N-.

In another embodiment, the compounds of the present invention are compounds represented by Formula I , and pharmaceutically acceptable salts thereof, wherein each of R ^a and R ^b is hydrogen.

In another embodiment, the compound of the present invention is a compound represented by formula I and pharmaceutically acceptable salts thereof, wherein p, q, r and s are each 1.

In another embodiment, the compounds of the present invention are compounds represented by Formula I and pharmaceutically acceptable salts thereof, wherein ^Rc is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by formula I and pharmaceutically acceptable salts thereof, wherein Q is _-NHCO2Me .

。In another embodiment, the compound of the present invention is a compound represented by formula I and pharmaceutically acceptable salts thereof, wherein V is _-CH2OMe ;

.

。In another embodiment, the compounds of the present invention are compounds represented by formula I and pharmaceutically acceptable salts thereof, wherein T is

.

其中Q、V、X、T、R^a 、R^b 、R^c 、R^d 、R^8a 、R^8b 、R^8c 、R^8d 、n、p、q、r、s及其餘變數係上文根據式I所定義。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae II-XVI :

Wherein Q, V, X, T, R ^a , R ^b , R ^c , R ^d , R ^8a , R ^8b , R ^8c , R ^8d , n, p, q, r, s and other variables are the above according to the formula as defined by I.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein at least one ^Ra is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein each R ^a is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein at least one R ^b is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein each R ^b is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^Rc is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^Rc is halo.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^Rc is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein each n is independently 0 or 1 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein n is 0.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rd is halo.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein each ^Rd is halo.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rd is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein each ^Rd is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein n is 1.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein n is 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX or XII-XVI , and pharmaceutically acceptable salts thereof, wherein n is 1 and ^Rd is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Q is -N(H)C(=O) OR.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I _- XVI , and pharmaceutically acceptable salts thereof, wherein Q is _-NHCO2CH3 .

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Q is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Q is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Q is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein p, qr, and s are 1.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein p, q and r are 1 and s is 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein p, r, and s are 1 and q is 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein q, r and s are 1 and p is 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein p, q and s are 1 and r is 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein p and q are 1 and r and s are 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formula IX , and pharmaceutically acceptable salts thereof, wherein p and q are 2 and r and s are 1 .

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein V is selected from the group consisting of: _-CH2OH , -CH ₂ OMe, -CH ₂ OEt, -CH ₂ NH ₂ , -CH ₂ NHMe, -CH ₂ NMe ₂ , cyano, -(C=O)H, -CO ₂ Me, -CO ₂ Et, - CH ₂ NR ¹ CO ₂ Me, -CH ₂ NR ¹ CO ₂ CD ₃ , -CH ₂ NR ¹ CO ₂ Et, -CH ₂ NR ¹ CO ₂ iPr, -CH ₂ NR ¹ CON(R ¹ ) ₂ , -CO 2H, _-CONH2 , _-CONHMe , _-CONMe2 , -CONHEt, _-CONEt2 , -CON(Me)(Et), -CON( _CD3 ) ₂ , -CON(Me)( _CD3 ), -CON (Et)(CD ₃ ), -CON(i-Pr)(CD ₃ ), -CH ₂ NHCONHCH ₂ CF ₃ ,

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein V is -CH ₂ NR ¹ CON(R ¹ ) _{2 or -CH2NHCONHCH2CF3 .}

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I _- XVI , and pharmaceutically acceptable salts thereof, wherein V is _-CH2NHCONH2 , _{-CH2NHCONHiPr} , -CH ₂ NHCONHMe or -CH ₂ NHCONHEt.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I _- XVI , and pharmaceutically acceptable salts thereof, wherein V is _-CH2NR1CO2Me , ^- _CH2NR1CO2CD3 ^, _{-CH2NR1CO2Et or} ^{-CH2NR1CO2iPr} _{. _ _} ^_ _{_}

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein V is _-CONH2 , -CONHMe, _-CONMe2 , -CONHEt, -CONEt ₂ , -CON(Me)(Et), -CON(CD ₃ ) ₂ , -CON(Me)(CD ₃ ), -CON(Et)(CD ₃ ), or -CON(i- Pr)(CD ₃ ).

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R ² is C ₁ -C ₄ alkyl and k is 0, 1, or 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein k is 0.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R ² is C ₁ -C ₄ alkyl and k is 1.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R ² is C ₁ -C ₄ alkyl and k is 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R is methyl and ^k is 0, 1 or 2.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R ² is methyl and k is 1 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R2 is methyl and k is ² .

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI and pharmaceutically acceptable salts thereof, wherein V is

.

其中各R^f 獨立地選自由以下組成之群：氫、甲基、乙基、異丙基及羥基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI and pharmaceutically acceptable salts thereof, wherein V is

wherein each ^{Rf is} independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and hydroxy.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rf is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein each ^Rf is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rf is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein each ^Rf is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rf is ethyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein each ^Rf is ethyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein one ^Rf is methyl and the other ^Rf is hydroxyl.

，其中各R^g 獨立地選自由以下組成之群：氫、甲基、乙基、異丙基及-NH₂ 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas II-XVI , and pharmaceutically acceptable salts thereof, wherein V is

, wherein each R ^g is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and _-NH2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rg is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein each ^Rg is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rg is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rg is ethyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rg is isopropyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one ^Rg is _-NH2 .

，其中R^g 選自由以下組成之群：氫、甲基、乙基、異丙基及-NH₂ 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI and pharmaceutically acceptable salts thereof, wherein V is

, wherein R ^g is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and -NH ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^Rg is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^Rg is ethyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^Rg is isopropyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^Rg is _-NH2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is T-1, T-2, T- 3. T-4, T-5, T-14, T-15, T-16, T-17, T-18, T-19, T-20, T-21, T-22, T-24, T-25, T-26, T-29, T-31, T-32 or T-36.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is T-6, T-7, T- 8. T-9, T-10, T-11, T-12, T-30, T-33, T-34 or T-35.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is T-27 or T-28.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is _C1 - _C4 alkyl, _C1 -C ₄ alkylsulfonyl, cycloalkylsulfonyl, -C ₁ -C ₄ alkylcarbonyl, arylcarbonyl or T-5.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is T-1, T-2, T- 3. T-29 or T-32.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is T-14, T-15, T- 16, T-17, T-18, T-19, T-24, T-25, T-26, T-31 or T-36.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is T-1, T-2, or T- 3.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is T-1 or T-2.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least two of them are hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least three of them are hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R ^8a , R ^8b , R ^8c and R ^8d are hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is a halogen group.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least two of them are halo groups.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least three of them are halo groups.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is fluorine.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least two of them are fluorine.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least three of them are fluorine.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is C ₁ -C ₄ alkyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least two of them are C ₁ -C ₄ alkyl groups.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least three of them are C ₁ -C ₄ alkyl groups.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least two of them are methyl groups.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least three of them are methyl groups.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is -CH ₂ NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is -C(O)NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d At least one of them is -C ₁ -C ₄ alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d at least one of

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein in R ^8a , R ^8b , R ^8c and R ^8d at least one of

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X- 3. X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19, X-20, X-21, X-22 or X-23.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-10, X- 16, X-17, X-18, X-19 or X-20.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-2 or X-3.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-5 or X-21.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-5.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-21.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-6.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-11 or X-12.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-13.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-14.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-16.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-18.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-19.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-20.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-22.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-23.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c The one is a halogen group.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c which is fluorine.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c is chlorine.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c which is a C ₁ -C ₄ alkyl group.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c The one is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c which is -CH ₂ NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c which is -C(O)NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c Either -C ₁ -C ₄ alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c for

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c for

.

。In another embodiment, the compounds of the present invention are compounds represented by formula I and pharmaceutically acceptable salts thereof, wherein T is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d The one is a halogen group.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d which is fluorine.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d is chlorine.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d which is a C ₁ -C ₄ alkyl group.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d The one is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d which is -CH ₂ NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d which is -C(O)NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8d Either -C ₁ -C ₄ alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c for

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a , R ^8b and R ^8c for

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is halo base.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is fluoro .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is chloro .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is C ₁ -C ₄ alkyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is methyl base.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^{8b is-} CH ₂ NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^{8b is-} C(O)NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^{8b is-} C ₁ -C ₄ alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is

.

。In another embodiment, the compounds of the present invention are compounds represented by formula I and pharmaceutically acceptable salts thereof, wherein T is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is halo base.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is fluoro .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is chloro .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is C ₁ -C ₄ alkyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is methyl base.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^{8c is-} CH ₂ NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^{8c is-} C(O)NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^{8c is-} C ₁ -C ₄ alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8b and R ^8c is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is cyano, haloalkyl, alkylsulfonate sulfonyl or cycloalkylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is cyano, alkylsulfonyl or cyclic Alkyl Sulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is cyano, _-CF3 , methylsulfonyl sulfonyl or cyclopropylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is cyano.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is _-CF3 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is _-NO2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is chloro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is alkylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is methylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is cycloalkylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Z is cyclopropylsulfonyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein T is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one W is N.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein each W is N.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein at least one W is -CH-.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein each W is -CH-.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein one W is -CH- and one W is -N -.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , wherein t is 1 and u is 1, and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein t is 0 and u is 0.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , wherein t is 0 and u is 1, and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein t is 1 and u is 0.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^R7 is cyano.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^R7 is _C1 - _C4 alkyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^R7 is alkylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein ^R7 is carboxamido.

In another embodiment, the compounds of the present invention are compounds represented by any ^one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R10 is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R ¹⁰ is C ₁ -C ₄ alkyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein R10 is ^-NHCOMe .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I _- XVI , and pharmaceutically acceptable salts thereof, wherein R10 is ^-NHSO2Me .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein Y is -C(=O)-.

， 其中X、R^c 、R^d 、R^g 、R^8a 、R^8b 及其餘變數係在上文根據式I所定義。In some embodiments, the present invention provides compounds selected from any one of formulae XVI-XXI :

, wherein X, R ^c , R ^d , R ^g , R ^8a , R ^8b and the rest of the variables are as defined above according to formula I.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rc is halo.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rc is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rc is halo and ^Rd is halo.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rc is fluoro and ^Rd is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rd is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rg is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rg is methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rg is ethyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein ^Rg is isopropyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein R ^8a and R ^8b are hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is halo base.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas XVI-XXI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is fluoro .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein R ^8a and R ^8b are fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas XVI-XXI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is C ₁ -C ₄ alkyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is methyl base.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas XVI-XXI , and pharmaceutically acceptable salts thereof, wherein R ^8a and R ^8b are methyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^{8b is-} CH ₂ NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^{8b is-} C(O)NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^{8b is-} C ₁ -C ₄ alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein at least one of R ^8a and R ^8b is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein X is _-CH3 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein X is _-NH2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X- 3. X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19, X-20, X-21, X-22 or X-23.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-10, X- 16, X-17, X-18, X-19 or X-20.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-2 or X-3.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-5 or X-21.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-5.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-21.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-6.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas XVI-XXI , and pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XVI-XXI , and pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-13.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-16.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-18.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-19.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-20.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae I-XVI , and pharmaceutically acceptable salts thereof, wherein X is X-22.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulas XVI-XXI , and pharmaceutically acceptable salts thereof, wherein Y is -C(=O)-.

， 其中V、X、R^8b 及其餘變數係在上文根據式I所定義。In some embodiments, the present invention provides compounds selected from any one of formulae XXII-XXVII :

, where V, X, R ^8b and the remaining variables are as defined above according to formula I.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII and pharmaceutically acceptable salts thereof.

，其中R^g 選自由以下組成之群：氫、甲基、乙基、異丙基及-NH₂ 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and -NH ₂ .

，其中R^g 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is hydrogen.

，其中R^g 為甲基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is methyl.

，其中R^g 為乙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is ethyl.

，其中R^g 為異丙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is isopropyl.

In another embodiment, the compounds of the present invention are compounds represented by formula XXII-XXVII and pharmaceutically acceptable salts thereof, wherein X is _-CH3 , _-NH2 , X-1, X-2, X- 3. X-5, X-16 or X-18.

In another embodiment, the compounds of the present invention are compounds represented by formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein X is _-CH3 .

In another embodiment, the compounds of the present invention are compounds represented by formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein X is _-NH2 .

In another embodiment, the compounds of the present invention are compounds represented by formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, the compounds of the present invention are compounds represented by formulas XXII-XXVII and pharmaceutically acceptable salts thereof, wherein X is X-2 or X-3.

In another embodiment, the compounds of the present invention are compounds represented by formulas XXII-XXVII and pharmaceutically acceptable salts thereof, wherein X is X-5.

In another embodiment, the compounds of the present invention are compounds represented by formulas XXII-XXVII and pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, the compounds of the present invention are compounds represented by formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, the compounds of the present invention are compounds represented by formulas XXII-XXVII and pharmaceutically acceptable salts thereof, wherein X is X-16.

In another embodiment, the compounds of the present invention are compounds represented by formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein X is X-18.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein Y is -C(=O)-.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein R ^8b is hydrogen, -CH ₂ NMe ₂ , - C(O)NMe ₂ , -C ₁ -C ₄ alkoxy, -CH ₂ OC ₁ -C ₄ alkyl,

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein ^R8b is hydrogen.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII _, and pharmaceutically acceptable salts thereof, wherein ^R8b is _-CH2NMe2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein ^R8b is -C(O) _NMe2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein ^R8b is _-C1 - _C4alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein R ^8b is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXII-XXVII , and pharmaceutically acceptable salts thereof, wherein R ^8b is

.

， 其中V、R^8b 、Z及其餘變數係在上文根據式I所定義。In some embodiments, the present invention provides compounds selected from any one of formulae XXVIII-XXXIII :

, where V, R ^8b , Z and the remaining variables are as defined above according to formula I.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII and pharmaceutically acceptable salts thereof.

，其中R^g 選自由以下組成之群：氫、甲基、乙基、異丙基及-NH₂ 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein V is

, wherein R ^g is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and -NH ₂ .

，其中R^g 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is hydrogen.

，其中R^g 為甲基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is methyl.

，其中R^g 為乙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is ethyl.

，其中R^g 為異丙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is isopropyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein Z is cyano, haloalkyl, alkylsulfonyl sulfonyl or cycloalkylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein Z is cyano, alkylsulfonyl or cyclic Alkyl Sulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein Z is cyano, _-CF3 , methylsulfonyl sulfonyl or cyclopropylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by formula XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein Z is cyano.

In another embodiment, the compounds of the present invention are compounds represented by formula XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein Z is methylsulfonyl.

In another embodiment, the compound of the present invention is a compound represented by formula XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein Z is _-CH3 .

In another embodiment, the compound of the present invention is a compound represented by formula XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein Z is cyclopropylsulfonyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein R ^8b is hydrogen, -CH ₂ NMe ₂ , - C(O)NMe ₂ , -C ₁ -C ₄ alkoxy, -CH ₂ OC ₁ -C ₄ alkyl,

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein ^R8b is hydrogen.

In another embodiment, the compound of the present invention is a compound represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂ NMe ₂ .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein ^R8b is -C(O) _NMe2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein ^R8b is _-C1 - _C4alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein R ^8b is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein R ^8b is

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXVIII-XXXIII , and pharmaceutically acceptable salts thereof, wherein ^R8b is (heterocyclyl)alkyl.

， 其中V、X、R^8b 及其餘變數係在上文根據式I所定義。In some embodiments, the present invention provides compounds selected from any one of formulae XXXIV-XXXIX :

, where V, X, R ^8b and the remaining variables are as defined above according to formula I.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of Formulae XXXIV-XXXIX and pharmaceutically acceptable salts thereof.

，其中R^g 選自由以下組成之群：氫、甲基、乙基、異丙基及-NH₂ 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein V is

, wherein R ^g is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and -NH ₂ .

，其中R^g 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is hydrogen.

，其中R^g 為甲基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is methyl.

，其中R^g 為乙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is ethyl.

，其中R^g 為異丙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is isopropyl.

In another embodiment, the compounds of the present invention are compounds of formula XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is _-CH3 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-2, X- 3. X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19, X-20, X-21, X-22 or X-23.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-1, X-10, X- 16, X-17, X-18, X-19 or X-20.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-1.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-2 or X-3.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX, and pharmaceutically acceptable salts thereof, wherein X is X-5 or X-21.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-5.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-21.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-6.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-11 or X-12.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-11.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-12.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-13.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-14.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-16.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-18.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-19.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-20.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-22.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein X is X-23.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein Y is -C(=O)-.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂ NMe ₂ , -C( O) NMe ₂ , -C ₁ -C ₄ alkoxy, -CH ₂ OC ₁ -C ₄ alkyl,

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX _, and pharmaceutically acceptable salts thereof, wherein ^R8b is _-CH2NMe2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein ^R8b is -C(O) _NMe2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein ^R8b is _-C1 - _C4alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein ^R8b is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XXXIV-XXXIX , and pharmaceutically acceptable salts thereof, wherein ^R8b is

.

， 其中V、R^8b 、Z及其餘變數係在上文根據式I所定義。In some embodiments, the present invention provides compounds selected from any one of formulae XL-XLV :

, where V, R ^8b , Z and the remaining variables are as defined above according to formula I.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV and pharmaceutically acceptable salts thereof.

，其中R^g 選自由以下組成之群：氫、甲基、乙基、異丙基及-NH₂ 。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein V is

, wherein R ^g is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and -NH ₂ .

，其中R^g 為氫。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is hydrogen.

，其中R^g 為甲基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is methyl.

，其中R^g 為乙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is ethyl.

，其中R^g 為異丙基。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein V is

, where R ^g is isopropyl.

In another embodiment, the compounds of the present invention are compounds represented by formula XL-XLV and pharmaceutically acceptable salts thereof, wherein Z is cyano, haloalkyl, alkylsulfonyl or cycloalkylsulfonyl base

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein Z is cyano, alkylsulfonyl or cyclic Alkyl Sulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein Z is cyano, _-CF3 , methylsulfonyl sulfonyl or cyclopropylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by formula XL-XLV , and pharmaceutically acceptable salts thereof, wherein Z is cyano.

In another embodiment, the compounds of the present invention are compounds represented by formula XL-XLV and pharmaceutically acceptable salts thereof, wherein Z is _-CH3 .

In another embodiment, the compounds of the present invention are compounds represented by formula XL-XLV and pharmaceutically acceptable salts thereof, wherein Z is methylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein Z is cyclopropylsulfonyl.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein Z is fluoro.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein Z is chloro.

。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula XL-XLV , and pharmaceutically acceptable salts thereof, wherein R ^8b is -CH ₂ NMe ₂ , -C( O) NMe ₂ , -C ₁ -C ₄ alkoxy, -CH ₂ OC ₁ -C ₄ alkyl,

.

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV _, and pharmaceutically acceptable salts thereof, wherein ^R8b is _-CH2NMe2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein ^R8b is -C(O) _NMe2 .

In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein ^R8b is _-C1 - _C4alkoxy or -CH ₂ OC ₁ -C ₄ alkyl.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein ^R8b is

.

。In another embodiment, the compounds of the present invention are compounds represented by any one or more of formulae XL-XLV , and pharmaceutically acceptable salts thereof, wherein ^R8b is

.

((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 679.30 2

((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 600.61 3

((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(2-(3-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 600.13 4

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 709.58 5

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 780.59 6

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 701.62 7

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 705.62 8

((1S,2R)-2-((1S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 693.17 9

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 750 10

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 724.4 11

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 671.4 12

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-乙基氮雜環丁烷-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 707.14 13

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)-1-(1-(2-(3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 772.07 14

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 744.08 15

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)-1-(1-(2-(4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 684.29 16

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)-1-(1-(2-(4-(N-甲基胺磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 698.31 17

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 685.35 18

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 693.34 19

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 713.38 20

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 614.50 21

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-羥基-3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 630.51 22

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-羥基乙基)環戊基)胺基甲酸甲酯 561.21 23

((1S,2R)-2-(1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-羥基乙基)環戊基)胺基甲酸甲酯 640.25 24

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-甲氧基乙基)環戊基)胺基甲酸甲酯 575.20 25

((1S,2R)-2-(1-(1-(2-(4-((1-丙烯醯基氮雜環丁烷-3-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-甲氧基乙基)環戊基)胺基甲酸甲酯 723.18 26

((1S,2R)-2-(1-(1-(2-(4-((1-(丁-2-炔醯基)氮雜環丁烷-3-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-甲氧基乙基)環戊基)胺基甲酸甲酯 735.25 27

2-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 589.20 28

2-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 668.30 29

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-乙氧基-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 589.28 30

2-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 646.23 31

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-脲基乙基)環戊基)胺基甲酸甲酯 713.3 32

((1S ,2R )-2-((S )-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-異丙基脲基)乙基)環戊基)胺基甲酸甲酯 724.45 33

((1S ,2R )-2-((S )-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-(2,2,2-三氟乙基)脲基)乙基)環戊基)胺基甲酸甲酯 764.50 34

((1S,2R)-2-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-(1-(2-(4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 672.70 35

((1S,2R)-2-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-(1-(2-(4-(N-甲基胺磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 686.57 36

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 618.91 37

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 689.93 38

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 662.70 39

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 676.84 40

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 728.3 41

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((異丙氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 646.54 42

((1S,2R)-2-((S)-1-(1-(2-(6-氰基-1-甲基-2-側氧基-1,2-二氫吡啶-3-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((異丙氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 677.58 43

((1S,2R)-2-(2-胺基-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 653.22 44

((1S,2R)-2-(1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(甲基胺基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 667.26 45

((1S,2R)-2-(1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 681.19 46

((1S,2R)-2-((S)-2-(雙(甲基-d3)胺基)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 687.32 47

((1S,2R)-2-((S)-2-(雙(甲基-d3)胺基)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 679.35 48

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 673.29 49

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 701.29 50

((1S,2R)-2-(1-(1-(2-(4-(((1S,4S)-5-丙烯醯基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 791.24 51

((1S,2R)-2-(2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基-1-(1-(2-(4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 656.18 52

((1S,2R)-2-(2-(二甲基胺基)-1-(3-氟苯基)-1-(1-(2-(4-(N-甲基胺磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 670.22 53

((1S,2R)-2-(2-(二甲基胺基)-1-(3-氟苯基)-1-(1-(2-(4-硝基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 622.17 54

((1S,2R)-2-(2-(二甲基胺基)-1-(3-氟苯基)-1-(1-(2-(4-(甲基磺醯胺基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 670.31 55

((1S,2R)-2-(2-(二甲基胺基)-1-(3-氟苯基)-1-(1-(2-((3-(甲基磺醯胺基)雙環[1.1.1]戊烷-1-基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 647.26 56

((1S,2R)-2-(1-(1-(2-(3-乙醯胺基雙環[1.1.1]戊烷-1-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 624.28 57

((1S,2R)-2-(1-(1-(2-(4-乙醯胺基雙環[2.2.2]辛烷-1-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 666.39 58

((1S,2R)-2-(2-(雙(甲基-d3)胺基)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 608.17 59

((1S,2R)-2-(2-(二甲基胺基)-1-(3-氟苯基)-1-(1-(2-(3-(甲基磺醯胺基)雙環[1.1.1]戊烷-1-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 660.22 60

((1S,2R)-2-(2-(二甲基胺基)-1-(3-氟苯基)-1-(1-(2-(4-(甲基磺醯胺基)雙環[2.2.2]辛烷-1-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 702.33 61

((1S,2R)-2-(2-(雙(甲基-d3)胺基)-1-(3-氟苯基)-1-(1-(2-(4-硝基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 628.19 62

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(乙基(甲基)胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 616.14 63

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(異丙基(甲基-d3)胺基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 633.30 64

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基-2-(吡咯啶-1-基)乙基)環戊基)胺基甲酸甲酯 707.12 65

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基-2-(吡咯啶-1-基)乙基)環戊基)胺基甲酸甲酯 699.25 66

(S)-2-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 660.14 67

(S)-2-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 688.32 68

(S)-2-(1-(2-(3-(二甲基胺甲醯基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 703.17 69

(S)-2-(3-氟苯基)-2-(1-(2-(3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 731.20 70

(S)-2-(1-(2-(4-((1-(丁-2-炔醯基)哌啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 777.11 71

(S)-2-(1-(2-(4-((4-(丁-2-炔醯基)哌𠯤-1-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 778.23 72

((1S ,2R )-2-((S )-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(4H -1,2,4-三唑-4-基)乙基)環戊基)胺基甲酸甲酯 691.55 73

((1S ,2R )-2-((S )-1-(1-(2-(4-(環丙基磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(4H -1,2,4-三唑-4-基)乙基)環戊基)胺基甲酸甲酯 709.38 74

((1S ,2R )-2-((S )-1-(1-(2-(4-(環丙基磺醯基)-3-((3-氟氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(4H -1,2,4-三唑-4-基)乙基)環戊基)胺基甲酸甲酯 778.44 75

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 718.56 76

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 639.61 77

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 710.03 78

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 696.43 79

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-氟-3-((3-氟氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 743.85 80

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 714.64 81

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-氟氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 725.36 82

((1S,2R)-2-((S)-1-(1-(2-(3-((1H-咪唑-1-基)甲基)-4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 719.93 83

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 737.63 84

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-氟-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 756.76 85

((1S,2R)-2-((S)-1-(1-(2-(3-胺甲醯基-4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 683.88 86

((1S,2R)-2-((S)-1-(1-(2-(4-(氮雜環丁烷-1-基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 733.60 87

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 704.58 88

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 625.33 89

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 696.74 90

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 686.78 91

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-氟-3-((3-氟氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 730.43 92

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 700.34 93

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-氟-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 742.51 94

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 724.63 95

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 803.59 96

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 775.56 97

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 739.14 98

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 766.90 99

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((1,1-二氧離子基硫代嗎啉基)甲基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 790.07 100

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-氟-3-(嗎啉基甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 742.19 101

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 682.41 102

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-((二甲基胺基)甲基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 700.68 103

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3,5-二氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 714.48 104

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3,5-二氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 742.83 105

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(嗎啉-4-羰基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 738.26 106

((1S,2R)-2-((S)-1-(1-(2-(3-(氮雜環丁烷-1-羰基)-4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 708.27 107

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(吡咯啶-1-羰基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 722.37 108

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(3-羥基-3-甲基氮雜環丁烷-1-羰基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 738.22 109

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(3-羥基-3-甲基氮雜環丁烷-1-羰基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 738.75 110

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(3-氟氮雜環丁烷-1-羰基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 726.24 111

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(4-羥基-4-甲基哌啶-1-羰基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 766.26 112

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 679.68 113

((1S,2R)-2-((S)-1-(1-(2-(4-(N,N-二甲基胺磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 707.82 114

((1S,2R)-2-((S)-1-(3,5-二氟苯基)-1-(1-(2-(3-(二甲基胺甲醯基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 757.57 115

((1S,2R)-2-((S)-1-(3,5-二氟苯基)-1-(1-(2-(3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 785.58 116

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 761.83 117

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3,5-二氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 779.55 118

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 801.14 119

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 689.18 120

((1S,2R)-2-((S)-1-(1-(2-(4-氯-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 705.24 121

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(4-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 704.26 122

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(4-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 696.32 123

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(4-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 724.23 124

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-丙烯醯基氮雜環丁烷-3-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 787.08 125

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    126

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 668.07 127

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 744.21 128

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 675.43 129

((1S,2R)-2-((S)-1-(1-(2-(4-氟-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 717.35 130

((1S,2R)-2-((S)-1-(1-(2-(4-((((R)-1-(丁-2-炔醯基)氮雜環丁烷-2-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 798.99 131

((1S,2R)-2-((S)-1-(1-(2-(4-((((R)-1-丙烯醯基氮雜環丁烷-2-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 787.02 132

((1S,2R)-2-((S)-1-(1-(2-(4-((((S)-1-(丁-2-炔醯基)氮雜環丁烷-2-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 798.96 133

((1S,2R)-2-((S)-1-(1-(2-(4-((((S)-1-丙烯醯基氮雜環丁烷-2-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 787.05 134

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 749.31 135

((1S,2R)-2-(1-(1-(2-(4-(((1S,4S)-5-丙烯醯基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 814.32 136

((1S,2R)-2-(1-(1-(2-乙醯基-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 566.19 137

((1S,2R)-2-(1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(甲基磺醯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 602.22 138

((1S,2R)-2-(1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-甲基-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 538.10 139

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(4-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    140

((1S,2R)-2-((S)-1-(1-(2-(4-氯苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    141

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(苯基磺醯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 664.14 142

((1S,2R)-2-((S)-1-(1-(2-苯甲醯基-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 628.29 143

((1S,2R)-2-((S)-1-(1-(2-(1,1-二氧離子基四氫-2H-硫哌喃-4-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 684.75 144

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(1-(甲基磺醯基)氮雜環丁烷-3-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 685.83 145

((1S,2R)-2-(1-(1-(2-(3-氟環丁烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 624.33 146

((1S,2R)-2-(1-(1-(2-(3,3-二氟環丁烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 642.25 147

((1S,2R)-2-(1-(1-(2-(3-氰基雙環[1.1.1]戊烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 643.12 148

((1S,2R)-2-(1-(1-(2-(3-氟雙環[1.1.1]戊烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 636.27 149

((1S,2R)-2-((1S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(1-甲基-2-側氧基哌啶-4-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 663.25 150

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(3-羥基-3-甲基環丁烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 636.30 151

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-(N-甲基胺磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 693.42 152

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(1-(甲基磺醯基)哌啶-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 685.67 153

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-(甲基磺醯基)環己基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 684.47 154

((1S,2R)-2-(1-(1-(2-((R)-1-乙醯基哌啶-3-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 677.33 155

((1S,2R)-2-(1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((R)-1-(甲基磺醯基)哌啶-3-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 713.28 156

((1S,2R)-2-(1-(1-(2-((S)-1-乙醯基哌啶-3-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 677.30 157

((1S,2R)-2-(1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((S)-1-(甲基磺醯基)哌啶-3-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 713.25 158

((1S,2R)-2-(1-(1-(2-(環丁基磺醯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 583.22 159

((1S,2R)-2-(1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((1s,4S)-4-(三氟甲基)環己烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 702.33 160

((1S,2R)-2-(1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((1r,4R)-4-(三氟甲基)環己烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 702.14 161

((1S,2R)-2-(1-(1-(2-(雙環[1.1.1]戊烷-1-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 618.25 162

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((1-(甲基磺醯基)哌啶-4-基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 698.52 163

((1S,2R)-2-((S)-1-(1-(2-(2-氟-4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 697.85 164

3-((6-(4-((S)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(2-甲基-1H-咪唑-1-基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)甲基)氮雜環丁烷-1-甲酸三級丁酯 693.35 165

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(4-羥基-4-甲基環己基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 636.41 166

((1S,2R)-2-((S)-1-(1-(2-(1-乙醯基氮雜環丁烷-3-羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 649.13 167

((1S,2R)-2-((S)-1-(1-(2-(環己烷基羰基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 634.38 168

(2S,4R)-2-(6-(4-((S)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(2-甲基-1H-咪唑-1-基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-羰基)-4-羥基吡咯啶-1-甲酸三級丁酯 737.36 169

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-(1-(甲基磺醯基)哌啶-4-基)乙醯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 727.22 170

((1S,2R)-2-((S)-1-(1-(2-((1-乙醯基氮雜環丁烷-3-基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 634.40 171

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((1-(甲基磺醯基)氮雜環丁烷-3-基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 671.25 172

((1S,2R)-2-((S)-1-(1-(2-((4-氰基苯基)磺醯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 689.16 173

3-((6-(4-((S)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(2-甲基-1H-咪唑-1-基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)甲基)吡咯啶-1-甲酸三級丁酯 707.33 174

((1S,2R)-2-((1S)-1-(1-(2-((1-乙醯基吡咯啶-3-基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 649.23 175

((1S,2R)-2-((S)-1-(1-(2-((1,1-二氧離子基四氫-2H-硫哌喃-4-基)磺醯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 720.17 176

((1S,2R)-2-(1-(1-(2-((3-氰基雙環[1.1.1]戊烷-1-基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 629.14 177

((1S,2R)-2-(1-(1-(2-((3-氟雙環[1.1.1]戊烷-1-基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 622.35 178

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 602.21 179

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-胺磺醯基環己基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 685.81 180

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 639.36 181

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 669.23 182

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 683.07 183

((1S,2R)-2-((S)-1-(1-(2-(3-乙醯胺基-4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 682.19 184

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 639.43 185

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-甲氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 655.33 186

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 735 187

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(((E)-3-(甲基磺醯基)烯丙基)氧基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 759 188

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-2-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 803 189

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-2-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 775 190

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-2-((3-氟氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 791 191

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-2-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 761 192

((1S,2R)-2-((S)-1-(1-(2-(5-(二甲基胺甲醯基)㗁唑-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 662 193

((1S,2R)-2-((S)-1-(1-(2-(5-(二甲基胺甲醯基)噻唑-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 678 194

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-((2-(N-甲基丙烯醯胺基)乙基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 775 195

((1S,2R)-2-((S)-1-(1-(2-(5-氰基-4-(二甲基胺甲醯基)嘧啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 698 196

1-((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)-3-甲基脲 734 197

((1S,2R)-2-((S)-1-(1-(2-(5-氰基-4-(二甲基胺甲醯基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 697 198

((1S,2R)-2-((S)-1-(1-(2-(4-((2-丙烯醯胺基乙基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 761 199

N-((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)丙醯胺 733 200

N-((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)乙醯胺 719 201

1-((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)-3-甲基咪唑啶-2-酮 760 202

1-((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)-1,3-二氫-2H-咪唑-2-酮 744 203

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(3-((N-甲基丙烯醯胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 775 204

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(((1r,4S)-4-(甲基磺醯胺基)環己基)甲基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 713 205

1-((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)-3-甲基-1,3-二氫-2H-咪唑-2-酮 758 206

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((R)-1-(甲基磺醯基)吡咯啶-3-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 671 207

((1S,2R)-2-((S)-1-(1-(2-(4-(二甲基胺甲醯基)-5-(甲基磺醯基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 750 208

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((S)-1-(甲基磺醯基)吡咯啶-3-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 671 209

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-2,6-二甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 732 210

((1S,2R)-2-((S)-1-(1-(2-(2,6-二甲基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 706 211

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2,6-二甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 653 212

((1S,2R)-2-((S)-1-(1-(2-(2-氟-4-((3-乙烯基吡啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 771 213

((1S,2R)-2-((S)-1-(1-(2-(2-氟-4-((5-乙烯基吡啶-2-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 771 214

((1S,2R)-2-((S)-1-(1-(2-(2-氟-4-((2-乙烯基吡啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 771 215

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-4-丙烯醯基-2-甲基哌𠯤-1-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 820 216

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-4-丙烯醯基-2-甲基哌𠯤-1-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 820 217

 ((1S ,2R )-2-((S )-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H -咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 611.50 218

((1S ,2R )-2-((S )-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(4H -1,2,4-三唑-4-基)乙基)環戊基)胺基甲酸甲酯 612.49 219

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3,5-二氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 629.54 220

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3,5-二氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 708.93 221

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 690.55 222

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 708.53 223

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(2-(4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 730.59 224

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-丙烯醯基吡咯啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 791.56 225

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-(丁-2-炔醯基)吡咯啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 803.55 226

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-丙烯醯基哌啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 805.60 227

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-丙烯醯基氮雜環庚烷-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 819.61 228

((1S,2R)-2-((S)-1-(1-(2-(7-氰基-1H-吲唑-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 651.57 229

((1S,2R)-2-((S)-1-(1-(2-(5-氰基異喹啉-8-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 662.53 230

((1S,2R)-2-((S)-1-(1-(2-(7-(環丙基磺醯基)-1,3-二側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 759.42 231

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-丙烯醯基吡咯啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 791.49 232

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-(丁-2-炔醯基)吡咯啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 803.68 233

((1S ,2R )-2-((S )-1-(1-(2-(4-(環丙基磺醯基)-3-((3-氟氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H -咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 777.60 234

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 751.45 235

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 749.66 236

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 682.35 237

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    238

((1S,2R)-2-((S)-1-(1-(2-(3-((1H-咪唑-1-基)甲基)-4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    239

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 710.26 240

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-氟-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 728.57 241

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-丙烯醯基哌啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 805.72 242

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-(丁-2-炔醯基)哌啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 818.67 243

((1S,2R)-2-((1S)-1-(1-(2-(4-(((S)-1-丙烯醯基吡咯啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(7-側氧基-6,7-二氫-5H-咪唑并[2,1-b][1,3]㗁 𠯤-1(8aH)-基)乙基)環戊基)胺基甲酸甲酯 863.74 244

((1S,2R)-2-((1S)-1-(1-(2-(4-(((S)-1-丙烯醯基哌啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(7-側氧基-6,7-二氫-5H-咪唑并[2,1-b][1,3]㗁 𠯤-1(8aH)-基)乙基)環戊基)胺基甲酸甲酯 877.91 245

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 747.52 246

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-(丁-2-炔醯基)哌啶-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 817.66 247

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-(丁-2-炔醯基)氮雜環庚烷-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 831.60 248

((1S,2R)-2-((S)-1-(1-(2-(4-((1-丙烯醯基氮雜環丁烷-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 777.50 249

((1S,2R)-2-((S)-1-(1-(2-(4-((1-(丁-2-炔醯基)氮雜環丁烷-3-基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 789.51 250

((1S,2R)-2-((S)-1-(1-(2-(3-((1H-咪唑-1-基)甲基)-4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 770.39 251

((1S,2R)-2-((S)-1-(1-(2-(3-((3-氟氮雜環丁烷-1-基)甲基)-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 817.55 252

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,4S)-5-丙烯醯基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 800.32 253

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,4S)-5-(2-氯乙醯基)-2,5-二氮雜雙環[2.2.1]庚烷-2-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 822.15 254

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,4S)-5-(丁-2-炔醯基)-2,5-二氮雜雙環[2.2.1]庚烷-2-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 812.26 255

((1S,2R)-2-((S)-1-(1-(2-(7-(環丙基磺醯基)-1-側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 745.69 256

((1S,2R)-2-((S)-1-(1-(2-(7-(環丙基磺醯基)-2-甲基-1,3-二側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 773.62 257

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3,5-二氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 700.71 258

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3,5-二氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 728.54 259

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-氟-3-(嗎啉基甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    260

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((1,1-二氧離子基硫代嗎啉基)甲基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    261

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 829.57 262

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 763.55 263

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 761.48 264

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-(嗎啉基甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 789.41 265

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,5S)-6-丙烯醯基-3,6-二氮雜雙環[3.2.0]庚烷-3-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 800.09 266

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,5S)-6-(丁-2-炔醯基)-3,6-二氮雜雙環[3.2.0]庚烷-3-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 812.11 267

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,5S)-6-(2-氯乙醯基)-3,6-二氮雜雙環[3.2.0]庚烷-3-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 822.13 268

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 787.41 269

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(2-(4-(乙烯基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 676.51 270

((1S,2R)-2-((S)-1-(1-(2-(4-((2-乙炔基吡啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 751.51 271

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-丙烯醯基氮雜環丁烷-3-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 773.45 272

((1S,2R)-2-((S)-1-(1-(2-(4-((1-丙烯醯基哌啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 787.55 273

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-(丁-2-炔醯基)氮雜環丁烷-3-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 785.09 274

((1S,2R)-2-((S)-1-(1-(2-(4-((1-(丁-2-炔醯基)哌啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 799.51 275

((1S,2R)-2-((1S)-1-(1-(2-(2-氟-4-((2-(N-甲基丙烯醯胺基)環丁基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 805.18 276

((1S,2R)-2-((1S)-1-(1-(2-(2-氟-4-((2-(N-甲基丁-2-炔醯胺基)環丁基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 817.26 277

((1S,2R)-2-((1S)-1-(1-(2-(4-((2-(2-氯-N-甲基乙醯胺基)環丁基)磺醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 827.14 278

((1S,2R)-2-((S)-1-(1-(2-(4-((4-((4-(二甲基胺基)-4-側氧基丁-2-炔-1-基)胺甲醯基)苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 878.36 279

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(2-(4-((4-((氰基甲基)胺甲醯基)苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 808.03 280

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(2-(4-((4-(丙-2-炔-1-基胺甲醯基)苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 807.10 281

((1S,2R)-2-((S)-1-(1-(2-(4-((3-((4-(二甲基胺基)-4-側氧基丁-2-炔-1-基)胺甲醯基)苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 878.29 282

((1S,2R)-2-((S)-1-(1-(2-(4-((3-((氰基甲基)胺甲醯基)苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 808.03 283

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(2-(4-((3-(丙-2-炔-1-基胺甲醯基)苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 807.04 284

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 732.14 285

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 653.17 286

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 724.59 287

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)-1-(1-(2-(4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 696.55 288

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)-1-(1-(2-(4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 706.60 289

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 697.29 290

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 711.33 291

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-甲氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 683.57 292

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(甲氧基甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 697.80 293

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((甲基磺醯基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 745.91 294

((1S,2R)-2-((S)-1-(1-(2-(2-氟-4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 725.39 295

((1S,2R)-2-((S)-1-(1-(2-(3,4-二氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 678.86 296

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(羥基甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 683.57 297

((1S,2R)-2-((S)-1-(1-(2-(6-氰基-1-甲基-2-側氧基-1,2-二氫吡啶-3-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 684.56 298

((1S,2R)-2-((S)-1-(1-(2-(7-氰基-1,3-二氫異苯并呋喃-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 695.35 299

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-吡唑-1-基)乙基)環戊基)胺基甲酸甲酯 721 300

((1S,2R)-2-((S)-2-(2-胺基-1H-咪唑-1-基)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 736 301

((1S,2R)-2-((S)-氰基(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 556.34 302

((1S,2R)-2-((S)-氰基(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 635.50 303

((1S,2R)-2-((S)-氰基(3-氟苯基)(1-(2-(4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)甲基)環戊基)胺基甲酸甲酯 675.53 304

((1S,2R)-2-((S)-氰基(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 627.53 305

((1S,2R)-2-((S)-氰基(1-(2-(4-氰基-3-((3-羥基-3-甲基氮雜環丁烷-1-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 655.53 306

甲基((1S,2R)-2-((S)-氰基(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 666.3 307

((1S,2R)-2-((S)-2-胺基-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 670.2 308

((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(7-(4-氰基苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 629.61 309

((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(7-(4-(環丙基磺醯基)苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 708.28 310

((1S,2R)-2-((S)-1-(1-(7-(4-(環丙基磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 736.44 311

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(7-(4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 758.60 312

((1S,2R)-2-(1-(1-(7-(4-((1-丙烯醯基氮雜環丁烷-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 805.26 313

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-丙烯醯基吡咯啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 819.33 314

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-丙烯醯基吡咯啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 819.83 315

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-(丁-2-炔醯基)吡咯啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 831.95 316

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-丙烯醯基哌啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 833.73 317

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-(丁-2-炔醯基)哌啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 845.61 318

((1S,2R)-2-((1S)-1-(1-(7-(4-(((S)-1-丙烯醯基哌啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(7-側氧基-6,7-二氫-5H-咪唑并[2,1-b][1,3]㗁 𠯤-1(8aH)-基)乙基)環戊基)胺基甲酸甲酯 905.67 319

((1S,2R)-2-((S)-1-(1-(7-(4-(環丙基磺醯基)-3-((3-氟氮雜環丁烷-1-基)甲基)苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 805.55 320

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-丙烯醯基哌啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 833.31 321

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-丙烯醯基氮雜環庚烷-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 847.29 322

((1S,2R)-2-(1-(1-(7-(4-((1-(丁-2-炔醯基)氮雜環丁烷-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 817.18 323

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-(丁-2-炔醯基)吡咯啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 831.22 324

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-(丁-2-炔醯基)哌啶-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 845.31 325

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-(丁-2-炔醯基)氮雜環庚烷-3-基)磺醯基)-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 859.23 326

((1S,2R)-2-(1-(1-(7-(2-氟-4-(((E)-3-(甲基磺醯基)烯丙基)胺甲醯基)苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 793.09 327

2-(1-(7-(4-丙烯醯胺基-2-氟苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸甲酯 679.12 328

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(7-(4-胺磺醯基環己基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 713.64 329

((1S,2R)-2-((S)-1-(1-(6-(4-氰基苯基)-6-氮雜螺[3.4]辛烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 625.50 330

((1S,2R)-2-((S)-1-(1-(6-(4-(環丙基磺醯基)苯基)-6-氮雜螺[3.4]辛烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 704.40 331

((1S,2R)-2-((1S)-2-(氮雜環丁烷-1-基)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.4]辛烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 614.45 332

((1S,2R)-2-((1S)-2-(氮雜環丁烷-1-基)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.4]辛烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 693.64 333

((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(2-(4-(環丙基磺醯基)苯基)-2-氮雜螺[3.5]壬烷-7-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 707.43 334

((1S,2R)-2-((S)-2-(氮雜環丁烷-1-基)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.5]壬烷-7-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 628.25 335

((1S,2R)-2-((S)-1-(1-(3-(4-氰基苯基)-3-氮雜螺[5.5]十一烷-9-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 667.43 336

((1S,2R)-2-((S)-1-(1-(3-(4-(環丙基磺醯基)苯基)-3-氮雜螺[5.5]十一烷-9-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 746.20 337

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基㗁唑啶-3-基)乙基)環戊基)胺基甲酸甲酯 630.84 338

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基吡咯啶-1-基)乙基)環戊基)胺基甲酸甲酯 628.91 339

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-((1r,4S)-4-(甲基磺醯胺基)環己基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯    340

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 656 341

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-丙烯醯基氮雜環丁烷-3-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 815.49 342

((1S,2R)-2-((S)-(1-(2-(4-(((1-丙烯醯基氮雜環丁烷-3-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)(氰基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 718.41 343

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-2,6-二甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 721 344

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 767 345

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 710 346

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2,6-二甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 642 347

((1S,2R)-2-((S)-1-(1-(2-(2,6-二甲基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 695 348

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2,6-二甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 681 349

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 728 350

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(甲氧基甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 662.9 351

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((甲基磺醯基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 710.7 352

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)-1-(1-(2-(4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 772.28 353

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-((乙氧基羰基)胺基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 632.38 354

((1S,2R)-2-(2-胺基-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 574.16 355

((1S,2R)-2-((S)-2-(2,4-二甲基-1H-咪唑-1-基)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 749 356

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 753 357

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基氮雜環丁烷-1-基)乙基)環戊基)胺基甲酸甲酯 714.4 358

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 763 359

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(4-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 639.4 360

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((四氫-2H-哌喃-4-基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    361

((1S,2R)-2-((S)-1-(1-(2-(3-((二甲基胺基)甲基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2,4,5-三甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 763 362

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(3-(甲基磺醯胺基)雙環[1.1.1]戊烷-1-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 683 363

((1S,2R)-2-((S)-2-(4-(三級丁基)-1H-咪唑-1-基)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 667.19 364

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 659.32 365

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 693.34 366

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-(環丙基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 738.3 367

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基㗁唑啶-3-基)乙基)環戊基)胺基甲酸甲酯 674.6 368

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基㗁唑啶-3-基)乙基)環戊基)胺基甲酸甲酯 688.4 369

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基吡咯啶-1-基)乙基)環戊基)胺基甲酸甲酯 672.5 370

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基吡咯啶-1-基)乙基)環戊基)胺基甲酸甲酯 686.7 371

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯       372

((1S,2R)-2-((S)-1-(1-(2-(4-((4-胺甲醯基苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 783 373

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 710 374

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 710 375

((1S,2R)-2-((S)-氰基((2R,6R)-1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)-2,6-二甲基哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 584 376

((1S,2R)-2-((S)-1-(1-(2-(4-((4-胺甲醯基苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 776 377

((1S,2R)-2-((S)-1-(1-(2-(5-氰基-6-(二甲基胺甲醯基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 697 378

((1S,2R)-2-((S)-氰基((2S,4s,6R)-1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)-2,6-二甲基哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 584 379

((1S,2R)-2-((S)-氰基((2R,4r,6S)-1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)-2,6-二甲基哌啶-4-基)(3-氟苯基)甲基)環戊基)胺基甲酸甲酯 584 380

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-脲基乙基)環戊基)胺基甲酸甲酯 688 381

((1S,2R)-2-((S)-1-(1-(2-(6-(二甲基胺甲醯基)-5-(甲基磺醯基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 750 382

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-((二甲基胺基)甲基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 696 383

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-脲基乙基)環戊基)胺基甲酸甲酯 674 384

((1S,2R)-2-((S)-1-(1-(2-(4-((4-胺甲醯基苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-脲基乙基)環戊基)胺基甲酸甲酯 761 385

((1S,2R)-2-((S)-1-(1-(2-(5-氰基-6-((二甲基胺基)甲基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 683 386

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 738 387

((1S,2R)-2-((S)-1-(1-(2-(4-((3-胺甲醯基苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 783 388

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 683 389

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-((二甲基胺基)甲基)-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 754 390

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-(二甲基胺甲醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 714 391

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 714 392

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-((二甲基胺基)甲基)-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 726 393

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 722 394

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 707 395

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基-5-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 683 396

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-(二甲基胺甲醯基)-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 740 397

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基-5-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 687 398

((1S,2R)-2-((S)-1-(1-(2-(3-氯-4-氰基-5-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 703 399

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(4-((3-氟苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 758 400

((1S,2R)-2-((S)-1-(1-(2-(5-氰基-6-乙氧基吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 670 401

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 669 402

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 724 403

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 696 404

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-乙氧基-2-氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 687 405

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 703 406

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 730 407

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 742 408

((1S,2R)-2-((S)-1-(3-氟苯基)-1-(1-(2-(4-((3-氟苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 751 409

((1S,2R)-2-((S)-1-(1-(2-(4-(環丙基磺醯基)-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 748 410

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-(二甲基胺甲醯基)-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-脲基乙基)環戊基)胺基甲酸甲酯 718 411

((1S,2R)-2-((S)-1-(1-(2-(2-氟-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 755 412

((1S,2R)-2-((S)-1-(1-(2-(4-((3-胺甲醯基苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 776 413

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-脲基乙基)環戊基)胺基甲酸甲酯 708 414

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 778 415

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-(吡啶-4-基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 741 416

((1S,2R)-2-((S)-1-(1-(2-(4-((4-胺甲醯基苯基)磺醯基)-3-((二甲基胺基)甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 833 417

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-(二甲基胺甲醯基)-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 733 418

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 703 419

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-((二甲基胺基)甲基)-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 719 420

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 723 421

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 771 422

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-(二甲基胺甲醯基)-2-甲氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 719 423

((1S,2R)-2-((S)-1-(1-(2-(5-氰基-6-((二甲基胺基)甲基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 676 424

((1S,2R)-2-((S)-1-(1-(2-(2-((二甲基胺基)甲基)-3-乙氧基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 779 425

((1S,2R)-2-((S)-1-(1-(2-(2-((二甲基胺基)甲基)-3-乙氧基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 772 426

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 743 427

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 719 428

((1S,2R)-2-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-(1-(2-(4-(吡啶-4-基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 734 429

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-(二甲基胺甲醯基)-2-甲氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 726 430

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 781 431

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 733 432

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 740 433

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 750 434

((1S,2R)-2-((S)-1-(1-(2-(2-氟-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 762.3 435

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-5-甲氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 719 436

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 726 437

((1S,2R)-2-((S)-1-(1-(2-(4-((1H-吡唑-4-基)磺醯基)-2-氯苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 764 438

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1-乙基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 792 439

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 788 440

((1S,2R)-2-((S)-1-(1-(2-(2-(二甲基胺甲醯基)-3-乙氧基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 786 441

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-2-甲基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 736 442

((1S,2R)-2-((S)-1-(1-(2-(2-(二甲基胺甲醯基)-3-乙氧基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 793 443

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1-異丙基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 806 444

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-4-胺磺醯基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 723 445

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-2-甲基-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 729 446

((1S,2R)-2-((S)-1-(1-(2-(2-氯-3-(二甲基胺甲醯基)-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 849 447

((1S,2R)-2-((S)-1-(1-(2-(5-氰基-6-((甲基胺基)甲基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 669 448

((1S,2R)-2-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-(1-(2-(4-((2-甲基吡啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 748.35 449

((1S,2R)-2-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-(1-(2-(4-((3-甲基吡啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 748.35 450

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-2-氟-4-((1-甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 833 451

((1S,2R)-2-((S)-1-(1-(2-(6-((二甲基胺基)甲基)-5-(甲基磺醯基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 729 452

((1S,2R)-2-((S)-1-(1-(2-(6-((二甲基胺基)甲基)-5-(甲基磺醯基)吡啶-2-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 736 453

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-2-甲基-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    454

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-硝基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    455

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-乙基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 724 456

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(二甲基胺基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 673 457

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-(2,2,2-三氟乙基)脲基)乙基)環戊基)胺基甲酸甲酯 685.5 458

((1S,2R)-2-(1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(乙基(甲基)胺基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 687.42 459

甲基-d3 ((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 713 460

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(7-甲基-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 552.6 461

((1S,2R)-2-((S)-1-(1-(7-乙醯基-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 580.8 462   

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(1H-咪唑-1-基)-1-(1-(7-(甲基磺醯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 616.5 463

((1S,2R)-2-((S)-1-(1-(7-(4-氰基苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    464

((1S,2R)-2-((S)-1-(1-(7-(4-氰基-3-乙氧基苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    465

((1S,2R)-2-((S)-1-(1-(7-(4-氰基苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    466

((1S,2R)-2-((S)-1-(1-(7-(4-氰基-3-乙氧基苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    467

((1S,2R)-2-((S)-1-(1-(7-(4-氰基-3-異丙氧基苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    468

((1S,2R)-2-((S)-1-(1-(7-(4-氰基-3-(二甲基胺甲醯基)苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    469

((1S,2R)-2-((S)-1-(1-(7-(4-氰基-2-((二甲基胺基)甲基)苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    470

((1S,2R)-2-((S)-1-(1-(7-(4-氰基-3-乙氧基苯基)-7-氮雜螺[3.5]壬烷-2-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 690.7 471

((1S,2R)-2-((S)-1-(1-(2-(7-氰基-2-甲基-1-側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 687 472

((1S,2R)-2-((S)-1-(1-(2-(7-氰基-2-甲基-1-側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 694 474

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-7-((1-甲基-1H-吡唑-4-基)磺醯基)-1-側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 813 475

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-7-((1-甲基-1H-吡唑-4-基)磺醯基)-1,3-二側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 827 476

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-7-(甲基磺醯基)異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 733 477

((1S,2R)-2-((S)-1-(1-(2-(7-氰基-1-側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 680 478

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-7-((1-甲基-1H-吡唑-4-基)磺醯基)異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 799 479

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-7-(甲基磺醯基)-1-側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 747 480

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-7-(甲基磺醯基)-1,3-二側氧基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 761 481

((1S,2R)-2-((S)-1-(1-(2-(7-氰基-2-異丙基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 708 482

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-側氧基乙基)環戊基)胺基甲酸甲酯 559.35 483

((1S,2R)-2-(1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基-2-側氧基咪唑啶-1-基)乙基)環戊基)胺基甲酸甲酯 643.48 484

((1S,2R)-2-(1-(1-(2-(4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基-2-側氧基咪唑啶-1-基)乙基)環戊基)胺基甲酸甲酯 687.55 485

((1S,2R)-2-(1-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(3-甲基-2-側氧基咪唑啶-1-基)乙基)環戊基)胺基甲酸甲酯 701.57 486

((1S,2R)-2-(1-(1-(2-(4-氰基-3-乙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基咪唑啶-1-基)乙基)環戊基)胺基甲酸甲酯 673.43 487

((1S,2R)-2-(1-(1-(2-(4-氰基-3-異丙氧基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基咪唑啶-1-基)乙基)環戊基)胺基甲酸甲酯 687.45 488

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-羥基-2-(1-甲基-1H-吡唑-3-基)乙基)環戊基)胺基甲酸甲酯 641 489

((1S,2R)-2-((R)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1-甲基-1H-吡唑-3-基)乙基)環戊基)胺基甲酸甲酯 625 490

((1S,2R)-2-((R)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(1H-吡唑-3-基)乙基)環戊基)胺基甲酸甲酯 611 491

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基哌啶-1-基)乙基)環戊基)胺基甲酸甲酯 642.7 492

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-側氧基-1,3-㗁 𠯤-3-基)乙基)環戊基)胺基甲酸甲酯 644.5 493

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(((甲氧基-d3)羰基)胺基)乙基)環戊基)胺基甲酸甲酯 706 494

((S)-2-(1-(2-(4-氰基-3-(二甲基胺甲醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)(甲基)胺基甲酸甲酯 703.6 495

((S)-2-(1-(2-(3-(二甲基胺甲醯基)-4-(甲基磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)(甲基)胺基甲酸甲酯 756.39 496

((1S,2R)-2-((S)-1-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(5,5-二甲基-2-側氧基㗁唑啶-3-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯 658.8 497   

((S)-2-(1-(2-(3-(二甲基胺甲醯基)-4-(三氟甲基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)(甲基)胺基甲酸甲酯 746.7 498

((S)-2-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)(甲基)胺基甲酸甲酯 717 499

((S)-2-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)(甲基)胺基甲酸甲酯 632.7 500

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(2-甲氧基乙氧基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    501

2-氰基-5-(6-(4-((S)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸    502

((1S,2R)-2-(1-(1-(2-(4-氰基-3-(2-甲基丙-1-烯-1-基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 707.62 503

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((四氫-2H-哌喃-4-基)氧基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-異丙基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 753.6 504

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((四氫-2H-哌喃-4-基)氧基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 718.8 505

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2,6-二甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 724 506

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2,6-二甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 717 507

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-2,6-二氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 732 508

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-((二甲基胺基)甲基)-2,6-二氟苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 718 509

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-((四氫-2H-哌喃-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 748 510

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(N,N-二甲基胺磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 732 511

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1-甲基-1H-吡唑-3-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 778 512

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-4-((3-氟苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 795 513

((1S,2R)-2-((S)-1-(1-(2-(3-乙氧基-4-((3-氟苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 802 514

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-((3-氟苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 829 515

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-((3-氟苯基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 822 516

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-(二甲基胺甲醯基)-3-氟-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 721 517

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-5-(二甲基胺甲醯基)-3-氟-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 728 518

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1,3-二甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 792 519

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-5-氟-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 728.4 520

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1,5-二甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 792 521

((1S,2R)-2-((S)-1-(1-(2-(2-氯-4-((1,3,5-三甲基-1H-吡唑-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 806 522

((1S,2R)-2-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-(1-(2-(4-((2-(三氟甲基)吡啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 802.32 523

((1S,2R)-2-((S)-1-(1-(2-(4-((1,7-㖠啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 785.34 524

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-羥基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    525

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-2-羥基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯    526

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(二甲基胺甲醯基)-5-氟-2-甲基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 721 527

5-(6-(4-((S)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(2-甲基-1H-咪唑-1-基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-硝基苯甲酸甲酯    528

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-乙醯基氮雜環丁烷-3-基)甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 768.31 529

3-(((4-(6-(4-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯基)磺醯基)甲基)氮雜環丁烷-1-甲酸甲酯 784.29 530

(S)-2-(((4-(6-(4-((S)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯基)磺醯基)甲基)氮雜環丁烷-1-甲酸甲酯 784.34 531

((1S,2R)-2-((S)-1-(1-(2-(4-((1-乙醯基哌啶-4-基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 782.32 532

5-(6-(4-((S)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(2-甲基-1H-咪唑-1-基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)-2-(三氟甲基)苯甲酸甲酯    533

2-氰基-5-(6-(4-(1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-(2-甲基-1H-咪唑-1-基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸甲酯 683.16 534

2-氰基-5-(6-(4-(1-(3-氟苯基)-2-((甲氧基羰基)胺基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸甲酯 676.17 535

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(((R)-四氫呋喃-3-基)氧基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 711.5 536

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(((S)-四氫呋喃-3-基)氧基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 711.7 537

((1S,2R)-2-((S)-1-(1-(2-(4-氰基-3-(三氟甲氧基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 709.8 538

((1S,2R)-2-((S)-1-(1-(2-(3-(二甲基胺甲醯基)-4-((三氟甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 803.37 539

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-((三氟甲基)磺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 732.23 540

2-氰基-5-(6-(4-(2-(乙基(甲基)胺基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)-2-側氧基乙基)哌啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲酸甲酯 674.48 541

((1S,2R)-2-((1S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-(S-甲基磺醯亞胺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 677.31 542

((1S,2R)-2-((1S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(4-(S-(三氟甲基)磺醯亞胺醯基)苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 731.33 543

((1S,2R)-2-((S)-1-(1-(2-(8-氰基-2-甲基-1-側氧基-1,2,3,4-四氫異喹啉-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-((甲氧基羰基)胺基)乙基)環戊基)胺基甲酸甲酯 701 544

((1S,2R)-2-((S)-1-(1-(2-(8-氰基-2-甲基-1-側氧基-1,2,3,4-四氫異喹啉-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 708 545

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-8-(甲基磺醯基)-1-側氧基-1,2,3,4-四氫異喹啉-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 761 546

((1S,2R)-2-((S)-1-(1-(2-(8-氰基-1-側氧基-1,2,3,4-四氫異喹啉-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 694 547

((1S,2R)-2-((S)-1-(1-(2-(8-氰基-2-甲基-3-側氧基-1,2,3,4-四氫異喹啉-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 708 548

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-甲基-8-((1-甲基-1H-吡唑-4-基)磺醯基)-1-側氧基-1,2,3,4-四氫異喹啉-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 827 549

((1S,2R)-2-((S)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)-1-(1-(2-(2-側氧基-2,3-二氫-1H-苯并[d]咪唑-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)乙基)環戊基)胺基甲酸甲酯 656 550

((1S,2R)-2-((S)-1-(1-(2-(2-乙醯基-7-氰基異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 708 551

((1S,2R)-2-((S)-1-(1-(2-(7-氰基-2-(氧雜環丁烷-3-基)異吲哚啉-4-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 722.4 552

((1S,2R)-2-((S)-1-(1-(2-(8-氰基-2-甲基-1,2,3,4-四氫異喹啉-5-基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-1-(3-氟苯基)-2-(2-甲基-1H-咪唑-1-基)乙基)環戊基)胺基甲酸甲酯 694 553

2-(1-(2-(4-氰基苯基)-2-氮雜螺[3.3]庚烷-6-基)哌啶-4-基)-2-(3-氟苯基)-2-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙酸 575.35 In another embodiment, the compound of the present invention is any one or more of the compounds of Table 1 and pharmaceutically acceptable salts thereof. Table 1 further provides the chemical names of the compounds of Table 1, which are provided by Chemdraw^® Index version 16.0 produced. If there is any ambiguity between its chemical structure and chemical name, the compounds of the present invention are defined by their chemical structure. Table 1 Compound number structure and name LCMS (ESI) m/z [M+H] ⁺ 1

((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl) -Methyl 2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 679.30 2

((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(2-(4-cyanophenyl)-2-azaspiro [3.3]Methyl heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 600.61 3

((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(2-(3-cyanophenyl)-2-azaspiro [3.3]Methyl heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 600.13 4

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)ethyl)cyclopentyl)amino methyl formate 709.58 5

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-(dimethylaminocarboxy)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidine-1 -yl)ethyl)cyclopentyl)carbamate 780.59 6

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)ethyl) Cyclopentyl) methyl carbamate 701.62 7

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)-2-fluorophenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidine-1 -yl)ethyl)cyclopentyl)carbamate 705.62 8

((1S,2R)-2-((1S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methylazetidin-1-yl)ethyl)cyclopentyl)carbamate 693.17 9

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((dimethylamino)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl )ethyl)cyclopentyl)carbamate 750 10

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl) Ethyl)cyclopentyl)carbamate 724.4 11

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl)cyclopentane base) methyl carbamate 671.4 12

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-2-(3-ethylazetidine-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 707.14 13

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)-1-(1 -(2-(3-((3-Hydroxy-3-methylazetidin-1-yl)methyl)-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3 ]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 772.07 14

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-(trifluoromethyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl )ethyl)cyclopentyl)carbamate 744.08 15

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)-1-(1 Methyl -(2-(4-Sulfamonophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 684.29 16

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)-1-(1 -(2-(4-(N-Methylaminosulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl) Methyl carbamate 698.31 17

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl)cyclopentyl) Methyl carbamate 685.35 18

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl)cyclopentyl)carbamate 693.34 19

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazacycle Butan-1-yl)ethyl)cyclopentyl)carbamate 713.38 20

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl)cyclopentyl)carbamate 614.50 twenty one

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)ethyl)cyclopentyl)carbamate 630.51 twenty two

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-hydroxyethyl)cyclopentyl)carbamate 561.21 twenty three

((1S,2R)-2-(1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)-1-(3-fluorophenyl)-2-hydroxyethyl)cyclopentyl)carbamate methyl ester 640.25 twenty four

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-methoxyethyl)cyclopentyl)carbamate 575.20 25

((1S,2R)-2-(1-(1-(2-(4-((1-propenylazetidin-3-yl)sulfonyl)phenyl)-2-aza Spiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-methoxyethyl)cyclopentyl)carbamate methyl ester 723.18 26

((1S,2R)-2-(1-(1-(2-(4-((1-(but-2-ynyl)azetidin-3-yl)sulfonyl)phenyl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-methoxyethyl)cyclopentyl)carbamic acid methyl ester 735.25 27

2-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)- Methyl 2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)acetate 589.20 28

2-(1-(2-(4-(Cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3 -Fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)acetate methyl ester 668.30 29

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 2-ethoxy-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 589.28 30

2-(1-(2-(4-Cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-( Methyl 3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)acetate 646.23 31

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)- Methyl 2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-ureidoethyl)cyclopentyl)carbamate 713.3 32

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-isopropylureido)ethyl)cyclopentyl)carbamate methyl ester 724.45 33

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-(2,2,2-trifluoroethyl)ureido)ethyl)cyclopentyl)amine methyl carboxylate 764.50 34

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)-1-(1-(2-(4-sulfasulfone) Acylphenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 672.70 35

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-((methoxycarbonyl)amino)-1-(1-(2-(4-(N -Methylaminosulfonyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 686.57 36

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 618.91 37

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 689.93 38

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 662.70 39

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 676.84 40

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentane base) methyl carbamate 728.3 41

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-((isopropoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 646.54 42

((1S,2R)-2-((S)-1-(1-(2-(6-cyano-1-methyl-2-oxy-1,2-dihydropyridin-3-yl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((isopropoxycarbonyl)amino)ethyl ) cyclopentyl) methyl carbamate 677.58 43

((1S,2R)-2-(2-Amino-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate methyl ester 653.22 44

((1S,2R)-2-(1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl-4-yl)-1-(3-fluorophenyl)-2-(methylamino)-2-oxyethyl)cyclopentyl)carbamate 667.26 45

((1S,2R)-2-(1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate 681.19 46

((1S,2R)-2-((S)-2-(bis(methyl-d3)amino)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate ester 687.32 47

((1S,2R)-2-((S)-2-(bis(methyl-d3)amino)-1-(1-(2-(4-cyano-3-(dimethylcarbamide) Acyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-oxoethyl)cyclopenta base) methyl carbamate 679.35 48

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptane-6-yl)piperidin-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)amino methyl formate 673.29 49

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)- Methyl 2-oxyethyl)cyclopentyl)carbamate 701.29 50

((1S,2R)-2-(1-(1-(2-(4-(((1S,4S)-5-propenyl-2,5-diazabicyclo[2.2.1]heptane -2-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(dimethylamino)-1-(3 -Fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate methyl ester 791.24 51

((1S,2R)-2-(2-(dimethylamino)-1-(3-fluorophenyl)-2-oxy-1-(1-(2-(4-sulfasulfone) methylphenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 656.18 52

((1S,2R)-2-(2-(dimethylamino)-1-(3-fluorophenyl)-1-(1-(2-(4-(N-methylaminosulfonyl) )phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-2-oxyethyl)cyclopentyl)carbamate methyl ester 670.22 53

((1S,2R)-2-(2-(dimethylamino)-1-(3-fluorophenyl)-1-(1-(2-(4-nitrophenyl)-2-nitrogen Methyl heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-2-oxyethyl)cyclopentyl)carbamate 622.17 54

((1S,2R)-2-(2-(dimethylamino)-1-(3-fluorophenyl)-1-(1-(2-(4-(methylsulfonamido)benzene yl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-2-oxyethyl)cyclopentyl)carbamate 670.31 55

((1S,2R)-2-(2-(dimethylamino)-1-(3-fluorophenyl)-1-(1-(2-((3-(methylsulfonamido) Bicyclo[1.1.1]pentan-1-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-pendoxoethyl)cyclopentane base) methyl carbamate 647.26 56

((1S,2R)-2-(1-(1-(2-(3-acetamidobicyclo[1.1.1]pentan-1-yl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate methyl ester 624.28 57

((1S,2R)-2-(1-(1-(2-(4-acetamidobicyclo[2.2.2]octan-1-yl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate methyl ester 666.39 58

((1S,2R)-2-(2-(bis(methyl-d3)amino)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptyl) Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate methyl ester 608.17 59

((1S,2R)-2-(2-(dimethylamino)-1-(3-fluorophenyl)-1-(1-(2-(3-(methylsulfonamido)bicyclo [1.1.1]Pentan-1-yl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-2-oxyethyl)cyclopentyl)amino methyl formate 660.22 60

((1S,2R)-2-(2-(dimethylamino)-1-(3-fluorophenyl)-1-(1-(2-(4-(methylsulfonamido)bicycle [2.2.2]Octan-1-yl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-2-oxyethyl)cyclopentyl)amino methyl formate 702.33 61

((1S,2R)-2-(2-(bis(methyl-d3)amino)-1-(3-fluorophenyl)-1-(1-(2-(4-nitrophenyl)) -Methyl 2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-oxyethyl)cyclopentyl)carbamate 628.19 62

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 2-(ethyl(methyl)amino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate 616.14 63

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-(isopropyl(methyl-d3)amino)-2-oxyethyl)cyclopentyl)carbamate 633.30 64

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-oxo-2-(pyrrolidin-1-yl)ethyl)cyclopentyl)carbamate 707.12 65

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-oxy-2-(pyrrolidin-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 699.25 66

(S)-2-(1-(2-(4-Cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)acetate methyl ester 660.14 67

(S)-2-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)methyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino ) cyclopentyl) methyl acetate 688.32 68

(S)-2-(1-(2-(3-(dimethylaminocarboxy)-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-6- Methyl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)acetate 703.17 69

(S)-2-(3-Fluorophenyl)-2-(1-(2-(3-((3-hydroxy-3-methylazetidin-1-yl)methyl)-4 -(Trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-((1R,2S)-2-((methoxy Carbonyl)amino)cyclopentyl)methyl acetate 731.20 70

(S)-2-(1-(2-(4-((1-(but-2-ynyl)piperidin-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl ) methyl acetate 777.11 71

(S)-2-(1-(2-(4-((4-(but-2-ynyl)piperidin-1-yl)sulfonyl)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl ) methyl acetate 778.23 72

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( 4H -1,2,4-triazol-4-yl)ethyl)cyclopentyl)amino methyl formate 691.55 73

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-(cyclopropylsulfonyl)-2-fluorophenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( 4H -1,2,4-triazol-4-yl)ethyl)cyclopentane base) methyl carbamate 709.38 74

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((3-fluoroazetidine-1 -yl)methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( 4H -1 ,2,4-Triazol-4-yl)ethyl)cyclopentyl)carbamate methyl ester 778.44 75

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 718.56 76

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 639.61 77

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)amine methyl carboxylate 710.03 78

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(methylaminocarboxy)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)amino methyl formate 696.43 79

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-fluoro-3-((3-fluoroazetidin-1-yl)methan yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3 -Fluorophenyl)ethyl)cyclopentyl)methylcarbamate 743.85 80

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)-2-fluorophenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl ) cyclopentyl) methyl carbamate 714.64 81

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-fluoroazetidin-1-yl)methyl)phenyl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl) )ethyl)cyclopentyl)carbamate 725.36 82

((1S,2R)-2-((S)-1-(1-(2-(3-((1H-imidazol-1-yl)methyl)-4-cyanophenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cycle Amyl) methyl carbamate 719.93 83

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-( 3-Fluorophenyl)ethyl)cyclopentyl)carbamate methyl ester 737.63 84

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-fluoro-3-((3-hydroxy-3-methylazetidine- 1-yl)methyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl) -Methyl 1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 756.76 85

((1S,2R)-2-((S)-1-(1-(2-(3-aminocarboxy-4-cyanophenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 683.88 86

((1S,2R)-2-((S)-1-(1-(2-(4-(azetidin-1-ylsulfonyl)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)amine methyl carboxylate 733.60 87

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 704.58 88

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 625.33 89

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 696.74 90

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(methylaminocarboxy)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 686.78 91

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-fluoro-3-((3-fluoroazetidin-1-yl)methan yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 730.43 92

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)-2-fluorophenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 700.34 93

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-fluoro-3-((3-hydroxy-3-methylazetidine- 1-yl)methyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl) Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 742.51 94

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate 724.63 95

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((3-hydroxy-3-methylazetidine) Alk-1-yl)methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2 -Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 803.59 96

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-(dimethylaminocarboxy)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 775.56 97

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-(trifluoromethyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 739.14 98

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(3-((3-hydroxy-3-methylazetidine) -1-yl)methyl)-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-methyl) Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 766.90 99

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((1,1-dioxothiomorpholinyl)methyl)- 2-Fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate 790.07 100

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-fluoro-3-(morpholinylmethyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 742.19 101

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 682.41 102

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-((dimethylamino)methyl)-2-fluorophenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 700.68 103

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3,5-difluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 714.48 104

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3,5-difluorophenyl)-2-(2-methyl) -1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 742.83 105

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(morpholine-4-carbonyl)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 738.26 106

((1S,2R)-2-((S)-1-(1-(2-(3-(azetidine-1-carbonyl)-4-cyanophenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 708.27 107

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(pyrrolidine-1-carbonyl)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 722.37 108

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(3-hydroxy-3-methylazetidine-1-carbonyl)benzene) yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 738.22 109

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(3-hydroxy-3-methylazetidine-1-carbonyl)benzene) yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 738.75 110

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(3-fluoroazetidine-1-carbonyl)phenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 726.24 111

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(4-hydroxy-4-methylpiperidine-1-carbonyl)phenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl yl)cyclopentyl)carbamate 766.26 112

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 4-Sulfamonophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 679.68 113

((1S,2R)-2-((S)-1-(1-(2-(4-(N,N-dimethylaminosulfonyl)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 707.82 114

((1S,2R)-2-((S)-1-(3,5-difluorophenyl)-1-(1-(2-(3-(dimethylaminocarboxy)-4- (Trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl yl)cyclopentyl)carbamate 757.57 115

((1S,2R)-2-((S)-1-(3,5-difluorophenyl)-1-(1-(2-(3-((3-hydroxy-3-methylaza Cyclobutan-1-yl)methyl)-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-( Methyl 2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 785.58 116

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((dimethylamino)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 761.83 117

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((dimethylamino)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3,5-difluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate 779.55 118

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazole -4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2 -Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 801.14 119

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-fluorophenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 689.18 120

((1S,2R)-2-((S)-1-(1-(2-(4-chloro-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 705.24 121

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(4-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 704.26 122

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(4-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 696.32 123

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(4-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate 724.23 124

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-propenylazetidin-3-yl)methyl)sulfonyl) Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate 787.08 125

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(trifluoromethyl)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 126

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 668.07 127

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 4-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl ) cyclopentyl) methyl carbamate 744.21 128

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-fluorophenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 675.43 129

((1S,2R)-2-((S)-1-(1-(2-(4-fluoro-3-((3-hydroxy-3-methylazetidin-1-yl)methan) yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 717.35 130

((1S,2R)-2-((S)-1-(1-(2-(4-((((R)-1-(but-2-ynyl)azetidine-2 -yl)methyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( Methyl 2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 798.99 131

((1S,2R)-2-((S)-1-(1-(2-(4-((((R)-1-propenylazetidin-2-yl)methyl) Sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate 787.02 132

((1S,2R)-2-((S)-1-(1-(2-(4-((((S)-1-(but-2-ynyl)azetidine-2 -yl)methyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( Methyl 2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 798.96 133

((1S,2R)-2-((S)-1-(1-(2-(4-((((S)-1-propenylazetidin-2-yl)methyl) Sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate 787.05 134

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-(methylsulfonamido)phenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 749.31 135

((1S,2R)-2-(1-(1-(2-(4-(((1S,4S)-5-propenyl-2,5-diazabicyclo[2.2.1]heptane -2-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2 -Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 814.32 136

((1S,2R)-2-(1-(1-(2-Acetyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 566.19 137

((1S,2R)-2-(1-(3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-(methylsulfonyl) yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 602.22 138

((1S,2R)-2-(1-(3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-methyl-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 538.10 139

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(4-fluorophenyl)-2-azaspiro[3.3]heptane -6-yl)piperidin-4-yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 140

((1S,2R)-2-((S)-1-(1-(2-(4-chlorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4- yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 141

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl phenylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 664.14 142

((1S,2R)-2-((S)-1-(1-(2-benzyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 628.29 143

((1S,2R)-2-((S)-1-(1-(2-(1,1-dioxionyltetrahydro-2H-thiopyran-4-carbonyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 684.75 144

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 1-(Methylsulfonyl)azetidine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)amine methyl carboxylate 685.83 145

((1S,2R)-2-(1-(1-(2-(3-Fluorocyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 624.33 146

((1S,2R)-2-(1-(1-(2-(3,3-difluorocyclobutane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 642.25 147

((1S,2R)-2-(1-(1-(2-(3-cyanobicyclo[1.1.1]pentane-1-carbonyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 643.12 148

((1S,2R)-2-(1-(1-(2-(3-Fluorobicyclo[1.1.1]pentane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 636.27 149

((1S,2R)-2-((1S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 1-Methyl-2-oxypiperidine-4-carbonyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamic acid methyl ester 663.25 150

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(3-hydroxy-3-methylcyclobutane-1-carbonyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 636.30 151

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 4-(N-methylaminosulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 693.42 152

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 1-(methylsulfonyl)piperidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate ester 685.67 153

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 4-(methylsulfonyl)cyclohexyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 684.47 154

((1S,2R)-2-(1-(1-(2-((R)-1-Acetylpiperidine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 677.33 155

((1S,2R)-2-(1-(3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-((R)- 1-(Methylsulfonyl)piperidine-3-carbonyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate ester 713.28 156

((1S,2R)-2-(1-(1-(2-((S)-1-Acetylpiperidine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 677.30 157

((1S,2R)-2-(1-(3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-((S)- 1-(Methylsulfonyl)piperidine-3-carbonyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate ester 713.25 158

((1S,2R)-2-(1-(1-(2-(Cyclobutylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 583.22 159

((1S,2R)-2-(1-(3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-((1s,4S )-4-(trifluoromethyl)cyclohexane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)amino methyl formate 702.33 160

((1S,2R)-2-(1-(3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-((1r,4R )-4-(trifluoromethyl)cyclohexane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)amino methyl formate 702.14 161

((1S,2R)-2-(1-(1-(2-(bicyclo[1.1.1]pentane-1-carbonyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 618.25 162

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( (1-(Methylsulfonyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl) Methyl carbamate 698.52 163

((1S,2R)-2-((S)-1-(1-(2-(2-Fluoro-4-sulfamoylphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 697.85 164

3-((6-(4-((S)-1-(3-fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)- 2-(2-Methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)azetidine -Tertiary butyl 1-carboxylate 693.35 165

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(4-hydroxy-4-methylcyclohexyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 636.41 166

((1S,2R)-2-((S)-1-(1-(2-(1-Acetylazetidine-3-carbonyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 649.13 167

((1S,2R)-2-((S)-1-(1-(2-(cyclohexanecarbonyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4- yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 634.38 168

(2S,4R)-2-(6-(4-((S)-1-(3-fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino) Cyclopentyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-4- Hydroxypyrrolidine-1-carboxylate tertiary butyl ester 737.36 169

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-(1-(Methylsulfonyl)piperidin-4-yl)acetinyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cycle Amyl) methyl carbamate 727.22 170

((1S,2R)-2-((S)-1-(1-(2-((1-acetylazetidin-3-yl)methyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 634.40 171

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( (1-(Methylsulfonyl)azetidine-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cycle Amyl) methyl carbamate 671.25 172

((1S,2R)-2-((S)-1-(1-(2-((4-cyanophenyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 689.16 173

3-((6-(4-((S)-1-(3-fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)- 2-(2-Methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)pyrrolidine-1- tertiary butyl formate 707.33 174

((1S,2R)-2-((1S)-1-(1-(2-((1-Acetylpyrrolidin-3-yl)methyl)-2-azaspiro[3.3]heptane -6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 649.23 175

((1S,2R)-2-((S)-1-(1-(2-((1,1-dioxionyltetrahydro-2H-thiopyran-4-yl)sulfonyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl yl)cyclopentyl)carbamate 720.17 176

((1S,2R)-2-(1-(1-(2-((3-cyanobicyclo[1.1.1]pentan-1-yl)methyl)-2-azaspiro[3.3]heptyl Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 629.14 177

((1S,2R)-2-(1-(1-(2-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-azaspiro[3.3]heptane -6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 622.35 178

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 2-(dimethylamino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate 602.21 179

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 4-Sulfamonocyclohexyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 685.81 180

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-methylphenyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 639.36 181

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 669.23 182

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 683.07 183

((1S,2R)-2-((S)-1-(1-(2-(3-acetamido-4-cyanophenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 682.19 184

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-methylphenyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 639.43 185

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-methoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 655.33 186

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl yl)cyclopentyl)carbamate 735 187

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(((E)-3-(methylsulfonyl)allyl)oxy yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 759 188

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-2-((3-hydroxy-3-methylazetidine) Alk-1-yl)methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2 -Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 803 189

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-2-(dimethylaminocarboxy)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 775 190

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-2-((3-fluoroazetidin-1-yl )methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate 791 191

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-2-((dimethylamino)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 761 192

((1S,2R)-2-((S)-1-(1-(2-(5-(dimethylaminocarboxy)oxazol-2-yl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 662 193

((1S,2R)-2-((S)-1-(1-(2-(5-(dimethylaminocarboxy)thiazol-2-yl)-2-azaspiro[3.3]heptyl Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 678 194

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 4-((2-(N-Methacrylamido)ethyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethane yl)cyclopentyl)carbamate 775 195

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-4-(dimethylaminocarboxy)pyrimidin-2-yl)-2-aza Spiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 698 196

1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)-3-methylurea 734 197

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-4-(dimethylaminocarboxy)pyridin-2-yl)-2-aza Spiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 697 198

((1S,2R)-2-((S)-1-(1-(2-(4-((2-propenamidoethyl)sulfonyl)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 761 199

N-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)propionamide 733 200

N-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)acetamide 719 201

1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)-3-methylimidazolidin-2-one 760 202

1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)-1,3-dihydro-2H-imidazol-2-one 744 203

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 3-((N-Methacrylamido)methyl)-4-(methylsulfonamido)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4- yl)ethyl)cyclopentyl)carbamate 775 204

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( ((1r,4S)-4-(methylsulfonamido)cyclohexyl)methyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cycle Amyl) methyl carbamate 713 205

1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)-3-methyl-1,3-dihydro-2H-imidazol-2-one 758 206

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( (R)-1-(Methylsulfonyl)pyrrolidin-3-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl) Methyl carbamate 671 207

((1S,2R)-2-((S)-1-(1-(2-(4-(dimethylaminocarboxy)-5-(methylsulfonyl)pyridin-2-yl)) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 750 208

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( (S)-1-(Methylsulfonyl)pyrrolidin-3-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl) Methyl carbamate 671 209

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-2,6-dimethylphenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 732 210

((1S,2R)-2-((S)-1-(1-(2-(2,6-dimethyl-4-(methylsulfonyl)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 706 211

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2,6-dimethylphenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 653 212

((1S,2R)-2-((S)-1-(1-(2-(2-fluoro-4-((3-vinylpyridin-4-yl)sulfonyl)phenyl)-2 - Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 771 213

((1S,2R)-2-((S)-1-(1-(2-(2-fluoro-4-((5-vinylpyridin-2-yl)sulfonyl)phenyl)-2 - Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 771 214

((1S,2R)-2-((S)-1-(1-(2-(2-fluoro-4-((2-vinylpyridin-4-yl)sulfonyl)phenyl)-2 - Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 771 215

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-4-propenyl-2-methylpiperidin-1-yl)sulfonyl yl)-2-fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 820 216

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-4-propenyl-2-methylpiperidin-1-yl)sulfonyl yl)-2-fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 820 217

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)-1-(3-fluorophenyl)-2-(1 H -imidazol-1-yl)ethyl)cyclopentyl)carbamate 611.50 218

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)-1-(3-fluorophenyl)-2-( 4H -1,2,4-triazol-4-yl)ethyl)cyclopentyl)carbamate 612.49 219

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3,5-difluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 629.54 220

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3,5-difluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 708.93 221

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 690.55 222

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptyl Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 708.53 223

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(2-(4-((1 -Methyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl) Methyl carbamate 730.59 224

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-propenylpyrrolidin-3-yl)sulfonyl)-2- Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethane yl)cyclopentyl)carbamate 791.56 225

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-(but-2-ynyl)pyrrolidin-3-yl)sulfone Acyl)-2-fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 803.55 226

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-propenylpiperidin-3-yl)sulfonyl)-2- Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethane yl)cyclopentyl)carbamate 805.60 227

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-propenylazepan-3-yl)sulfonyl) -2-Fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 819.61 228

((1S,2R)-2-((S)-1-(1-(2-(7-cyano-1H-indazol-4-yl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 651.57 229

((1S,2R)-2-((S)-1-(1-(2-(5-cyanoisoquinolin-8-yl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 662.53 230

((1S,2R)-2-((S)-1-(1-(2-(7-(Cyclopropylsulfonyl)-1,3-dioxyisoindolin-4-yl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 759.42 231

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-propenylpyrrolidin-3-yl)sulfonyl)-2- Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethane yl)cyclopentyl)carbamate 791.49 232

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-(but-2-ynyl)pyrrolidin-3-yl)sulfone Acyl)-2-fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 803.68 233

((1 S ,2 R )-2-(( S )-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((3-fluoroazetidine-1 -yl)methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( 1H -imidazole -1-yl)ethyl)cyclopentyl)carbamate 777.60 234

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((dimethylamino)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 751.45 235

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((dimethylamino)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 749.66 236

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 682.35 237

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)-2-fluorophenyl)-2 - Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 238

((1S,2R)-2-((S)-1-(1-(2-(3-((1H-imidazol-1-yl)methyl)-4-cyanophenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 239

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 710.26 240

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-fluoro-3-((3-hydroxy-3-methylazetidine- 1-yl)methyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 728.57 241

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-propenylpiperidin-3-yl)sulfonyl)-2- Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethane yl)cyclopentyl)carbamate 805.72 242

((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-(but-2-ynyl)piperidin-3-yl)sulfone Acyl)-2-fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 818.67 243

((1S,2R)-2-((1S)-1-(1-(2-(4-(((S)-1-propenylpyrrolidin-3-yl)sulfonyl)-2- Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(7-pendoxyl-6,7 Methyl dihydro-5H-imidazo[2,1-b][1,3]㗁𠯤-1(8aH)-yl)ethyl)cyclopentyl)carbamate 863.74 244

((1S,2R)-2-((1S)-1-(1-(2-(4-(((S)-1-propenylpiperidin-3-yl)sulfonyl)-2- Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(7-pendoxyl-6,7 Methyl dihydro-5H-imidazo[2,1-b][1,3]㗁𠯤-1(8aH)-yl)ethyl)cyclopentyl)carbamate 877.91 245

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-((dimethylamino)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 747.52 246

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-(but-2-ynyl)piperidin-3-yl)sulfone Acyl)-2-fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 817.66 247

((1S,2R)-2-((S)-1-(1-(2-(4-(((R)-1-(but-2-ynyl)azepan-3- yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( 1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 831.60 248

((1S,2R)-2-((S)-1-(1-(2-(4-((1-propenylazetidin-3-yl)sulfonyl)-2-fluoro Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 777.50 249

((1S,2R)-2-((S)-1-(1-(2-(4-((1-(but-2-ynyl)azetidin-3-yl)sulfonyl yl)-2-fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 789.51 250

((1S,2R)-2-((S)-1-(1-(2-(3-((1H-imidazol-1-yl)methyl)-4-(cyclopropylsulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 770.39 251

((1S,2R)-2-((S)-1-(1-(2-(3-((3-fluoroazetidin-1-yl)methyl)-4-((1- Methyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorobenzene yl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 817.55 252

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,4S)-5-propenyl-2,5-diazabicyclo[2.2. 1]Heptan-2-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)- Methyl 2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 800.32 253

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,4S)-5-(2-chloroacetyl)-2,5-diazo Heterobicyclo[2.2.1]heptan-2-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 822.15 254

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,4S)-5-(but-2-ynyl)-2,5-di azabicyclo[2.2.1]heptan-2-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3 -Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 812.26 255

((1S,2R)-2-((S)-1-(1-(2-(7-(cyclopropylsulfonyl)-1-oxyisoindolin-4-yl)-2 - Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 745.69 256

((1S,2R)-2-((S)-1-(1-(2-(7-(Cyclopropylsulfonyl)-2-methyl-1,3-dioxyisoindole Lin-4-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 773.62 257

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3,5-difluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 700.71 258

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3,5-difluorophenyl)-2-(1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 728.54 259

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-fluoro-3-(morpholinylmethyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 260

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((1,1-dioxothiomorpholinyl)methyl)- 2-Fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 261

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(3-((3-hydroxy-3-methylazetidine) -1-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl) Methyl piperidin-4-yl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 829.57 262

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(3-((3-hydroxy-3-methylazetidine) -1-yl)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate 763.55 263

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-(dimethylaminocarboxy)phenyl)-2 - Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 761.48 264

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-(morpholinylmethyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 789.41 265

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,5S)-6-propenyl-3,6-diazabicyclo[3.2. 0]Heptan-3-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)- Methyl 2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 800.09 266

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,5S)-6-(but-2-ynyl)-3,6-di azabicyclo[3.2.0]heptan-3-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3 -Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 812.11 267

((1S,2R)-2-((S)-1-(1-(2-(4-(((1S,5S)-6-(2-chloroacetyl)-3,6-diazo Heterobicyclo[3.2.0]heptan-3-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 822.13 268

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazole -4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate 787.41 269

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(2-(4-(vinyl) Sulfonyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate methyl ester 676.51 270

((1S,2R)-2-((S)-1-(1-(2-(4-((2-ethynylpyridin-4-yl)sulfonyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 751.51 271

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-propenylazetidin-3-yl)methyl)sulfonyl) Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 773.45 272

((1S,2R)-2-((S)-1-(1-(2-(4-((1-propenylpiperidin-4-yl)sulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 787.55 273

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-(but-2-ynanoyl)azetidin-3-yl)methan yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 785.09 274

((1S,2R)-2-((S)-1-(1-(2-(4-((1-(but-2-ynyl)piperidin-4-yl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 799.51 275

((1S,2R)-2-((1S)-1-(1-(2-(2-fluoro-4-((2-(N-methacrylamido)cyclobutyl)sulfonyl) )phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethane yl)cyclopentyl)carbamate 805.18 276

((1S,2R)-2-((1S)-1-(1-(2-(2-fluoro-4-((2-(N-methylbut-2-ynamido)cyclobutyl )sulfonyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate 817.26 277

((1S,2R)-2-((1S)-1-(1-(2-(4-((2-(2-chloro-N-methylacetamido)cyclobutyl)sulfonyl )-2-Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate 827.14 278

((1S,2R)-2-((S)-1-(1-(2-(4-((4-((4-(dimethylamino)-4-oxybutan-2- alkyn-1-yl)carbamoyl)phenyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 878.36 279

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(2-(4-((4 -((Cyanomethyl)carbamoyl)phenyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cycle Amyl) methyl carbamate 808.03 280

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(2-(4-((4 -(Prop-2-yn-1-ylaminocarbamoyl)phenyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl yl)cyclopentyl)carbamate 807.10 281

((1S,2R)-2-((S)-1-(1-(2-(4-((3-((4-(dimethylamino)-4-oxybutan-2- alkyn-1-yl)carbamoyl)phenyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 878.29 282

((1S,2R)-2-((S)-1-(1-(2-(4-((3-((cyanomethyl)carbamoyl)phenyl)sulfonyl)phenyl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 808.03 283

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(2-(4-((3 -(Prop-2-yn-1-ylaminocarbamoyl)phenyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl yl)cyclopentyl)carbamate 807.04 284

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 732.14 285

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 653.17 286

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 724.59 287

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)-1-(1-(2- Methyl (4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 696.55 288

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)-1-(1-(2- Methyl (4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 706.60 289

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 697.29 290

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 711.33 291

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-methoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 683.57 292

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(methoxymethyl)phenyl)-2-azaspiro[3.3]heptyl) Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 697.80 293

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((methylsulfonyl)methyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 745.91 294

((1S,2R)-2-((S)-1-(1-(2-(2-Fluoro-4-sulfamoylphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 725.39 295

((1S,2R)-2-((S)-1-(1-(2-(3,4-dicyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 678.86 296

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(hydroxymethyl)phenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 683.57 297

((1S,2R)-2-((S)-1-(1-(2-(6-cyano-1-methyl-2-oxy-1,2-dihydropyridin-3-yl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 684.56 298

((1S,2R)-2-((S)-1-(1-(2-(7-cyano-1,3-dihydroisobenzofuran-4-yl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 695.35 299

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-pyrazol-1-yl)ethyl)cyclopentane base) methyl carbamate 721 300

((1S,2R)-2-((S)-2-(2-amino-1H-imidazol-1-yl)-1-(1-(2-(3-((dimethylamino) Methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethane yl)cyclopentyl)carbamate 736 301

((1S,2R)-2-((S)-cyano(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 556.34 302

((1S,2R)-2-((S)-cyano(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 635.50 303

((1S,2R)-2-((S)-cyano(3-fluorophenyl)(1-(2-(4-((1-methyl-1H-pyrazol-4-yl)sulfonyl) yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)methyl)cyclopentyl)carbamate 675.53 304

((1S,2R)-2-((S)-cyano(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 627.53 305

((1S,2R)-2-((S)-cyano(1-(2-(4-cyano-3-((3-hydroxy-3-methylazetidin-1-yl)) Methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 655.53 306

Methyl((1S,2R)-2-((S)-cyano(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl) )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 666.3 307

((1S,2R)-2-((S)-2-amino-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl) )phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 670.2 308

((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(7-(4-cyanophenyl)-7-azaspiro [3.5]Nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate methyl ester 629.61 309

((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(7-(4-(cyclopropylsulfonyl)phenyl) -7-Azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 708.28 310

((1S,2R)-2-((S)-1-(1-(7-(4-(cyclopropylsulfonyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane Alk-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 736.44 311

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(7-(4-((1 -Methyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)ethyl)cyclopentyl) Methyl carbamate 758.60 312

((1S,2R)-2-(1-(1-(7-(4-((1-propenylazetidin-3-yl)sulfonyl)-2-fluorophenyl)- 7-Azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 805.26 313

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-propenylpyrrolidin-3-yl)sulfonyl)-2-fluorophenyl) -7-Azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 819.33 314

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-propenylpyrrolidin-3-yl)sulfonyl)-2- Fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethane yl)cyclopentyl)carbamate 819.83 315

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-(but-2-ynyl)pyrrolidin-3-yl)sulfone Acyl)-2-fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 831.95 316

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-propenylpiperidin-3-yl)sulfonyl)-2- Fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethane yl)cyclopentyl)carbamate 833.73 317

((1S,2R)-2-((S)-1-(1-(7-(4-(((S)-1-(but-2-ynyl)piperidin-3-yl)sulfone Acyl)-2-fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 845.61 318

((1S,2R)-2-((1S)-1-(1-(7-(4-(((S)-1-propenylpiperidin-3-yl)sulfonyl)-2- Fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(7-oxy-6,7 Methyl dihydro-5H-imidazo[2,1-b][1,3]㗁𠯤-1(8aH)-yl)ethyl)cyclopentyl)carbamate 905.67 319

((1S,2R)-2-((S)-1-(1-(7-(4-(cyclopropylsulfonyl)-3-((3-fluoroazetidin-1-yl )methyl)phenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 805.55 320

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-propenylpiperidin-3-yl)sulfonyl)-2-fluorophenyl) -7-Azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 833.31 321

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-propenylazepan-3-yl)sulfonyl)-2-fluoro Phenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 847.29 322

((1S,2R)-2-(1-(1-(7-(4-((1-(but-2-ynyl)azetidin-3-yl)sulfonyl)-2 -Fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 817.18 323

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-(but-2-ynyl)pyrrolidin-3-yl)sulfonyl)- 2-Fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 831.22 324

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-(but-2-ynyl)piperidin-3-yl)sulfonyl)- 2-Fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 845.31 325

((1S,2R)-2-(1-(1-(7-(4-(((R)-1-(but-2-ynyl)azepan-3-yl)sulfonyl yl)-2-fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 859.23 326

((1S,2R)-2-(1-(1-(7-(2-Fluoro-4-(((E)-3-(methylsulfonyl)allyl)carbamoyl)benzene yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 793.09 327

2-(1-(7-(4-Propenamido-2-fluorophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-2-(3 -Fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)acetate methyl ester 679.12 328

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(7-( Methyl 4-Sulfamonocyclohexyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 713.64 329

((1S,2R)-2-((S)-1-(1-(6-(4-cyanophenyl)-6-azaspiro[3.4]octan-2-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 625.50 330

((1S,2R)-2-((S)-1-(1-(6-(4-(cyclopropylsulfonyl)phenyl)-6-azaspiro[3.4]octane-2- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 704.40 331

((1S,2R)-2-((1S)-2-(azetidin-1-yl)-1-(1-(2-(4-cyanophenyl)-2-azaspiro [3.4]Octan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate methyl ester 614.45 332

((1S,2R)-2-((1S)-2-(azetidin-1-yl)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl) -Methyl 2-azaspiro[3.4]octan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 693.64 333

((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl) -Methyl 2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 707.43 334

((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(2-(4-cyanophenyl)-2-azaspiro [3.5]Nonan-7-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 628.25 335

((1S,2R)-2-((S)-1-(1-(3-(4-cyanophenyl)-3-azaspiro[5.5]undecan-9-yl)piperidine- Methyl 4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 667.43 336

((1S,2R)-2-((S)-1-(1-(3-(4-(cyclopropylsulfonyl)phenyl)-3-azaspiro[5.5]undecane-9 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 746.20 337

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-oxyoxazolidine-3-yl)ethyl)cyclopentyl)carbamate 630.84 338

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-oxypyrrolidin-1-yl)ethyl)cyclopentyl)carbamate 628.91 339

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( (1r,4S)-4-(Methylsulfonamido)cyclohexyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)amine methyl carboxylate 340

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Pendant oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethane yl)cyclopentyl)carbamate 656 341

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-propenylazetidin-3-yl)methyl)sulfonyl) Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 815.49 342

((1S,2R)-2-((S)-(1-(2-(4-(((1-propenylazetidin-3-yl)methyl)sulfonyl)phenyl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl)carbamate 718.41 343

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-2,6-dimethylphenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl)cyclopentane base) methyl carbamate 721 344

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-(trifluoromethyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 767 345

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 710 346

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2,6-dimethylphenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl)cyclopentyl)carbamate ester 642 347

((1S,2R)-2-((S)-1-(1-(2-(2,6-dimethyl-4-(methylsulfonyl)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl)cyclopentyl ) methyl carbamate 695 348

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2,6-dimethylphenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 681 349

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-(trifluoromethyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethyl) Cyclopentyl) methyl carbamate 728 350

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(methoxymethyl)phenyl)-2-azaspiro[3.3]heptyl) Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 662.9 351

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((methylsulfonyl)methyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamic acid methyl ester 710.7 352

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)-1-(1-(2- (4-((1-Methyl-1H-pyrazol-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethane yl)cyclopentyl)carbamate 772.28 353

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-2-((ethoxycarbonyl)amino)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 632.38 354

((1S,2R)-2-(2-amino-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine- Methyl 4-yl)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate 574.16 355

((1S,2R)-2-((S)-2-(2,4-dimethyl-1H-imidazol-1-yl)-1-(1-(2-(3-((dimethyl Amino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorobenzene yl)ethyl)cyclopentyl)carbamate 749 356

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(trifluoromethyl)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl yl)cyclopentyl)carbamate 753 357

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(trifluoromethyl)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methylazetidin-1-yl)ethane yl)cyclopentyl)carbamate 714.4 358

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 763 359

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-2-(4-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 639.4 360

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((tetrahydro-2H-pyran-4-yl)methyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 361

((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2,4,5-trimethyl-1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 763 362

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 3-(Methylsulfonamido)bicyclo[1.1.1]pentan-1-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl) ring Amyl) methyl carbamate 683 363

((1S,2R)-2-((S)-2-(4-(tertiarybutyl)-1H-imidazol-1-yl)-1-(1-(2-(4-cyanophenyl) )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 667.19 364

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl) Methyl piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 659.32 365

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane -6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 693.34 366

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptyl) Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 738.3 367

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-oxyoxazolidine-3-yl)ethyl)cyclopentyl)carbamate 674.6 368

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-oxyoxazolidine-3-yl)ethyl)cyclopentyl)carbamate 688.4 369

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-oxypyrrolidin-1-yl)ethyl)cyclopentyl)carbamate 672.5 370

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-oxypyrrolidin-1-yl)ethyl)cyclopentyl)carbamate 686.7 371

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-((dimethylamino)methyl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 372

((1S,2R)-2-((S)-1-(1-(2-(4-((4-carbamoylphenyl)sulfonyl)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 783 373

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-(dimethylaminocarboxy)-2-methylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 710 374

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 710 375

((1S,2R)-2-((S)-cyano((2R,6R)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptane-6- yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 584 376

((1S,2R)-2-((S)-1-(1-(2-(4-((4-carbamoylphenyl)sulfonyl)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate ester 776 377

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-6-(dimethylaminocarboxy)pyridin-2-yl)-2-aza Spiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 697 378

((1S,2R)-2-((S)-cyano((2S,4s,6R)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptane- 6-yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 584 379

((1S,2R)-2-((S)-cyano((2R,4r,6S)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptane- 6-yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate 584 380

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-ureidoethyl)cyclopentyl)carbamate methyl ester 688 381

((1S,2R)-2-((S)-1-(1-(2-(6-(dimethylaminocarboxy)-5-(methylsulfonyl)pyridin-2-yl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 750 382

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-((dimethylamino)methyl)-2-methylphenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl yl)cyclopentyl)carbamate 696 383

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-ureidoethyl)cyclopentyl)carbamate 674 384

((1S,2R)-2-((S)-1-(1-(2-(4-((4-carbamoylphenyl)sulfonyl)phenyl)-2-azaspiro[ 3.3] Methyl heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-ureidoethyl)cyclopentyl)carbamate 761 385

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-6-((dimethylamino)methyl)pyridin-2-yl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 683 386

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 738 387

((1S,2R)-2-((S)-1-(1-(2-(4-((3-carbamoylphenyl)sulfonyl)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 783 388

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxy-2-methylphenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 683 389

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-((dimethylamino)methyl)-3-ethoxyphenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 754 390

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-(dimethylaminocarboxy)-2-fluorophenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 714 391

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-fluorophenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 714 392

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-((dimethylamino)methyl)-3-ethoxyphenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 726 393

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 722 394

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-fluorophenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)amine methyl carboxylate 707 395

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxy-5-methylphenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino methyl formate 683 396

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-(dimethylaminocarboxy)-3-ethoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 740 397

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxy-5-fluorophenyl)-2-azaspiro[3.3]heptyl Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 687 398

((1S,2R)-2-((S)-1-(1-(2-(3-chloro-4-cyano-5-ethoxyphenyl)-2-azaspiro[3.3]heptyl Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 703 399

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(4-((3-fluorophenyl)sulfonyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 758 400

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-6-ethoxypyridin-2-yl)-2-azaspiro[3.3]heptane -6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ester 670 401

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-ethoxyphenyl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 669 402

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl) Methyl carbamate 724 403

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 696 404

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-ethoxy-2-fluorophenyl)-2-azaspiro[3.3]heptyl Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 687 405

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptyl Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 703 406

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-cyano-3-(dimethylaminocarboxy)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 730 407

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-(methylsulfonamido)phenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl) Methyl carbamate 742 408

((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(1-(2-(4-((3-fluorophenyl)sulfonyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 751 409

((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)-3-ethoxyphenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 748 410

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-(dimethylaminocarboxy)-3-ethoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-ureidoethyl)cyclopentyl)carbamate 718 411

((1S,2R)-2-((S)-1-(1-(2-(2-fluoro-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl ) cyclopentyl) methyl carbamate 755 412

((1S,2R)-2-((S)-1-(1-(2-(4-((3-carbamoylphenyl)sulfonyl)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate ester 776 413

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-cyano-3-(dimethylaminocarboxy)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-ureidoethyl)cyclopentyl)carbamate methyl ester 708 414

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 778 415

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 4-(pyridin-4-ylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 741 416

((1S,2R)-2-((S)-1-(1-(2-(4-((4-carbamoylphenyl)sulfonyl)-3-((dimethylamino )methyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl) Amino)ethyl)cyclopentyl)methylcarbamate 833 417

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-(dimethylaminocarboxy)-3-ethoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl ) methyl carbamate 733 418

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl) Methyl carbamate 703 419

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-((dimethylamino)methyl)-3-ethoxyphenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cycle Amyl) methyl carbamate 719 420

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-cyano-3-(dimethylaminocarboxy)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)amine methyl carboxylate 723 421

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl ) cyclopentyl) methyl carbamate 771 422

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-(dimethylaminocarboxy)-2-methoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl ) methyl carbamate 719 423

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-6-((dimethylamino)methyl)pyridin-2-yl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl) Methyl carbamate 676 424

((1S,2R)-2-((S)-1-(1-(2-(2-((dimethylamino)methyl)-3-ethoxy-4-(methylsulfonyl) yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 779 425

((1S,2R)-2-((S)-1-(1-(2-(2-((dimethylamino)methyl)-3-ethoxy-4-(methylsulfonyl) yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino )ethyl)cyclopentyl)carbamate 772 426

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-aminosulfonylphenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamic acid methyl ester 743 427

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl ) methyl carbamate 719 428

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-((methoxycarbonyl)amino)-1-(1-(2-(4-(pyridine) -4-ylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 734 429

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-(dimethylaminocarboxy)-2-methoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 726 430

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl )phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino) Ethyl)cyclopentyl)carbamate 781 431

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-ethoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl ) methyl carbamate 733 432

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-ethoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 740 433

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-aminosulfonylphenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 750 434

((1S,2R)-2-((S)-1-(1-(2-(2-fluoro-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 762.3 435

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-5-methoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl ) methyl carbamate 719 436

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methoxyphenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 726 437

((1S,2R)-2-((S)-1-(1-(2-(4-((1H-pyrazol-4-yl)sulfonyl)-2-chlorophenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 764 438

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 792 439

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl )phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate 788 440

((1S,2R)-2-((S)-1-(1-(2-(2-(dimethylaminocarboxy)-3-ethoxy-4-(methylsulfonamido) Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl yl)cyclopentyl)carbamate 786 441

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-2-methyl-4-(methylsulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 736 442

((1S,2R)-2-((S)-1-(1-(2-(2-(dimethylaminocarboxy)-3-ethoxy-4-(methylsulfonamido) Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate 793 443

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl) Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate 806 444

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-4-sulfamonophenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate methyl ester 723 445

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-2-methyl-4-(methylsulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)amine methyl carboxylate 729 446

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-3-(dimethylaminocarboxy)-4-((1-methyl-1H- Pyrazol-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2- Methyl (2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 849 447

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-6-((methylamino)methyl)pyridin-2-yl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 669 448

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-((methoxycarbonyl)amino)-1-(1-(2-(4-(( 2-Methylpyridin-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamic acid methyl ester 748.35 449

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-((methoxycarbonyl)amino)-1-(1-(2-(4-(( 3-Methylpyridin-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamic acid methyl ester 748.35 450

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-2-fluoro-4-((1-methyl-1H- Pyrazol-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2- Methyl (2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 833 451

((1S,2R)-2-((S)-1-(1-(2-(6-((dimethylamino)methyl)-5-(methylsulfonyl)pyridine-2- yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl ) cyclopentyl) methyl carbamate 729 452

((1S,2R)-2-((S)-1-(1-(2-(6-((dimethylamino)methyl)-5-(methylsulfonyl)pyridine-2- yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 736 453

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-2-methyl-4-(trifluoromethyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 454

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-nitrophenyl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 455

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-ethylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 724 456

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamic acid methyl ester 673 457

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(3-(2,2,2-trifluoroethyl)ureido)ethyl)cyclopentyl)carbamate 685.5 458

((1S,2R)-2-(1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-2-(ethyl(methyl)amino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamic acid methyl ester 687.42 459

Methyl-d3 ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 713 460

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(7-methyl-7-nitrogen) Heterospiro[3.5]nonan-2-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 552.6 461

((1S,2R)-2-((S)-1-(1-(7-Acetyl-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1 Methyl -(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 580.8 462

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)-1-(1-(7-(methylsulfonyl) )-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 616.5 463

((1S,2R)-2-((S)-1-(1-(7-(4-cyanophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 464

((1S,2R)-2-((S)-1-(1-(7-(4-cyano-3-ethoxyphenyl)-7-azaspiro[3.5]nonane-2- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 465

((1S,2R)-2-((S)-1-(1-(7-(4-cyanophenyl)-7-azaspiro[3.5]nonan-2-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 466

((1S,2R)-2-((S)-1-(1-(7-(4-cyano-3-ethoxyphenyl)-7-azaspiro[3.5]nonane-2- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 467

((1S,2R)-2-((S)-1-(1-(7-(4-cyano-3-isopropoxyphenyl)-7-azaspiro[3.5]nonane-2 -yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 468

((1S,2R)-2-((S)-1-(1-(7-(4-cyano-3-(dimethylaminocarboxy)phenyl)-7-azaspiro[3.5 ]nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 469

((1S,2R)-2-((S)-1-(1-(7-(4-cyano-2-((dimethylamino)methyl)phenyl)-7-azaspiro [3.5]Nonan-2-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 470

((1S,2R)-2-((S)-1-(1-(7-(4-cyano-3-ethoxyphenyl)-7-azaspiro[3.5]nonane-2- yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate 690.7 471

((1S,2R)-2-((S)-1-(1-(2-(7-cyano-2-methyl-1-oxyisoindolin-4-yl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl) Methyl carbamate 687 472

((1S,2R)-2-((S)-1-(1-(2-(7-cyano-2-methyl-1-oxyisoindolin-4-yl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate 694 474

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-oxyisoindolin-4-yl)-2-azaspiro[3.3 ]heptane-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 813 475

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,3-di-oxyisoindolin-4-yl)-2-aza Spiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate methyl ester 827 476

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-7-(methylsulfonyl)isoindolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cycle Amyl) methyl carbamate 733 477

((1S,2R)-2-((S)-1-(1-(2-(7-cyano-1-oxyisoindolin-4-yl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 680 478

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-7-((1-methyl-1H-pyrazol-4-yl)sulfonyl)isoindolin-4-yl)-2-azaspiro[3.3]heptane-6- yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 799 479

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-7-(methylsulfonyl)-1-oxyisoindolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4- yl)ethyl)cyclopentyl)carbamate 747 480

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-7-(methylsulfonyl)-1,3-di-oxyisoindolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)ethyl)cyclopentyl)carbamate 761 481

((1S,2R)-2-((S)-1-(1-(2-(7-cyano-2-isopropylisoindolin-4-yl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 708 482

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate 559.35 483

((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)- Methyl 1-(3-fluorophenyl)-2-(3-methyl-2-oxyimidazolidin-1-yl)ethyl)cyclopentyl)carbamate 643.48 484

((1S,2R)-2-(1-(1-(2-(4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)-1-(3-fluorophenyl)-2-(3-methyl-2-oxyimidazolidin-1-yl)ethyl)cyclopentyl)carbamate methyl ester 687.55 485

((1S,2R)-2-(1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-(3-methyl-2-oxyimidazolidin-1-yl)ethyl)cyclopentyl)carbamate 701.57 486

((1S,2R)-2-(1-(1-(2-(4-cyano-3-ethoxyphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)-1-(3-fluorophenyl)-2-(2-oxyimidazolidin-1-yl)ethyl)cyclopentyl)carbamate 673.43 487

((1S,2R)-2-(1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-(2-oxyimidazolidin-1-yl)ethyl)cyclopentyl)carbamate 687.45 488

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate 641 489

((1S,2R)-2-((R)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate 625 490

((1S,2R)-2-((R)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate 611 491

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-oxypiperidin-1-yl)ethyl)cyclopentyl)carbamate 642.7 492

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-1-(3-fluorophenyl)-2-(2-oxo-1,3-p-3-yl)ethyl)cyclopentyl)carbamate 644.5 493

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(((methoxy-d3)carbonyl)amino)ethyl) Cyclopentyl) methyl carbamate 706 494

((S)-2-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Perid-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)amine methyl carboxylate 703.6 495

((S)-2-(1-(2-(3-(Dimethylaminocarbamoyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl) Methyl (methyl)carbamate 756.39 496

((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4 -yl)-2-(5,5-dimethyl-2-oxyoxazolidine-3-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate 658.8 497

((S)-2-(1-(2-(3-(dimethylaminocarboxy)-4-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)( Methyl)carbamate 746.7 498

((S)-2-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2-methylphenyl)-2-azaspiro[3.3]heptane- 6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl) Methyl (methyl)carbamate 717 499

((S)-2-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3- Fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)(methyl)carbamate 632.7 500

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(2-methoxyethoxy)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate 501

2-cyano-5-(6-(4-((S)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)-1-(( 1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzoic acid 502

((1S,2R)-2-(1-(1-(2-(4-cyano-3-(2-methylprop-1-en-1-yl)phenyl)-2-azaspiro [3.3]Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl)ethyl)cyclopentane base) methyl carbamate 707.62 503

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-isopropyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 753.6 504

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cycle Amyl) methyl carbamate 718.8 505

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2,6-dimethylphenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 724 506

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2,6-dimethylphenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cycle Amyl) methyl carbamate 717 507

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2,6-difluorophenyl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl yl)cyclopentyl)carbamate 732 508

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-((dimethylamino)methyl)-2,6-difluorophenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 718 509

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 4-((Tetrahydro-2H-pyran-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cycle Amyl) methyl carbamate 748 510

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(N,N-dimethylaminosulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 732 511

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1-methyl-1H-pyrazol-3-yl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 778 512

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-4-((3-fluorophenyl)sulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)amine methyl carboxylate 795 513

((1S,2R)-2-((S)-1-(1-(2-(3-ethoxy-4-((3-fluorophenyl)sulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Amyl) methyl carbamate 802 514

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-((3-fluorophenyl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 829 515

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-((3-fluorophenyl)sulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl ) cyclopentyl) methyl carbamate 822 516

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-(dimethylaminocarboxy)-3-fluoro-2-methylphenyl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl) Cyclopentyl) methyl carbamate 721 517

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-5-(dimethylaminocarboxy)-3-fluoro-2-methylphenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 728 518

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl) yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 792 519

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-5-fluoro-2-methylphenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 728.4 520

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl) yl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate 792 521

((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1,3,5-trimethyl-1H-pyrazol-4-yl)) Sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate 806 522

((1S,2R)-2-((S)-1-(3-Fluorophenyl)-2-((methoxycarbonyl)amino)-1-(1-(2-(4-(( 2-(Trifluoromethyl)pyridin-4-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl ) methyl carbamate 802.32 523

((1S,2R)-2-((S)-1-(1-(2-(4-((1,7-ethidin-4-yl)sulfonyl)phenyl)-2-aza spiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)amino methyl formate 785.34 524

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-hydroxyphenyl)-2-azaspiro[3.3]heptan-6-yl) Methyl piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 525

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-2-hydroxyphenyl)-2-azaspiro[3.3]heptan-6-yl) Methyl piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate 526

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-5-fluoro-2-methylphenyl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl) Cyclopentyl) methyl carbamate 721 527

5-(6-(4-((S)-1-(3-Fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)-2 -(2-Methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-2-nitrobenzoic acid methyl ester 528

((1S,2R)-2-((S)-1-(1-(2-(4-(((1-acetylazetidin-3-yl)methyl)sulfonyl) Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl yl)cyclopentyl)carbamate 768.31 529

3-(((4-(6-(4-((S)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)-1-((1R,2S)- 2-((Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)methane yl) azetidine-1-carboxylic acid methyl ester 784.29 530

(S)-2-(((4-(6-(4-((S)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)-1-((1R ,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)phenyl)sulfonic acid Acyl)methyl)azetidine-1-carboxylate methyl ester 784.34 531

((1S,2R)-2-((S)-1-(1-(2-(4-((1-Acetylpiperidin-4-yl)sulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)amine methyl carboxylate 782.32 532

5-(6-(4-((S)-1-(3-Fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)-2 -(2-Methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-2-(trifluoromethyl) methyl benzoate 533

2-cyano-5-(6-(4-(1-(3-fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)- Methyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzoate 683.16 534

2-cyano-5-(6-(4-(1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)-1-((1R,2S)-2-(( Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzoic acid methyl ester 676.17 535

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 711.5 536

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate 711.7 537

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(trifluoromethoxy)phenyl)-2-azaspiro[3.3]heptyl) Alk-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid methyl ester 709.8 538

((1S,2R)-2-((S)-1-(1-(2-(3-(dimethylaminocarboxy)-4-((trifluoromethyl)sulfonyl)phenyl )-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) )ethyl)cyclopentyl)carbamate 803.37 539

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( Methyl 4-((trifluoromethyl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate ester 732.23 540

2-cyano-5-(6-(4-(2-(ethyl(methyl)amino)-1-(3-fluorophenyl)-1-((1R,2S)-2-(( Methoxycarbonyl)amino)cyclopentyl)-2-oxyethyl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzoic acid methyl ester 674.48 541

((1S,2R)-2-((1S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 4-(S-Methylsulfoimidoyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamic acid methyl ester 677.31 542

((1S,2R)-2-((1S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 4-(S-(trifluoromethyl)sulfonimidyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl ) methyl carbamate 731.33 543

((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-1-oxy-1,2,3,4-tetrahydroiso Quinolin-5-yl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl) Amino)ethyl)cyclopentyl)methylcarbamate 701 544

((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-1-oxy-1,2,3,4-tetrahydroiso Quinolin-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate 708 545

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-8-(methylsulfonyl)-1-oxy-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-azaspiro[3.3]heptane -6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate methyl ester 761 546

((1S,2R)-2-((S)-1-(1-(2-(8-cyano-1-oxy-1,2,3,4-tetrahydroisoquinoline-5- yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate 694 547

((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-3-oxy-1,2,3,4-tetrahydroiso Quinolin-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate 708 548

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Methyl-8-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-oxy-1,2,3,4-tetrahydroisoquinoline-5- yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate 827 549

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2-( 2-Pendant oxy-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethane yl)cyclopentyl)carbamate 656 550

((1S,2R)-2-((S)-1-(1-(2-(2-Acetyl-7-cyanoisoindolin-4-yl)-2-azaspiro[3.3 ]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amine methyl carboxylate 708 551

((1S,2R)-2-((S)-1-(1-(2-(7-cyano-2-(oxetan-3-yl)isoindolin-4-yl)) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate 722.4 552

((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentyl)carbamate 694 553

2-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)- 2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)acetic acid 575.35

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.

In another embodiment, the compounds of the present invention are enantiomerically enriched, eg, the compounds have an enantiomeric excess or "ee" of about 5% or more, as determined by chiral HPLC Measure. In another embodiment, the ee is about 10%. In another embodiment, the ee is about 20%. In another embodiment, the ee is about 30%. In another embodiment, the ee is about 40%. In another embodiment, the ee is about 50%. In another embodiment, the ee is about 60%. In another embodiment, the ee is about 70%. In another embodiment, the ee is about 80%. In another embodiment, the ee is about 85%. In another embodiment, the ee is about 90%. In another embodiment, the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.

The present invention encompasses the preparation and use of salts of the compounds of the present invention. As used herein, a drug "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound of the present invention. Salts of compounds of the present invention can be prepared during the final isolation and purification of the compounds, or separately by reacting the compounds with a suitable acid. The pharmaceutically acceptable salts of the compounds of the present invention may be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric; and organic acids such as oxalic, maleic, succinic, and citric . Non-limiting examples of salts of the compounds of the present invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, Hydrogen Phosphate, Acetate, Adipate, Alginate, Aspartate, Benzoate, Hydrogen Sulfate, Butyrate, Camphorate, Camphorsulfonate, Digluconate, Glycerophosphate, hemisulfate, heptanoate, caproate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicyl acid salt, methane sulfonate, mesitylene sulfonate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectate, persulfate , 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, Undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate and p-toluenesulfonate. In addition, the available amine groups present in the compounds of the present invention can be quaternary amonized with each of the following: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl , dibutyl and dipentyl sulfates; decyl, lauryl, myristyl and sterol chlorides, bromides and iodides; and benzyl and phenethyl bromides. In view of the foregoing, any reference to compounds of the invention appearing herein is intended to include compounds of the compounds of the invention as well as pharmaceutically acceptable salts thereof. II. The therapeutic method of the present invention.

The compounds of the present invention inhibit menin and are useful in the treatment of a variety of diseases and conditions. In particular, the compounds of the present invention are useful in methods of treating diseases or conditions in which inhibition of menin provides benefit, such as cancer and proliferative diseases. The methods of the present invention comprise administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention. The methods of the present invention also encompass administering to an individual a second therapeutic agent in addition to a compound of the present invention. The second therapeutic agent is selected from drugs known to be suitable for the treatment of diseases or conditions afflicting individuals in need thereof, such as chemotherapeutic agents and/or radiation known to be suitable for the treatment of certain cancers.

The present invention provides compounds of the present invention as menin inhibitors for use in the treatment of diseases and conditions in which inhibition of menin has beneficial effects. The compounds of the invention typically have less than 100 μM, eg, less than 50 μM, less than 25 μM, and less than 5 μM, less than about 1 μM, less than about 0.5 μM, less than about 0.1 μM, less than about 0.05 μM, or less than about 0.01 μM, for menin Binding affinity ( _IC50 ). In one embodiment, the present invention pertains to a method of treating an individual suffering from a disease or condition in which inhibition of menin provides benefit, the method comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention.

Since the compounds of the present invention are inhibitors of the menin protein, a variety of menin-mediated diseases and conditions can be treated by the use of these compounds. Accordingly, the present invention is generally directed to a method for treating an animal (eg, a human) suffering from or at risk of suffering from a condition or disorder responsive to menin inhibition, the method comprising administering to the animal An effective amount of one or more compounds of the present invention.

The present invention is further directed to a method of inhibiting menin in an individual in need thereof, the method comprising administering to the animal an effective amount of at least one compound of the present invention.

The methods of the present invention can be carried out by administering the compounds of the present invention as pure compounds or in pharmaceutical compositions. Administration of pharmaceutical compositions or pure compounds of the compounds of the present invention can be performed during or after the onset of the disease or condition of interest. Typically, pharmaceutical compositions are sterile and do not contain toxic, carcinogenic or mutagenic compounds that would cause adverse reactions when administered. Kits are further provided comprising a compound of the invention and an optional second therapeutic agent, individually or together, and instructions with instructions for using these active agents.

In one embodiment, the compounds of the present invention are administered in combination with a second therapeutic agent suitable for treating a disease or condition in which inhibition of menin provides benefit. The second therapeutic agent is different from the compound of the present invention. The compounds of the present invention and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. Furthermore, the compounds of the present invention and the second therapeutic agent can be administered from a single composition or from two separate compositions.

The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. Effective dosage ranges for each second therapeutic agent are known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.

The compound of the present invention and the second therapeutic agent may be administered together in a single unit dose or separately in multiple unit doses, wherein the compound of the present invention is administered before the second therapeutic agent or vice versa. One or more doses of a compound of the invention and/or one or more doses of a second therapeutic agent may be administered. Thus, the compounds of the present invention can be used in combination with one or more second therapeutic agents such as, but not limited to, anticancer agents.

Diseases and conditions that can be treated by the methods of the present invention include, but are not limited to, cancer and other proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections. In one embodiment, a human patient is treated with a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, wherein the compound is administered in an amount sufficient to inhibit menin activity in the patient. In another embodiment, the human patient is a human adult over 18 years of age in need of treatment of the disease. In another embodiment, the human patient is a human child up to 18 years of age in need of treatment of the disease.

In another aspect, the present invention provides a method of treating cancer in an individual comprising administering a therapeutically effective amount of a compound of the present invention. Although not limited to a particular mechanism, in some embodiments, the compounds of the present invention treat cancer by inhibiting menin. Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table 2. Table 2 adrenal cancer acinar cell carcinoma acoustic neuroma acral lentigious melanoma acral hidradenoma acute eosinophilic leukemia acute red blood cell leukemia acute lymphoblastic leukemia acute megakaryoblastic leukemia acute monocytic leukemia acute promyeloid leukemia adenocarcinoma adenoid cystic carcinoma adenoma adenomatous odontogenic tumor adenosquamous carcinoma adipose tissue tumor adrenocortical carcinoma Adult T-cell leukemia/lymphoma aggressive NK cell leukemia AIDS-related lymphoma Alveolar rhabdomyosarcoma Soft tissue alveolar sarcoma ameloblastoma fibroma degenerative large cell lymphoma Degenerative Thyroid Cancer angioimmunoblastic T-cell lymphoma angiomyolipoma Angiosarcoma astrocytoma atypical teratoid rhabdoid tumor B-cell chronic lymphocytic leukemia B-cell prelymphocytic leukemia B cell lymphoma Basal cell carcinoma Biliary tract cancer Bladder Cancer blastoma bone cancer Brenner tumor brown tumor Burkitt's lymphoma breast cancer brain cancer cancer carcinoma in situ Carcinosarcoma cartilage tumor chalk tumor myelosarcoma chondroma Chordoma choriocarcinoma choroid plexus papilloma renal clear cell sarcoma Craniopharyngioma Cutaneous T-cell lymphoma cervical cancer colorectal cancer Degos disease desmoplastic small round cell tumor diffuse large B-cell lymphoma dysembryoplastic neuroepithelioma dysgerminoma embryonal carcinoma endocrine gland tumor endodermal sinus tumor enteropathy-associated T-cell lymphoma Esophageal cancer intrauterine embryo Fibroma fibrosarcoma follicular lymphoma follicular thyroid cancer gangliocytoma Gastrointestinal cancer germ cell tumor choriocarcinoma in pregnancy giant cell fibroblastoma giant cell tumor of bone glial tumor glioblastoma multiforme Glioma Too much glia in the brain Glucagonoma gonadoblastoma granulosa cell tumor Semi-yin-yang blastoma gallbladder cancer Gastric cancer hairy cell leukemia hemangioblastoma head and neck cancer hemangiopericytoma blood cancer hepatoblastoma Hepatosplenic T-cell lymphoma Hodgkin's lymphoma non-Hodgkin's lymphoma invasive lobular carcinoma bowel cancer kidney cancer throat cancer Malignant lentigo fatal midline cancer leukemia leydig cell tumor liposarcoma lung cancer lymphangioma Lymphangiosarcoma lymphoepithelioma lymphoma acute lymphoblastic leukemia acute myeloid leukemia chronic lymphocytic leukemia liver cancer Small Cell Lung Cancer non-small cell lung cancer MALT lymphoma malignant fibrous histiocytoma Malignant peripheral nerve sheath tumor malignant triton tumor mantle cell lymphoma marginal zone B-cell lymphoma mast cell leukemia Mediastinal germ cell tumor breast medullary carcinoma medullary thyroid cancer Neuroblastoma melanoma meningioma Merkel cell cancer mesothelioma metastatic urothelial carcinoma mixed Müllerian tumor mucinous tumor multiple myeloma muscle tissue tumor Mycosis fungoides myxoliposarcoma myxoma myxosarcoma nasopharyngeal carcinoma Schwannoma neuroblastoma neurofibromas neuroma nodular melanoma eye cancer oligodendritic astrocytoma Oligodendritic Glioma eosinophilic adenoma Optic nerve sheath meningioma optic nerve tumor Oral Cancer osteosarcoma ovarian cancer superior sulcus tumor papillary thyroid cancer paraganglioma pineoblastoma pineal cell tumor pituitary cell tumor Pituitary adenoma Pituitary tumor plasmacytoma polyblastoma precursor T lymphoblastic lymphoma primary central nervous system lymphoma primary effusion lymphoma primary peritoneal carcinoma prostate cancer Pancreatic cancer Pharyngeal cancer Pseudomyxoma peritoneum renal cell carcinoma renal medullary carcinoma retinoblastoma Rhabdomyomas Rhabdomyosarcoma Richter's transformation rectal cancer sarcoma Schwannomatosis Seminoma Sertoli cell tumor Gender gonadal stromal tumor ring cell carcinoma skin cancer small blue round cell tumor small cell carcinoma soft tissue sarcoma somatostatinoma soot wart spinal tumor Splenic marginal zone lymphoma squamous cell carcinoma synovial sarcoma Sezary's disease small bowel cancer squamous carcinoma stomach cancer T cell lymphoma testicular cancer theca cell tumor Thyroid cancer transitional cell carcinoma Throat Cancer Urachal cancer Urogenital cancer urothelial carcinoma uveal melanoma uterine cancer verrucous carcinoma visual pathway glioma Vulvar cancer vaginal cancer Waldenstrom's macroglobulinemia Warthin's tumor Wilms'tumor Ewing's sarcoma endometrial cancer myelodysplastic syndrome myelodysplasia/myeloproliferative neoplasia Pure hematopoiesis of unknown significance (CHIP)

In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is blood cancer. Exemplary blood cancers include, but are not limited to, the cancers listed in Table 3. In another embodiment, the blood cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. In another embodiment, the blood cancer is myelodysplastic syndrome. table 3 acute lymphocytic leukemia (ALL) acute eosinophilic leukemia acute myeloid leukemia (AML) acute red blood cell leukemia Chronic lymphocytic leukemia (CLL) acute lymphoblastic leukemia Small lymphocytic lymphoma (SLL) acute megakaryoblastic leukemia Multiple Myeloma (MM) acute monocytic leukemia Hodgkin's Lymphoma (HL) acute promyeloid leukemia Non-Hodgkin's Lymphoma (NHL) acute myeloid leukemia mantle cell lymphoma (MCL) B-cell prelymphocytic leukemia marginal zone B-cell lymphoma B cell lymphoma Splenic marginal zone lymphoma MALT lymphoma follicular lymphoma (FL) precursor T lymphoblastic lymphoma Waldenstrom's macroglobulinemia (WM) T cell lymphoma Diffuse large B-cell lymphoma (DLBCL) mast cell leukemia Marginal zone lymphoma (MZL) Adult T-cell leukemia/lymphoma Hairy Cell Leukemia (HCL) aggressive NK cell leukemia Burkitt's lymphoma (BL) angioimmunoblastic T-cell lymphoma Richter transformation myelodysplastic syndrome

In another embodiment, the cancer is a leukemia, eg, a leukemia selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia (MLL). In another embodiment, the leukemia is NPM1c mutant acute myeloid leukemia. In another embodiment, the leukemia is MLL-r acute myeloid leukemia. In another embodiment, the leukemia is MLL-r acute lymphoblastic leukemia. In another embodiment, the cancer is NUT-midline cancer. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is Ewing's sarcoma.

In another embodiment, the present invention provides a method of treating benign proliferative disorders such as, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulation tumors, Lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinomas, cerebral pseudotumors, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic tumors, hemangiomas, vocal cord nodules , Polyps and Cysts, Castleman's Disease, Chronic Latent Hair Disease, Dermatofibroma, Hair Cysts, Pyogenic Granuloma, and Juvenile Polyposis Syndrome.

The compounds of the present invention can also be used to treat infectious and non-infectious inflammatory events and autoimmune and other inflammatory diseases by administering an effective amount of the present compounds to mammals (particularly humans) in need of such treatment. Examples of autoimmune and inflammatory diseases, disorders and syndromes treated using the compounds and methods described herein include: inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis , nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, intestinal irritation Manic syndrome, ulcerative colitis, Sjogren's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis, and thrombocytopenia Conditions, Goodpasture's Syndrome, Atherosclerosis, Addison's Disease, Parkinson's Disease, Alzheimer's Disease, Type I Diabetes, Septic Shock , systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, Myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's ) disease, scleredema, mycosis fungoides, acute inflammatory reactions such as acute respiratory distress syndrome and ischemia/reperfusion injury, and Graves' disease.

In another embodiment, the present invention provides a treatment for endotoxic shock and/or bacteria such as LPS-induced by administering to a mammal (specifically a human) in need of such treatment an effective amount of a compound of the present invention Methods of Inducing Systemic Inflammatory Response Syndrome of Sepsis.

In another embodiment, the present invention provides a method for treating viral infections and diseases. Examples of viral infections and diseases that are treated using the compounds and methods described herein include episomal-based DNA viruses including, but not limited to, human papilloma virus, herpes virus, Epstein-Barr ) II virus, human immunodeficiency virus, hepatitis B virus and hepatitis C virus.

In another embodiment, the present invention provides in vivo regulation of protein methylation, gene expression, cell proliferation, cell differentiation in the above-mentioned diseases, in particular cancer, inflammatory diseases and/or viral diseases and/or methods of treatment of apoptosis provided by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the invention.

In another embodiment, the present invention provides a method of modulating the activity of an endogenous or heterologous promoter by contacting a cell with a compound of the present invention.

In the methods of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a human in need thereof, usually formulated in accordance with the practice of medicine. Whether such treatment is indicated is on an individual basis and is subject to a medical assessment (diagnosis) that takes into account signs, symptoms and/or dysfunction and other factors that are at risk of producing specific signs, symptoms and/or dysfunction .

The compounds of the present invention may be administered by any suitable route, for example, by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal administration via lumbar puncture, Transurethral, transnasal, percutaneous (ie, transdermal) or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at specific sites). Parenteral administration can be accomplished using a puncture and syringe or using high pressure techniques.

Pharmaceutical compositions include those in which the compounds of the present invention are administered in effective amounts to achieve their intended purpose. The precise formulation, route of administration, and dosage are determined by the individual physician in view of the condition or disease being diagnosed. Doses and intervals can be adjusted individually to provide levels of the compounds of the invention sufficient to maintain therapeutic effect.

Toxicity and therapeutic efficacy of the compounds of the present invention can be determined by standard pharmaceutical procedures in cell cultures or in experimental animals, eg, for determining the maximum tolerated dose (MTD) of the compounds, which is defined as the maximum tolerated dose (MTD) in animals The highest dose that does not produce toxicity in vivo. The dose ratio between the maximum tolerated dose and the therapeutic effect (eg, inhibition of tumor growth) is the therapeutic index. The dosage may vary within this range depending upon the dosage form employed and the route of administration employed. Determination of a therapeutically effective amount is well within the ability of those skilled in the art, especially in light of the detailed disclosure provided herein.

The therapeutically effective amount of a compound of the invention required for therapy will vary with the nature of the condition being treated, the length of time of desired activity, and the age and condition of the patient, and is ultimately at the discretion of the attending physician. Doses and intervals can be adjusted individually to provide plasma levels of the menin inhibitor sufficient to maintain the desired therapeutic effect. The desired dose may conveniently be administered as a single dose, or as multiple doses at appropriate intervals, eg, as one, two, three, four or more sub-doses per day. Multiple doses are often desired or necessary. For example, a compound of the present invention may be administered at the following frequency: four doses delivered as a daily dose at four-day intervals (q4d x 4); four doses as a daily dose delivered at three-day intervals (q3d x 4) ); daily doses delivered at five-day intervals (qd × 5); weekly doses for three weeks (qwk3); five daily doses with two days rest and five additional daily doses (5/2/5 ); or any dosage regimen determined to be suitable for the situation.

The compounds of the invention for use in the methods of the invention may be about 0.005 to about 1 gram per dose, about 0.005 to about 500 mg per dose, about 0.05 to about 500 mg per dose, about 0.05 to about 250 mg per dose or about An amount of 0.5 to about 100 mg is administered. For example, the compounds of the present invention may be administered in the following amounts per dose: about 0.005 mg, about 0.05 mg, about 0.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1 gram, including all doses between 0.005 mg and 1 gram.

The dosage of a composition containing a compound of the present invention or a composition containing the same may be about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg mg/kg. The dosage of the composition can be at any dosage, including but not limited to about 1 μg/kg. The dosage of the composition can be at any dosage, including but not limited to about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, About 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, About 950 μg/kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg or more. The above dosages are illustrative of the average case, but there may be individual instances where higher or lower dosages are required, and such dosages are within the scope of the present invention. In practice, the physician determines the actual dosing regimen most suitable for an individual patient, which may vary with the age, weight, and response of a particular patient.

As stated above, the compounds of the present invention can be administered in combination with a second therapeutically active agent. In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets epigenetic regulators. Examples of epigenetic regulators include histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase, and DNA methyltransferase. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

In another embodiment, chemotherapeutic or other antiproliferative agents can be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that may be used in combination with the compounds of the present invention include surgery, radiation therapy (eg, gamma radiation, neutron beam radiation therapy, electron radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy , biological response modifiers (eg, interferons, interleukins, tumor necrosis factor (TNF), hyperthermia and hypothermia therapy, agents to attenuate any adverse effects (eg, antiemetics), and any other approved chemotherapeutic drugs.

In another embodiment, the compounds and pharmaceutical compositions of the invention described herein may be used in combination with one or more substances selected from the group consisting of: anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors drug, autophagy inhibitor, phagocytosis inhibitor, demethylating agent, DOT1L inhibitor, IDH1 inhibitor, IDH2 inhibitor, IDH1/IDH2 dual inhibitor, LSD1 inhibitor, XPO1 inhibitor, or dasatinib (dastinib). In another embodiment, the compounds of the present invention may be used in combination with a second therapeutic agent selected from the group consisting of demethylating agents, DOT1L inhibitors, IDH1 inhibitors, IDH2 inhibitors, dual IDH1/IDH2 inhibitors, LSD1 inhibitors agents, XPO1 inhibitors, and dasatinib.

Demethylating agents include substances that inhibit or interfere with DNA methylation. In some examples, the demethylating agent is a DNA methyltransferase inhibitor. Exemplary non-limiting demethylating agents include 5-azacytidine, decitabine, methotrexate, edatrexate, 2'-deoxy-5-azacytidine glycoside, 6-thioguanine, 5-fluoro-2'-deoxycytidine, pseudoisocytidine, 5,6-dihydro-5-azacytidine, fazarabine, zebu zebularine, 2'-deoxy-5,6-dihydro-5-azacytidine, 4'-thio-2'-deoxycytidine, 5-aza-4'-thio -2'-Deoxycytidine, RX-3117, SGI-110, NPEOC-DAC, CP-4200 and 2'3'5'triacetoxy-5-azacytidine.

Non-limiting examples of inhibitors of the histone methyltransferase DOT1L include EPZ-5676, SGC-0946, and EPZ004777.

Exemplary non-limiting IDH1 inhibitors include Tibsovo® (ivosidnib), AG-881, AG-120, FT-2102 (olutasidenib), BAY1436032, IDH-305 and ZX-06. Illustrative non-limiting examples of IDH2 inhibitors include Idhifa® (enasidenib; AG-221), AG-881, AG1-6780, SH1573, and TQ05310. Exemplary non-limiting dual IDH1/IDH2 inhibitors include HMPL-306.

Illustrative, non-limiting examples of LSD1 inhibitors include ORY-1001, OG-L002, SP2509, 4SC-202, GSK2879552, T-3775440, and RN-1.

Illustrative, non-limiting examples of XPO1 inhibitors include selinexor (KPT-330), KPT-8602, KPT251, and SL-801.

Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors can be used with the invention described herein The compound and the pharmaceutical composition are used in combination. Exemplary non-limiting anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, Sunitinib and bevacizumab. Exemplary non-limiting COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Exemplary non-limiting matrix metalloproteinase inhibitors include those described in: WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European patent application Patent Application No. 97304971.1 (filed on July 8, 1997), European Patent Application No. 99308617.2 (filed on October 29, 1999), WO 98/07697 (published on February 26, 1998), WO 98/03516 ( Published on Jan. 29, 1998), WO 98/34918 (published on Aug. 13, 1998), WO 98/34915 (published on Aug. 13, 1998), WO 98/33768 (published on Aug. 6, 1998) , WO 98/30566 (published on July 16, 1998), European Patent Publication 606,046 (published on July 13, 1994), European Patent Publication 931,788 (published on July 28, 1999), WO 90/05719 ( Published on May 31, 1990), WO 99/52910 (published on October 21, 1999), WO 99/52889 (published on October 21, 1999), WO 99/29667 (published on June 17, 1999) , PCT International Application No. PCT/IB98/01113 (filed on July 21, 1998), European Patent Application No. 99302232.1 (filed on March 25, 1999), British Patent Application No. 9912961.1 (June 1999) filed on August 3), US Provisional Application No. 60/148,464 (filed on August 12, 1999), US Patent 5,863,949 (issued January 26, 1999), US Patent 5,861,510 (issued January 19, 1999) ) and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. In certain embodiments, MMP-2 and MMP-9 inhibitors have little or no activity in inhibiting MMP-1. In certain embodiments, relative to other matrix metalloproteinases (eg, MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12 and MMP-13), MMP-2 and MMP-9 inhibitors selectively inhibit MMP-2 and/or AMP-9. Exemplary non-limiting MMP inhibitors include AG-3340, RO 32-3555 and RS 13-0830.

Exemplary non-limiting autophagy inhibitors include chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4 -Imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine glycosides, LY204002, N6-mercaptopurine riboside and vinblastine. In addition, antisense or siRNA that inhibit the expression of proteins, including but not limited to ATG5 (which is involved in autophagy), can also be used.

Exemplary non-limiting phage inhibitors include Hu5F9-G4 (Forty-Seven), CC-90002 (Celgene), TTI-621 (Trillium), ALX148 (Alexo Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui) ) and IBI188 (Innovent Biologics).

Examples of antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; antiandrogens; gonadotropin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; Tube Actives; Alkylating Agents; Retinoids, Carotenoids, or Tocopherols; Cyclooxygenase Inhibitors; MMP Inhibitors; mTOR Inhibitors; Antimetabolites; Platinum Compounds; Methionine Amino Peptides Enzyme Inhibitors; Bisphosphonates; Antiproliferative Antibodies; Heparinase Inhibitors; Ras Carcinogenic Isoform Inhibitors; Telomerase Inhibitors; Proteasome Inhibitors; Compounds for the Treatment of Hematological Malignancies; Flt-3 Inhibitor; Hsp90 Inhibitor; Kinesin Spindle Protein Inhibitor; MEK Inhibitor; Antitumor Antibiotic; Nitrosourea; / Compounds that reduce protein or lipid phosphatase activity or any other anti-angiogenic compound.

Non-limiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane; and non-steroids, such as amineglomib Aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, Fadrol fadrozole, anastrozole and letrozole.

Non-limiting antiestrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.

Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and analogs thereof, 9-nitro Camptothecin and macromolecular camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin ) and nemorubicin; anthraquinones such as mitoxantrone and losoxantrone; and podophyllotoxins such as etoposide and teniposide ).

Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and tubulin polymerization inhibitors include, but are not limited to, taxanes such as paclitaxel and docetaxel; Vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine and vincristine sulfate and vinorelbine; discodermolide; autumn Narcissine (cochicine) and epothilone (epothilone) and their derivatives.

Exemplary non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas such as carmustine and lomustine.

Exemplary non-limiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib, rofecoxib ( rofecoxib), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids such as lumiracoxib.

Exemplary non-limiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetic and non-peptidimetic inhibitors, tetracycline derivatives, batimastat, marimastat, Prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B and AAJ996.

Exemplary non-limiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity, such as sirolimus, everolimus, CCI-779 and ABT578 .

Exemplary non-limiting antimetabolites include 5-fluorouracil (5-FU); capecitabine; gemcitabine; DNA demethylation compounds such as 5-azacytidine and decitabine ( decitabine); methotrexate and edatrexate; and folic acid antagonists such as pemetrexed.

Exemplary non-limiting platinum compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.

Exemplary non-limiting methionine aminopeptidase inhibitors include benzoguanidine or derivatives thereof and PPI-2458.

Exemplary non-limiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.

Exemplary non-limiting anti-proliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab ), PR064553 and 2C4. The term "antibody" is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

Exemplary non-limiting heparanase inhibitors include compounds that target, reduce or inhibit degradation of heparin sulfate, such as PI-88 and OGT2115.

As used herein, the term "inhibitor of an oncogenic isoform of Ras" (such as H-Ras, K-Ras, or N-Ras) refers to a compound that targets Ras, reducing or inhibiting its oncogenic activity, such as farnesyl ( farnesyl) transferase inhibitors such as L-744832, DK8G557, tipifarnib and lonafarnib.

Exemplary non-limiting telomerase inhibitors include compounds that target telomerase, reduce or inhibit its activity, such as compounds that inhibit the telomerase receptor, such as telomestatin.

Exemplary non-limiting proteasome inhibitors include compounds that target, reduce or inhibit the activity of the proteasome, including, but not limited to, bortezomid.

As used herein, the phrase "use of a compound in the treatment of hematological malignancies" includes FMS-like tyrosine kinase inhibitors that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) the compounds of ; interferon, 1-beta-D arabinofuranocytosine (ara-c) and busulfan (bisulfan); ALK inhibitors, which are compounds that target, reduce or inhibit degenerative lymphoma kinase; and BH3 mimetics, which are compounds that target, reduce or inhibit anti-apoptotic proteins from the BCL-2 family.

Exemplary non-limiting Flt-3 inhibitors include gilteritinib, PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

Exemplary non-limiting HSP90 inhibitors include compounds that target the intrinsic ATPase of HSP90, reduce or inhibit its activity; or degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the activity of the intrinsic ATPase of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-desmethoxygeldanamycin (17AAG) (a geldanamycin derivative); other geldanamycin-related compounds; radicicol; and HDAC inhibitors.

Exemplary non-limiting BH3 mimetics include venetoclax.

As used herein, the phrase "a compound that targets a protein or lipid kinase/reduces its activity; or a compound that targets a protein or lipid phosphatase/reduces its activity; or any other anti-angiogenic compound" includes protein tyrosine kinases and A serine and/or threonine kinase inhibitor or a lipid kinase inhibitor, such as a) a compound that targets platelet-derived growth factor receptor (PDGFR), reduces or inhibits its activity, such as targets PDGFR, reduces or inhibits Compounds that inhibit its activity, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) targeting fibroblast growth factor receptor (FGFR) , compounds that reduce or inhibit its activity; c) compounds that target insulin-like growth factor receptor I (IGF-IR), reduce or inhibit its activity, such as compounds that target IGF-IR, reduce or inhibit its activity; d ) A compound targeting the Trk receptor tyrosine kinase family, reducing or inhibiting its activity, or an ephrin B4 inhibitor; e) targeting the Axl receptor tyrosine kinase family, reducing or inhibiting its activity f) compounds targeting Ret receptor tyrosine kinase, reducing or inhibiting its activity; g) compounds targeting Kit/SCFR receptor tyrosine kinase, reducing or inhibiting its activity, such as imatinib; h) compounds that target c-Kit receptor tyrosine kinase, reduce or inhibit its activity, such as imatinib; i) target members of the c-Abl family, gene fusion products thereof (eg Bcr-Abl kinase) and Mutants, compounds that reduce or inhibit their activity, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or Dasa dasatinib; j) protein kinase C (PKC) targeting serine/threonine kinases and members of the Raf family, members of MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/MAPK family members and/or members of the cyclin-dependent kinase family (CDK), compounds that reduce or inhibit their activity, such as staurosporine derivatives disclosed in US Pat. No. 5,093,330, such as midostaurin; others Examples of compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isoquinoline compounds; farnesyltransferase inhibitors; PD184352 or QAN697 or AT7519; k) Targeted proteins - tyrosine Kinases, compounds that reduce or inhibit their activity, such as imatinib mesylate or tyrphostin, such as typhostin A23/RG-50810; AG 99; typhostin AG 213; typhostin Taferstin AG 1748; Taferstin AG 490; Taferstin B44; Taferstin B44 (+) enantiomer; Taferstin AG 555; AG 494; Taferstin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adastin); 1) targeting receptor tyrosine Epidermal growth factor family of amino acid kinases (EGFR, ErbB2, ErbB3, ErbB4 in homo- or heterodimeric form) and mutants thereof, compounds that reduce or inhibit their activity, such as CP 358774, ZD 1839, ZM 105180; Tocilizumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies El.l, E2. 4. E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) targeting c- Met receptors, compounds that reduce or inhibit their activity.

Exemplary compounds that target protein or lipid phosphatases, reduce or inhibit their activity include phosphatase 1 inhibitors, phosphatase 2A inhibitors, or CDC25 inhibitors, such as okadaic acid or derivatives thereof.

Other anti-angiogenic compounds include compounds that have another mechanism of activity (eg, unrelated to protein or lipid kinase inhibition), such as thalidomide and TNP-470.

Additional non-limiting exemplary chemotherapeutic compounds include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idamycin idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladrix cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-lH-isoindole-l,3-dione derivatives, 1-(4-chloroanilino)- 4-(4-Pyridylmethyl)phthalein or its pharmaceutically acceptable salt, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalein succinate, vascular Somatostatin, endostatin, anthranilamide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitor, FLT-3 inhibitor , VEGFR-2 IgG1 antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocortical Alcohol, corticosterone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, plant alkaloids, hormonal compounds and/or antagonists , biological response modifiers (such as lymphatic mediators or interferons), antisense oligonucleotides or oligonucleotide derivatives, shRNA and siRNA, one or more of these chemotherapeutic compounds may be combined with the compounds of the invention used in combination.

Other examples of second therapeutic agents include, but are not limited to: for the treatment of Alzheimer's disease, such as donepezil and rivastigmine; for the treatment of Parkinson's disease, such as L -DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl and amantadine; agents used in the treatment of multiple sclerosis (MS), such as beta interferons (eg AVONEX® and REBIF®), glatiramer acetate, and mitoxal Anthraquinones; used in the treatment of asthma, such as albuterol and montelukast; used in the treatment of schizophrenia, such as zyprexa, risperdal, Syrup seroquel and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators, including immunosuppressants , such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole or antiparkinsonian agents; agents for the treatment of cardiovascular disease, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, or statins; agents used to treat liver disease, such as corticosteroids, cholestyramine, interferons, and Viral agents; agents for the treatment of blood disorders, such as corticosteroids, anti-leukemia agents, or growth factors; or agents for the treatment of immunodeficiency disorders, such as gamma globulin, one or more of these second therapeutic agents also It can also be combined with the compounds of the present invention.

The second therapeutically active agents described above are prepared and administered as described in the art, and one or more of these second therapeutically active agents may be used in combination with the compounds of the present invention.

The compounds of the present invention are generally administered in admixture with a pharmaceutical carrier selected for the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients which facilitate processing of the compounds of the present invention and/or auxiliaries.

Such pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-forming, emulsifying, encapsulating, coating, or lyophilizing processes. Appropriate formulations depend on the route of administration chosen. When a therapeutically effective amount of a compound of the present invention is administered orally, the composition is usually in the form of a lozenge, capsule, powder, solution or elixir. When administered in tablet form, the compositions may additionally contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules and powders contain from about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of the invention. When administered in liquid form, liquid carriers such as water, petroleum or oils of animal or vegetable origin can be added. Compositions in liquid form may further contain physiological saline solution, dextrose or other sugar solutions or glycols. When administered in liquid form, the compositions contain from about 0.1% to about 90% by weight, and preferably from about 1% to about 50% by weight, of a compound of the present invention.

When a therapeutically effective amount of a compound of the present invention is administered by intravenous, dermal or subcutaneous injection, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. It is within the skill of the art to prepare such parenterally acceptable solutions with due regard to pH, isotonicity, stability and the like. Preferred compositions for intravenous, dermal or subcutaneous injection typically contain an isotonic vehicle.

The compounds of the present invention can be readily combined with pharmaceutically acceptable carriers well known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th Ed. 1995. Such carriers enable the active agent to be formulated for oral ingestion by a patient to be treated as lozenges, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Pharmaceutical preparations for oral use can be obtained by adding a compound of the present invention to a solid excipient, grinding the resulting mixture as appropriate, and processing the mixture of granules, after adding suitable auxiliaries, if necessary, to obtain lozenges or Dragee cores. Suitable excipients include, for example, fillers and cellulosic preparations. If necessary, a disintegrant can be added.

The compounds of the present invention can be formulated for parenteral administration by injection (eg, by bolus injection or continuous infusion). Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of the compounds of the present invention may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, the present compositions may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

The compounds of the present invention may also be formulated in transrectal compositions such as, for example, suppositories or retention enemas containing conventional suppository bases. In addition to the formulations previously described, the compounds of the present invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins.

In particular, the compounds of the present invention may be in the form of lozenges containing excipients such as starch or lactose, or in the form of capsules or oval suppositories (alone or in admixture with excipients) or in the form of flavoring or coloring agents The dose is administered orally, bucally or sublingually in the form of an elixir or suspension. Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspending agents. Parenteral injections, eg, intravenous, intramuscular, subcutaneous or intracoronary injection, of the compounds of the invention may also be used. For parenteral administration, the compounds of the present invention are typically used in the form of sterile aqueous solutions that may contain other substances, such as salts or monosaccharides, such as mannitol or dextrose, to make solutions isotonic with blood.

The present invention provides the following specific examples related to the treatment of a disease in an individual.

Example 1. A method of treating an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of the present invention, wherein the individual has cancer.

Embodiment 2. The method of embodiment 1, wherein the cancer is any one or more of the cancers of Table 2.

Embodiment 3. The method of embodiment 2, wherein the cancer is a blood cancer.

Embodiment 4. The method of embodiment 3, wherein the blood cancer is any one or more of the cancers of Table 3.

Embodiment 5. The method of any one of Embodiments 1-4, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating cancer.

Example 6. A pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier for use in the treatment of cancer.

Embodiment 7. The pharmaceutical composition of embodiment 6, wherein the cancer is any one or more of the cancers of Table 2.

Embodiment 8. The pharmaceutical composition of embodiment 7, wherein the cancer is blood cancer.

Embodiment 9. The pharmaceutical composition of embodiment 8, wherein the blood cancer is any one or more of the cancers of Table 3.

Example 10. A compound of the present invention for use in the treatment of cancer.

Embodiment 11. The compound of embodiment 10, wherein the cancer is any one or more of the cancers of Table 2.

Embodiment 12. The compound of embodiment 11, wherein the cancer is hematological cancer.

Embodiment 13. The compound of embodiment 12, wherein the blood cancer is any one or more of the cancers of Table 3.

Example 14. Use of a compound of the present invention in the manufacture of a medicament for the treatment of cancer.

Embodiment 15. The use of embodiment 14, wherein the cancer is any one or more of the cancers of Table 2.

Embodiment 16. The use of embodiment 15, wherein the cancer is a blood cancer.

Embodiment 17. The use of embodiment 16, wherein the blood cancer is any one or more of the cancers of Table 3. III. The kit of the present invention

In another embodiment, the present invention provides kits comprising the compounds of the present invention (or compositions comprising the compounds of the present invention) encapsulated in a manner that facilitates their use in practicing the methods of the present invention . In one embodiment, a kit includes a compound of the present invention (or a composition comprising a compound of the present invention) packaged in a container, such as a sealed vial or vessel, with instructions describing methods of using the compound or composition to practice the present invention. Labels affixed to containers or included in kits. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may further comprise a device suitable for administering the composition according to the intended route of administration. IV. Definitions

In the present invention, the term "halo" as used by itself or as part of another group refers to -Cl, -F, -Br or -I.

In the present invention, the term "nitro" as used alone or as part of another group refers to _-NO2 .

In the present invention, the term "cyano" as used alone or as part of another group refers to -CN.

In the present invention, the term "hydroxyl" as used by itself or as part of another group refers to -OH.

In the present invention, the term "alkyl" as used alone or as part of another group refers to an unsubstituted straight or branched chain aliphatic hydrocarbon containing from one to twelve carbon atoms , that is, C _1-12 alkyl; or specify the number of carbon atoms, such as C ₁ alkyl (such as methyl), C ₂ alkyl (such as ethyl), C ₃ alkyl (such as propyl or isopropyl) , C _1-3 alkyl (such as methyl, ethyl, propyl or isopropyl) and the like. In one embodiment, the alkyl group is a C _1-10 alkyl group. In another embodiment, the alkyl group is a C _1-6 alkyl group. In another embodiment, the alkyl group is a C _1-4 alkyl group. In another embodiment, the alkyl group is a straight chain C _1-10 alkyl group. In another embodiment, the alkyl group is a branched _C3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C _1-6 alkyl group. In another embodiment, the alkyl group is a branched _C3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C _1-4 alkyl group. In another embodiment, the alkyl group is a straight chain _C3-4 alkyl group. In another embodiment, the alkyl group is a straight or branched chain _C3-4 alkyl group. Non-limiting exemplary _C1-10 alkyl groups include: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, isobutyl, 3-pentyl, hexyl, Heptyl, octyl, nonyl and decyl. Non-limiting exemplary _C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary-butyl, and isobutyl.

In the present invention, the term "optionally substituted alkyl" as used alone or as part of another group means unsubstituted or independently selected from one, two or Alkyl substituted with three substituents: nitro, haloalkoxy, aryloxy, aralkoxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonamido, aryl Sulfonyl, carboxyl, carboxyalkyl and alkylcarbonyloxy. In one embodiment, optionally substituted alkyl is substituted with two substituents. In another embodiment, optionally substituted alkyl is substituted with one substituent. In another embodiment, an optionally substituted alkyl group is unsubstituted. Non _{- limiting exemplary} substituted _{alkyl groups include -CH2CH2NO2 , -CH2SO2CH3} , _{-CH2CH2CO2H , -CH2SCH3 , -CH2CH2SO2CH 3.} -CH ₂ CH ₂ COPh and -CH ₂ OC(=O)CH ₃ .

In the present invention, the term "cycloalkyl" as used alone or as part of another group refers to a group containing one to three having from three to twelve carbon atoms (ie, a C _3-12 cycloalkyl group). ) or an unsubstituted saturated or partially unsaturated (eg containing one or two double bond) cycloaliphatic hydrocarbon of a ring of the specified number of carbons. In one embodiment, a cycloalkyl group has two rings. In another embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is saturated. In another embodiment, the cycloalkyl group is unsaturated. In another embodiment, the cycloalkyl group is a C _3-8 cycloalkyl group. In another embodiment, the cycloalkyl group is a C _3-6 cycloalkyl group. The term "cycloalkyl" is intended to include groups in which ring _-CH2- is replaced by -C(=O)-. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl and cyclopentanone.

(包括

)及

。In the present invention, the term "optionally substituted cycloalkyl" as used alone or as part of another group refers to one, two, unsubstituted or independently selected from the group consisting of or cycloalkyl substituted with three substituents: halo, nitro, cyano, hydroxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, amino, haloalkyl, hydroxyalkyl, alkoxy, Haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfoamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted hetero Cyclic, alkoxyalkyl, (amino)alkyl, (carbamido)alkyl, (heterocyclyl)alkyl, -OC(=O)-amino, -N(R ^19a )C (=O)-R ^19b and -N(R ^20a )SO ₂ -R ^20b , wherein R ^19a is selected from the group consisting of hydrogen and alkyl, and R ^19b is selected from amine, alkoxy, alkyl (such as C ₁ -C ₆ alkyl) and optionally substituted aryl group, R ^20a is selected from the group consisting of hydrogen and alkyl, and R ^20b is selected from the group consisting of amine, alkyl and optionally substituted A group of aryl groups. The term optionally substituted cycloalkyl includes cycloalkyl groups having a fused optionally substituted aryl group (eg, phenyl) or a fused optionally substituted heteroaryl group (eg, pyridyl). An optionally substituted cycloalkyl group having a fused optionally substituted aryl group or a fused optionally substituted heteroaryl group can be attached to the rest of the molecule at any available carbon atom on the cycloalkyl ring. connect. In one embodiment, an optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, an optionally substituted cycloalkyl is substituted with one substituent. In another embodiment, an optionally substituted cycloalkyl is unsubstituted. Non-limiting exemplary substituted cycloalkyl groups include:

(include

)and

.

。In the present invention, the term "cycloalkylene" as used herein alone or as part of another group refers to the divalent form of an optionally substituted cycloalkyl. In one embodiment, the cycloextended alkyl group is a 4-membered cycloextended alkyl group. In another embodiment, the cycloextended alkyl group is a 5-membered cycloextended alkyl group. In another embodiment, the cycloextended alkyl group is a 6-membered cycloextended alkyl group. Non-limiting exemplary cycloextended alkyl groups include:

.

In the present invention, the term "aryl" as used alone or as part of another group refers to an unsubstituted monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms, ie C _6-14 Aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthryl, anthracenyl, indenyl, azulenyl, biphenyl, biextended, and indenyl. In one embodiment, the aryl group is phenyl or naphthyl.

In the present invention, the term "optionally substituted aryl" as used herein by itself or as part of another group means unsubstituted or substituted with one to five independently selected from the group consisting of aryl substituted: halo, nitro, cyano, hydroxyl, amino, -CO- ₂ CH ₂ Ph, alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl , hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonamido , haloalkylsulfonyl, cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, carboxyl, carboxyalkyl , optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, alkoxycarbonyl, alkoxyalkane group, (amino)alkyl, (carbamido)alkyl, (heterocyclyl)alkyl, -N(R ^19a )C(=O)-R ^19b and -N(R ^20a )SO _2- R ^20b , wherein R ^19a , R ^19b , R ^20a and R ^20b are as defined for optionally substituted cycloalkyl.

。In one embodiment, optionally substituted aryl is optionally substituted phenyl. In another embodiment, an optionally substituted phenyl group has four substituents. In another embodiment, an optionally substituted phenyl group has three substituents. In another embodiment, an optionally substituted phenyl group has two substituents. In another embodiment, the optionally substituted phenyl group has one substituent. In another embodiment, the optionally substituted phenyl is unsubstituted. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl , 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4- Chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3, 4-Di-methoxyphenyl, 3,5-di-fluorophenyl, 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro- 3-chlorophenyl, 3-chloro-4-fluorophenyl, 4-(pyridin-4-ylsulfonyl)phenyl. The term optionally substituted aryl includes phenyl with fused optionally substituted cycloalkyl or fused optionally substituted heterocyclyl. An optionally substituted phenyl group with a fused optionally substituted cycloalkyl group or a fused optionally substituted heterocyclyl group can be attached to the rest of the molecule at any available carbon atom on the benzene ring. Non-limiting examples include:

.

。Additional non-limiting examples of optionally substituted aryl groups include:

.

In the present invention, the term "alkenyl" as used alone or as part of another group refers to an alkyl group containing one, two or three carbon-carbon double bonds. In one embodiment, the alkenyl group has one carbon-carbon double bond. In another embodiment, the alkenyl group is a C _2-6 alkenyl group. In another embodiment, the alkenyl group is a C _2-4 alkenyl group. Non-limiting exemplary alkenyl groups include: vinyl, propenyl, isopropenyl, butenyl, second butenyl, pentenyl, hexenyl, and -CH=C( _CH3 ) ₂ .

In the present invention, as used herein alone or as part of another group, the term "optionally substituted alkenyl" means unsubstituted or independently selected from one, two of the group consisting of Alkenyl substituted with one or three substituents: halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy, Aryloxy, Aralkoxy, Alkylthio, Carboxamido, Sulfonamido, Alkylcarbonyl, Arylcarbonyl, Alkylsulfonyl, Arylsulfonyl, Carboxyl, Carboxyalkane , optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, heteroaryl, and optionally substituted heterocyclyl.

In the present invention, the term "alkynyl" as used alone or as part of another group refers to an alkyl group containing one to three carbon-carbon linkages. In one embodiment, the alkynyl group has one carbon-carbon double bond. In another embodiment, the alkynyl group is a C _2-6 alkynyl group. In another embodiment, the alkynyl group is a _C2-4alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.

In the present invention, the term "optionally substituted alkynyl" as used herein, alone or in part, means unsubstituted or substituted with one, two or three independently selected from the group consisting of Alkynyl substituted with: halo, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy group, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkyl, as appropriate Substituted alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and heterocyclyl.

In the present invention, the term "haloalkyl" as used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is a C _1-4 haloalkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and trichloromethyl.

In the present invention, the term "hydroxyalkyl" as used alone or as part of another group refers to an alkyl group substituted with one, two or three hydroxy groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, that is, a hydroxyalkyl group substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, that is, a hydroxyalkyl group substituted with two hydroxy groups. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxyl propyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl and 1,3-dihydroxypropan-2-yl.

。In the present invention, the term "heteroaralkyl" as used alone or as part of another group refers to an alkyl group substituted with one, two or three optionally substituted heteroaryl groups. In one embodiment, heteroaralkylalkyl is C _1-4 alkyl substituted with one optionally substituted heteroaryl. Non-limiting exemplary heteroaralkyl groups include:

.

。In the present invention, the term "(cycloalkyl)alkyl," as used alone or as part of another group, refers to an alkyl group substituted with an optionally substituted cycloalkyl group. In one embodiment, (cycloalkyl)alkyl is "(C _3-6 cycloalkyl)C _1-4 alkyl," ie, C substituted with optionally substituted C _3-6 cycloalkyl _1-4 alkyl. Non-limiting exemplary (cycloalkyl)alkyl groups include:

.

In the present invention, the term "alkanesulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with an optionally substituted alkyl group, ie, _-SO2- . In one embodiment, the alkylsulfonyl group is a C _1-4 alkylsulfonyl group. A non _- limiting exemplary alkylsulfonyl group is _-SO2CH3 .

In the present invention, the term "haloalkylsulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with a haloalkyl group, ie _-SO2- . A non _- limiting exemplary alkylsulfonyl group is _-SO2CF3 .

In the present invention, the term "cycloalkylsulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with an optionally substituted cycloalkyl group, ie, _-SO2- . Non-limiting exemplary alkylsulfonyl groups include _-SO2 -cyclopropyl and _-SO2 -cyclopentyl.

。In the present invention, when used alone as part of another group, the term "(cycloalkyl)alkylsulfonyl" refers to a sulfonyl group substituted with a (cycloalkyl)alkyl group, ie -SO ₂ -. Non-limiting exemplary (cycloalkyl)alkylsulfonyl groups include:

.

In the present invention, the term "arylsulfonyl," as used alone or as part of another group, refers to a sulfonyl group substituted with an optionally substituted aryl group, ie, _-SO2- . A non-limiting exemplary arylsulfonyl group is _-SO2Ph .

。In the present invention, the term "heteroarylsulfonyl," as used alone or as part of another group, refers to a sulfonyl group substituted with an optionally substituted heteroaryl group, ie, _-SO2- . Non-limiting exemplary heteroarylsulfonyl groups include:

.

。In the present invention, the term "heterocyclic sulfonyl" as used alone or as part of another group refers to a sulfonyl group substituted with an optionally substituted heterocyclyl group, ie, _-SO2- . Non-limiting exemplary heterocyclic sulfonyl groups include:

.

。In the present invention, the term "(heterocyclyl)alkylsulfonyl," as used alone or as part of another group, refers to a sulfonyl group substituted with a (heterocyclyl)alkyl group, i.e. -SO _2- . Non-limiting exemplary (heterocyclyl)alkylsulfonyl groups include:

.

In the present invention, the term "sulfonamido" as used alone or as part of another group refers to a group of _formula ^{-SO2NR21aR21b} , wherein ^R21a and ^{R21b are} each independently selected from hydrogen , an optionally substituted alkyl group and an optionally substituted aryl group, or R ^21a and R ^21b together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic group. Non-limiting exemplary sulfonamido groups include _-SO2NH2 , _-SO2N (H) _CH3 , _-SO2N ( _CH3 ) ₂ , and _{-SO2N (} H)Ph.

In the present invention, the term "alkoxy" as used alone or as part of another group refers to an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyl group, optionally attached to a terminal oxygen atom Substituted alkenyl or optionally substituted alkynyl. In one embodiment, an alkoxy group is an optionally substituted alkyl group attached to a terminal oxygen atom. In one embodiment, the alkoxy group is a _C1-6 alkyl group attached to a terminal oxygen atom. In another embodiment, the alkoxy group is a _C1-4 alkyl group attached to a terminal oxygen atom. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tertiary butoxy, and isopropoxy.

。In the present invention, the term "heterocyclyloxy" as used alone or as part of another group refers to an oxy group substituted with an optionally substituted heterocyclyl group, ie -O-. Non-limiting exemplary heterocyclic sulfonyl groups include:

.

In the present invention, the term "alkylthio" as used alone or as part of another group refers to an optionally substituted alkyl group attached to a terminal sulfur atom. In one embodiment, the alkylthio group is a C _1-4 alkylthio group. Non _- limiting exemplary alkylthio groups include _-SCH3 and _-SCH2CH3 .

In the present invention, the term "alkoxyalkyl" as used alone or as part of another group refers to an optional alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl group, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tertiary butoxymethyl, isobutoxy methyl, second butoxymethyl and pentoxymethyl.

In the present invention, the term "haloalkoxy" as used alone or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

In the present invention, the term "aryloxy" as used alone or as part of another group refers to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

In the present invention, the term "aralkoxy" as used alone or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. Non _- limiting exemplary aralkoxy groups include _PhCH2O- and _PhCH2CH2O- .

In the present invention, the term "heteroaryl" refers to unsubstituted monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms, ie 5 to 14 membered heteroaryl groups, wherein one of the rings is At least one carbon atom is replaced with a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur. In one embodiment, a heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. In one embodiment, the heteroaryl group has three heteroatoms. In another embodiment, a heteroaryl group has two heteroatoms. In another embodiment, the heteroaryl group has one heteroatom. In another embodiment, the heteroaryl group is a 5 to 10 membered heteroaryl group. In another embodiment, the heteroaryl group is a 5- or 6-membered heteroaryl group. In another embodiment, a heteroaryl group has 5 ring atoms, such as thienyl, a 5-membered heteroaryl group having four carbon atoms and one sulfur atom. In another embodiment, a heteroaryl group has 6 ring atoms, eg, pyridyl, a 6-membered heteroaryl group having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thienyl, furyl, benzofuranyl, piperanyl, isophenyl furanyl, benzoketone, alkenyl, alkenyl, 2H -pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, isoindole base, 3 H -indolyl, indolyl, indazolyl, purinyl, isoquinolinyl, quinolinyl, phthaloyl, ethidyl, ethidyl, quinazolinyl, pteridyl, 4a H -carbazolyl, carbazolyl, β-carbolinyl, phenanthroid, acridine, pyrimidinyl, phenanthroline, phenanthyl, thiazolyl, isothiazolyl, benzothiazolyl, isothiazolyl oxazolyl, furanyl and phenanthyl. In one embodiment, the heteroaryl group is selected from the group consisting of: thienyl (eg, thien-2-yl and thien-3-yl), furyl (eg, 2-furyl and 3-furyl), pyrrole (eg 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (eg 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (eg 1H-pyrazole -3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (eg pyridin-2-yl, pyridin-3-yl and pyridin-4-yl), pyrimidinyl ( such as pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl), thiazolyl (such as thiazol-2-yl, thiazol-4-yl and thiazol-5-yl), isothiazolyl (such as isothiazole -3-yl, isothiazol-4-yl and isothiazol-5-yl), oxazolyl (eg oxazol-2-yl, oxazol-4-yl and oxazol-5-yl), isoxazole radicals (eg isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl) and indazolyl (eg 1H-indazol-3-yl). The term "heteroaryl" is also intended to include possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

In one embodiment, the heteroaryl group is a 5- or 6-membered heteroaryl group. In one embodiment, a heteroaryl group is a 5-membered heteroaryl group, that is, a heteroaryl group is a monocyclic aromatic ring system having 5 ring atoms, wherein at least one carbon atom of the ring is independently selected from nitrogen, oxygen, and Heteroatom replacement of sulfur. Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl. In another embodiment, a heteroaryl group is a 6-membered heteroaryl group, eg, a heteroaryl group is a monocyclic aromatic ring system having 6 ring atoms wherein at least one carbon atom of the ring is replaced with a nitrogen atom. Non-limiting exemplary 6-membered heteroaryl groups include pyridyl, pyridyl, pyrimidinyl, and pyridyl.

In the present invention, the term "optionally substituted heteroaryl" as used alone or as part of another group means one, two, three, unsubstituted or independently selected from the group consisting of Heteroaryl substituted with one or four substituents: halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, halo Alkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkane Sulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkane alkynyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, alkoxyalkyl, (amino)alkyl, (formyl Amino)alkyl, (heterocyclyl)alkyl, -N(R ^19a )C(=O)-R ^19b and -N(R ^20a )SO ₂ -R ^20b , wherein R ^19a , R ^19b , R ^20a and R ^20b is as defined for optionally substituted cycloalkyl. In one embodiment, the optionally substituted heteroaryl has one substituent. In another embodiment, the optionally substituted heteroaryl is unsubstituted. Any available carbon or nitrogen atom may be substituted. The term optionally substituted heteroaryl includes heteroaryl groups having a fused optionally substituted cycloalkyl group or a fused optionally substituted heterocyclyl group. An optionally substituted heteroaryl group having a fused optionally substituted cycloalkyl group or a fused optionally substituted heterocyclyl group can be attached to the rest of the molecule at any available carbon atom on the heteroaryl ring. connect.

。 5員伸雜芳基之另外非限制性實例包括：

。 在另一實施例中，伸雜芳基為6員伸雜芳基。6員伸雜芳基之非限制性實例包括：

。In the present invention, the term "heteroaryl" as used herein by itself or as part of another group refers to the divalent form of an optionally substituted heteroaryl. In one embodiment, the heteroaryl group is a 5-membered heteroaryl group. Non-limiting examples of 5-membered heteroaryl groups include:

. Additional non-limiting examples of 5-membered heteroaryl groups include:

. In another embodiment, the heteroaryl group is a 6-membered heteroaryl group. Non-limiting examples of 6-membered heteroaryl groups include:

.

In the present invention, the term "heterocyclyl" as used alone or as part of another group refers to an unsubstituted saturated ring containing one, two or three rings having three to fourteen ring members and partially unsaturated (eg containing one or two double bonds) cyclic groups, ie, 3 to 14 membered heterocyclyl groups wherein at least one carbon atom of one of the rings is replaced by a heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur (including sulfite and sulfite), and/or a nitrogen atom (which may be oxidized or quaternary amonized). The term "heterocyclyl" includes groups in which ring _-CH2- is replaced by -C(=O)-, eg, cyclic ureido groups, such as 2-imidazolidinone, and cyclic amido groups, such as beta-lactam. Amines, gamma-lactam, delta-lactam, ε-lactam and hexapiperidin-2-one. The term "heterocyclyl" also includes groups having a fused optionally substituted aryl group, such as indolinyl or oxalan-4-yl. In one embodiment, the heterocyclyl group is a _C4-6 heterocyclyl group, ie, a 4-, 5- or 6-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclyl group is a _C4-6 heterocyclyl group containing one ring and one nitrogen atom. A heterocyclyl group is optionally attached to the rest of the molecule via any available carbon or nitrogen atom. Non-limiting exemplary heterocyclyl groups include azacyclylbutyl, dioxanylhexyl, tetrahydropyranyl, 2-oxypyrrolidin-3-yl, piperazine-2-one, Piperidine-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperidine, pyrrolidinyl and indolinyl. Additional non-limiting examples of heterocyclyl include oxetanyl and tetrahydrofuranyl.

。 另外非限制性例示性經取代之雜環基包括：

。In the present invention, the term "optionally substituted heterocyclyl" as used alone or as part of another group means one, two, three, unsubstituted or independently selected from the group consisting of Heterocyclyl substituted with one or four substituents: halo, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, halo Alkoxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfoamido, cycloalkylcarbonyl, alkoxycarbonyl, CF ₃ C(=O)-, arylcarbonyl, alkane Sulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl groups, optionally substituted heterocyclyl, alkoxyalkyl, (amino)alkyl, (carbamido)alkyl, (heterocyclyl)alkyl, hydroxyalkylcarbonyl, and -N(R ^19a ) C(=O)-R ^19b and -N(R ^20a )SO ₂ -R ^20b , wherein R ^19a , R ^19b , R ^20a and R ^20b are as defined for optionally substituted cycloalkyl. Substitution can occur on any available carbon atom or nitrogen atom or both. Non-limiting exemplary substituted heterocyclyl groups include:

. Additional non-limiting exemplary substituted heterocyclyl groups include:

.

In the present invention, the term "amino" as used alone or as part of another group refers to a group of formula -NR ^22a R ^22b , wherein R ^22a and R ^22b are independently selected from the group consisting of: hydrogen , alkyl, alkenylcarbonyl, alkoxy, aralkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted The heteroaryl, (heterocyclyl)alkyl and (heteroaryl)alkyl groups, or R ^22a and R ^22b together form a 3- to 8-membered optionally substituted heterocyclyl. Non-limiting exemplary amine groups include _-NH2 , -N(H)( _CH3 ), -N( _CH3 ) ₂ .

In the present invention, the term "(amino)alkyl" as used alone or as part of another group refers to an alkyl group substituted with an optionally substituted amino group. Non _- limiting exemplary (amino)alkyl groups include _-CH2CH2NH2 and _-CH2CH2N (H) _CH3 , _{-CH2CH2N ( CH3 ) 2} and _{-CH2N (} H )-cyclopropyl. Additional non-limiting exemplary (amino)alkyl groups include _{-CH2N(CH3)2 and -CH2NH} ( _{CH3 )} . Additional non-limiting exemplary (amino)alkyl groups include _-CH2N ( _CH3 )(COCH= _CH2 ).

。 另外非限制性例示性甲醯胺基包括：

。In the present invention, the term "formamido" as used alone or as part of another group refers to a group of formula -C(=O)NR ^23a R ^23b , wherein R ^23a and R ^23b are each independently Selected from the group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted Substituted heteroaryl, or R ^23a and R ^23b together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclyl. In one embodiment, R ^23a and R ^23b are each independently hydrogen or optionally substituted alkyl. In one embodiment, R ^23a and R ^23b are taken together to form, together with the nitrogen to which they are attached, a 3- to 8-membered optionally substituted heterocyclyl. Non-limiting exemplary formamide groups include _-CONH2 , -CON(H) _CH3 , -CON( _CH3 ) ₂ , -CON(H)Ph,

. Additional non-limiting exemplary formamide groups include:

.

In the present invention, the term "alkylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an alkyl group, ie -C(=O)-. In one embodiment, the alkylcarbonyl group is a C _1-4 alkyl group attached to a carbonyl group. In another embodiment, the alkoxy group is a _C1-4 alkyl group attached to a terminal oxygen atom. Non-limiting exemplary alkylcarbonyl groups include -C(=O) _CH3 , -C(=O) _CH2CH3 , _-C (=O) _CH2CH2CH3 , and _-C ( ₌ O) _CH2 CH ₂ CH ₂ CH ₃ .

In the present invention, the term "hydroxyalkylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with a hydroxyalkyl group, ie -C(=O)-. Non-limiting exemplary alkylcarbonyl groups include _-C (=O)C( _CH3 )2OH and _-C (=O _{) CH2CH2CH2OH} .

In the present invention, the term "cycloalkylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with a cycloalkyl group, ie -C(=O)-. A non-limiting exemplary cycloalkylcarbonyl group is -C(=O)-cyclopropyl.

In the present invention, the term "arylcarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an optionally substituted aryl group, ie -C(=O)-. A non-limiting exemplary arylcarbonyl group is -COPh.

In the present invention, the term "alkoxycarbonyl" as used alone or as part of another group refers to a carbonyl group substituted with an alkoxy group, ie -C(=O)-. In one embodiment, the alkoxy group is a C _1-4 alkoxy group. Non-limiting exemplary alkoxycarbonyl groups include -C(=O)OMe, -C(=O)OEt, and -C(=O)OtBu.

In the present invention, the term "(alkoxycarbonyl)alkyl" as used alone or as part of another group refers to an alkyl group substituted with an alkoxycarbonyl group. In one embodiment, the alkoxy group is a C _1-4 alkoxy group. Non-limiting exemplary (alkoxycarbonyl)alkyl groups include _-CH2C (=O)OMe, _-CH2C (=O)OEt, and _-CH2C (=O)OtBu.

In the present invention, the term "alkenylcarbonyl" as used alone or as part of another group refers to a carbonyl substituted with an alkenyl group, ie, -C(=O)-. In one embodiment, the alkenyl group is a C _2-6 alkenyl group. In another embodiment, the alkenyl group is a C _2-4 alkenyl group. Non-limiting exemplary alkenylcarbonyl groups include -C(=O)CH= _CH2 , -C(=O)CH2CH= _CH2 , and _-C (=O _{) CH2CH2CH} = _CH2 .

In the present invention, the term "carboxy", as used alone or as part of another group, refers to a group of formula _-CO2H .

In the present invention, the term "carboxyalkyl" as used alone or as part of another group refers to an alkyl group substituted with _-CO2H . A non _- limiting exemplary carboxyalkyl group is _-CH2CO2H .

In the present invention, the term "thioamide", as used alone or as part of another group, refers to a group of formula -C(=S)NR ^23a R ^23b , wherein R ^23a and R ^23b are each independently selected The group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted The heteroaryl group, or R ^23a and R ^23b are taken together with the nitrogen to which they are attached to form a 3- to 8-membered optionally substituted heterocyclyl. In one embodiment, R ^23a and R ^23b are each independently hydrogen or optionally substituted alkyl. In one embodiment, R ^23a and R ^23b are taken together to form, together with the nitrogen to which they are attached, a 3- to 8-membered optionally substituted heterocyclyl. Non-limiting exemplary formamido groups include -C(=S) _NH2 , -C(=S)N(H) _CH3 , -C(=S)N( _CH3 ) ₂ , -C(=S )N(H)Ph.

In the present invention, the term "aralkyl" as used alone or as part of another group refers to an alkyl group substituted with one, two or three optionally substituted aryl groups. In one embodiment, aralkyl is C _1-4 alkyl substituted with one optionally substituted C ₅ or C ₆ aryl. In another embodiment, aralkyl is Ci alkyl substituted with _one optionally substituted aryl. In another embodiment, aralkyl is _C2 alkyl substituted with one optionally substituted aryl. _In another embodiment, aralkyl is C3 alkyl substituted with one optionally substituted aryl. In one embodiment, aralkyl is a _C1 or _C2 alkyl substituted with one optionally substituted phenyl. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, _-CHPh2 , -CH( _CH3 )Ph, _-CH2 (4-F-Ph), _-CH2 (4-Me-Ph) , -CH ₂ (4-CF ₃ -Ph) and -CH(4-F-Ph) ₂ .

。 另外非限制性例示性(雜環基)烷基包括：

。In the present invention, the term "(heterocyclyl)alkyl," as used alone or as part of another group, refers to an alkyl group substituted with an optionally substituted heterocyclyl group. In one embodiment, (heterocyclyl)alkyl is C _1-4 alkyl substituted with one optionally substituted heterocyclyl. Non-limiting exemplary (heterocyclyl)alkyl groups include:

. Additional non-limiting exemplary (heterocyclyl)alkyl groups include:

.

。In the present invention, the term "(heteroaryl)alkyl," as used alone or as part of another group, refers to an alkyl group substituted with an optionally substituted heteroaryl group. In one embodiment, (heteroaryl)alkyl is C _1-4 alkyl substituted with one optionally substituted heteroaryl. In another embodiment, (heteroaryl)alkyl is Ci alkyl substituted with _one optionally substituted heteroaryl. Non-limiting exemplary (heteroaryl)alkyl groups include:

.

In the present invention, the term "(carbamido)alkyl" as used alone or as part of another group refers to an alkyl group substituted with one or two carboxamido groups. In one embodiment, (carbamido)alkyl is C _1-4 alkyl substituted with one formamido, ie (carbamido)C _1-4 alkyl. In another embodiment, (carbamido)alkyl is C _1-4 alkyl substituted with two carboxamido groups. Non-limiting exemplary (carbamido)alkyl groups include _-CH2CONH2 , -C(H) _{CH3 -} CONH2, and _-CH2CON (H _{) CH3} .

In the present invention, the term "(aryloxy)alkyl" as used alone or as part of another group refers to an alkyl group substituted with an aryloxy group. In one embodiment, "(aryloxy)alkyl" is C _1-4 alkyl substituted with aryloxy. In one embodiment, "(aryloxy)alkyl" is _C2-4 alkyl substituted with aryloxy. Non _- limiting exemplary ₍ aryloxy ₎ alkyl groups include _-CH2CH2OPh and _{-CH2CH2CH2OPh} .

In the present invention, the term "alkylcarbonyloxy" as used alone or as part of another group refers to an oxy group substituted with an alkylcarbonyl group, eg -O-. Non-limiting exemplary "alkylcarbonyloxy" include -OC(=O) _CH2CH3 , -OC( ₌ O) _CH3 , ie acetoxy, -OC(=O _{) CH2CH2} CH ₃ and -OC(=O)CH(CH ₃ ) ₂ .

In the present invention, the term "cycloalkylcarbonyloxy" as used alone or as part of another group refers to an oxy group substituted with a cycloalkylcarbonyl group, eg -O-. Non-limiting exemplary "cycloalkylcarbonyloxy" include -OC(=O)-cyclopropyl and -OC(=O)-cyclopentyl.

。In the present invention, the term "aminocarbonyloxy" as used alone or as part of another group refers to an oxy group substituted with an aminocarbonyl group, ie -O-. Non-limiting exemplary formamidooxy groups include:

.

As used herein, the term "menin inhibitor" or "inhibitor of menin" refers to a compound that interferes with (eg inhibits) the interaction of a menin-MLL fusion protein.

The term "disease or condition in which inhibition of menin provides a benefit" refers to a disease or condition in which menin and/or the interaction of menin and menin-interacting proteins is important or necessary for, for example, the onset, progression or manifestation of that disease or condition. symptoms, or diseases or conditions known to be treated by menin inhibitors. Examples of such conditions include, but are not limited to, cancer, chronic autoimmune diseases, inflammatory diseases, proliferative diseases, sepsis, and viral infections. Those of ordinary skill in the art are readily able to determine whether a compound treats a disease or condition mediated by menin of any particular cell type, eg, by assays that can be suitably used to assess the activity of a particular compound.

The term "second therapeutic agent" refers to a therapeutic agent other than a compound of the present invention and known to treat the disease or condition of interest. For example, when cancer is the disease or condition of interest, the second therapeutic agent may be known chemotherapeutic drugs such as paclitaxel or radiation, for example.

The terms "disease" or "condition" refer to disorders and/or abnormalities, which are generally considered to be pathological conditions or functions and which manifest themselves in the form of specific signs, symptoms and/or dysfunctions. As demonstrated below, the compounds of the present invention are menin inhibitors and are useful in the treatment of diseases and conditions in which menin inhibition provides benefits.

As used herein, the terms "treat/treating/treatment" and the like refer to eliminating, alleviating or ameliorating a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require complete elimination of the disease, condition, or symptoms associated therewith. As used herein, the terms "treat/treating/treatment" and the like may include "prophylactic treatment," which refers to reducing the chance of recurrence of a disease or condition in an individual or recurrence of a previously controlled disease or condition The probability that the individual does not have the disease or condition but is at risk of, or susceptible to, or susceptible to a recurrence of a disease or condition or a recurrence of a disease or condition. The terms "treatment" and synonyms encompass the administration of a therapeutically effective amount of a compound of the present invention to an individual in need of such treatment.

"Treatment" within the meaning of the present invention also includes relapse prevention or stage prevention and treatment of acute or chronic signs, symptoms and/or dysfunctions. Treatment may be symptom-directed, eg, to suppress symptoms. It may be affected over a short period of time, directed over an intermediate period of time or may be a long-term treatment, such as in the context of maintenance therapy.

As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of an active ingredient that, when administered by the methods of the present invention, is sufficient to effectively deliver to an individual in need thereof the active ingredient for the treatment of the condition or disease of interest quantity. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent can reduce (ie, delay to some extent and preferably stop) unwanted cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit ( that is, to some extent delay and preferably stop) cancer cell infiltration into surrounding organs; inhibit (that is, to some extent delay and preferably stop) tumor metastasis; inhibit tumor growth to some extent; reduce target cells and/or alleviate to some extent one or more of the symptoms associated with cancer. Where the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.

The term "container" means any container and closure thus suitable for storing, transporting, dispensing and/or manipulating a medicinal product.

The term "insert label" means the information accompanying a medicinal product that provides a description of how to administer the product and the safety and efficacy information needed to allow physicians, pharmacists and patients to make informed decisions considering the product's use. Drug inserts are generally regarded as the "label" of a medicinal product.

"Concurrent administration," "combination administration," "simultaneous administration," and similar phrases mean that two or more agents are administered concurrently to an individual being treated. "Concurrent" means that the agents are administered simultaneously or sequentially at different time points in any order. However, if not administered simultaneously, it is meant that the agents are administered to the subject in an order and sufficiently close in time to provide the desired therapeutic effect and to act synergistically. For example, a compound of the present invention can be administered as a second therapeutic agent simultaneously or sequentially at different time points in any order. The compounds of the present invention and the second therapeutic agent can be administered separately in any suitable form and by any suitable route. When the compound of the present invention and the second therapeutic agent are not administered concurrently, it is understood that they can be administered to an individual in need thereof in any order. For example, the compounds of the invention can be administered to an individual in need thereof prior to administration of a second therapeutic agent treatment modality (eg, radiation therapy) (eg, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours) hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks ago), at the same time or at the same time as After that (e.g. 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks). In various embodiments, the compound of the invention and the second therapeutic agent are 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart , 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, Administrations are performed 10 to 11 hours apart, 11 to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, the components of the combination therapy are administered about 1 minute to about 24 hours apart.

Unless otherwise indicated, use of the terms "a/an", "the" and similar references in the context of the present invention (especially in the context of technical solutions) should be construed to encompass the singular and plural of both. Unless otherwise indicated herein, the recitation of ranges of values herein are intended to serve as a shorthand method of referring to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. . Unless otherwise claimed, the use of any and all examples or illustrative language (eg, "such as") provided herein is intended to better illustrate the invention and not to limit the scope of the invention. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.

As used herein, the term "about" when used in combination with a value or range of values means that the value or range of values can deviate to the extent deemed reasonable to one of ordinary skill in the art.

The compounds of the present invention possess asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention contemplates the use of all such possible forms, as well as their racemic and analytical forms, and mixtures thereof. In view of the present invention, individual enantiomers can be separated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise specified. The present invention also encompasses all tautomers. For the purposes of this application, in some embodiments, certain compounds have been assigned to have a particular stereochemical configuration, which has not been confirmed by x-ray crystallography or any other means. One of ordinary skill in the art can confirm the presence of compounds disclosed herein using one or more well-known methods, including x-ray crystallography, or by other spectroscopic techniques, such as NMR (using parachiral derivatizing agents, Mosher ester analysis, etc.) The absolute configuration of either.

As used herein, the term "stereoisomer" is a generic term for all isomers of an individual molecule that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereomers).

The term "opposite chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

The terms "enantiomer" and "enantiomer" refer to molecules that cannot be superimposed on their mirror images and are therefore optically active, wherein the enantiomer rotates the plane of polarization in one direction and the mirror image compound in the opposite direction Direction rotates the polarizing plane.

The term "racemic" refers to a mixture of equal parts of enantiomers and the mixture is optically inactive. In one embodiment, the compounds of the present invention are racemic.

The term "absolute configuration" refers to the spatial arrangement of atoms of a chiral molecular entity (or group) and its stereochemical description, eg, R or S.

Unless otherwise indicated, stereochemical terms and conventions used in this specification are intended to be consistent with those described in Pure & Appl. Chem 68 :2193 (1996).

The term "enantiomeric excess" or "ee" refers to a measure of how much one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as | RS |*100, where R and S are the respective molar or weight fractions of the enantiomers in the mixture such that R + S = 1. With knowledge of the optical rotation of chiral substances, the percent enantiomeric excess is defined as ([α] _obs /[α] _max )×100, where [α] _obs is the optical rotation of the mixture of enantiomers and [α] _max is the optical rotation of the pure enantiomer. Enantiomeric excess can be determined using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or polarimetry. In one embodiment, ee is determined by chiral HPLC. V. Synthesis of Compounds of the Invention

The compounds of the present invention can be prepared by the methods described in the Examples and by related methods known in the art.

For example, compounds of formula I can be prepared by the general method shown in Scheme 1 . Reductive amination between amine 1-A and ketone 1-B affords azaspiro 1-C, which can be used to generate intermediate 1-D after deprotection of the protecting group (PG=protecting group) Any suitable amine protecting group (eg, carboxybenzyl (Cbz)) known in . Azaspironone 1-B can be obtained from commercially available amines (eg 2-azaspiro[3.3]heptan-6-one, 2-azaspiro[3.5]nonan-7-one, 2-azaspiro[3.4]octane -6-one, 6-azaspiro[3.4]oct-2-one, 7-azaspiro[3.5]nonan-2-one and 3-azaspiro[5.5]undecan-9-one) preparation , followed by addition of suitable amine protecting groups by methods known in the art. Intermediates 1-D can then be used in the coupling reactions described in general schemes 4-6 to give compounds of formula I. Process 1

。 流程2

Alternatively, compounds of formula I can be prepared by the general method shown in Scheme 2. Reductive amination reaction between amine 2-A and ketone 1-B affords intermediate 2-B, which yields intermediate 2-C after deprotection of the protecting group PG ² on azaspiro 2-C. Any suitable amine protecting group known in the art can be used, but when multiple amine protecting groups are present, they should be different (eg PG ¹ can be tertiary butoxycarbonyl (BOC) and PG ² can be Cbz). Intermediate 2-C can then be used in the coupling reactions described in Schemes 4 to 6, followed by deprotection of the remaining protecting group PG ¹ and formation of the Q substituent, where Q is -N(H)C(=O)OR, -N(R)C(=O)OR, -N(H)C(=O)R, -N(H)C(O)NHR, -N(H)C(O)NR ₂ , -

. Process 2

。 流程3

Alternatively, compounds of formula I can be prepared by the general method shown in Scheme 3. Reductive amination reaction between amine 3-A and ketone 1-B affords intermediate 3-B, which yields intermediate 3-C after deprotection of the protecting group PG ² on azaspiro 3-B. Any suitable amine protecting group known in the art can be used, but when multiple amine protecting groups are present, they should be different (eg PG can be tertiary butoxycarbonyl ⁽ BOC) and PG can be Cbz ). Intermediate 3-C can then be used in the coupling reactions described in Schemes ₄ to ₆ , followed by deprotection of the remaining protecting groups and formation ^of the V substituent, where V is _-CH2NR1CO2Me , ^-CH2NR1 CO ₂ CD ₃ , -CH ₂ NR ¹ CO ₂ Et, -CH ₂ NR ¹ CO ₂ iPr, -CH ₂ NR ¹ CONH ₂ , -CH ₂ NHCONHCH ₂ CF ₃ , -CH ₂ NHCONHiPr, -CH ₂ NHCONHMe, - CH ₂ NHCONHEt,

. Process 3

As an example of a coupling reaction, compounds of formula I can be prepared by the general method shown in Scheme 4, wherein T is T-1, T-2, T-3, T-4, T-6, T-7, T -8, T-9, T-10, T-12, T-27, T-28, T-29, T-32, T-33, T-34 and T-35. Between azaspiro 1-D and arylfluoride 1-E or between azaspiro 1-D and arylsulfonylmethyl ₁ -F in the presence _of a base such as K2CO3 or DIPEA A nucleophilic aromatic substitution reaction occurs to give compounds of formula I. Process 4

Alternatively, compounds of formula I can be prepared by the general method shown in Scheme 5, wherein T is T-1, T-2, T-4, T-6, T-7, T-8, T-9, T -10, T-11, T-12, T-29, T-30, T-32, T-33, T-34 and T-35. A Buchwald-Hartwig amination reaction occurs between azaspiro 1-D and aryl bromide 1-F to obtain the compound of formula I. Process 5

實例 實例1Alternatively, compounds of formula I can be prepared by the general methods shown in Scheme 6 or by other methods known in the art for the preparation of sulfonamides and carbamates, wherein T is _C1 -C 4Alkylsulfonyl, cycloalkylsulfonyl, -C ₁ -C ₄ alkylcarbonyl, arylcarbonyl, T- ₅ , T-14, T-15, T-16, T-17, T- 18, T-19, T-20, T-21, T-22, T-23, T-24, T-25, T-26 and T-31. Nucleophilic substitution reaction between azaspiro 1-D and electrophile 1-G (LG=leaving group) in the presence of a base (eg K ₂ CO ₃ ) affords compounds of formula I. Process 6

Example Example 1

Synthetic intermediate S 7

synthesis S1

To (1R,2S)-2-aminocyclobutane hydrochloride SO (11 g, 79.9 mmol) and Boc2O (20.9 _g , 95.9 mmol) in dichloromethane (200 mL) at 0 °C To this solution was added _Et3N (20.9 mL, 119.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was washed with saturated brine, and the aqueous phase was extracted twice with dichloromethane. The combined organic solvents _were dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give Intermediate S1 (15.5 g, 96%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.85 (s, 1H), 4.16 (s, 1H), 3.80 (s, 1H), 2.02-1.95 (m, 1H), 1.93-1.87 (m, 1H), 1.86-1.77 (m, 2H), 1.70-1.65 (m, 1H), 1.59-1.51 (m, 2H), 1.45 (s, 9H).

synthesis S2

To a solution of thionite dichloride (7 mL, 96.3 mmol) in dry acetonitrile (150 mL) at -35 °C was added a solution of intermediate S1 (15.5 g, 77.0 mmol) in acetonitrile (150 mL) . Next, pyridine (18.7 mL, 231 mmol) was added dropwise, and the reaction mixture was slowly warmed to room temperature. After stirring overnight, the reaction mixture was concentrated, and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic solvents _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to give Intermediate S2 (18.8 g, 98%) as an oil. 1H NMR (400 MHz, CDCl3) δ 5.74 (t, J = 4.6 Hz, 1H), 4.46 (s, 1H), 2.14-2.09 (m, 1H), 1.90-1.68 (m, 5H), 1.52 (s, 9H).

synthesis S3

To a solution of intermediate S2 (18.8 g, 76 mmol) in acetonitrile (100 mL) and _H2O (100 mL) at 0 °C was added _NaIO4 (24.4 g, 114 mmol) in portions followed by RuCl _3.3H2O (315 _mg , 1.5 mmol). The reaction was stirred at room temperature for 2 hours. Next, the aqueous layer was extracted three times with diethyl ether. The combined organic solvents _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to give the title compound S3 (19 g, 95%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.18-5.15 (m, 1H), 4.56-4.53 (m, 1H), 2.23-2.18 (m, 1H), 2.06-1.95 (m, 3H), 1.87-1.77 (m, 2H), 1.55 (s, 9H). ESI-MS calculated for _C10H17NO5S [M+Na] ⁺ = _286.07 , found: _286.10 .

synthesis S5

To a solution of 2-(3-fluorophenyl)acetonitrile (5 g, 37.01 mmol) in MeOH (50 mL) was added sodium methoxide (12 mL, 55.52 mmol, 25 wt% in methanol) and stirred briefly. To this solution was added 1-benzylpiperidin-4-one (7.01 g, 37.01 mmol) and the reaction was brought to reflux. After overnight, the solvent was removed, water and EtOAc were added and the separation was performed. The aqueous layer was extracted two more times with EtOAc, dried _{over Na2SO4} , filtered and concentrated to give S4 , which was used without further purification.

Crude S4 (37.01 mmol) was redissolved in MeOH (50 mL) and NaBH4 (4.2 g, _111.03 mmol) was added slowly. After overnight, the reaction was checked by TLC (if the reaction was incomplete, more NaBH4 was added ₎ . After the conversion of S4 to S5 was complete, 8 mL of water was added and the reaction was concentrated. Additional _H2O and EtOAc were added and the layers were separated. The aqueous layer was extracted three times with EtOAc, dried _{over Na2SO4} , filtered, concentrated and purified by column chromatography (DCM/EtOAc gradient) to give S5 as an oil. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.44-7.38 (m, 1H), 7.32-7.28 (m, 4H), 7.27-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.13 -7.05 (m, 2H), 3.98 (d, J = 7.1 Hz, 1H), 3.48 (s, 2H), 2.96-2.87 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m , 1H), 1.79-1.72 (m, 1H), 1.59-1.52 (m, 1H), 1.50-1.39 (m, 2H); ESI-MS calculated for C ₂₀ H ₂₁ FN ₂ [M + H] ⁺ = 309.17, experimental value: 309.16.

Synthesis of S7 and S8

To a dry round bottom flask were added compound S5 (2.18 g, 7.07 mmol), 18-crown-6 (5.61 g, 21.21 mmol) and compound S3 (5.58 g, 21.21 mmol). Next, cover the flask with wipes and dry under vacuum in a desiccator for 1 to 2 days. After the drying step, the flask was removed from the desiccator and quickly capped with a septum. The system was evacuated and protected under nitrogen atmosphere. Next, the contents of the flask were completely dissolved with 60 mL of freshly distilled THF. Next, the solution was evacuated briefly and then placed under a nitrogen atmosphere. (This purge was repeated two additional times). The reaction was cooled to 0°C, KHMDS (0.5M in toluene, 42.4 mL, 21.21 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and stirred overnight. After overnight, a solution of concentrated _H2SO4 (0.6 mL, 11.31 mmol) in _H2O ( ₁₀ mL) was added (note: pH of the solution should be < 7), and the solution was stirred vigorously overnight. Next, the reaction mixture was slowly quenched with saturated NaHCO ₃ , basified, and extracted three times with ethyl acetate. The combined organic solvents _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography to give a 3:2 mixture of diastereomers as a yellow solid (2.5 g, 73%). The diastereomers were then separated by reverse phase preparative HPLC to give the enantiomerically pure title compounds S7 (1.2 g, 36%) and S8 (0.8 g, 24%), respectively, as trifluoroacetate salts.

Enantiopure compound S7 was also isolated by recrystallization from a 4:1 ratio of hexane to dichloromethane solution. Information on S7 : ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.44-7.39 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.31-7.22 (m, 6H), 7.11- 7.06 (m, 1H), 3.82-3.77 (m, 1H), 3.46 (s, 2H), 2.91 (t, J = 12.5 Hz, 2H), 2.81-2.76 (m, 1H), 2.07-1.93 (m, 5H), 1.80-1.72 (m, 1H), 1.62-1.46 (m, 5H), 1.33 (s, 9H), 1.27-1.17 (m, 2H); C ₃₀ H ₃₈ FN ₃ O ₂ [M + H] ESI-MS calculated for ⁺ = 492.29, found: 492.36. [α] _E9 ⁰ = + 23.1, (c 1.17×10 ^-3 g/mL, MeOH); t _R (UPLC) = 4.46 min. Information on S8 : ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.50-7.43 (m, 6H), 7.27 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H) , 7.14 (t, J = 8.3 Hz, 1H), 4.24 (s, 2H), 4.02-3.98 (m, 1H), 3.54-3.45 (m, 2H), 3.08 (t, J = 11.4 Hz, 2H), 2.88-2.83 (m, 2H), 2.59 (t, J = 11.8 Hz, 1H), 2.25 (d, J = 14.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.79-1.74 (m, 1H) , 1.67-1.57 (m, 3H), 1.46 (s, 9H), 1.43-1.37 (m, 2H), 1.33-1.18 (m, 1H); C ₃₀ H ₃₈ FN ₃ O ₂ [M + H] ⁺ ESI-MS calculated = 492.29, found: 492.36. [α] _E9 ⁰ = + 9.4, (c 1.07 × 10 ^-3 g/mL, MeOH); t _R (UPLC) = 4.63 min. The absolute stereochemistry of S7 and S8 was determined by single crystal x-ray analysis of S7. See S. Xu et al., "Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction", 57 Angew. Chem. Int. Ed. 1601-05 (2018). Example 2

Synthesis of intermediate ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidine- 4-yl)ethyl)cyclopentyl)carbamate ( E5 )

((1S,2R)-Methyl 2-((S)-(1-benzylpiperidin-4-yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl)carbamate ( E3 ): Compound S7 (1.0 g, 2.04 mmol) was dissolved in DCM ( ₂ mL), and then _CF3CO2H (6 mL) was added. After 15 minutes, the reaction was complete and the solvent was removed in vacuo to yield El, which was used without purification. Dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution of El and _Et3N (1.13 mL, 8.16 mmol) in DCM (30 mL) at 0 °C. After 2 hours, the reaction was concentrated and purified by column chromatography to give E2 (770 mg).

((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl ) Methyl carbamate ( E3 ): Diisobutylaluminum hydride (3.90 mL, 6.86 mmol) was slowly added to a solution of E2 (770 mg, 1.715 mmol) in toluene (17 mL) at 0 °C. After 1 hour at 0°C, the reaction was allowed to warm to room temperature for 15 minutes and then slowly quenched with 2M NaOH. The quenched reaction was diluted with ethyl acetate, brine and extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated and evacuated to remove residual solvent. This crude product was redissolved in methanol and then treated with NaBH4 ₍ 130 mg, 3.43 mmol). After overnight, the reaction was quenched with 2M NaOH, diluted with ethyl acetate, brine, and then extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered, concentrated and evacuated to remove residual solvent to give crude E3 (775 mg).

((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate ( E4 ): At 0 °C, ammonium acetate (340 mg, 4.42 mmol), glyoxal (641 µL, 40% in water, 4.42 mmol) and acetaldehyde (495 µL, 8.83 mmol)) were added to a solution of E3 (400 mg, 0.883 mmol) in methanol (25 mL). After stirring at 0°C for 30 minutes, the reaction was removed from the ice bath and allowed to stir at room temperature for 1 hour, then heated to 60°C. After heating at 60°C overnight, the reaction was concentrated and purified by preparative HPLC to yield E4 (406 mg).

((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidin-4-yl )ethyl)cyclopentyl)carbamate ( E5 ): Dissolve E4 (406 mg, 0.784 mmol) with 10 mL of methanol, and purge the solution twice by evacuation briefly followed by the addition of an atmosphere of nitrogen. Pd/C (200 mg, 10%/carbon) was added quickly, then the reaction was evacuated and placed under an atmosphere of H2 for ₂ hours. After filtering off the Pd/C catalyst through celite, the solvent was removed in vacuo to give E5 (318 mg) which was used without further purification. Example 3

Preparation of intermediate ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(piperidin-4-yl)-2-(4H-1,2,4-tris oxazol-4-yl)ethyl)cyclopentyl)carbamate ( E7 )

Step A: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(4H-1, Methyl 2,4-triazol-4-yl)ethyl)cyclopentyl)carbamate ( E6 )

A solution of triethyl orthoformate (1.29 mL, 7.716 mmol, 1.8 equiv), carboxylhydrazine (397 mg, 6.614 mmol, 1.5 equiv) in MeOH (10 mL) was refluxed at 70 °C. Then the ((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl) ring Amyl)carbamate ( E3 ) (2 g, 4.409 mmol, 1.0 equiv) was added to the above solution. The mixture was further refluxed overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give E6 (1.8 g, 81% yield) as a white solid. LC-MS: 506 (M+H) ⁺ .

Step B: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(piperidin-4-yl)-2-(4H-1,2,4-tris oxazol-4-yl)ethyl)cyclopentyl)carbamate ( E7 )

To ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(4H-1,2, To a mixture of methyl 4-triazol-4-yl)ethyl)cyclopentyl)carbamate ( E6 ) (1.8 g, 3.56 mmol, 1.0 equiv) in _CF3CH2OH ( ₁₈ mL) was added 20 % Pd(OH) ₂ /C (0.36 g, 10% w/wt). The reaction was stirred at 25 °C for 16 h under a _H2 atmosphere (1 atm). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give E7 (1.4 g, 95% yield), which was used directly in the next step. LC-MS: 416 (M+1) ⁺ . Example 4

Preparation of intermediate ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(piperidin-4-yl)-2-(1H-pyrazol-1-yl) Ethyl)cyclopentyl)carbamate ( E11 )

Step A: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-((3-( Trimethylsilyl)prop-2-yn-1-yl)amino)ethyl)cyclopentyl)carbamate ( E8 )

((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl Methyl)cyclopentyl)carbamate ( E3 ) (2 g, 4.42 mmol, 1.0 equiv) and 3-(trimethylsilyl)propanal (668 mg, 5.3 mmol, 1.2 equiv) in DCE (15 mL) for 3 hours. To the above solution was then added _NaBH3CN (1.388 g, 22.1 mmol, 5 equiv) and the mixture was stirred at room temperature overnight. The reaction was then quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give E8 (2.3 g, 93% yield) as a white solid. LC-MS: 564 (M+1) ⁺ .

Step B: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(propan-2- Alkyn-1-ylamino)ethyl)cyclopentyl)carbamate ( E9 )

((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-((3 -(Trimethylsilyl)prop-2-yn-1-yl)amino)ethyl)cyclopentyl)carbamate ( E8 ) (2.3 g, 4.08 mmol, 1.0 equiv) and K ₂ CO A mixture of ₃ (1.69 g, 12.24 mmol, 3.0 equiv) in MeOH (15 mL) for 4 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give E9 (1 g, 95% yield) as a white solid. LC-MS: 492 (M+1) ⁺ .

Step C: 1-((S)-2-(1-benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methyl Oxycarbonyl)amino)cyclopentyl)ethyl)-1H-pyrazole 2-oxide ( E10 )

((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(propane- Methyl 2-yn-1-ylamino)ethyl)cyclopentyl)carbamate ( E9 ) (700 mg, 1.43 mmol, 1.0 equiv), NaNO ₂ (295 mg, 4.28 mmol, 3 equiv) and AgOTf (36 mg, 0.14 mmol, 0.1 equiv) in _CHCl3 (10 mL), and then acetic acid (2.5 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into water (10 mL) and diluted with saturated aqueous NaHCO ₃ (15 mL) and extracted with DCM (20 mL×3). The organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give E10 (500 mg, 92% yield) as a white solid. LC-MS: 521 (M+1) ⁺ .

Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-1-(piperidin-4-yl)-2-(1H-pyrazol-1-yl) Ethyl)cyclopentyl)carbamate ( E11 )

1-((S)-2-( ₁ -benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-( (1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)-1H-pyrazole 2-oxide ( E10 ) (500 mg, 0.96 mmol) and 20% Pd(OH) ) ₂ /C (100 mg, 20% w/wt) in CF ₃ CH ₂ OH (15 ml) for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give E11 (270 mg, 68% yield) as a white solid. LC-MS: 415(M+1) ⁺ . Example 5

Synthetic Intermediate A14

Synthesis of cyclopropyl(4-fluorophenyl)sulfane ( A13 ): To a stirred solution of A12 (2.0 mL, 18.7 mmol) in DMSO (50 mL) was added cyclopropyl bromide (1.6 mL) under _N2 atmosphere , 20.6 mmol) and t-BuONa (4.49 g, 46.8 mmol). The reaction mixture was then heated at 80°C for 24 hours. After cooling to room temperature, the mixture was poured into _H2O (250 mL) and extracted three times with _Et2O . The combined organic phases were washed with brine, dried _{over Na2SO4} and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc 100:1 to 15:1) to give A13 (1.32 g, 42%).

Synthesis of 1-(cyclopropylsulfonyl)-4-fluorobenzene ( A14 ): m-CPBA (4.28 g, 17.4 mmol, 70%) was added to A13 (1.46 g, 8.68 mmol) in DCM at 0 °C (80 mL) in a stirred solution. After 2 hours, the reaction mixture was quenched with 1M NaOH (aq) and extracted three times with DCM. The combined organic phases were washed with brine, dried _{over Na2SO4} and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc 10:1 to 1:1) to give A14 (1.58 g, 91%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 - 7.91 (m, 2H), 7.28 - 7.22 (m, 2H), 2.47 (tt, 1H), 1.40 - 1.34 (m, 2H), 1.11 - 1.03 (m , 2H). Example 6

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-azaspiro[ 3.3] Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)ethyl ) cyclopentyl) methyl carbamate ( compound 6 )

Step A: ((1S,2R)-2-((S)-(1-benzylpiperidin-4-yl)(cyano)(3-fluorophenyl)methyl)cyclopentyl)amino Methyl formate (J-1)

Compound S7 (1.0 g, 2.04 mmol) was dissolved in DCM ( ₂ mL), and then _CF3CO2H (6 mL) was added. After 15 minutes, the reaction was complete and the solvent was removed by rotary evaporation to give a residue that was used without purification. Dimethyl dicarbonate (410 mg, 3.05 mmol) was added to a solution of crude deprotected S7 and _Et3N (1.13 mL, 8.16 mmol) in DCM (30 mL) at 0 °C. After 2 hours, the reaction was concentrated and purified by column chromatography to give J-1 (770 mg). ESI-MS calculated for _C27H33FN3O2 [ _{M +} H] ⁺ = _450.25 , found: 450.45.

Step B: ((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl) Cyclopentyl) Methyl Carbamate (J-2)

Diisobutylaluminum hydride (3.90 mL, 6.86 mmol) was added to a solution of J-1 (770 mg, 1.715 mmol) in toluene (17 mL) at 0 °C. After 1 hour at 0°C, the reaction was allowed to warm to room temperature for 15 minutes and then slowly quenched with 2M NaOH. The quenched reaction was diluted with ethyl acetate and brine and extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered through celite, concentrated and evacuated to remove residual solvent. This crude product was redissolved in methanol and treated with NaBH4 ₍ 130 mg, 3.43 mmol). After stirring overnight, the reaction was quenched with 2M NaOH, diluted with ethyl acetate and brine, and extracted 3 times. The combined organic layers were dried over sodium sulfate, filtered, concentrated and evacuated to remove residual solvent to give crude J-2 (775 mg). ESI-MS calculated for _C27H37FN3O2 [ _{M +} H] ⁺ = _454.28 , found: 454.41.

Step C: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy- 3-Methylazetidin-1-yl)ethyl)cyclopentyl)carbamate (J-4)

In a microwave reaction tube, compound J-2 (300 mg, 0.662 mmol) and epoxide J-3 (70 mg, 0.662 mmol) were dissolved in n-butanol (6 mL), and the reaction was carried out at 140 °C microwave for 20 hours. After cooling, the reaction was diluted with MeOH/ _H2O (1:1), acidified with trifluoroacetic acid and purified by preparative HPLC to give J-4 (140 mg). ESI-MS calculated for _C31H43FN3O3 [ _M +H] ⁺ _{= 524.69} , found: 524.22.

Step D: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)-1 -(Piperidin-4-yl)ethyl)cyclopentyl)carbamate (J-5)

Compound J-4 (140 mg, 0.267 mmol) was dissolved with 4 mL of methanol and the solution was purged twice by a brief vacuum followed by the addition of a nitrogen atmosphere. Pd/C (50 mg, 10% wt) was added quickly, then the reaction was evacuated and placed under an atmosphere of H2 for ₂ hours. After filtering off the Pd/C catalyst through celite, the solvent was removed by rotary evaporation to give the product J-5 (113 mg), which was used without further purification. ESI-MS calculated for _{C24H37FN3O3 [ M} +H] ⁺ ₌ 434.57, found: 434.23.

Step E: ((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3 -Fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl)ethyl)cyclopentyl)carbamate (J-7)

Triethylamine (0.096 mL, 0.692 mmol) was added to a solution of J-5 (100 mg, 0.231 mmol) in 1,2-dichloroethane (2.5 mL) and the reaction was stirred for 10 minutes. Compound J-6 (73 mg, 0.347 mmol) was added to the reaction and stirred for 1 hour. Next, sodium triacetoxyborohydride (195 mg, 0.924 mmol) was added, and the reaction was stirred. After 2 hours, the reaction was complete as detected by UPLC, so it was diluted with methanol, concentrated, and then purified by preparative HPLC. The solvent was removed by rotary evaporation and the residue was treated with _CF3CO2H ( ₁ mL) to remove the Boc protection of the amine. After 10 minutes, the trifluoroacetic acid was removed and the remaining product was dissolved in acetonitrile, water, and lyophilized to give J-7 (94 mg). ESI-MS calculated for _C30H46FN4O3 [ _{M +} H] ⁺ ₌ 529.71, found: 529.53.

Step F: ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)phenyl)-2-aza Spiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-hydroxy-3-methylazetidin-1-yl) Ethyl)cyclopentyl)methylcarbamate ( Compound 6)

Potassium carbonate (20 mg, 0.144 mmol) was added to a solution of J-7 (19 mg, 0.0360 mmol) and J-8 (10.4 mg, 0.0540 mmol) in DMSO (0.5 mL), and the reaction was heated to 90°C. After 1 hour, the reaction was complete, so it was cooled to room temperature and water, methanol and trifluoroacetic acid were added. The solution was purified by preparative HPLC to give compound 6 (14 mg) as a white powder. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 (d, 1H), 7.45 (q, 1H), 7.19 - 7.08 (m, 2H), 7.06 - 6.97 (m, 1H), 6.48 (dd, 1H) ), 6.36 (d, 1H), 4.72 - 4.61 (m, 1H), 4.55 - 4.39 (m, 2H), 4.32 - 4.19 (m, 2H), 4.04 (s, 2H), 3.91 (s, 2H), 3.86 (s, 1H), 3.60 - 3.51 (m, 1H), 3.46 - 3.41 (m, 1H), 3.22 (s, 3H), 3.11 (s, 3H), 2.92 (s, 3H), 2.87 - 2.67 ( m, 4H), 2.66 - 2.57 (m, 2H), 2.44 - 2.33 (m, 2H), 2.16 - 2.04 (m, 2H), 2.04 - 1.94 (m, 2H), 1.84 - 1.59 (m, 6H), 1.53 (s, 2H), 1.45 - 1.29 (m, 2H), 0.94 - 0.80 (m, 1H). ESI-MS calculated for _{C40H54FN6O4 [} M ₊ H] ⁺ = _701.90 , found: 701.62. Example 7

Preparation of ((1S,2R)-2-(1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate ( Compound 45 )

Synthetic A1

To a solution of S7 (15 g, 30.5 mmol) in methanol/THF (150/75 mL) was added acetic acid (3.5 mL, 61.1 mmol) and Pd/C (1.5 g, 10 wt%) under _N2 atmosphere . The mixture was then stirred at room temperature under a hydrogen atmosphere (normal pressure). After 4 hours, the Pd/C catalyst was filtered off and the solvent was removed by rotary evaporation to give A1 which was used without further purification.

Synthetic A2

The A1 obtained in the previous step was dissolved in DCM (250 mL). Triethylamine (10.6 mL, 76.3 mmol) and N-(benzyloxycarbonyloxy)butanediimide (7.6 g, 30.5 mmol) were then added. The mixture was then stirred at room temperature for 1 h. After stirring at room temperature for 1 h, the solvent was removed by rotary evaporation. The mixture was purified by flash column chromatography (hexane/EtOAc as eluent) to give A2 as a white foam.

Synthesis of Pt catalyst

[PtH(PMe ₂ OH)(PMe ₂ O) ₂ H] was prepared according to the procedure set forth in Tetrahedron Letter , 1995 , 36 , 8657. The reaction time was extended to 5 hours.

Synthesis of A3 (see J. Org. Chem . 2004 , 69 , 2327)

To a solution of A2 (3.93 g, 6.83 mmol) in ethanol/ _H2O (30/10 mL) was added [PtH( _PMe2OH )( _{PMe2O )} 2H] (146 mg, 0.341 mmol). The mixture was heated at 120°C for 4 days in a sealed tube. The solvent was removed by rotary evaporation and the mixture was purified by flash column chromatography (hexane/EtOAc as eluent) to give A3 (1.33 g, 34%, 62% brsm) as a white foam.

Synthetic A4

A3 (1.33 g, 2.40 mmol) was dissolved in dichloromethane (7 mL) and trifluoroacetic acid (3.5 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo to give A4 , which was used without further purification.

Synthetic A5

A4 obtained in the previous step was dissolved in acetonitrile/ _H2O (12/6 mL). K2CO3 _{( 2.0} g, 14.4 mmol) and propene bromide (0.83 mL, 9.60 mmol) were then added. The mixture was stirred at room temperature overnight. Water was then added and the mixture was extracted three times with EtOAc, concentrated and purified by flash column chromatography (DCM/MeOH as eluent) to give A5 (1.27 g, 99%) as a white solid.

Synthetic A6

A5 (250 mg, 0.47 mmol) was dissolved in THF (5 mL). NaH (68 mg, 2.82 mmol) was added at 0 °C and the mixture was stirred for 30 min. Then MeI (116 μL, 1.88 mmol) was added, and the mixture was stirred overnight. Water was then added and the mixture was extracted three times with EtOAc, concentrated and purified by flash column chromatography (DCM/MeOH as eluent) to give A6 (150 mg, 58%).

Synthetic A7

A6 (150 mg, 0.274 mmol) was dissolved in DMF (2 mL). NaH (44 mg, 1.10 mmol) was added at 0 °C and the mixture was stirred for 30 min. Then MeI (101 μL, 1.64 mmol) was added and the mixture was stirred overnight. Water was then added and the mixture was extracted three times with EtOAc, concentrated and purified by flash column chromatography (DCM/MeOH as eluent) to give A7 (103 mg, 67%).

Synthetic A8

Pd( _PPh3 ) ₄ (51 mg, 0.44 mmol) and barbituric acid (400 mg, 2.64 mmol) were added to A7 (245 mg, 0.44 mmol) in DCM (6 mL) under argon atmosphere in solution. The mixture was heated at 35°C for 5 hours and then cooled to room temperature. DIPEA (768 µL, 4.4 mmol) and dimethyl dicarbonate (118 mg, 0.88 mmol) were added. After stirring at room temperature for 2 hours, water was added and the mixture was extracted three times with DCM, concentrated and purified by flash column chromatography (DCM/MeOH as eluent) to give A8 (145 mg, 61%).

Synthetic A9

To a solution of A8 (145 mg, 0.268 mmol) in methanol (4 mL) was added acetic acid (31 μL, 0.536 mmol) and Pd/C (40 mg, 10 wt%) under N ₂ atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere (normal pressure). After 4 hours, the Pd/C catalyst was filtered off and the solvent was removed by rotary evaporation to give the amide A9 , which was used without further purification.

Synthetic A11

To a solution of A9 (110 mg, 0.272 mmol) in DCE (3 mL) was then added _Et3N (94 μL, 0.679 mmol), AcOH (47 μL, 0.816 mmol) and A10 (86 mg, 0.408 mmol). After 3 hours, NaBH(OAc) ₃ (173 mg, 0.816 mmol) was added. The mixture was stirred overnight, quenched with water, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to give the title compound A11 as the trifluoroacetate salt (132 mg, 81% yield).

Synthesis of ((1S,2R)-2-(1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-2-(dimethylamino)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate ( Compound 45 )

Compound A11 (60 mg, 0.100 mmol) was dissolved in DCM (2 mL) followed by the addition of trifluoroacetic acid (0.2 mL). After stirring at room temperature for 2 hours, the reaction mixture was evaporated to give the crude title product without further purification.

The crude deprotected product and K2CO3 ( _{55 mg} , 0.400 mmol) were added to a solution of Intermediate A14 (30 mg, 0.150 mmol) in DMSO (1.5 mL). The mixture was stirred at 80°C overnight. The mixture was quenched with water and purified by reverse phase preparative HPLC to give compound 45 as the trifluoroacetate salt (42 mg, 61% yield). ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 11.18 (s, 1H), 7.71 - 7.59 (m, 2H), 7.53 - 7.32 (m, 1H), 7.19 (s, 1H), 7.14 - 6.92 (m , 2H), 6.54 - 6.44 (m, 2H), 5.74 (s, 1H), 4.03 (s, 2H), 3.92 (d, 2H), 3.78 (s, 1H), 3.64 (s, 3H), 3.52 ( d, 3H), 3.13 (s, 2H), 2.92 (s, 3H), 2.68 - 2.58 (m, 5H), 2.52 - 2.45 (m, 3H), 2.19 (s, 2H), 2.08 (d, 1H) , 1.89 (d, 1H), 1.51 (d, 3H), 1.37 (s, 2H), 1.30 (s, 2H), 1.16 - 1.08 (m, 2H), 1.01 - 0.91 (m, 2H). ESI-MS calculated for _C37H50FN4O5S [M ₊ H] ⁺ = _681.35 , found: _681.19 . Example 8

Preparation ((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl) -Methyl 1-(3-fluorophenyl)-2-methoxyethyl)cyclopentyl)carbamate ( Compound 24 )

Synthesis of ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-iminoethyl) ring Amyl) tertiary butyl carbamate ( S9 )

S7 (2 g, 4.1 mmol), dry toluene (40 ml) were added to the flask and cooled to 0 °C in an ice bath. Diisobutylaluminum hydride (25% in toluene, 10.8 mL, 16.3 mmol) was slowly injected into the reaction mixture with a syringe at 0 °C with stirring. The ice bath was removed and the reaction was monitored using UPLC-mass spectrometry (about 4 hours). After the mass of S7 (492) disappeared, 20 ml of NaOH (1 M) solution was slowly added to the reaction mixture at 0 °C to quench the reaction. After stirring for 5 minutes, the ice bath was removed and 20 ml of saturated brine was added. After adding about 50 mL of EtOAc, a gel formed. The gel was filtered through celite, washed with EtOAc and the solvents were combined. The solution was extracted twice with EtOAc and DCM. The organic solvent was dried _{over Na2SO4} , filtered, and concentrated in vacuo to give the crude product S9 without further purification.

Synthesis of ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-oxyethyl) ring Amyl) tertiary butyl carbamate ( B1 )

S9 (obtained in the previous step) was dissolved in 1,4-dioxane (30 mL). _H2O and acetic acid (5 mL) were added, and the mixture was heated at reflux overnight. A saturated solution of _NaHCO3 was then carefully added to the mixture, and the solution was extracted three times with EtOAc. The organic solvent was dried _{over Na2SO4} , filtered and concentrated in vacuo to give the crude product B1 (1.86 g) without further purification. ESI-MS calculated for _C30H40FN2O3 [M ₊ H] ⁺ _{= 495.30} , found: 495.51.

Synthetic C3

C3 was prepared from B1 according to the procedure described for the preparation of A5 .

Synthetic C4

To a solution of C3 (400 mg, 0.77 mmol) in MeOH/THF (9/3 mL) at 0 °C was slowly added NaBH4 (114 mg, 3.08 mmol, ₄ equiv) and the reaction mixture was stirred at room temperature 2 hours. The reaction mixture was concentrated and diluted with water. The solution was extracted with EtOAc. The organic solvent was dried _{over Na2SO4} , filtered and concentrated under rotary vacuum. The mixture was purified by flash column chromatography (DCM/MeOH as eluent) to give C4 as a white foam.

Synthetic C5

C4 (278 mg, 0.535 mmol) was dissolved in THF (3 mL). NaH (43 mg, 1.07 mmol) was added at 0 °C and the mixture was stirred for 30 min. Then MeI (100 μL, 1.61 mmol) was added and the mixture was stirred overnight. Water was then added and the mixture was extracted three times with EtOAc, concentrated and purified by flash column chromatography (DCM/MeOH as eluent) to give C5 .

Synthetic C7

C7 was prepared according to the procedure described for the preparation of A9 .

Synthesis of ((1S,2R)-2-(1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl) -Methyl 1-(3-fluorophenyl)-2-methoxyethyl)cyclopentyl)carbamate ( Compound 24 )

Compound 24 was prepared from C7 according to the procedure described for the preparation of compound 45 . ESI-MS calculated for _C34H44FN4O3 [M ₊ H] ⁺ _{= 575.34} , found: 575.20. Example 9

Synthesis of ((1S,2R)-2-(1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxyethyl)cyclopentyl)carbamate ( Compound 23)

Synthetic D1

D1 was prepared according to the procedure described for the preparation of C4 starting from B1 .

Synthetic D4

D4 was prepared according to the procedure described for the preparation of B5 starting from D1 .

Synthesis of ((1S,2R)-2-(1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxyethyl)cyclopentyl)carbamate ( Compound 23)

Compound 23 was prepared from C4 according to the procedure described for the preparation of compound 45 . ESI _- MS calculated for _C35H47FN3O5S [ _M +H] ⁺ = _640.32 , found: 640.25. Example 10

Synthesis of ((1S,2R)-2-((S)-1-(1-(2-(4-(cyclopropylsulfonyl)phenyl)-2-azaspiro[3.3]heptane-6 -yl)piperidin-4-yl)-1-(3,5-difluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ( Compound 220 )

Intermediate F3 was prepared according to the procedure described for the preparation of S7 , the corresponding mono-F analog of F3 .

Compound F3 (1.2 g, 2.4 mmol) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (5 mL) was added slowly at 0 °C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under vacuum and redissolved in 50 mL of DCM. Amberlyst® A21 (2 g) (resin, Sigma cat. no. 216410) was added and stirred for 30 minutes to neutralize the TFA. Next, the resin was filtered and the organic solvent was concentrated to give crude F5 without further purification. ESI-MS: 424.7.

F5 (402 mg, 0.95 mmol) was dissolved in dry dichloromethane (10 mL). DIPEA (0.66 mL, 3.8 mmol) and dimethyl dicarbonate (152 mg, 1.1 mmol) were added at 0 °C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase preparative HPLC to give F6 . ESI-MS: 482.5.

F6 (294 mg, 0.61 mmol) was added to a dry RB flask, which was evacuated under _N2 atmosphere. Anhydrous toluene (5 ml, Sigma cat. no. 244511) was added to the flask and the flask was cooled to 0°C in an ice bath. Diisobutylaluminum hydride (25% in toluene, 1.6 mL) was slowly injected into the reaction mixture with a syringe at 0 °C with stirring. The ice bath was then removed, and the reaction was monitored using UPLC-mass spectrometry (about 4 hours). 2 ml of NaOH (1M) solution was slowly added to the reaction mixture at 0°C to quench the reaction. After stirring for 5 minutes, the ice bath was removed and 2 ml of saturated brine was added. After adding about 10 mL of EtOAc, a gel formed. The gel was filtered through celite, washed with EtOAc and the solvents were combined. The solution was extracted twice with EtOAc and DCM, respectively. The organic solvent was dried _{over Na2SO4} , filtered and concentrated under rotary vacuum. Then DCM (5 ml) was added and concentrated again. The residue was then redissolved in MeOH ( ₁₀ mL) and NaBH4 (46 mg, 1.2 mmol) was added slowly at 0 °C. The reaction mixture was stirred at room temperature and monitored using UPLC-Mass Spectrometry. The reaction mixture was concentrated and diluted with water. The solution was extracted twice with EtOAc and DCM, respectively. The organic solvent was dried _{over Na2SO4} , filtered, and concentrated in vacuo to give crude product F7 . ESI-MS: 382.9.

To a solution of Intermediate F7 (200 mg, 0.52 mmol) in methanol (10 mL) was added glyoxal (40% in water, 0.24 mL, 2.6 mmol), ammonium acetate (200 mg, 2.6 mmol) at room temperature ) and formaldehyde (37% aqueous solution, 0.43 mL, 5.2 mmol). The mixture was stirred at 60°C for 1 to 2 days. Next, the mixture was concentrated and purified by reverse phase preparative HPLC to give F8 . ESI-MS: 433.8.

Compound 220 was prepared from F8 according to the procedure described for the preparation of compound 45 . 1H NMR (400 MHz, methanol- d ₄ ) δ 8.98 (s, 1H), 7.71 - 7.62 (m, 2H), 7.61 - 7.51 (m, 2H), 7.39 - 7.24 (m, 2H), 7.07 (tt, 1H), 6.63 - 6.42 (m, 2H), 5.05 (q, 2H), 4.05 (s, 2H), 3.92 (s, 2H), 3.58-3.50 (m, 4H), 3.46-3.43 (m, 1H) , 2.92 - 2.79 (m, 1H), 2.77 - 2.38 (m, 8H), 2.30 - 2.17 (m, 1H), 2.10 - 1.88 (m, 2H), 1.65-1.56 (m, 1H), 1.51 - 1.28 ( m, 7H), 1.20-1.14 (m, 3H), 1.03-1.00 (m, 2H). Example 11

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine- Methyl 4-yl)-1-(3-fluorophenyl)-2-((methoxycarbonyl)amino)ethyl)cyclopentyl)carbamate ( Compound 36 )

G1 was prepared from S7 according to the procedure described for the preparation of F7 .

G1 (908 mg, 2 mmol) was dissolved in dry dichloromethane (20 mL). Next, DIPEA (1.4 mL, 8 mmol) and dimethyl dicarbonate (321 mg, 2.4 mmol) were added at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase preparative HPLC to give G2 . ESI-MS: 512.9.

To a solution of G2 (500 mg, 0.98 mmol) in methanol (15 mL) was added acetic acid (31 μL, 0.536 mmol) and Pd/C (150 mg, 10 wt%) under _N2 atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere (normal pressure). After 4 hours, the Pd/C catalyst was filtered off, and the solvent was removed by rotary evaporation to give G3 , which was used without further purification. ESI-MS: 422.7.

Compound 36 was prepared from G3 according to the procedure described for the preparation of compound 45 . 1H NMR (400 MHz, methanol - d ₄ ) δ 7.48 - 7.40 (m, 2H), 7.40 - 7.34 (m, 1H), 7.27 - 7.14 (m, 2H), 7.06 - 6.95 (m, 1H), 6.52 - 6.32 (m, 2H), 4.17 - 3.95 (m, 3H), 3.90 - 3.77 (m, 4H), 3.65 (s, 3H), 3.61 - 3.42 (m, 6H), 2.76-2.73 (m, 1H), 2.68 - 2.54 (m, 3H), 2.50-2.48 (m, 1H), 2.42 - 2.32 (m, 2H), 2.27-2.20 (m, 2H), 1.99 - 1.80 (m, 2H), 1.70 - 1.17 (m , 7H). ESI-MS: 618.91. Example 12

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(((E)-3-(methylsulfonyl)allyl)) Oxy)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate ( compound 187 )

Step A: (E)-3-Bromo-1-(methylsulfonyl)prop-1-ene

Stir 1,2-dibromo-3-(methylsulfonyl)propane (22 g, 78.58 mmol, 1.0 equiv; Ref: Journal of Organic Chemistry; 48; 23; (1983); pp. 4393-4394) and A mixture of _Na2CO3 (16.66 _g , 157.15 mmol, 2.0 equiv) in acetone (250 mL) and refluxed at 60 °C for 2 h. The mixture was filtered and concentrated under reduced pressure. Then, the mixture was diluted with _H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (E)-3-bromo-1-(methylsulfonyl)prop-1-ene (13 g, 83% yield) as a yellow solid. LC-MS: 199 (M+H) ⁺ .

Step B: (E)-4-Fluoro-2-((3-(methylsulfonyl)allyl)oxy)benzonitrile

To 4-fluoro-2-hydroxybenzonitrile (1 g, 7.29 mmol, 1.0 equiv) and (E)-3-bromo-1-(methylsulfonyl)prop-1-ene (1.45 equiv) at room temperature g, 7.29 mmol, 1.0 equiv) in DMF ( ₁₅ mL) was added K2CO3 (3.02 _g , 21.88 mmol, 3.0 equiv). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (E)-4-fluoro-2-((3-(methylsulfonyl)allyl)oxy)benzonitrile ( 60 mg, 3% yield). LC-MS: 256 (M+H) ⁺ .

Step C: (( 1S , 2R )-2-(( S )-1-(1-(2-(4-cyano-3-((( E )-3-(methylsulfonyl) Allyl)oxy)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl) Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ( Compound 187 )

To ((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluoro Phenyl)-methyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (60 mg, 0.115 mmol, 1.0 equiv) and (E)-4-fluoro - To a solution of 2-((3-(methylsulfonyl)allyl)oxy)benzonitrile (32 mg, 0.126 mmol, 1.1 equiv) in _CH3CN (10 mL) was added _{K2CO 3} (95 mg, 0.687 mmol, 6.0 equiv). The mixture was stirred at 80 °C overnight under _N2 atmosphere. The mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound 187 (20 mg, 23% yield) as a white solid. LC-MS: 759 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.49 - 7.42 (m, 2H), 7.38 (d, 2H), 7.11 (t, 1H), 7.02 ( d, 1H), 6.74 (d, 2H), 6.16 (dd, 1H), 6.11 (d, 1H), 5.16 (td, 1H), 4.59 (d, 1H), 4.38 (d, 1H), 4.03 - 3.96 (m, 6H), 3.92 - 3.79 (m, 3H), 3.64 (s, 3H), 3.09 - 3.02 (m, 1H), 2.99 (s, 3H), 2.96 - 2.89 (m, 1H), 2.87 - 2.76 (m, 1H), 2.67 - 2.58 (m, 1H), 2.51 (s, 3H), 2.44 - 2.35 (m, 2H), 2.34 - 2.23 (m, 1H), 2.17 - 2.06 (m, 3H), 2.00 - 1.85 (m, 3H), 1.77 - 1.69 (m, 1H), 1.53 - 1.45 (m, 1H), 1.37 - 1.31 (m, 2H), 1.22 - 1.16 (m, 1H), 0.84 - 0.66 (m, 1H) Example 13

((1S,2R)-2-((S)-1-(1-(2-(5-cyano-4-(dimethylaminocarboxy)pyrimidin-2-yl)-2-aza Spiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentane yl) methyl carbamate ( compound 195 )

Step A: 5-Bromo-N,N-dimethyl-2-(methylsulfanyl)pyrimidine-4-carboxamide

To 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (3 g, 12 mmol), HATU (6.87 g, 18 mmol) and DIPEA (6 mL, 36 mmol) in THF at room temperature To the mixture in (20 ml) was added dimethylamine (2 M in THF, 12 ml, 24 mmol). The mixture was stirred overnight. The reaction was concentrated and the residue was purified by silica gel flash column chromatography to give 5-bromo-N,N-dimethyl-2-(methylsulfanyl)pyrimidine-4-carboxamide ( 2.8 g, 84% yield). LC-MS: 276/278 (M+H) ⁺ .

Step B: 5-cyano-N,N-dimethyl-2-(methylthio)pyrimidine-4-carboxamide

5-Bromo-N,N-dimethyl-2-(methylsulfanyl)pyrimidine-4-carboxamide (1.1 g, 4 mmol), Zn(CN) _{2 were} stirred at 100 °C under N atmosphere (940 mg, 8 mmol), a mixture of Pd(t- _Bu3P ) ₂ (204 mg, 0.4 mmol) and dppf (221 mg, 0.4 mmol) in DMAc (10 ml) overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 5-cyano-N,N-dimethyl-2-(methylsulfanyl)pyrimidine-4-carboxamide (800 mg, yield) as a white solid. rate 90%). LC-MS: 223 (M+H) ⁺ .

Step C: 5-Cyano-N,N-dimethyl-2-(methylsulfonyl)pyrimidine-4-carboxamide

To a mixture of 5-cyano-N,N-dimethyl-2-(methylthio)pyrimidine-4-carboxamide (440 mg, 1.98 mmol) in DCM (10 ml) at 0 °C m -CPBA (1 g, 5.94 mmol) was added in portions. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 5-cyano-N,N-dimethyl-2-(methylsulfonyl)pyrimidine-4-carboxamide as a white solid (100 mg, yield 20%). LC-MS: 255 (M+H) ⁺ .

Step D: ((1S,2R)-2-((S)-1-(1-(2-(5-cyano-4-(dimethylaminocarboxy)pyrimidin-2-yl)-2 -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl ) cyclopentyl) methyl carbamate ( compound 195 )

((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1- (3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (50 mg, 0.095 mmol), 5-cyano-N , N-Dimethyl-2-(methylsulfonyl)pyrimidine-4-carboxamide (29 mg, 0.115 mmol) and K ₂ CO ₃ (39 mg, 0.286 mmol) in MeCN (10 ml) mixture overnight. The reaction mixture was concentrated, and the residue was purified by preparative TLC and RP-preparative HPLC to give compound 195 (20 mg, 30% yield) as a white solid. LC-MS: 698 (M+H) ⁺ . 1H NMR (400 MHz, methanol- d ₄ ) δ 8.63 (s, 1H), 7.49 - 7.41 (m, 2H), 7.36 (d, 1H), 7.10 (t, 1H), 6.71 (d, 1H), 6.66 (d, 1H), 4.56 (d, 1H), 4.36 (d, 1H), 4.22 (d, 2H), 4.09 (d, 2H), 4.03 - 3.93 (m, 1H), 3.60 (s, 3H), 3.10 (s, 3H), 3.03 - 2.79 (m, 6H), 2.75 - 2.68 (m, 1H), 2.65 - 2.60 (m, 1H), 2.45 (s, 3H), 2.41 - 2.35 (m, 2H), 2.26 - 2.20 (m, 1H), 2.12 - 1.99 (m, 3H), 1.90 - 1.77 (m, 3H), 1.70 (d, 1H), 1.54 - 1.44 (m, 1H), 1.39 - 1.18 (m, 2H) ), 1.24 - 1.13 (m, 2H), 0.78 - 0.66 (m, 1H). Example 14

Preparation of 1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)-3-methylimidazolidin-2-one ( Compound 201 )

Step A: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl) -1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate tertiary butyl ester

In a sealed tube, stir ((1S,2R)-2-(((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluoro) at 50°C Phenyl)ethyl)cyclopentyl)carbamate (18 g, 39.683 mmol, 1 equiv), glyoxal (10 mL, 87.302 mmol, 2 equiv), acetaldehyde (23.4 mL, 416.667 mmol) , 10 equiv) and _NH4OAC (6.73 g, 87.302 mmol, 2 equiv) in MeOH (135 mL) for 36 h. The reaction mixture was cooled to 25°C, poured into 300 ml of water and extracted with EtOAc (400 ml x 2). The combined organic phases were washed with saturated aqueous NaHCO ₃ (400 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)- as a yellow oil Tertiary butyl 1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (5.6 g, 41% yield). LC-MS: 561 (M+H) ⁺ .

Step B: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidine- 4-yl)ethyl)cyclopentyl)carbamate tertiary butyl ester

To ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -Imidazol-1-yl)ethyl)cyclopentyl)carbamate tert-butyl ester (5.6 g, 9.986 mmol) in CF3CH2OH ( ₂₀₀ mL) was added 20% Pd(OH _{) 2} /C (1.8 g, 20% w/wt). The reaction was stirred at 25 °C for 72 h under a _H2 atmosphere (1 atm). The solution was filtered and the filtrate was concentrated under reduced pressure to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole) as a white solid -1-yl)-1-(piperidin-4-yl)ethyl)cyclopentyl)carbamate tert-butyl ester (4.5 g, 95% yield). LC-MS: 471 (M+H) ⁺ .

Step C: 6-(4-((S)-1-((1R,2S)-2-((tertiary butoxycarbonyl)amino)cyclopentyl)-1-(3-fluorophenyl) -2-(2-Methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid benzyl

Stir ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(piperidine) at room temperature Tri-butyl pyridin-4-yl)ethyl)cyclopentyl)carbamate (4.8 g, 10.199 mmol, 1 equiv), AcOH (1.753 mL, 30.597 mmol, 3 equiv) and 6-pendoxo-2 - A solution of benzyl azaspiro[3.3]heptane-2-carboxylate (1.08 g, 11.219 mmol, 1.1 equiv) in DCM (40 mL) for 2 h. NaBH(OAc) ₃ (1.03 g, 30.597 mmol, 3 equiv) was added and the solution was stirred at room temperature overnight. The reaction was washed with _NaHCO3 (40 mL) and brine (40 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography to give 6-(4-((S)-1-((1R,2S)-2-((tris as a yellow solid (3-butoxycarbonyl)amino)cyclopentyl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl) - Benzyl 2-azaspiro[3.3]heptane-2-carboxylate (3.2 g, 57% yield). LC-MS: 700 (M+H) ⁺ .

Step D: ((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3 -Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate tertiary butyl ester

To 6-(4-((S)-1-((1R,2S)-2-((tertiary butoxycarbonyl)amino)cyclopentyl)-1- under H atmosphere ( ₁ atm) (3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid benzene A solution of methyl ester (3.2 g, 5.81 mmol) and 20% Pd(OH) ₂ -C (0.64 g, 20% w/wt) in 2,2,2-trifluoroethan-1-ol (30 mL) Stir for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give ((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl) as a yellow solid )piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamic acid tertiary butyl ester ( 3 g, 92% yield). LC-MS: 566 (M+H) ⁺ .

Step E: 1-(5-Fluoro-2-(methylsulfonyl)phenyl)-N,N-dimethylmethanamine

To 1-(2-bromo-5-fluorophenyl)-N,N-dimethylmethanamine (400 mg, 1.73 mmol, 1.0 equiv, see: Journal of the American Chemical Society, 2017, Vol. 139, # 28, pp. 9519-9522) in NMP (5 mL) was added sodium methanesulfinate (194 mg, 1.89 mmol, 1.09 equiv), CuCl (85 mg, 0.86 mmol, 0.5 equiv) and quinoline ( 111 mg, 0.86 mmol, 0.5 equiv). The mixture was stirred at 110 °C for 3 h under _N2 atmosphere. The reaction was quenched with water (15 mL) and extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1-(5-fluoro-2-(methylsulfonyl)phenyl)-N,N-dimethylmethylamine (80 mg) as a white solid , the yield is 20%). LC-MS: 232 (M+H) ⁺ .

Step F: ((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate tertiary butyl ester

To ((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluoro Phenyl)-tert-butyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (3 g, 5.302 mmol, 1 equiv) and 1-(5- Fluoro-2-(methylsulfonyl)phenyl)-N,N-dimethylmethanamine (1.47 g, 6.363 mmol, 1.2 equiv) in DMF (30 mL) was added K ₂ CO ₃ ( 1.47 g, 10.605 mmol, 2 equiv). The reaction mixture was stirred at 80 °C overnight under _N2 atmosphere. Then, the mixture was diluted with _H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamine) as a yellow oil yl)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl) )-tert-butyl 2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (2.3 g, 56% yield). LC-MS: 777 (M+H) ⁺ .

Step G: (1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl )-2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl )ethyl)cyclopentan-1-amine

To ((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) To a solution of tert-butyl ethyl)cyclopentyl)carbamate (2.3 g, 2.960 mmol) in DCM (9 mL) was added TFA (3 mL). The reaction solution was then stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give (1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)) as a yellow oil -4-(Methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( 2-Methyl-1H-imidazol-1-yl)ethyl)cyclopentan-1-amine (1.9 g, 95% yield). LC-MS: 677 (M+H) ⁺ .

Step H: (2-((( 1S , 2R )-2-((( S )-1-(1-(2-(3-((dimethylamino)methyl)-4-(methyl) sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl- 1 H -imidazol-1-yl)ethyl)cyclopentyl)amino)ethyl)(methyl)carbamate tert-butyl ester

(1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)) with stirring at room temperature Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentan-1-amine (250 mg, 0.603 mmol, 1.0 equiv) and tert-butyl methyl(2-oxyethyl)carbamate (140 mg, 0.663 mmol, 1.1 equiv.) in DCM (5 mL) and MeOH (1 mL) for 2 h. NaBH(OAc) ₃ (30 mg, 0.886 mmol, 1.5 equiv) was added to the above solution at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with _H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (2-(((1S,2R)-2-((S)-1-(1-(2-(3-(( as a yellow oil Dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3 - Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino)ethyl)(methyl)carbamate (200 mg, yield 81%). LC-MS: 834 (M+H) ⁺ .

Step I; N1 -(( 1S , 2R )-2-(( S )-1-(1-(2-(3-((dimethylamino)methyl)-4-(methyl) Sulfonyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1 H -imidazol-1-yl)ethyl)cyclopentyl) -N 2-methylethane-1,2-diamine

To (2-(((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methyl) at room temperature sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl- 1H-imidazol-1-yl)ethyl)cyclopentyl)amino)ethyl)(methyl)carbamate (200 mg, 0.24 mmol, 1.0 equiv) in DCM (5 mL) TFA (1 mL) was added to the solution. The solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give N1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino) as a dark yellow oil )methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl) -2-(2-Methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)-N2-methylethane-1,2-diamine (500 mg, 93% yield), which was directly used in the next step. LC-MS: 734 (M+H) ⁺ .

Step J: 1-(( 1S , 2R )-2-((( S )-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl) Acyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl- 1H -imidazol-1-yl)ethyl)cyclopentyl)-3-methylimidazolidin-2-one ( compound 201 )

To N1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonic acid) at room temperature Acyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)-N2-methylethane-1,2-diamine (170 mg, 0.2 mmol, 1.0 equiv) in THF (10 mL) was added 1- ( 1H -imidazole-1-carbonyl ) -1H-imidazole (0.027 mL, 0.221 mmol, 1.1 equiv) and TEA (0.139 mL, 1.002 mmol, 5.0 equiv). The mixture was stirred at 30 °C overnight under _N2 atmosphere. The mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography and RP-preparative HPLC to give compound 201 (25 mg, 16% yield) as a white solid. LC-MS: 760 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.86 (d, 1H), 7.59 - 7.47 (m, 3H), 7.33 - 7.27 (m, 1H), 7.25 - 7.18 (m, 1H), 6.99 - 6.91 (m, 1H), 6.63 - 6.54 (m, 2H), 4.58 (d, 1H), 4.47 (s, 2H), 4.44 - 4.38 (m, 1H), 4.13 - 4.07 (m, 2H), 3.96 (s , 2H), 3.62 - 3.56 (m, 2H), 3.50 - 3.38 (m, 4H), 3.13 (s, 3H), 2.88 (s, 6H), 2.82 - 2.70 (m, 9H), 2.66 - 2.59 (m , 2H), 2.57 - 2.45 (m, 3H), 2.22 - 2.14 (m, 1H), 2.00 - 1.90 (m, 2H), 1.65 - 1.38 (m, 4H), 1.37 - 1.27 (m, 2H), 1.19 - 1.10 (m, 2H), 0.91 - 0.80 (m, 1H). Example 15

Preparation of 1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)benzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)-3-methyl-1,3-dihydro-2H-imidazol-2-one ( Compound 205 )

Step A: 1-(2,2-Dimethoxyethyl)-3-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethyl Amino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorobenzene yl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)-1-methylurea

To (1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl) at 0°C Phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentan-1-amine (100 mg, 0.148 mmol, 1.0 equiv) and TEA (0.11 mL, 0.791 mmol, 5.3 equiv) in THF (25 mL) was added 4-chloroformic acid A solution of nitrophenyl ester (80 mg, 0.397 mmol, 2.6 equiv) in THF (25 mL). After 1 hour, 2,2-dimethoxy-N-methylethan-l-amine (0.05 mL, 0.420 mmol, 2.8 equiv) was added to the above solution at 0 °C. The reaction solution was stirred at room temperature for 3 hours. The mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1-((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2- as a yellow oil Methyl-1H-imidazol-1-yl)-1-(1-(2-(3-((methylamino)methyl)-4-(methylsulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)-3-methyl-1H-imidazol-2(3H)-one (48 mg, 40% yield ). LC-MS: 822 (M+H) ⁺ .

Step B: 1-((1S,2R)-2-((S)-1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl )phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole- 1-yl)ethyl)cyclopentyl)-3-methyl-1,3-dihydro-2H-imidazol-2-one ( Compound 205 )

Stir 1-((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1- at 0°C (1-(2-(3-((Methylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine -4-yl)ethyl)cyclopentyl)-3-methyl-lH-imidazol-2(3H)-one (40 mg, 0.049 mmol) in sulfuric acid (2 mL) for 10 min. The mixture was then stirred at 50°C for 1 hour. The mixture was quenched with saturated aqueous NaHCO ₃ (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 205 (10 mg, 28% yield) as a white solid. LC-MS: 758 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 7.67 (d, 1H), 7.44 - 7.29 (m, 3H), 7.04 - 7.97 (m, 1H), 6.63 - 6.54 (m, 3H), 6.39 (d , 1H), 6.34 - 6.28 (m, 2H), 4.55 (d, 1H), 4.44 - 4.38 (m, 1H), 4.28 (d, 1H), 3.88 (s, 2H), 3.75 - 3.68 (m, 4H) ), 3.16 - 3.11 (m, 6H), 2.84 - 1.97 (m, 1H), 2.70 - 2.60 (m, 2H), 2.57 - 2.48 (m, 1H), 2.40 (s, 3H), 2.28 - 2.16 (m , 8H), 2.14 - 2.08 (m, 1H), 1.96 - 1.87 (m, 3H), 1.73 - 1.65 (m, 1H), 1.59 - 1.50 (m, 2H), 1.49 - 1.40 (m, 2H), 1.37 - 1.18 (m, 3H), 1.08 - 0.97 (m, 2H), 0.55 - 0.45 (m, 1H) Example 16

Synthesis of ((1S,2R)-2-((S)-1-(1-(2-(4-(((S)-1-propenylpiperidin-3-yl)sulfonyl)-2 -Fluorophenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl) Ethyl)cyclopentyl)carbamate ( Compound 241 ) and ((1S,2R)-2-((1S)-1-(1-(2-(4-(((S)-1-) Acryloylpiperidin-3-yl)sulfonyl)-2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3- Fluorophenyl)-2-(7-oxy-6,7-dihydro-5H-imidazo[2,1-b][1,3]㗁𠯤-1(8aH)-yl)ethyl) Cyclopentyl) methyl carbamate ( compound 244 )

Acrylic anhydride (14 mg) was added to a solution of 1 (50 mg) and DIEA (0.06 mL) in DCM (4 mL). The mixture was stirred for 2 hours and the solvent was evaporated. The residue was purified and both compound 241 (ESI-MS: 805.7) and compound 244 (ESI-MS: 877.8) were obtained. Example 17

Synthesis of ((1S,2R)-2-((S)-1-(1-(2-(7-(cyclopropylsulfonyl)-1-oxyisoindolin-4-yl)- 2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl)cyclopentyl ) methyl carbamate ( compound 255 )

Cyclopropanethiol (250 mg) and _{Cs2CO3 (} 1.4 g) were added to a solution of J-10 (580 mg) in DMF (5 mL). The mixture was stirred at 80°C overnight. The mixture was quenched with water and purified by flash column chromatography to give J-11 .

mCPBA (492 mg) was slowly added to a solution of J-11 (254 mg) in DCM (10 mL) at 0 °C. The mixture was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was washed with saturated sodium sulfite solution (aqueous) and brine. The organic solvent was dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give J-12 .

Compound 255 was prepared from J-12 according to the procedure described for the preparation of compound 45. ESI-MS: 745.6. Example 18

Synthesis of ((1S,2R)-2-((S)-1-(1-(2-(7-(cyclopropylsulfonyl)-2-methyl-1,3-dioxyisoindole) Indol-4-yl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(1H-imidazol-1- yl)ethyl)cyclopentyl)carbamate ( Compound 256 )

NaH (7 mg) was added to a solution of J-13 (33 mg) in THF (3 mL), and the mixture was stirred at 0 °C for 0.5 h. MeI (22 mg) was then added, and the resulting mixture was heated to 50°C for 5 hours. Water was added and the mixture was extracted three times with EtOAc, concentrated and purified by flash column chromatography to give J-14 .

Compound 256 was prepared from J-14 according to the procedure described for the preparation of compound 45 . ESI-MS: 745.6. Example 19

Preparation of ((1S,2R)-2-((S)-2-(2-amino-1H-imidazol-1-yl)-1-(1-(2-(3-((dimethylamino )methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl) Ethyl)cyclopentyl)methylcarbamate ( Compound 300 )

Step A: N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-[(1R,2S)-2-[(methyl oxycarbonyl)amino]cyclopentyl]ethyl]carbamate tert-butyl ester

((1S,2R)-2-((S)-2-amino-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)ethyl Methyl)cyclopentyl)carbamate ( E3 ) (3 g, 6.6 mmol, 1.0 equiv), Boc2O (2.16 _g , 9.9 mmol 1.5 equiv) and TEA (1.8 mL, 13 mmol, 2 equiv) were placed in The mixture was mixed in DCM (25 mL) for 2 hours. The reaction mixture was diluted with _H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-(3-fluorophenyl) as a white solid - Tert-butyl 2-[(1R,2S)-2-[(methoxycarbonyl)amino]cyclopentyl]ethyl]carbamate (3 g, 82% yield). LC-MS: 554 (M+H) ⁺ .

Step B: N-[(2S)-2-(3-Fluorophenyl)-2-[(1R,2S)-2-[(methoxycarbonyl)amino]cyclopentyl]-2-(piperidine Tri-butyl pyridin-4-yl)ethyl]carbamate

To N-[(2S)-2-(1-benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-[(1R,2S)-2-[(methoxy To a solution of tert-butyl carbonyl)amino]cyclopentyl]ethyl]carbamate ( ₃ g, 5.4 mmol) in CF3CH2OH (60 mL) was added 20% Pd(OH _{)2 /} C (0.7 g, 20% w/wt). The reaction was stirred at 25 °C for 16 h under a _H2 atmosphere (1 atm). The solution was filtered and the filtrate was concentrated under reduced pressure to give N-[(2S)-2-(3-fluorophenyl)-2-[(1R,2S)-2-[( as a white solid without any further purification Methoxycarbonyl)amino]cyclopentyl]-2-(piperidin-4-yl)ethyl]carbamic acid tert-butyl ester (2.5 g, 99% yield). LC-MS: 464 (M+H) ⁺ .

Step C: 6-(4-((S)-2-((tertiary butoxycarbonyl)amino)-1-(3-fluorophenyl)-1-((1R,2S)-2-( (Methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid benzyl ester

Stir N-[(2S)-2-(3-fluorophenyl)-2-[(1R,2S)-2-[(methoxycarbonyl)amino]cyclopentyl]-2- at room temperature (Piperidin-4-yl)ethyl]carbamate tertiary butyl ester (2.2 g, 4.7 mmol, 1.0 equiv), AcOH (0.28 g, 4.7 mmol, 1.0 equiv) and 6-pendant oxy-2-nitrogen A solution of benzyl heterospiro[3.3]heptane-2-carboxylate (1.16 g, 4.746 mmol, 1.1 equiv) in DCM (30 mL) for 2 h. Then NaBH(OAc) ₃ (2 g, 9.4 mmol, 2.0 equiv) was added to the above solution. The mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NaHCO ₃ (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-(4-((S)-2-((tertiary butoxycarbonyl)amino)-1-(3-fluorobenzene as a white solid) yl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptane- Benzyl 2-carboxylate (2.7 g, 82% yield). LC-MS: 693 (M+H) ⁺ .

Step D: ((S)-2-(1-(2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-( (1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)carbamate

To 6-(4-((S)-2-((tertiary butoxycarbonyl)amino)-1-(3-fluorophenyl)-1-((1R,2S)-2-((methyl Oxycarbonyl)amino)cyclopentyl)ethyl)piperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid benzyl (2.7 g, 3.8 mmol) in _CF3CH To a solution in ₂ OH (40 mL) was added 20% Pd(OH) ₂ /C (0.6 g, 20% w/wt). The reaction was stirred at 25 °C for 16 h under a _H2 atmosphere (1 atm). The solution was filtered and the filtrate was concentrated under reduced pressure to give ((S)-2-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4 as a white solid without any further purification -yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)carbamate (2 g , the yield is 91%). LC-MS: 559 (M+H) ⁺ .

Step E: ((S)-2-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[ 3.3] Heptane-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentane tertiary)ethyl)carbamate

Stir ((S)-2-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2 at 80°C -((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)carbamate (2.3 g, 4.1 mmol, 1.0 equiv), K ₂ CO ₃ (1.7 g , 12.3 mmol, 3.0 equiv) and 1-(5-fluoro-2-(methylsulfonyl)phenyl)-N,N-dimethylmethanamine (1.0 g, 4.5 mmol, 1.1 equiv) in DMSO ( 35 mL) overnight. The reaction mixture was diluted with _H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((S)-2-(1-(2-(3-((dimethylamino)methyl)-4-(methyl) as a white solid Sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)- Tertiary butyl 2-((methoxycarbonyl)amino)cyclopentyl)ethyl)carbamate (1.5 g, 47% yield). LC-MS: 770 (M+H) ⁺ .

Step F: ((1S,2R)-2-((S)-2-amino-1-(1-(2-(3-((dimethylamino)methyl)-4-(methyl) Sulfonyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamic acid methyl ester

Stir ((S)-2-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-aza at room temperature Spiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino) A solution of tert-butyl cyclopentyl)ethyl)carbamate (1.5 g, 1.9 mmol) in DCM (7 mL) and TFA (2 mL) for 2 h. The resulting reaction was concentrated under reduced pressure and diluted with saturated aqueous NaHCO ₃ (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give ((1S,2R)-2-((S)-2-amino- as a white solid 1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-l-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (1.2 g, 92% yield). LC-MS: 670 (M+H) ⁺ .

Step G: (( 1S , 2R )-2-(( S )-2-((2,2-dimethoxyethyl)amino)-1-(1-(2-(3-( (Dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-( 3-Fluorophenyl)ethyl)cyclopentyl)carbamate methyl ester

((1S,2R)-2-((S)-2-amino-1-(1-(2-(3-((dimethylamino)methyl)-4-( Methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)amine Methyl carboxylate (400 mg, 0.597 mmol, 1.0 equiv), 2,2-dimethoxyacetaldehyde (0.065 mL, 0.717 mmol, 1.2 equiv) and AcOH (0.103 mL, 1.791 mmol, 3.0 equiv) in DCM ( 10 mL) for 1 hour. Then NaBH(OAc) ₃ (253.17 mg, 1.194 mmol, 2.0 equiv) was added to the mixture. The reaction was stirred at room temperature for 3 hours, diluted with water (20 mL), adjusted to pH ~ 8 with saturated aqueous NaHCO ₃ and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-2-((2,2-dimethoxyethyl)amino)- as a white solid 1-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-l-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (300 mg, 66% yield). LC-MS: 758 (M+H) ⁺ .

Step H: (( Z ) -N '-(tertiary butoxycarbonyl)-N-(2,2-dimethoxyethyl) -N -( (S ) -2-(1-(2- (3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl) -2-(3-Fluorophenyl)-2-((1 R ,2 S )-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)carboxamidinyl)-12-azane tertiary butyl formate

To ((1S,2R)-2-((S)-2-((2,2-dimethoxyethyl)amino)-1-(1-(2-(3-( (Dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-( Methyl 3-fluorophenyl)ethyl)cyclopentyl)carbamate (300 mg, 0.396 mmol, 1.0 equiv), TEA (0.28 mL, 1.979 mmol, 5.0 equiv) and (E)-(((tertiary) To a solution of butoxycarbonyl)imino)(methylthio)methyl)-l2-azanecarboxylate (253 mg, 0.871 mmol, 2.2 equiv) in DMF (5 mL) was added HgCl ₂ (440 mg, 1.624 mmol, 4.0 equiv). The mixture was stirred at room temperature for 2 hours under _N2 atmosphere. The mixture was filtered through a pad of celite, and the filtrate was diluted with _H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((Z)-N'-(tertiary butoxycarbonyl)-N-(2,2-dimethoxyethyl)-N as a white solid -((S)-2-(1-(2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3] Heptan-6-yl)piperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl) Ethyl)formamidino)-l2-azanecarboxylic acid tert-butyl ester (320 mg, 81% yield). LC-MS: 1000 (M+H) ⁺ .

Step 1: ((1S,2R)-2-((S)-2-(2-amino-1H-imidazol-1-yl)-1-(1-(2-(3-((dimethyl Amino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorobenzene yl)ethyl)cyclopentyl)carbamate ( compound 300 )

Stir ((Z)-N'-(tertiary butoxycarbonyl)-N-(2,2-dimethoxyethyl)-N-((S)-2-(1-() at room temperature 2-(3-((dimethylamino)methyl)-4-(methylsulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine-4- yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)formamidinyl)-l2-azane A solution of tertiary butyl formate (300 mg, 0.3 mmol) in DCM (6 mL) and TFA (2 mL) for 2 h. The reaction was then concentrated under reduced pressure. The residue was dissolved in toluene (10 mL) and the solution was stirred at 70 °C overnight. The reaction was concentrated under reduced pressure and purified by prep-TLC and RP-prep HPLC to give compound 300 (30 mg, 14% yield) as a white solid. LC-MS: 736 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.77 (d, 1H), 7.43 - 7.38 (m, 2H), 7.33 (d, 1H), 7.08 - 7.02 (m, 1H), 6.44 - 6.34 (m , 4H), 4.39 (dd, 2H), 4.05 (dd, 1H), 3.97 (s, 2H), 3.83 (s, 2H), 3.71 (d, 2H), 3.49 (s, 3H), 3.25 (s, 3H), 2.91 (d, 1H), 2.84 (d, 1H), 2.72 - 2.60 (m, 2H), 2.38 - 2.28 (m, 2H), 2.25 - 2.23 (m, 6H), 2.18 - 2.10 (m, 1H), 2.07 - 2.05 (m, 1H), 2.03 - 2.00 (m, 1H), 1.95 (d, 1H), 1.84 - 1.74 (d, 3H), 1.73 - 1.66 (m, 1H), 1.52 - 1.44 ( m, 1H), 1.39 - 1.29 (m, 3H), 1.27 - 1.18 (m, 2H), 1.04 - 0.94 (m, 1H). Example 20

Preparation of compound 337

2-Chloroethyl chloroformate (189 mg, 1.3 mmol) was added to a solution of E3 (500 mg, 1.1 mmol) and trimethylamine (0.48 mL, 3.3 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to remove dichloromethane, and the residue was purified by flash column chromatography (DCM/MeOH as eluent) to give H2 . ESI-MS: 560.6.

H2 (320 mg, 0.57 mmol) was dissolved in THF (3 mL). NaH (92 mg, 2.28 mmol) was added and the mixture was heated to 60 °C for 5 hours. Water was then added and the mixture was extracted three times with EtOAc, concentrated and purified by flash column chromatography (DCM/MeOH as eluent) to give H3 . ESI-MS: 524.4.

To a solution of H3 (180 mg, 0.34 mmol) in methanol (5 mL) was added acetic acid (31 µL, 0.536 mmol) and Pd/C (50 mg, 10 wt%) under _N2 atmosphere. The mixture was then stirred at room temperature under a hydrogen atmosphere (normal pressure). After 4 hours, the Pd/C catalyst was filtered off and the solvent was removed by rotary evaporation to give H4 which was used without further purification. ESI-MS: 434.7.

Compound 337 was prepared from H4 according to the procedure described for the preparation of compound 45. ESI-MS: 630.84. Example 21

Preparation of compound 338

Compound 338 was prepared starting from E3 and 4-chlorobutyryl chloride using a procedure similar to that described for the preparation of compound 337. ESI-MS: 628.91. Example 23

Preparation of ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-(2- (2-Oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl) Ethyl)cyclopentyl)methylcarbamate ( Compound 340 )

Step A: 5-Bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of 5-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one (4 g, 18.8 mmol) in DMF (40 mL) at 0 °C was added NaH (60% in mineral oil, 1.9 g, 46.9 mmol) and the mixture was stirred at this temperature for 10 minutes. A solution of (2-(chloromethoxy)ethyl)trimethylsilane (7.2 g, 43.2 mmol) in THF (10 mL) was added to the reaction at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was then poured into saturated aqueous _NH4Cl (50 mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with water, brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography to give 5-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H as a white solid - Benzo[d]imidazol-2-one (5.3 g, 59% yield). LC-MS: 473, 475 (M+H) ⁺ .

Step B: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( 2-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5- yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate

((1S,2R)-2-((S)-1-(1-( ₂ -azaspiro[3.3]heptan-6-yl)piperidin-4- yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (84 mg, 0.16 mmol), 5 -Bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (33 mg, 0.18 mmol), X-Phos (8 mg, 0.016 mmol), Pd2(dba _{)3 (} 13 mg, 0.016 mmol) and a mixture of _{Cs2CO3 (} 157 mg, 0.48 mmol) in toluene (5 mL) overnight . The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-) as a yellow liquid Imidazol-1-yl)-1-(1-(2-(2-oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-di Hydro-1H-benzo[d]imidazol-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate methyl ester (40 mg, 33% yield). LC-MS: 916 (M+H) ⁺ .

Step C: ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1-( 2-(2-Oxy-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4- yl)ethyl)cyclopentyl)carbamate ( Compound 340 )

Stir ((1S,2R)-2-((S)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-1-(1 -(2-(2-Oxy-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole -5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)ethyl)cyclopentyl)carbamate (40 mg, 0.044 mmol) and TFA ( 1 mL) in DCM (3 mL) for 1 h and concentrated under reduced pressure. The residue was then dissolved in MeOH ( ₃ mL) and _NH3H2O (1 mL) was added. The mixture was stirred for an additional 0.5 h at room temperature. The reaction was then concentrated under reduced pressure. The residue was purified by RP-preparative HPLC to give compound 340 (10 mg, 37% yield) as a yellow solid. LC-MS: 656 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.51 - 7.30 (m, 3H), 7.15 - 7.03 (m, 1H), 6.85 (d, 1H), 6.67 (d, 2H), 6.26 - 6.19 (m , 2H), 4.59 - 4.50 (m, 1H), 4.40 - 4.33 (m, 1H), 4.08 - 3.95 (m, 1H), 3.78 (s, 2H), 3.65 (s, 2H), 3.60 (s, 3H) ), 2.97 - 2.87 (m, 1H), 2.85 - 2.76 (m, 1H), 2.70 - 2.57 (m, 2H), 2.48 (s, 3H), 2.35 - 2.25 (m, 2H), 2.23 - 2.16 (m , 1H), 2.07 - 1.97 (m, 3H), 1.91 - 1.81 (m, 1H), 1.80 - 1.61 (m, 3H), 1.53 - 1.45 (m, 1H), 1.47 - 1.18 (m, 5H), 0.80 - 0.67 (m, 1H). Example 24

Preparation of ((1S,2R)-2-((S)-cyano((2R,6R)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptane-6 -yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate ( compound 375 )

Step A: 2-((2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)-2-(3-fluorophenyl)acetonitrile (trans configuration, rather than absolute configuration)

To (2R,6R) _-1 -benzyl-2,6-dimethylpiperidin-4-one (5 g, 23 mmol; Ref: PCT Int. Appl., 2020119819, Jun 18, 2020 ) and 2- ( 3 -fluorophenyl)acetonitrile (3.2 mL, 27.6 mmol) in THF (50 mL) was added NaHMDS (2 M in THF, 13.8 mL, 27.6 mmol). The mixture was stirred at 60°C overnight. The reaction was then quenched with saturated aqueous _NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 2-((2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)- as a yellow oil 2-(3-Fluorophenyl)acetonitrile (7.1 g, 92% yield). LC-MS: 335 (M+H) ⁺ .

Step B: 2-((2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile

To 2-((2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)-2-(3-fluorophenyl)acetonitrile (7.1 g, 21.2 mmol) and To a mixture of Mg (5.2 g, 212 mmol) in MeOH (100 mL) was added _I2 (9.4 g, 21.2 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was then quenched with water (200 mL) and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether (PE): EtOAc = 0 to 50%) to give a mixture which was then separated by supercritical fluid chromatography (SFC) to give 2-( as a yellow solid (2R,6R)-1-Benzyl-2,6-dimethylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile (3 g, 42% yield). LC-MS: 337 (M+H) ⁺ .

Step C: ((1S,2R)-2-((S)-((2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)(cyano)(3 -Fluorophenyl)methyl)cyclopentyl)carbamate

2-((2R,6R)-1-benzyl-2,4,6-trimethylpiperidin-4-yl)-2-(3-fluorobenzene was added to 2-((2R,6R)-1-benzyl-2,4,6-trimethylpiperidin-4-yl)-2-( ₃ -fluorobenzene under N (3aS,6aR)-tetrahydrocyclopenta[d][1,2,3]thiazole-3(3aH)-carboxylate methyl ester 2,2-dioxide (197 mg, 0.9 mmol) and DMPU (0.2 mL) in THF (2 mL) was added dropwise LiHMDS (1 M in THF; 0.7 mL, 0.7 mmol). The mixture was stirred at room temperature overnight. 2 N HCl (0.5 mL) was then added to the above solution and the mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 8 with saturated aqueous NaHCO ₃ and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE:EtOAc = 0 to 50%) to give a mixture (200 mg) which was then separated by SFC (2 peaks) to give (() as a white solid (main peak) 1S,2R)-2-((S)-((2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)(cyano)(3-fluorophenyl) Methyl)cyclopentyl)carbamate (136 mg, 48% yield). LC-MS: 478 (M+H) ⁺ .

Step D: ((1S,2R)-2-((S)-cyano((2R,6R)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl) Cyclopentyl) methyl carbamate

To ((1S,2R)-2-((S)-((2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)(cyano)(3-fluoro To a solution of methyl phenyl)methyl)cyclopentyl)carbamate (136 mg, 0.3 mmol) in 2,2,2-trifluoroethan-1-ol (5 mL) was added 10% Pd(OH ) ₂ /C (40 mg, 30% wt/wt). The mixture was stirred at room temperature for 12 hours under a _H2 atmosphere (1 atm). The reaction mixture was filtered through a pad of celite and washed with MeOH. The filtrate was concentrated under reduced pressure to give ((1S,2R)-2-((S)-cyano((2R,6R)-2,6-dimethylpiperidin-4-yl) as a yellow oil )(3-fluorophenyl)methyl)cyclopentyl)carbamate (100 mg, crude). LC-MS: 388 (M+H) ⁺ .

Step E: ((1S,2R)-2-((S)-cyano((2R,6R)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptane -6-yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate ( Compound 375 )

((1S,2R)-2-((S)-cyano((2R,6R)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methane was stirred at room temperature yl)cyclopentyl)carbamate (50 mg, 0.13 mmol) and 4-(6-oxy-2-azaspiro[3.3]heptan-2-yl)benzonitrile (33 mg, 0.16 mmol) in DCM (3 mL) for 2 h. Subsequently, NaBH(OAc) ₃ (54 mg, 0.26 mmol) was added, and the mixture was stirred at 50° C. for 48 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 375 (7.8 mg, 10% yield) as a white solid. LC-MS: 584 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.39 - 7.32 (m, 3H), 7.30 - 7.25 (m, 1H), 7.21 (d, 1H), 7.06 - 7.00 (m, 1H), 6.33 (d , 2H), 3.89 (s, 2H), 3.82 (q, 1H), 3.74 (s, 2H), 3.42 - 3.30 (m, 4H), 2.97 - 2.78 (m, 1H), 2.69 (q, 1H), 2.53 - 2.35 (m, 3H), 2.32 - 2.21 (m, 1H), 2.18 - 2.10 (m, 1H), 2.05 - 1.87 (m, 2H), 1.73 - 1.61 (m, 1H), 1.55 - 1.37 (m , 5H), 1.33 - 1.18 (m, 3H), 1.04 (d, 3H), 0.95 (d, 3H). Example 25

Preparation of ((1S,2R)-2-((S)-cyano((2S,4s,6R)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptane -6-yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate ( Compound 378 )

Step A: Diethyl 2,6-Dimethyl-4-oxypiperidine-3,5-dicarboxylate

To a solution of diethyl 3-oxypentanedioate (9 mL, 49 mmol) and 98% acetaldehyde (5.6 mL, 98.9 mmol) in EtOH (100 mL) was added dropwise 28 at 0 °C % _{NH3H2O (} 6.7 mL, 49 mmol). The mixture was stirred at room temperature for 48 hours. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give diethyl 2,6-dimethyl-4-oxypiperidine-3,5-dicarboxylate (11 g, yield) as a yellow oil. rate 82%). LC-MS: 272 (M+H) ⁺ .

Step B: 2,6-Dimethylpiperidin-4-one

A mixture of diethyl 2,6-dimethyl-4-pentoxypiperidine-3,5-dicarboxylate (11 g, 40.5 mmol) in concentrated HCl (50 mL) was stirred at 70 °C overnight. The reaction mixture was then concentrated under reduced pressure to give 2,6-dimethylpiperidin-4-one (5 g, crude product), which was used in the next step without further purification. LC-MS: 128 (M+H) ⁺ .

Step C: (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one

2,6-Dimethylpiperidin-4-one ( ₅ g, 39.3 mmol), K2CO3 (10.9 _g , 78.6 mmol) and BnBr (6.95 mL, 59 mmol) were stirred at 60 °C under _N2 atmosphere ) in MeCN (60 mL) overnight. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (4 g, 47% yield) as a yellow solid ; cis configuration rather than absolute configuration) and (2S,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (0.5 g, yield 6) as a yellow oil %; cis configuration rather than absolute configuration). LC-MS: 218 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (d, 2H), 7.24 (dd, 2H), 7.19 - 7.11 (m, 1H), 3.77 (s, 2H), 3.12 - 2.92 (m, 2H), 2.26 (dd, 4H), 1.07 (d, 6H) (cis configuration).

Step D: (E)-2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)-2-(3-fluorophenyl)acetonitrile

To (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (4 g, 18.4 mmol) and 2-(3-fluorobenzene) were added to (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one ( ₄ g, 18.4 mmol) at room temperature under N atmosphere yl)acetonitrile (2.6 mL, 22 mmol) in THF (50 mL) was added NaHMDS (2 M in THF, 11 mL, 22 mmol). The mixture was stirred at 60°C overnight. The reaction mixture was quenched with saturated aqueous _NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give (E)-2-((2R,6S)-1-benzyl-2,6-dimethylpiperidine-4- as a yellow oil subunit)-2-(3-fluorophenyl)acetonitrile (5 g, 81% yield). LC-MS (ESI): m/z 335 (M+H) ⁺ .

Step E: 2-((2R,4s,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile and 2-(( 2R,4r,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile

To (E)-2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)-2-(3-fluorophenyl)acetonitrile (5 g, 15 mmol) and Mg (3.6 g, 149.5 mmol) in MeOH (100 mL) was added _I2 (0.7 g, 1.5 mmol). The mixture was stirred at 50°C for 2 hours. The reaction mixture was quenched with water (200 mL) and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE: EtOAc = 0 to 50%) to give 2-((2R,4s,6S)-1-benzyl-2,6-dimethyl as a yellow solid ylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile (2.2 g, 44% yield) and 2-((2S,4r,6R)-1-benzyl- 2,6-Dimethylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile (1.85 g, 37% yield). LC-MS: 337 (M+H) ⁺ .

2-((2R,4s,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 - 7.19 (m, 5H), 7.17 - 7.11 (m, 1H), 7.02 - 6.91 (m, 3H), 3.72 - 3.64 (m, 3H), 2.94 - 2.85 (m, 1H), 2.85 - 2.76 (m, 1H), 2.22 - 2.12 (m, 1H), 1.82 - 1.72 (m, 1H), 1.69 - 1.60 (m, 1H), 1.34 (t, 2H), 0.99 (d, 3H), 0.90 (d, 3H).

2-((2S,4r,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-(3-fluorophenyl)acetonitrile: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31 - 7.24 (m, 3H), 7.23 - 7.17 (m, 2H), 7.11 (t, 1H), 7.02 - 6.90 (m, 3H), 3.71 (s, 2H), 3.50 (d, 1H) ), 2.52 - 2.33 (m, 2H), 1.85 - 1.73 (m, 1H), 1.71 - 1.63 (m, 1H), 1.45 - 1.37 (m, 1H), 1.24 - 1.11 (m, 2H), 1.00 (dd , 6H).

Step F: ((1S,2R)-2-((S)-((2S,4s,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)(cyano) (3-Fluorophenyl)methyl)cyclopentyl)carbamate

2-((2R,4s,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-(3-fluorobenzene was added to 2-((2R,4s,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-( ₃ -fluorobenzene under N (3aS,6aR)-tetrahydrocyclopenta[d][1,2,3]thiazole-3(3aH)-carboxylate methyl ester 2,2-dioxide (197 mg, 0.9 mmol) and DMPU (0.2 mL) in THF (2 mL) was added dropwise LiHMDS (1 M in THF; 0.6 mL, 0.6 mmol).

The mixture was stirred at room temperature overnight. 2 N HCl (0.5 mL) was then added to the above solution and the mixture was stirred at room temperature for 1 hour. The mixture was adjusted to pH 8 with saturated aqueous NaHCO ₃ and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (PE:EtOAc = 0 to 50%) to give a mixture (200 mg) which was then separated by SFC (2 peaks) to give (() as a white solid (main peak) 1S,2R)-2-((S)-((2S,4s,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)(cyano)(3-fluorobenzene yl)methyl)cyclopentyl)carbamate (120 mg, 42% yield). LC-MS: 478 (M+H) ⁺ .

Step G: ((1S,2R)-2-((S)-cyano((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methane yl)cyclopentyl)carbamate

To ((1S,2R)-2-((S)-((2S,4s,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)(cyano)(3 To a solution of methyl-fluorophenyl)methyl)cyclopentyl)carbamate (120 mg, 0.25 mmol) in 2,2,2-trifluoroethan-1-ol (5 mL) was added 10% Pd (OH) ₂ /C (35 mg, 30% wt/wt). The mixture was stirred at room temperature for 12 hours under a _H2 atmosphere (1 atm). The reaction mixture was filtered through a pad of celite and washed with MeOH. The filtrate was concentrated under reduced pressure to give ((1S,2R)-2-((S)-cyano((2S,4s,6R)-2,6-dimethylpiperidine-4 as a yellow oil -yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate (90 mg, crude). LC-MS: 388 (M+H) ⁺ .

Step H: ((1S,2R)-2-((S)-cyano((2S,4s,6R)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3] Methyl heptan-6-yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate ( Compound 378 )

Stir ((1S,2R)-2-((S)-cyano((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl) at room temperature )methyl)cyclopentyl)carbamate (90 mg, 0.2 mmol) and 4-(6-oxy-2-azaspiro[3.3]heptan-2-yl)benzonitrile (59 mg, 0.3 mmol) in DCM (5 mL) for 2 h. Then NaBH(OAc) ₃ (99 mg, 0.5 mmol) was added, and the mixture was stirred at 50°C for 48 hours. The reaction mixture was quenched with water and extracted with DCM. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC to give compound 378 (13.3 mg, 10%) as a white solid. LC-MS: 584 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.37 - 7.22 (m, 4H), 7.18 (d, 1H), 7.05 - 6.98 (m, 1H), 6.32 (d, 2H), 3.94 - 3.79 (m , 3H), 3.71 (s, 2H), 3.39 - 3.26 (m, 4H), 3.08 - 2.97 (m, 2H), 2.75 (q, 1H), 2.55 - 2.39 (m, 1H), 2.30 - 2.15 (m , 2H), 2.05 - 1.95 (m, 1H), 1.89 - 1.76 (m, 3H), 1.73 - 1.65 (m, 1H), 1.58 - 1.47 (m, 2H), 1.45 - 1.33 (m, 3H), 1.30 - 1.18 (m, 2H), 1.04 - 0.93 (m, 6H). Example 26

Preparation of ((1S,2R)-2-((S)-cyano((2R,4r,6S)-1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptane -6-yl)-2,6-dimethylpiperidin-4-yl)(3-fluorophenyl)methyl)cyclopentyl)carbamate ( Compound 379 )

Compound 379 was prepared via the procedure for compound 378 (step FH) from 2-((2S,4r,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl)-2-( 3-Fluorophenyl)acetonitrile was synthesized as a white solid. LC-MS: 584 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 - 7.42 (m, 3H), 7.38 (d, 1H), 7.30 (d, 1H), 7.18 - 7.12 (m, 1H), 6.44 (d, 2H) ), 4.00 - 3.87 (m, 3H), 3.84 (s, 2H), 3.52 - 3.36 (m, 4H), 2.87 - 2.63 (m, 3H), 2.48 - 2.31 (m, 5H), 2.10 - 2.00 (m , 1H), 1.95 - 1.84 (m 1H), 1.82 - 1.71 (m, 1H), 1.69 - 1.44 (m, 5H), 1.35 - 1.26 (m, 2H), 1.23 (d, 3H), 1.17 (d, 3H). Example 27

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(6-((dimethylamino)methyl)-5-(methylsulfonyl)pyridine-2 -yl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate ( compound 452 )

Step A: 1-(3,6-Bis(methylthio)pyridin-2-yl)-N,N-dimethylmethanamine

To a solution of 1-(3-bromo-6-fluoropyridin-2-yl)-N,N-dimethylmethanamine (220 mg, 0.79 mmol) in DMF (3 ml) was added MeSNa (516 mg, 3.14 mmol). The mixture was stirred at 80°C overnight. The reaction was then quenched with 20 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1-(3,6-bis(methylthio)pyridin-2-yl)-N,N-dimethylmethanamine ( 120 mg, 67% yield). LC-MS: 229 (M+H) ⁺ .

Step B: 1-(3,6-Bis(methylsulfonyl)pyridin-2-yl)-N,N-dimethylmethanamine

1-(3,6-Bis(methylthio)pyridin-2-yl)-N,N-dimethylmethanamine (220 mg, 0.97 mmol) and potassium hydrogen persulfate (13 g) were stirred at room temperature , 2.12 mmol) in acetone (3 mL) and water (3 mL) overnight. The reaction was then diluted with 10 mL of water and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with saturated aqueous Na ₂ S ₂ O ₃ (20 mL) and brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1-(3,6-bis(methylsulfonyl)pyridin-2-yl)-N,N-dimethylmethanamine (120) as a white solid mg, 42% yield). LC-MS: 293 (M+H) ⁺ .

Step C: ((1S,2R)-2-((S)-1-(1-(2-(6-((dimethylamino)methyl)-5-(methylsulfonyl)pyridine -2-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole -1-yl)ethyl)cyclopentyl)carbamate ( compound 452 )

((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1- (3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (60 mg, 0.12 mmol), 1-(3,6 - Bis(methylthio)pyridin-2-yl)-N,N-dimethylmethanamine (50 mg, 0.17 mmol) and DIPEA (0.1 mL, 0.6 mmol) in MeCN (5 mL) overnight . The mixture was then diluted with 10 mL of water and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 452 (15 mg, 18% yield) as a white solid. LC-MS: 736 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.93 (d, 1H), 7.50 - 7.40 (m, 2H), 7.39 - 7.31 (m, 1H), 7.13 - 7.05 (m, 1H), 6.71 - 6.61 (m, 2H), 6.29 (d, 1H), 4.59 - 4.50 (m, 1H), 4.42 - 4.31 (m, 1H), 4.11 (s, 2H), 4.04 - 3.98 (m, 1H), 3.97 (s , 2H), 3.79 (s, 2H), 3.60 (s, 3H), 3.26 (s, 3H), 2.95 - 2.88 (m, 1H), 2.85 - 2.78 (m, 1H), 2.66 - 2.58 (m, 2H) ), 2.45 (s, 3H), 2.36 - 2.30 (m, 2H), 2.27 (s, 6H), 2.23 - 2.14 (m, 1H), 2.10 - 1.98 (m, 3H), 1.92 - 1.82 (m, 1H) ), 1.80 - 1.64 (m, 3H), 1.54 - 1.44 (m, 1H), 1.42 - 1.26 (m, 3H), 1.25 - 1.14 (m, 2H), 0.80 - 0.63 (m, 1H). Example 28

Preparation ((1S,2R)-2-(1-(1-(2-(4-cyano-3-isopropoxyphenyl)-2-azaspiro[3.3]heptan-6-yl) Methyl piperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methyl-2-oxyimidazolidin-1-yl)ethyl)cyclopentyl)carbamate ( Compound 485 )

Step-1: (2-((2-(1-Benzylpiperidin-4-yl)-2-(3-fluorophenyl)-2-((1R,2S)-2-((methoxy tert-butylcarbonyl)amino)cyclopentyl)ethyl)amino)ethyl)(methyl)carbamate ( H8 )

To a solution of E3 (200 mg, 0.441 mmol) in DCE (4 mL) was added tert-butyl methyl(2-oxyethyl)carbamate (76 mg, 0.441 mmol) and AcOH (50 µL) , 0.882 mmol). The mixture was stirred at room temperature for 2 hours before NaBH(OAc) ₃ was added. The mixture was stirred overnight, quenched with water and purified by reverse phase preparative HPLC to give H8 (248 mg, 92%). ESI-MS calculated for _C35H52FN4O4 [M ₊ H] ₊ = _611.40 , found: 611.48.

Step-2: ((1S,2R)-2-(1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(3-methyl-2- Pendant oxyimidazolidin-1-yl)ethyl)cyclopentyl)carbamate ( H9 )

Compound H8 (248 mg, 0.406 mmol) was dissolved in DCM (6 mL), and then trifluoroacetic acid (0.6 mL, 8.12 mmol) was added. After stirring at room temperature for 2 hours, the reaction mixture was evaporated to give the product without further purification. The resulting residue was then dissolved in THF (4 mL). DIPEA (212 µL, 1.21 mmol) and CDI (99 mg, 0.609 mmol) were then added. The mixture was stirred overnight, quenched with water and purified by reverse phase preparative HPLC to give H9 (114 mg, 52%). ESI-MS calculated for _C31H42FN4O3 [M ₊ H]+ _{= 537.32} , found: 537.35.

Synthesis of compound 485: Compound 485 was synthesized according to the same procedure used for compound 6 using compound H9 and 4-fluoro-2-isopropoxybenzonitrile. Example 29

Preparation of ((1S,2R)-2-((R)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine- Methyl 4-yl)-1-(3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate ( Compound 489 )

Step A: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-iminoethyl ) cyclopentyl) methyl carbamate

((1S,2R)-2-((S)-( ₁ -benzylpiperidin-4-yl)(cyano)(3-fluorophenyl)methyl )cyclopentyl)carbamate (1 g, 2.2 mmol) in toluene (15 mL) was added dropwise DIBAL-H (1.5 M in toluene, 8.9 mL, 13.3 mmol). The mixture was then stirred at room temperature for 2 hours and quenched with Rochelle's salt (2 M in water, 20 mL) at 0 °C. The suspension was filtered, and the filtrate was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give ((1S,2R)-2-((S)-1-(1- as a white solid) Benzylpiperidin-4-yl)-l-(3-fluorophenyl)-2-iminoethyl)cyclopentyl)carbamate (1 g, crude). The residue was used directly in the next step. LC-MS: 452 (M+H) ⁺ .

Step B: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-pendoxoethyl ) cyclopentyl) methyl carbamate

To ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-iminoethyl) ring To a solution of methyl pentyl)carbamate (2 g, 4.4 mmol) in THF (20 mL) was added _H2SO4 ( ₅ % in water, 4 mL). The solution was stirred at room temperature for 2 hours. The mixture was then adjusted to pH 7-8 with saturated aqueous NaHCO ₃ and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1- as a white solid Methyl (3-fluorophenyl)-2-oxyethyl)cyclopentyl)carbamate (1.4 g, 70% yield). LC-MS: 453 (M+H) ⁺ .

Step C: ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-pendoxoethyl )cyclopentyl)(4-methoxybenzyl)methylcarbamate

((1S,2R)-2-((S)-1-( ₁ -benzylpiperidin-4-yl)-1-(3-fluorophenyl)- Methyl 2-oxyethyl)cyclopentyl)carbamate (300 mg, 0.66 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 40 mg, 0.99 mmol) . After 0.5 hours, 1-(chloromethyl)-4-methoxybenzene (0.1 mL, 0.8 mmol) was added to the above mixture and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with 20 mL of saturated aqueous _NH4Cl and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((S)-1-(1-benzylpiperidin-4-yl)-1- as a white solid Methyl (3-fluorophenyl)-2-oxyethyl)cyclopentyl)(4-methoxybenzyl)carbamate (270 mg, 71% yield). LC-MS: 573 (M+H) ⁺ .

Step D: ((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-2 -(1-Methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)(4-methoxybenzyl)carbamate

To ₃ -bromo-1-methyl-1H-pyrazole (1.1 g, 6.9 mmol) and ((1S,2R)-2-((S)-1-(1) under N atmosphere at -65 °C -Benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-oxyethyl)cyclopentyl)(4-methoxybenzyl)carbamate ( To a solution of 1 g, 1.7 mmol) in dry THF (20 mL) was added n-BuLi (2.5 M in hexanes, 2.8 mL, 7 mmol) dropwise. The reaction was then stirred at this temperature for 1 hour. The reaction was quenched with saturated aqueous _NH4Cl (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)- as a yellow solid 1-(3-Fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)(4-methoxybenzyl)amino Methyl formate (500 mg, 44% yield). LC-MS: 655 (M+H) ⁺ .

Step E: ((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(1- Methyl-1H-pyrazol-3-yl)-2-(((methylthio)carbosulfinyl)oxy)ethyl)cyclopentyl)(4-methoxybenzyl)amino methyl formate

((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)-1-( ₃ -fluorophenyl) under N atmosphere with stirring at 0 °C )-methyl 2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)(4-methoxybenzyl)carbamate (650 mg, 0.99 mmol) and NaH (60% in mineral oil, 99 mg, 2.48 mmol) in dry THF (10 mL) for 1 h. Then carbon disulfide (0.2 mL, 3.47 mmol) was added. After stirring at 0°C for 30 minutes, MeI (211 mg, 1.49 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. Subsequently, the reaction was cooled to -10°C and quenched with saturated aqueous NaHCO ₃ (15 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give ((1S,2R)-2-((1S,2S)-1 as a yellow oil -(1-Benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-2-(((methyl Thio)carbothiolanyl)oxy)ethyl)cyclopentyl)(4-methoxybenzyl)carbamate (450 mg, crude). The residue was used directly in the next step. LC-MS: 745 (M+H) ⁺ .

Step F: ((1S,2R)-2-((R)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(1-methyl) -1H-Pyrazol-3-yl)ethyl)cyclopentyl)(4-methoxybenzyl)carbamate methyl ester

((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-( 1-Methyl-1H-pyrazol-3-yl)-2-(((methylthio)carbosulfinyl)oxy)ethyl)cyclopentyl)(4-methoxybenzyl) A mixture of methyl carbamate (450 mg, 0.6 mmol), AIBN (10 mg, 0.06 mmol) and tributylstannane (0.26 mL, 1 mmol) in 10 mL of dry toluene overnight. The reaction was then concentrated under reduced pressure. And the residue was purified by silica gel flash column chromatography to give ((1S,2R)-2-((R)-1-(1-benzylpiperidin-4-yl)-1- as a yellow solid Methyl (3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)(4-methoxybenzyl)carbamate (250 mg , the yield is 65%). LC-MS: 639 (M+H) ⁺ .

Step G: ((1S,2R)-2-((R)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(1-methyl) -1H-Pyrazol-3-yl)ethyl)cyclopentyl)carbamate methyl ester

((1S,2R)-2-((R)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(1- A solution of methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)(4-methoxybenzyl)carbamate (250 mg, 0.39 mmol) in TFA (5 mL) 3h. The reaction was then concentrated under reduced pressure. And the residue was diluted with water (10 mL), and the solution was adjusted to pH 7-8 with saturated aqueous NaHCO ₃ . The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give ((1S,2R)-2-((R)-1-(1- as a yellow solid) Benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate methyl ester (200 mg, crude product). The residue was used directly in the next step. LC-MS: 519 (M+H) ⁺ .

Step H: ((1S,2R)-2-((R)-1-(3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-1-(piperidine -4-yl)ethyl)cyclopentyl)carbamate

((1S,2R)-2-((R)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorobenzene) was stirred at room temperature under a hydrogen atmosphere (1 atm) (200 mg, 0.39 mmol) and 10% Pd(OH) ₂ /C ( 20 mg, 10% w/t) in _CF3CH2OH ( ₇ mL) overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give ((1S,2R)-2-((R)-1-(3-fluorophenyl)-2-(1-methyl) as a white solid methyl-lH-pyrazol-3-yl)-l-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (100 mg, crude). The residue was used directly in the next step. LC-MS: 429 (M+H) ⁺ .

Step 1: ((1S,2R)-2-((R)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate (Compound 489)

((1S,2R)-2-((R)-1-(3-fluorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-1-( Methyl piperidin-4-yl)ethyl)cyclopentyl)carbamate (50 mg, 0.12 mmol), 4-(6-oxy-2-azaspiro[3.3]heptan-2-yl ) A mixture of benzonitrile (30 mg, 0.14 mmol) and AcOH (2 drops) in DCM (5 mL) for 1.5 h. Then NaBH(OAc) ₃ (74 mg, 0.35 mmol) was added and the mixture was stirred at room temperature for an additional 2 hours. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 489 (3.2 mg, 4% yield) as a white solid. LC-MS: 625 (M+H)+. 1H NMR (400 MHz, methanol- d ₄ ) δ 7.38 - 7.19 (m, 6H), 6.93 - 6.84 (m, 1H), 6.32 (d, 2H), 5.82 (d, 1H), 4.07 - 3.91 (m, 1H), 3.86 (s, 2H), 3.74 (s, 3H), 3.72 (s, 2H), 3.40 (s, 3H), 3.32 - 3.23 (m, 1H), 3.21 - 3.13 (m, 2H), 2.88 - 2.70 (m, 2H), 2.68 - 2.49 (m, 2H), 2.31 - 2.19 (m, 2H), 2.01 - 1.95 (m, 2H), 1.84 - 1.78 (m, 1H), 1.77 - 1.61 (m, 3H), 1.53 - 1.45 (m, 1H), 1.42 - 1.30 (m, 2H), 1.26 - 1.22 (m, 1H), 1.16 - 1.04 (m, 3H), 1.04 - 0.94 (m, 1H). Example 30

Preparation of ((1S,2R)-2-((1S,2S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine Methyl pyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate ( Compound 488 )

Step A: ((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-2 -(1-Methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate methyl ester

Stir ((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-hydroxyl at room temperature Methyl 2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)(4-methoxybenzyl)carbamate (200 mg, 0.31 mmol) in TFA ( 6 mL) for 5 hours. The reaction was then concentrated under reduced pressure. The residue was diluted with water (10 mL), and the solution was adjusted to pH 7-8 with saturated aqueous NaHCO ₃ . The mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give ((1S,2R)-2-((1S,2S)-1-( as a white solid 1-Benzylpiperidin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl ) methyl carbamate (190 mg, crude). The residue was used directly in the next step. LC-MS: 535 (M+H) ⁺ .

Step B: ((1S,2R)-2-((1S,2S)-1-(3-fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl) -Methyl 1-(piperidin-4-yl)ethyl)cyclopentyl)carbamate

((1S,2R)-2-((1S,2S)-1-(1-benzylpiperidin-4-yl)-1-(3- Fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamate (190 mg, 0.36 mmol) and 10% Pd ( OH) ₂ /C (95 mg, 50% w/t) in _CF3CH2OH ( ₁₀ mL) for 4 days. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give ((1S,2R)-2-((1S,2S)-1-(3-fluorophenyl)-2-hydroxy- as a white solid Methyl 2-(1-methyl-1H-pyrazol-3-yl)-1-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (120 mg, crude). The residue was used directly in the next step. LC-MS: 445 (M+H) ⁺ .

Step C: ((1S,2R)-2-((1S,2S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl )piperidin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)ethyl)cyclopentyl)carbamic acid Methyl ester ( compound 488 )

((1S,2R)-2-((1S,2S)-1-(3-fluorophenyl)-2-hydroxy-2-(1-methyl-1H-pyrazole-3- yl)-1-(piperidin-4-yl)ethyl)cyclopentyl)carbamate (120 mg, 0.27 mmol), 4-(6-oxy-2-azaspiro[3.3] A mixture of heptan-2-yl)benzonitrile (63 mg, 0.3 mmol) and AcOH (2 drops) in DCM (5 mL) for 1.5 h. Then NaBH(OAc) ₃ (114 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for an additional 2 hours. The resulting solution was diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 488 (5 mg, 3% yield) as a white solid. LC-MS: 641 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.44 - 7.14 (m, 7H), 6.92 - 6.81 (m, 1H), 6.33 (d, 2H), 4.20 - 4.05 (m, 1H), 3.87 (s , 2H), 3.82 - 3.71 (m, 5H), 3.55 - 3.35 (m, 4H), 3.05 - 2.61 (m, 5H), 2.33 - 2.24 (m, 2H), 2.08 - 1.95 (m, 3H), 1.80 - 1.63 (m, 3H), 1.48 - 1.32 (m, 3H), 1.24 - 1.10 (m, 4H), 0.91 - 0.67 (m, 1H). Example 31

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(4-cyanophenyl)-2-azaspiro[3.3]heptan-6-yl)piperidine- 4-yl)-2-(5,5-dimethyl-2-oxyoxazolidine-3-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate Esters ( compound 496 )

To a solution of 1-chloro-2-methylpropan-2-ol (120 mg) in DCM (5 mL) was added triphosgene (150 mg) in DCM (5 mL). The resulting mixture was stirred for 10 minutes, and then pyridine (0.1 mL) was added and stirred at room temperature for 1 hour. A solution of E3 (500 mg) and trimethylamine (0.48 mL) in dichloromethane (5 mL) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure to remove dichloromethane, and the residue was purified by flash column chromatography (DCM/MeOH as eluent) to give H10 . ESI-MS: 588.5.

H10 (336 mg, 0.57 mmol) was dissolved in THF (3 mL). NaH (92 mg, 2.28 mmol) was added and the mixture was heated to 60 °C for 5 hours. Water was then added and the mixture was extracted three times with EtOAc, concentrated and purified by flash column chromatography (DCM/MeOH as eluent) to give H11 . ESI-MS: 552.4.

To a solution of H11 (195 mg) in methanol (5 mL) was added acetic acid (31 μL, 0.536 mmol) and Pd/C (50 mg, 10 wt%) under N ₂ atmosphere. The mixture was then stirred at room temperature under a hydrogen atmosphere (normal pressure). After 4 hours, the Pd/C catalyst was filtered off, and the solvent was removed by rotary evaporation to give H12 , which was used without further purification. ESI-MS: 462.7.

Compound 496 was prepared from H12 according to the procedure described for the preparation of compound 45. ESI-MS: 658.7. Example 32

Preparation ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2,6-difluorophenyl)) -2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl) Ethyl)cyclopentyl)methylcarbamate ( Compound 507 )

Step A: 6-Bromo-2,3,4-trifluorobenzaldehyde

To a stirred mixture of 5-bromo-1,2,3-trifluorobenzene (2 g, 9.48 mmol) in THF (20 mL) at -65 °C was added LDA (2 M in THF, 5.7 mL) , 11.37 mmol) for 30 min. Next, DMF (1.1 mL, 14.22 mmol) was added to the above solution. The reaction mixture was stirred at this temperature for 3 hours. The mixture was then quenched with saturated aqueous _NH4Cl (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-bromo-2,3,4-trifluorobenzaldehyde (1.4 g, 62% yield) as a yellow solid. LC-MS: 239, 241 (M+H) ⁺ .

Step B: 6-Bromo-2,3,4-trifluorobenzoic acid

Stir 6-bromo-2,3,4-trifluorobenzaldehyde (750 mg, 3.14 mmol), 2-methyl-2-butene (2.6 mL, 31.38 mmol), NaClO ₂ (1.4 g, 15.61 mmol) and _{NaH2PO4 (} 1.3 mL, 15.69 mmol) in t-BuOH (20 mL) and THF (10 mL) for 30 min. The mixture was adjusted to pH about 3 with 1 N aqueous HCl and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 6-bromo-2,3,4-trifluorobenzoic acid (1 g, crude) as a white solid product). LC-MS: 255, 257 (M+H) ⁺ .

Step C: 6-Bromo-2,3,4-trifluoro-N,N-dimethylbenzamide

Stir 6-bromo-2,3,4-trifluorobenzoic acid (500 mg, 1.96 mmol), dimethylamine hydrochloride (190 mg, 2.35 mmol), DIPEA (1.3 mL, 7.84 mmol) and A mixture of HATU (1.49 g, 3.92 mmol) in DCM (20 mL) for 3 h. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-bromo-2,3,4-trifluoro-N,N-dimethylbenzamide (260 mg, 47% yield) as a white solid . LC-MS: 282, 284 (M+H) ⁺ .

Step D: 6-Cyano-2,3,4-trifluoro-N,N-dimethylbenzamide

₆ -Bromo-2,3,4-trifluoro-N,N-dimethylbenzamide (140 mg, 0.49 mmol), dppf (55 mg, 0.09 mmol) were stirred at 100 °C under N atmosphere , Pd(t- _Bu3P ) ₂ (50 mg, 0.09 mmol) and a mixture of Zn(CN) ₂ (87 mg, 0.74 mmol) in DMAc (5 mL) for 2 h. The cooled mixture was filtered through a pad of celite, and the filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 6-cyano-2,3,4-trifluoro-N,N-dimethylbenzamide (100 mg, 88% yield) as a white solid ). LC-MS: 229 (M+H) ⁺ .

Step E: ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-2,6-difluorobenzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate ( Compound 507 )

((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1- (3-Fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (50 mg, 0.095 mmol), 6-cyano-2 A mixture of ,3,4-trifluoro-N,N-dimethylbenzamide (26 mg, 0.11 mmol) and K2CO3 (40 _mg , 0.29 mmol) in DMSO ( ₅ mL) overnight. The cooled mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 507 (7 mg, 10% yield) as a white solid. LC-MS: 732 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.50 - 7.24 (m, 4H), 7.13 - 7.04 (m, 1H), 6.74 - 6.59 (m, 2H), 4.54 (d, 1H), 4.42 - 4.29 (m, 3H), 4.23 (s, 2H), 4.03 - 3.93 (m, 1H), 3.60 (s, 3H), 3.35 - 3.31 (m, 1H), 3.12 (s, 3H), 2.98 - 2.88 (m , 4H), 2.84 - 2.76 (m, 1H), 2.66 - 2.53 (m, 2H), 2.44 (s, 3H), 2.38 - 2.30 (m, 2H), 2.23 - 2.15 (m, 1H), 2.06 - 1.96 (m, 3H), 1.79 - 1.64 (m, 3H), 1.53 - 1.42 (m, 1H), 1.30 - 1.06 (m, 5H), 0.79 - 0.64 (m, 1H). Example 33

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(N,N-dimethylaminosulfonyl)phenyl)-2- Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl) Cyclopentyl) methyl carbamate ( Compound 510 )

Step A: 2-(Benzylthio)-4-fluorobenzonitrile

2-Bromo-4-fluorobenzonitrile (500 mg, 2.5 mmol), Pd2(dba) ₃ (115 mg, 0.13 mmol), Xant-Phos (72 mg, 0.13 mmol ₎ were stirred at 100 °C under _N2 mmol), DIEA (1.2 mL, 7.5 mmol) and BnSH (0.3 mL, 2.75 mmol) in toluene (10 mL) overnight. The mixture was washed with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 2-(benzylthio)-4-fluorobenzonitrile (469 mg, 77% yield) as a brown solid. LC-MS: 244 (M+H) ⁺ .

Step B: 2-Cyano-5-fluorobenzenesulfonyl chloride

To a solution of 2-(benzylthio)-4-fluorobenzonitrile (469 mg, 1.93 mmol) in MeCN (8 mL) was added 1,3-dichloro-5,5 at -15 °C - Dimethylimidazolidine-2,4-dione (570 mg, 2.89 mmol), 1 N aqueous HCl (0.2 mL) and water (0.4 mL). The mixture was stirred at 0°C for 2 hours. The mixture was then diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 2-cyano-5-fluorobenzenesulfonyl chloride (400 mg, crude) as a brown solid . LC-MS: 220 (M+H) ⁺ .

Step C: 2-Cyano-5-fluoro-N,N-dimethylbenzenesulfonamide

Stir 2-cyano-5-fluorobenzenesulfonyl chloride (400 mg, 0.91 mmol), TEA (0.383 mL, 2.73 mmol) and dimethylamine (2 M in THF, 1.8 mL, 3.64 mmol) at 0 °C Mixture in DCM (10 mL) for 2 hours. The mixture was washed with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 2-cyano-5-fluoro-N,N-dimethylbenzene-1-sulfonamide (103 mg, 50% yield) as a brown solid . LC-MS: 229 (M+H) ⁺ .

((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(N,N-dimethylaminosulfonyl)phenyl)-2-nitrogen Heterospiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cycle Methyl pentyl)carbamate ( compound 510 ) was prepared from ((1S,2R)-2-((S)-1-(1-(2-azaspiro[3.3]) following the procedure for compound 6 Heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)amino Methyl formate and 2-cyano-5-fluoro-N,N-dimethylbenzene-1-sulfonamide were synthesized as white solids. LC-MS: 732 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 (d, 1H), 7.47 - 7.41 (m, 2H), 7.36 (m, 1H), 7.09 (t, 1H), 6.79 (d, 1H), 6.69 (d, 1H), 6.65 (s, 1H), 6.60 (dd, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.05 (s, 2H), 4.02 - 3.96 (m, 1H) , 3.91 (s, 2H), 3.60 (s, 3H), 2.93 (d, 1H), 2.86 - 2.74 (m, 8H), 2.68 - 2.58 (m, 2H), 2.45 (s, 3H), 2.40 - 2.32 (m, 2H), 2.25 - 2.16 (m, 1H), 2.12 - 1.98 (m, 3H), 1.91 - 1.83 (m, 1H), 1.80 - 1.64 (m, 3H), 1.52 - 1.43 (m, 1H) , 1.34 - 1.18 (m, 4H), 0.79 - 0.66 (m, 1H). Example 34

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1,3-dimethyl-1H-pyrazol-4-yl)sulfonic acid) Acyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H- Imidazol-1-yl)ethyl)cyclopentyl)carbamate ( compound 518 )

Step A: 4-((3-Chloro-4-fluorophenyl)sulfanyl)-1,3-dimethyl-1H-pyrazole

3-Chloro-4-fluorobenzenethiol (162 mg, 1 mmol), 4-iodo-1,3-dimethyl-1H-pyrazole (266 mg, 1.2 mmol) were stirred at 100 °C under _N2 ), CuI (190 mg, 1 mmol), 1,10-phenanthroline (180 mg, 1 mmol) and a mixture of _CS2CO3 (977 mg, ₃ mmol) in toluene (6 mL) overnight. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried _{over Na2SO4} , and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-((3-chloro-4-fluorophenyl)sulfanyl)-1,3-dimethyl-1H-pyrazole (93 mg) as a yellow solid , the yield is 36%). LC-MS: 257 (M+H) ⁺ .

Step B: 4-((3-Chloro-4-fluorophenyl)sulfonyl)-1,3-dimethyl-1H-pyrazole

4-((3-Chloro-4-fluorophenyl)sulfanyl)-1,3-dimethyl-1H-pyrazole (90 mg, 0.35 mmol) and potassium hydrogen persulfate (432 mg) were stirred at room temperature , 0.7 mmol) in acetone (4 mL) and water (4 mL) overnight. The reaction mixture was then diluted with water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with aqueous Na ₂ S ₂ O ₃ (20 mL) and brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 4-((3-chloro-4-fluorophenyl)sulfonyl)-1,3-dimethyl-1H-pyrazole (90) as a white solid mg, 89% yield). LC-MS: 289 (M+H) ⁺ .

Subsequently, ((1S,2R)-2-((S)-1-(1-(2-(2-chloro-4-((1,3-dimethyl-1H-pyrazol-4-yl) Sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -imidazol-1-yl)ethyl)cyclopentyl)carbamate ( compound 518) was followed by the procedure for compound 45 from ((1S,2R)-2-((S)-1-( 1-(2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate and 4-((3-chloro-4-fluorophenyl)sulfonyl)-1,3-dimethyl-1H-pyrazole were synthesized as white solids . LC-MS: 792 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.73 (s, 1H), 7.62 (d, 1H), 7.58 (dd, 1H), 7.47 - 7.41 (m, 2H), 7.35 (d, 1H), 7.12 - 7.06 (m, 1H), 6.71 - 6.62 (m, 2H), 6.53 (d, 1H), 4.54 (d, 1H), 4.37 (d, 1H), 4.18 (s, 2H), 4.04 (s, 2H), 4.01 - 3.94 (m, 1H), 3.76 (s, 3H), 3.60 (s, 3H), 2.94 - 2.89 (m, 1H), 2.83 - 2.77 (m, 1H), 2.65 - 2.57 (m, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.34 - 2.28 (m, 2H), 2.22 - 2.15 (m, 1H), 2.05 - 1.97 (m, 3H), 1.88 - 1.82 (m, 1H), 1.77 - 1.64 (m, 3H), 1.51 - 1.45 (m, 1H), 1.35 - 1.29 (m, 3H), 1.25 - 1.17 (m, 2H), 0.77 - 0.65 (m, 1H). Example 35

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-5-fluoro-2-methylbenzene yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate ( Compound 519 )

Step A: 3-Fluoro-2-iodo-6-methylbenzoic acid

5-Fluoro-2-methylbenzoic acid (5 g, 32.4 mmol), NIS (8 g, 35.7 mmol) and Pd(OAc) ₂ (0.4 g, 1.62 mmol) were stirred at 100 °C under _N2 The mixture was mixed in DMF (20 ml) for 16 hours. _The reaction was then quenched with saturated aqueous Na2SO3 ( ₂ mL). The resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 3-fluoro-2-iodo-6-methylbenzoic acid (7 g, crude) as a white solid product). The residue was used directly in the next step. LC-MS: 279(MH) ⁺ .

Step B: 3-Bromo-5-fluoro-6-iodo-2-methylbenzoic acid

To a solution of 3-fluoro-2-iodo-6-methylbenzoic acid ( ₃ g, 10.7 mmol) in concentrated _H2SO4 (30 ml) was added NBS (1.91 g, 10.7 mmol) portionwise at 0 °C ). The reaction was stirred at room temperature for 16 hours. The mixture was then slowly mixed into ice water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 3-bromo-5-fluoro-6-iodo-2-methylbenzoic acid as a white solid ( 3 g, crude product). The residue was used directly in the next step. LC-MS: 357, 359 (MH) ⁺ .

Step C: 3-Bromo-5-fluoro-6-iodo-N,N,2-trimethylbenzamide

Stir 3-bromo-5-fluoro-6-iodo-2-methylbenzoic acid (720 mg, 2 mmol), HATU (1.1 g, 3 mmol), DIPEA (0.65 mL, 4 mmol) and dimethicone at room temperature A solution of methylamine (2 M in THF, 2 mL, 4 mmol) in DCM (15 ml) for 2 hours. The resulting solution was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 3-bromo-5-fluoro-6-iodo-N,N,2-trimethylbenzamide (500 mg, yield 64) as a white solid %). LC-MS: 386 (M+H) ⁺ .

Step D: 3-Bromo-6-cyano-5-fluoro-N,N,2-trimethylbenzamide

3-Bromo-5-fluoro-6-iodo-N,N,2-trimethylbenzamide (300 mg, 0.78 mmol), Zn(CN) ₂ (110 mmol) were stirred at 100 °C under _N2 atmosphere mg, 0.94 mmol), dppf (40 mg, 0.08 mmol) and a mixture of Pd(t- _Bu3P ) ₂ (43 mg, 0.08 mmol) in DMAc (3 mL) for 2 h. The cooled mixture was filtered through a pad of celite, and the filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 3-bromo-6-cyano-5-fluoro-N,N,2-trimethylbenzamide (30 mg, yield) as a white solid 14%). LC-MS: 285 (M+H) ⁺ .

Step E: ((1S,2R)-2-((S)-1-(1-(2-(4-cyano-3-(dimethylaminocarboxy)-5-fluoro-2-methyl ylphenyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole- 1-yl)ethyl)cyclopentyl)carbamate ( Compound 519 )

3-Bromo-6-cyano-5-fluoro-N,N, ₂ -trimethylbenzamide (20 mg, 0.07 mmol), ((1S,2R) were stirred at 100 °C under N atmosphere -2-((S)-1-(1-(2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-( Methyl 2-methyl-1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate (37 mg, 0.07 mmol), Pd2(dba _{)3 (} 6 mg, 0.007 mmol), Ru-Phos (6 mg, 0.014 mmol) and a mixture _{of CS2CO3} (46 mg, 0.14 mmol) in toluene (1 ml) for 16 hours. The cooled mixture was filtered through a pad of celite, and the filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC and RP-preparative HPLC to give compound 519 (2 mg, 4% yield) as a white solid. LC-MS: 728 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 - 7.40 (m, 2H), 7.36 (d, 1H), 7.09 (t, 1H), 6.69 (d, 1H), 6.65 (s, 1H), 6.23 (d, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.17 (s, 2H), 4.04 (s, 2H), 4.02 - 3.95 (m, 1H), 3.60 (s, 3H) , 3.12 (s, 3H), 3.01 - 2.86 (m, 4H), 2.86 - 2.76 (m, 1H), 2.69 - 2.54 (m, 2H), 2.45 (s, 3H), 2.37 - 2.27 (m, 2H) , 2.25 - 2.14 (m, 1H), 2.07 (s, 3H), 2.03 - 1.97 (m, 2H), 1.92 - 1.81 (m, 1H), 1.80 - 1.63 (m, 3H), 1.54 - 1.43 (m, 1H), 1.40 - 1.28 (m, 3H), 1.28 - 1.10 (m, 3H), 0.80 - 0.62 (m, 1H). Example 36

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-1-oxy-1,2,3,4-tetrahydro) Isoquinolin-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl- Methyl 1H-imidazol-1-yl)ethyl)cyclopentyl)carbamate ( Compound 544 )

Step A: 2-(5-Bromo-2-fluorophenyl)ethan-1-amine

To a solution of 2-(5-bromo-2-fluorophenyl)acetonitrile (13 g, 60.7 mmol) in THF (100 mL) was added BH3 _- THF (2 M in THF, 121.4 mL) at room temperature , 242.8 mmol). The mixture was then stirred at 80°C for 18 hours. The cooled mixture was quenched with MeOH (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 2-(5-bromo-2-fluorophenyl)ethan-l-amine (6.3 g, 47% yield) as a yellow oil. LC-MS: 218, 220 (M+H) ⁺ .

Step B: Methyl (5-bromo-2-fluorophenethyl)carbamate

To a solution of 2-(5-bromo-2-fluorophenyl)ethan-1-amine (4 g, 18.3 mmol) and DIPEA (6.7 mL, 36.7 mmol) in DCM (40 mL) was added at 0 °C Methyl chloroformate (1.7 mL, 22 mmol). The mixture was then stirred at room temperature for 1.5 hours. The reaction was poured into ice water (40 mL) and extracted with DCM (40 mL x 2). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give methyl (5-bromo-2-fluorophenethyl)carbamate (4 g, 79% yield) as a yellow oil. LC-MS: 276, 278 (M+H) ⁺ .

Step C: 8-Bromo-5-fluoro-3,4-dihydroisoquinolin-1(2H)-one

A solution of methyl (5-bromo-2-fluorophenethyl)carbamate (5.3 g, 19.2 mmol) in TfOH (25 mL) was stirred at 100 °C for 4 h. The mixture was poured into ice water (100 mL) and extracted with EtOAc (100 mL x 2). The organic phase was washed with saturated aqueous NaHCO ₃ (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 8-bromo-5-fluoro-3,4-dihydroisoquinolin-1(2H)-one (500 mg, 10% yield) as a white solid . LC-MS: 244, 246 (M+H) ⁺ .

Step D: 8-Bromo-5-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one

To a solution of 8-bromo-5-fluoro-3,4-dihydroisoquinolin-1(2H)-one (430 mg, 1.8 mmol) in DMF (5 mL) at 0 °C was added NaH (60 % in mineral oil, 106 mg, 2.6 mmol). The mixture was stirred at 0°C for 20 minutes. MeI (0.17 mL, 2.6 mmol) was then added and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous _NH4Cl (30 mL) and extracted with EtOAc (30 mL x 2). The organic phase was washed with brine (30 mL), dried _{over Na2SO4} and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 8-bromo-5-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (420 mg, yield 92%). LC-MS: 258, 260 (M+H) ⁺ .

Step E: 5-Fluoro-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile

8-Bromo-5-fluoro-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (120 mg, 0.46 mmol), Zn(CN) ₂ was stirred at 100 °C under microwave (82 mg, 0.7 mmol), a mixture of Pd(t- _Bu3P ) ₂ (48 mg, 0.09 mmol) and dppf (52 mg, 0.09 mmol) in DMAc (1 mL) for 1 hour. The reaction mixture was then filtered, and the filtrate was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried _{over Na2SO4} , and concentrated under reduced pressure. The residue was purified by flash chromatography to give 5-fluoro-2-methyl-1-oxy-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile (68 mg) as a white solid , the yield is 72%). LC-MS: 205 (M+H) ⁺ .

((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-1-oxy-1,2,3,4-tetrahydroiso Quinolin-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H -imidazol-1-yl)ethyl)cyclopentyl)carbamate ( compound 544 ) was followed by the procedure for compound 6 from ((1S,2R)-2-((S)-1-( 1-(2-Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate and 5-fluoro-2-methyl-1-oxy-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile were synthesized as White solid. LC-MS: 708 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.54 - 7.36 (m, 4H), 7.14 (t, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 6.64 (d, 1H), 4.66 (d, 1H), 4.42 (d, 1H), 4.10 (s, 2H), 4.00 - 3.96 (m, 3H), 3.62 (s, 3H), 3.53 - 3.48 (m, 2H), 3.25 - 3.14 ( m, 2H), 3.12 (s, 3H), 2.91 - 2.85 (m, 2H), 2.66 - 2.61 (m, 1H), 2.57 (s, 3H), 2.53 - 2.45 (m, 3H), 2.40 - 2.30 ( m, 3H), 2.23 - 2.12 (m, 2H), 1.90 - 1.80 (m, 2H), 1.65 - 1.50 (m, 2H), 1.35 - 1.28 (m, 4H), 1.27 - 1.18 (m, 1H), 0.80 - 0.70 (m, 1H). Example 37

Preparation of ((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-5- yl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1- yl)ethyl)cyclopentyl)carbamate ( Compound 552 )

Step A: N-(5-Bromo-2-fluorophenethyl)-2,2,2-trifluoroacetamide

To a mixture of 2-(5-bromo-2-fluorophenyl)ethan-1-amine (4.5 g, 21 mol) and Py (5 mL, 63 mol) in DCM (80 mL) was added at 0 °C ( _CF3CO ) _2O (5.76 mL, 42 mol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ice water (100 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give N-(5-bromo-2-fluorophenethyl)-2,2,2-trifluoroacetamide (5.3 g, yield 82) as a white solid %). LC-MS: 314, 316 (M+H) ⁺ .

Step B: 1-(8-Bromo-5-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

To N-(5-bromo- ₂ -fluorophenethyl)-2,2,2-trifluoroacetamide (5.3 g, 17 mol) in AcOH/ _H2SO4 (60 mL/15 mol) at 0 °C mL) was added HCHO (37% in water, 6.8 mL, 84 mol). The mixture was stirred at 50°C for 16 hours. The reaction mixture was then diluted with ice water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 1-(8-bromo-5-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2, as a white solid 2-Trifluoroethan-1-one (1.35 g, 24% yield). LC-MS: 326, 328 (M+H) ⁺ .

Step C: 8-Bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline

1-(8-Bromo-5-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (1.35 g) was stirred at 80 °C , 4.15 mmol) and K ₂ CO ₃ (1.7 g, 12.46 mmol) in EtOH/H ₂ O (15 mL/15 mL) for 3 h. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 8-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (910 mg, 95% yield) as a white solid. LC-MS: 230, 232 (M+H) ⁺ .

Step D: 8-Bromo-5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline

8-Bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline (910 mg, 3.74 mmol), HCHO (37% in water, 561 mg, 18.7 mmol) and AcOH ( 2 drops) in MeOH (15 mL) for 30 min. Subsequently, _NaBH3CN (706 mg, 11.2 mmol) was added. The reaction was stirred at this temperature for an additional 16 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give 8-bromo-5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (860 mg, yield 82) as a yellow solid %). LC-MS: 244, 246 (M+H) ⁺ .

Step E: 5-Fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile

8-Bromo-5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (500 mg, 2.05 mmol), Zn(CN) ₂ (288 mg) were stirred at 110 °C under microwave , 2.46 mmol), dppf (115 mg, 0.2 mmol) and a mixture of Pd(t- _Bu3P ) ₂ (116 mg, 0.2 mmol) in DMAc (3 ml) for 1 hour. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography to give 5-fluoro-2-methyl as a yellow solid yl-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile (310 mg, 79% yield). LC-MS: 191 (M+H) ⁺ .

Subsequently, ((1S,2R)-2-((S)-1-(1-(2-(8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-5 -yl)-2-azaspiro[3.3]heptane-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazole-1 -yl)ethyl)cyclopentyl)carbamate ( compound 552 ) was followed by the procedure for compound 6 from ((1S,2R)-2-((S)-1-(1-(2) -Azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethyl )cyclopentyl)carbamate and 5-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carbonitrile were synthesized as white solids. LC-MS: 694 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.50 - 7.46 (m, 2H), 7.37 (d, 2H), 7.13 - 7.10 (m, 1H), 6.72 (d, 2H), 6.35 (d, 1H) ), 4.57 - 4.55 (d, 1H), 4.39 - 4.37 (d, 1H), 4.07 (s, 2H), 4.01 - 3.97 (m, 1H), 3.96 (s, 2H), 3.68 (s, 2H), 3.61 (s, 3H), 3.11 - 3.04 (m, 1H), 3.00 - 2.77 (m, 2H), 2.75 - 2.70 (m, 4H), 2.67 - 2.60 (m, 1H), 2.50 (s, 3H), 2.48 (s, 3H), 2.41 - 2.37 (m, 2H), 2.35 - 2.28 (m, 1H), 2.20 - 2.02 (m, 4H), 1.98 - 1.80 (m, 3H), 1.77 - 1.70 (m, 1H) ), 1.54 - 1.48 (m, 1H), 1.39 - 1.28 (m, 2H), 1.24 - 1.18 (m, 2H), 0.79 - 0.68 (m, 1H). Example 38 Synthesis and Characterization of Compounds of the Invention

Other compounds of the invention can be prepared using the methods described in the preceding schemes and in the preceding examples, and related methods, see eg WO 2017/192543, WO 2018/183857, WO 2019/191526, WO 2020/072391 and PCT/US2020/053186. LCMS (ESI) data for representative compounds of the invention prepared by these methods are provided in Table 1.

of additional compounds of the present invention¹ H NMR is provided in Table 4. Table 4 Compound number ¹ H NMR 4 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 (d, 2H), 7.46 (q, 1H), 7.20 - 7.09 (m, 2H), 7.06 - 6.98 (m, 1H), 6.50 (d, 2H) ), 4.74 - 4.62 (m, 1H), 4.55 - 4.41 (m, 2H), 4.35 - 4.18 (m, 2H), 4.02 (s, 2H), 3.89 (s, 2H), 3.86 (s, 1H), 3.55 (t, 1H), 3.47 - 3.38 (m, 1H), 3.21 (s, 3H), 2.85 - 2.68 (m, 3H), 2.67 - 2.59 (m, 2H), 2.58 - 2.50 (m, 1H), 2.42 - 2.30 (m, 2H), 2.18 - 1.95 (m, 5H), 1.85 - 1.59 (m, 6H), 1.53 (s, 2H), 1.41 - 1.27 (m, 2H), 1.19 - 1.10 (m, 2H) ), 1.03 - 0.94 (m, 2H), 0.87 - 0.75 (m, 1H) 5 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.63 (d, 1H), 7.46 (q, 1H), 7.20 - 7.09 (m, 2H), 7.06 - 6.98 (m, 1H), 6.50 (dd, 1H) ), 6.27 (d, 1H), 4.73 - 4.63 (m, 1H), 4.55 - 4.40 (m, 2H), 4.34 - 4.19 (m, 2H), 4.04 (s, 2H), 3.91 (s, 2H), 3.86 (s, 1H), 3.55 (t, 1H), 3.43 (d, 1H), 3.21 (s, 3H), 3.05 (s, 3H), 2.88 - 2.68 (m, 7H), 2.68 - 2.58 (m, 2H), 2.41 - 2.30 (m, 2H), 2.19 - 2.04 (m, 3H), 2.03 - 1.96 (m, 1H), 1.85 - 1.60 (m, 6H), 1.53 (s, 2H), 1.39 - 1.28 ( m, 3H), 1.06 - 0.87 (m, 4H), 0.86 - 0.75 (m, 1H) 9 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.75 (d, 1H), 7.43 - 7.36 (m, 1H), 7.16 (d, 2H), 7.08 - 7.02 (m, 1H), 6.58 (d, 2H) ), 4.46 (s, 2H), 4.09 (d, 3H), 3.96 (s, 3H), 3.74 (s, 1H), 3.52 (s, 2H), 3.47 (dd, 1H), 3.42 (s, 3H) , 3.37 (d, 2H), 2.87 - 2.76 (m, 7H), 2.70 (s, 1H), 2.66 - 2.53 (m, 4H), 2.46 (s, 3H), 2.06 (d, 2H), 1.86 (d , 2H), 1.74 - 1.49 (m, 6H), 1.43 (s, 2H), 1.31 (d, 1H), 1.23 - 1.17 (m, 4H), 1.09 - 0.98 (m, 3H) 10 ¹ H NMR (400 MHz, methanol- d ₄ ) 7.76 (d, 1H), 7.20-7.31 (m, 2H), 7.12-7.19 (m, 1H), 6.86-6.93 (m, 1H), 6.41 (d, 1H), 6.38 (dd, 1H), 3.95 -4.01 (m, 1H), 3.98 (s, 2H), 3.84 (2, 2H), 3.72 (s, 2H), 3.44-3.52 (m, 1H), 3.47 (s, 3H), 3.25 (s, 3H), 2.96-3.11 (m, 2H), 2.81-2.93 (m, 4H), 2.52-2.67 (m, 2H), 2.30-2.45 (m, 3H), 2.23 (s, 6H), 2.03-2.11 (m, 2H), 1.22-1.94 (m, 14H), 1.14 (d, 3H) 11 ¹ H NMR (400 MHz, methanol- d ₄ ) 7.43 (d, 1H), 7.21-7.31 (m, 2H), 7.13-7.19 (m, 1H), 6.87-6.94 (m, 1H), 6.48 (d, 1H), 6.36 (dd, 1H), 3.94-4.01 (m, 1H), 3.97 (s, 2H), 3.84 (s, 2H), 3.54 (s, 3H), 3.48-3.53 (m, 1H), 3.47 (s, 2H), 2.82-3.14 (m, 6H), 2.62-2.75 (m, 1H), 2.51-2.61 (m, 1H), 2.32-2.50 (m, 3H), 2.27 (s, 6H), 2.04 -2.14 (m, 2H), 1.22-1.97 (m, 14H), 1.15 (d, 3H) 12 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.64 (d, 2H), 7.49 - 7.42 (m, 1H), 7.19 - 7.10 (m, 2H), 7.07 - 6.98 (m, 1H), 6.50 (d , 2H), 4.69 - 4.59 (m, 1H), 4.49 - 4.35 (m, 2H), 4.24 - 4.10 (m, 2H), 4.02 (s, 2H), 3.89 (s, 2H), 3.75 (d, 1H) ), 3.55 (t, 1H), 3.46 - 3.39 (m, 2H), 3.23 (s, 1H), 2.83 - 2.68 (m, 4H), 2.66 - 2.59 (m, 2H), 2.58 - 2.51 (m, 1H) ), 2.43 - 2.35 (m, 2H), 2.13 - 1.95 (m, 5H), 1.84 - 1.76 (m, 2H), 1.74 - 1.58 (m, 6H), 1.42 - 1.31 (m, 2H), 1.17 - 1.10 (m, 2H), 1.01 - 0.96 (m, 2H), 0.94 - 0.87 (m, 4H) 13 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.56 (d, 1H), 7.45 (q, 1H), 7.18 - 7.09 (m, 2H), 7.07 - 6.99 (m, 1H), 6.58 - 6.50 (m , 2H), 4.58 - 4.41 (m, 4H), 4.29 - 4.14 (m, 4H), 4.06 (d, 2H), 4.02 (s, 2H), 3.94 - 3.84 (m, 3H), 3.56 (t, 1H) ), 3.43 (d, 2H), 3.23 (s, 2H), 2.87 - 2.66 (m, 4H), 2.67 - 2.57 (m, 2H), 2.49 - 2.36 (m, 3H), 2.18 - 1.92 (m, 5H) ), 1.85 - 1.60 (m, 6H), 1.52 (s, 6H), 1.35 - 1.30 (m, 1H) 14 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.49 (d, 1H), 7.48 - 7.42 (m, 1H), 7.15 (t, 2H), 7.07 - 6.97 (m, 1H), 6.52 (d, 1H) ), 6.27 (d, 1H), 4.55 - 4.40 (m, 2H), 4.34 - 4.18 (m, 2H), 3.99 (s, 2H), 3.93 - 3.80 (m, 3H), 3.54 (t, 1H), 3.47 - 3.38 (m, 2H), 3.22 (s, 3H), 3.07 (s, 3H), 2.86 - 2.67 (m, 6H), 2.65 - 2.56 (m, 2H), 2.41 - 2.31 (m, 2H), 2.18 - 1.96 (m, 5H), 1.83 - 1.56 (m, 7H), 1.53 (s, 3H), 1.37 - 1.31 (m, 1H) 17 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 (d, 1H), 7.46 (q, 1H), 7.19 - 7.10 (m, 2H), 7.09 - 6.95 (m, 1H), 6.48 (dd, 1H) ), 6.36 (d, 1H), 4.71 - 4.56 (m, 1H), 4.43 (t, 1H), 4.34 - 4.08 (m, 3H), 4.08 - 3.94 (m, 3H), 3.91 (s, 2H), 3.87 - 3.70 (m, 1H), 3.55 (t, 1H), 3.47 - 3.38 (m, 2H), 3.24 (s, 1H), 3.11 (s, 3H), 2.92 (s, 3H), 2.85 - 2.66 ( m, 3H), 2.68 - 2.57 (m, 2H), 2.47 - 2.34 (m, 2H), 2.08 (d, 2H), 2.04 - 1.91 (m, 2H), 1.89 - 1.54 (m, 6H), 1.46 - 1.22 (m, 5H), 1.10 - 0.77 (m, 2H) twenty one ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.51 - 7.41 (m, 3H), 7.20 - 7.09 (m, 2H), 7.07 - 6.97 (m, 1H), 6.44 (d, 2H), 4.74 - 4.61 (m, 1H), 4.55 - 4.38 (m, 2H), 4.35 - 4.18 (m, 2H), 3.99 (s, 2H), 3.96 - 3.83 (m, 3H), 3.54 (t, 1H), 3.44 (d , 1H), 3.22 (s, 3H), 2.88 - 2.67 (m, 4H), 2.68 - 2.56 (m, 2H), 2.43 - 2.29 (m, 2H), 2.16 - 1.95 (m, 4H), 1.87 - 1.59 (m, 6H), 1.53 (s, 2H), 1.41 - 1.28 (m, 2H), 0.91 - 0.76 (m, 1H). 27 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.51 - 7.45 (m, 2H), 7.40 - 7.31 (m, 1H), 7.10 - 6.95 (m, 3H), 6.48 - 6.40 (m, 2H), 5.74 (d, 1H), 3.99 (s, 2H), 3.98 - 3.91 (m, 1H), 3.87 (s, 2H), 3.75 (s, 3H), 3.60 (s, 3H), 3.50 - 3.36 (m, 3H) ), 2.90 (q, 1H), 2.65 - 2.58 (m, 5H), 2.17 - 2.05 (m, 2H), 1.92 - 1.83 (m, 1H), 1.62 - 1.45 (m, 2H), 1.44 - 1.36 (m , 2H), 1.36 - 1.18 (m, 2H), 1.09 (s, 1H). 28 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.66 - 7.60 (m, 2H), 7.36 (td, 1H), 7.06 (dt, 3H), 6.52 - 6.45 (m, 2H), 5.75 (d, 1H) ), 4.01 (s, 2H), 3.99 - 3.91 (m, 1H), 3.89 (s, 2H), 3.75 (s, 3H), 3.60 (s, 3H), 3.43 (dd, 9.7 Hz, 2H), 2.94 - 2.86 (m, 2H), 2.68 - 2.52 (m, 5H), 2.52 - 2.44 (m, 2H), 2.16 - 2.04 (m, 1H), 1.92 - 1.82 (m, 1H), 1.64 - 1.44 (m, 2H), 1.44 (s, 2H), 1.32 - 1.18 (m, 2H), 1.15 - 1.07 (m, 3H), 0.99 - 0.91 (m, 2H). 29 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 10.28 (s, 1H), 7.51 - 7.46 (m, 2H), 7.36 (td, 1H), 7.21 (dd, 2H), 7.05 - 6.97 (m, 1H) ), 6.47 - 6.41 (m, 2H), 5.56 (d, 1H), 4.07 (s, 1H), 4.00 (s, 2H), 3.89 (s, 3H), 3.72 (d, 1H), 3.57 (s, 3H), 3.51 (q, 3H), 3.46 - 3.40 (m, 1H), 3.35 (d, 1H), 2.64 - 2.56 (m, 3H), 2.56 - 2.48 (m, 2H), 2.33 (t, 2H) , 2.09 (d, 1H), 1.92 - 1.85 (m, 1H), 1.74 (dd, 2H), 1.57 (d, 1H), 1.46 (s, 2H), 1.36 (td, 1H), 1.23 (d, 2H) ), 1.18 (t, 3H). 31 ¹ H NMR (400 MHz, methanol- d ₄ ) 7.76 (d, 1H), 7.34-7.41 (m, 1H), 7.16-7.28 (m, 2H), 6.96-7.03 (m, 1H), 6.42 (d, 1H), 6.39 (dd, 1H), 4.00-4.07 (m, 1H), 3.98 (s, 2H), 3.84 (s, 2H), 3.74 (s, 2H), 3.73 (s, 2H), 3.52 (s , 3H), 3.25 (s, 3H), 2.87-2.96 (m, 2H), 2.60-2.70 (m, 1H), 2.47-2.57 (m, 1H), 2.31-2.39 (m, 2H), 2.24 (s , 6H), 2.02-2.11 (m, 2H), 1.67-1.95 (m, 7H), 1.24-1.60 (m, 8H). 32 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 (d, 2H), 7.44-7.39 (m, 1H), 7.28-7.21 (m, 2H), 7.06-7.01 (m, 1H), 6.50 (d , 2H), 4.06-4.00 (m, 3H), 3.92 (s, 2H), 3.84-3.72 (m, 3H), 3.66-3.43 (m, 6H), 2.79-2.39 (m, 8H), 2.29-2.18 (m, 2H), 1.94-1.85 (m, 2H), 1.65-1.36 (m, 6H), 1.27-1.08 (m, 9H), 1.02-0.96 (m, 2H) 33 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 (d, 2H), 7.45-7.39 (m, 1H), 7.28-7.22 (m, 2H), 7.07-7.02 (m, 1H), 6.51 (d , 2H), 4.04-4.00 (m, 3H), 3.95-3.76 (m, 6H), 3.66-3.43 (m, 6H), 2.79-2.38 (m, 8H), 2.22-2.18 (m, 2H), 1.97 -1.87 (m, 2H), 1.62-1.31 (m, 7H), 1.16-1.12 (m, 2H), 1.01-0.96 (m, 2H). 37 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.55 (d, 1H), 7.44-7.38 (m, 1H), 7.30 - 7.15 (m, 2H), 7.07-7.02 (m, 1H), 6.51 (dd , 1H), 6.40 (d, 1H), 4.17 - 4.03 (m, 3H), 4.02 - 3.77 (m, 4H), 3.69 (s, 3H), 3.65 - 3.37 (m, 6H), 3.13 (s, 3H) ), 2.95 (s, 3H), 2.84 - 2.73 (m, 1H), 2.72-2.63 (m, 3H), 2.56-2.50 (m, 1H), 2.46-2.41 (m, 2H), 2.30-2.23 (m , 2H), 2.03 - 1.83 (m, 2H), 1.73 - 1.25 (m, 7H). 40 ¹ H NMR (400 MHz, methanol- d ₄ ) 7.76 (d, 1H), 7.32-7.39 (m, 1H), 7.16-7.27 (m, 2H), 6.95-7.01 (m, 1H), 6.42 (d, 1H), 6.37 (dd, 1H), 4.04-4.12 (m, 1H), 3.98 (s, 2H), 3.85 (s, 2H), 3.75-3.80 (m, 2H), 3.73 (s, 2H), 3.66 (s, 3H), 3.50 (s, 3H), 3.25 (s, 3H), 2.84-2.94 (m, 2H), 2.60-2.70 (m, 1H), 2.43-2.53 (m, 1H), 2.32-2.40 (m, 2H), 2.23 (s, 6H), 2.02-2.10 (m, 2H), 1.62-1.98 (m, 6H), 1.32-1.57 (m, 5H), 1.15-1.28 (m, 2H). 43 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.64 - 7.55 (m, 2H), 7.24 (t, 1H), 7.12 (dd, 2H), 6.99 (t, 1H), 6.44 (d, 1H), 6.15 (s, 1H), 5.52 (d, 1H), 4.03 (s, 1H), 3.90 (d, 3H), 3.46 - 3.26 (m, 3H), 3.16 (d, 3H), 2.79 (d, 1H) , 2.71 - 2.40 (m, 8H), 1.89 (s, 3H), 1.55 (s, 4H), 1.30 (d, 3H), 1.08 (dt, 2H), 0.97 - 0.87 (m, 2H). 44 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.65 - 7.54 (m, 2H), 7.25 (t, 1H), 7.02 (dd, 3H), 6.51 - 6.40 (m, 2H), 5.56 (d, 1H) ), 3.91 (d, 4H), 3.45 - 3.19 (m, 5H), 2.86 - 2.70 (m, 4H), 2.61 - 2.44 (m, 9H), 1.90 - 1.82 (m, 3H), 1.71 (s, 1H) ), 1.51 (s, 4H), 1.24 (d, 2H), 1.11 - 1.03 (m, 2H), 0.99 - 0.87 (m, 2H). 50 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.61 (dd, 2H), 7.56 - 7.30 (m, 2H), 7.29 - 6.94 (m, 3H), 6.62 - 6.43 (m, 2H), 6.35 - 6.12 (m, 2H), 5.74 (s, 1H), 5.68 - 5.59 (m, 1H), 4.74 - 4.37 (m, 3H), 4.01 (d, 1H), 3.90 (s, 1H), 3.78 (s, 1H) ), 3.64 (s, 3H), 3.58 - 3.40 (m, 4H), 3.39 - 3.24 (m, 2H), 3.18 (dd, 2H), 2.91 (s, 2H), 2.63 (dt, 5H), 2.42 ( s, 4H), 2.10 - 1.92 (m, 2H), 1.67 (dd, 2H), 1.52 (d, 2H), 1.30 (s, 5H), 1.18 (d, 1H), 0.90 (d, 1H). 51 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 8.03 (dd, 1H), 7.98 - 7.91 (m, 1H), 7.68 - 7.61 (m, 2H), 7.38 (t, 1H), 7.35 - 7.27 (m , 1H), 7.14 - 7.05 (m, 1H), 6.50 - 6.43 (m, 1H), 5.74 (s, 1H), 5.41 (s, 1H), 4.00 (s, 1H), 3.88 (s, 1H), 3.78 (s, 1H), 3.64 (s, 2H), 3.52 (d, 1H), 3.44 (d, 2H), 3.13 (s, 1H), 2.91 (s, 3H), 2.63 (dt, 6H), 2.21 - 2.04 (m, 6H), 1.87 (s, 2H), 1.52 (d, 2H), 1.30 (s, 4H). 53 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 8.10 - 8.03 (m, 2H), 7.37 (d, 1H), 7.20 (s, 1H), 7.14 - 6.92 (m, 2H), 6.45 - 6.35 (m , 2H), 5.77 (s, 1H), 4.10 (s, 2H), 3.98 (d, 2H), 3.78 (s, 1H), 3.64 (s, 3H), 3.52 (d, 1H), 3.44 (d, 2H), 3.13 (dd, 1H), 2.92 (s, 3H), 2.71 - 2.54 (m, 5H), 2.42 (s, 5H), 2.14 - 2.03 (m, 2H), 1.92 - 1.84 (m, 1H) , 1.55 (dd, 2H), 1.37 (s, 2H), 1.27 (dd, 7.0 Hz, 2H). 54 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.40 (s, 1H), 7.15 - 7.02 (m, 5H), 6.72 - 6.66 (m, 1H), 6.52 - 6.46 (m, 1H), 5.75 (s , 1H), 3.91 (s, 1H), 3.79 (d, 2H), 3.63 (s, 3H), 3.58 (s, 1H), 3.48 (d, 4H), 3.22 (d, 1H), 3.15 (s, 2H), 2.93 (s, 4H), 2.87 - 2.84 (m, 4H), 2.59 - 2.54 (m, 2H), 2.43 (s, 4H), 2.23 (t, 2H), 2.11 - 2.02 (m, 1H) , 1.93 - 1.84 (m, 2H), 1.59 - 1.43 (m, 3H), 1.42 - 1.34 (m, 2H), 1.30 (s, 2H). 55 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 11.62 (s, 1H), 11.24 (s, 1H), 7.52 - 7.31 (m, 1H), 7.18 (s, 2H), 7.14 - 6.90 (m, 1H) ), 6.09 (s, 1H), 5.79 (s, 1H), 4.38 (s, 1H), 4.25 (s, 1H), 3.99 - 3.85 (m, 2H), 3.77 (s, 1H), 3.63 (s, 3H), 3.56 - 3.32 (m, 6H), 3.30 (d, 3H), 3.11 (d, 2H), 2.91 (d, 6H), 2.78 - 2.64 (m, 4H), 2.61 - 2.50 (m, 4H) , 2.41 (s, 3H), 2.22 - 2.11 (m, 1H), 1.92 - 1.82 (m, 1H), 1.65 - 1.46 (m, 2H), 1.36 (s, 2H), 1.29 (s, 2H). 56 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.51 - 7.31 (m, 1H), 7.18 (s, 1H), 7.09 (td, 1H), 7.00 (s, 1H), 5.77 (s, 1H), 4.20 - 3.85 (m, 4H), 3.77 (s, 1H), 3.63 (s, 3H), 3.48 (d, 1H), 3.44 - 3.34 (m, 2H), 3.11 (s, 2H), 2.91 (s, 5H), 2.67 (d, 4H), 2.60 (d, 5H), 2.41 (s, 3H), 2.22 - 2.12 (m, 2H), 2.07 (d, 1H), 1.85 (s, 4H), 1.48 (d , 3H), 1.36 (s, 2H), 1.30 (s, 2H). 57 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 11.30 (s, 1H), 11.06 (s, 1H), 7.56 - 7.30 (m, 1H), 7.28 - 7.15 (m, 1H), 7.13 - 6.91 (m , 2H), 6.15 (s, 1H), 5.83 (s, 1H), 4.03 (d, 2H), 4.00 - 3.94 (m, 1H), 3.94 - 3.84 (m, 1H), 3.77 (s, 1H), 3.62 (s, 3H), 3.55 - 3.30 (m, 8H), 3.13 (s, 2H), 2.91 (s, 3H), 2.74 - 2.65 (m, 2H), 2.64 - 2.47 (m, 4H), 2.41 ( s, 3H), 1.94 - 1.83 (m, 1H), 1.82 - 1.69 (m, 9H), 1.62 - 1.42 (m, 3H), 1.37 (s, 2H), 1.29 (s, 2H), 0.72 (s, 1H). 58 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 10.60 (s, 1H), 7.51 - 7.46 (m, 2H), 7.46 - 7.33 (m, 1H), 7.22 (d, 1H), 7.10 (td, 2H) ), 6.49 - 6.41 (m, 2H), 5.77 (d, 1H), 4.00 (s, 2H), 3.90 (s, 2H), 3.78 (s, 1H), 3.64 (s, 3H), 3.56 - 3.38 ( m, 2H), 3.20 - 3.08 (m, 1H), 2.65 - 2.55 (m, 5H), 2.42 (s, 2H), 2.26 - 2.12 (m, 2H), 2.08 (d, 1H), 1.88 (t, 1H), 1.48 (d, 2H), 1.38 (s, 2H), 1.30 (s, 2H). 68 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.83 (dd, 1H), 7.49 (d, 1H), 7.42 - 7.16 (m, 2H), 7.06 (t, 3H), 6.48 (dd, 1H), 6.27 (d, 1H), 5.75 (d, 1H), 3.98 (s, 2H), 3.85 (s, 2H), 3.75 (s, 2H), 3.60 (s, 3H), 3.50 - 3.33 (m, 3H) , 3.05 (s, 1H), 3.01 (s, 2H), 2.90 (q, 1H), 2.79 (s, 1H), 2.76 (s, 2H), 2.56 (m, 4H), 2.15 - 2.08 (m, 3H) ), 1.87 (d, 1H), 1.65 - 1.44 (m, 3H), 1.40 (q, 2H), 1.35 - 1.17 (m, 2H), 1.08 (s, 1H). 69 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.51 (d, 1H), 7.37 - 7.28 (m, 2H), 7.01 (d, 4H), 6.61 (s, 1H), 6.43 (d, 1H), 5.73 (d, 1H), 4.42 (s, 2H), 4.21 (s, 2H), 3.96 (s, 2H), 3.84 (s, 2H), 3.72 (s, 5H), 3.58 (d, 6H), 3.46 - 3.31 (m, 5H), 2.87 (s, 2H), 2.64 - 2.55 (m, 4H), 2.55 - 2.44 (m, 6H), 1.43 (s, 4H), 1.37 (d, 6H), 1.25 - 1.18 (m, 4H), 0.87 (d, 4H). 72 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.66 (s, 2H), 7.64 (d, 2H), 7.57-7.40 (m, 2H), 7.18-7.14 (m, 1H), 6.52-6.49 (m , 2H), 4.99-4.94 (m, 2H), 4.02-4.00 (m, 3H), 3.91 (s, 2H), 3.62-3.51 (m, 5H), 3.42-3.39 (m, 1H), 2.84-2.40 (m, 9H), 2.25-2.21 (m, 1H), 1.94-1.90 (m, 2H), 1.57-1.12 (m, 8H), 1.05-0.96 (m, 3H). 73 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.64 (s, 2H), 7.55-7.41 (m, 5H), 7.18-7.14 (m, 1H), 6.59 (t, 1H), 4.99-4.89 (m , 2H), 4.16 (s, 2H), 4.05-4.02 (m, 3H), 3.64-3.52 (m, 5H), 3.43-3.39 (m, 1H), 2.84-2.39 (m, 9H), 2.26-2.22 (m, 1H), 1.94-1.90 (m, 2H), 1.57-1.11 (m, 8H), 1.04-0.99 (m, 3H). 74 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.72 (s, 1H), 7.75 (d, 1H), 7.55-7.40 (m, 5H), 7.18-7.14 (m, 1H), 6.65 (s, 1H) ), 6.57 (dd, 1H), 5.48-5.34 (m, 1H), 5.00-4.87 (m, 2H), 4.74 (s, 2H), 4.58-4.41 (m, 4H), 4.10 (s, 2H), 4.02-3.98 (m, 3H), 3.65-3.54 (m, 5H), 3.43-3.40 (m, 1H), 2.84-2.66 (m, 6H), 2.54-2.47 (m, 3H), 2.24-2.21 (m , 1H), 1.92-1.90 (m, 2H), 1.59-1.13 (m, 8H), 1.10-0.96 (m, 3H). 103 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.54 (d, 1H), 7.37-7.33 (m, 3H), 7.13-7.07 (m, 1H), 7.05 (d, 1H), 6.50 (dd, 1H) ), 6.39 (d, 1H), 4.82 (d, 1H), 4.64 (d, 1H), 4.07 (s, 2H), 3.96-3.93 (m, 3H), 3.70 - 3.54 (m, 5H), 3.43 ( d, 1H), 3.13 (s, 3H), 2.95 (s, 3H), 2.84 - 2.60 (m, 9H), 2.56-2.48 (m, 2H), 2.32 (d, 1H), 2.07 - 1.88 (m, 2H), 1.66 - 1.50 (m, 2H), 1.49 - 1.14 (m, 5H), 1.06-099 (m, 1H). 104 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.58 (d, 1H), 7.39 - 7.29 (m, 3H), 7.19 - 7.07 (m, 1H), 7.05 (d, 1H), 6.62 - 6.48 (m , 2H), 4.82 (d, 1H), 4.65-4.53 (m, 3H), 4.29 - 4.05 (m, 5H), 3.98-3.92 (m, 3H), 3.67-3.60 (m, 5H), 3.47-3.40 (m, 2H), 2.83 - 2.50 (m, 11H), 2.33 (d, 1H), 2.06 - 1.89 (m, 2H), 1.60-1.55(s, 4H), 1.47 - 1.17 (m, 6H), 1.04 -0.94 (m, 1H). 112 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.77 - 7.67 (m, 2H), 7.65 - 7.41 (m, 3H), 7.32 (d, 1H), 7.24-7.19 (m, 1H), 6.97 (d , 1H), 6.56 - 6.39 (m, 2H), 4.83 (d, 1H), 4.58 (d, 1H), 4.06 - 3.92 (m, 3H), 3.85 (s, 2H), 3.71 - 3.52 (m, 4H) ), 3.47 (d, 1H), 3.42 - 3.35 (m, 1H), 2.87 - 2.43 (m, 11H), 2.29 (d, 1H), 2.07 - 1.88 (m, 2H), 1.66 - 1.47 (m, 2H) ), 1.42-1.31 (m, 3H), 1.20 (m, 2H), 1.04 - 0.82 (m, 1H). 113 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 - 7.53 (m, 3H), 7.53 - 7.42 (m, 2H), 7.34 (d, 1H), 7.29 - 7.16 (m, 1H), 6.98 (d , 1H), 6.57 - 6.47 (m, 2H), 4.83 (d, 1H), 4.59 (d, 1H), 4.14 - 3.95 (m, 3H), 3.90 (s, 2H), 3.74 - 3.52 (m, 5H) ), 3.41 (d, 1H), 2.84-2.62 (m, 15H), 2.54-2.47 (m, 2H), 2.32 (d, 1H), 2.09 - 1.84 (m, 2H), 1.66 - 1.14 (m, 7H) ), 1.05 - 0.85 (m, 1H). 114 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 (d, 1H), 7.40 (d, 1H), 7.35-7.33 (m, 2H), 7.16 - 6.96 (m, 2H), 6.59 - 6.50 (m , 1H), 6.30 (d, 1H), 4.82 (d, 1H), 4.66 (d, 1H), 4.03 (s, 2H), 3.95-3.89 (m, 3H), 3.65 (s, 5H), 3.45 ( d, 1H), 3.09 (s, 3H), 2.95 - 2.57 (m, 11H), 2.54 - 2.41 (m, 2H), 2.32 (d, 1H), 2.06-1.95 (m, 2H), 1.60 - 1.00 ( m, 8H). 121 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 8.82 - 8.76 (m, 1H), 7.64 (d, 2H), 7.58 - 7.39 (m, 3H), 7.23 - 7.13 (m, 2H), 6.50 (d , 2H), 4.99 (d, 1H), 4.03 (s, 2H), 3.97 - 3.86 (m, 3H), 3.65 - 3.48 (m, 5H), 3.42 (d, 1H), 2.80 (t, 1H), 2.73 - 2.42 (m, 8H), 2.34 - 2.29 (m, 3H), 2.23 (d, 1H), 1.98 - 1.84 (m, 2H), 1.65 - 1.51 (m, 1H), 1.49 - 1.18 (m, 6H) ), 1.14 (tt, 2H), 1.06 - 0.94 (m, 3H) 122 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.79 (s, 1H), 7.56 - 7.37 (m, 4H), 7.23 - 7.11 (m, 2H), 6.48 (dd, 1H), 6.37 (d, 1H) ), 4.99 (d, 1H), 4.05 (s, 2H), 3.99 - 3.85 (m, 3H), 3.65 - 3.49 (m, 5H), 3.42 (d, 1H), 3.11 (s, 3H), 2.93 ( s, 3H), 2.80 (t, 1H), 2.75 - 2.58 (m, 4H), 2.58 - 2.42 (m, 3H), 2.31 (s, 3H), 2.23 (d, 1H), 1.99 - 1.85 (m, 2H), 1.65 - 1.52 (m, 1H), 1.51 - 1.17 (m, 6H), 1.13 - 0.94 (m, 1H) 124 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 (d, 2H), 7.59 - 7.51 (m, 1H), 7.50 - 7.41 (m, 2H), 7.33 (d, 1H), 7.24 - 7.17 (m , 1H), 6.97 (d, 1H), 6.51 (d, 2H), 6.30 - 6.15 (m, 2H), 5.70 (dd, 1H), 4.79 (s, 1H), 4.58 (d, 1H), 4.37 ( t, 1H), 4.10 - 3.95 (m, 5H), 3.91 (s, 2H), 3.70 - 3.52 (m, 6H), 3.54 - 3.47 (m, 2H), 3.41 (d, 1H), 3.11 - 2.96 ( m, 1H), 2.80 (t, 1H), 2.74 - 2.58 (m, 8H), 2.50 (q, 2H), 2.32 (d, 1H), 2.02 (d, 1H), 1.98 - 1.87 (m, 1H) , 1.65 - 1.48 (m, 2H), 1.44 - 1.32 (m, 2H), 1.30 - 1.15 (m, 2H), 0.95 (q, 1H) 131 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.66 (d, 2H), 7.60 - 7.50 (m, 1H), 7.50 - 7.40 (m, 2H), 7.34 (d, 1H), 7.21 (t, 1H) ), 6.99 (s, 1H), 6.51 (d, 2H), 6.25 - 6.11 (m, 2H), 5.68 (dd, 1H), 4.79 (s, 1H), 4.66 - 4.54 (m, 2H), 4.27 - 4.08 (m, 2H), 4.05 (s, 2H), 4.01 - 3.85 (m, 4H), 3.70 - 3.54 (m, 6H), 3.42 (d, 1H), 2.81 (t, 1H), 2.75 - 2.59 ( m, 7H), 2.56 - 2.18 (m, 6H), 2.03 (d, 1H), 1.99 - 1.88 (m, 1H), 1.62 - 1.48 (m, 2H), 1.46 - 1.33 (m, 2H), 1.29 - 1.14 (m, 2H), 1.03 - 0.88 (m, 1H) 133 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.68 (d, 2H), 7.59 - 7.54 (m, 1H), 7.52 - 7.43 (m, 2H), 7.36 (d, 1H), 7.23 (t, 1H) ), 7.01 (s, 1H), 6.53 (d, 2H), 6.27 - 6.13 (m, 2H), 5.70 (dd, 1H), 4.69 - 4.51 (m, 2H), 4.29 - 4.10 (m, 2H), 4.07 (s, 2H), 4.03 - 3.87 (m, 4H), 3.78 - 3.52 (m, 6H), 3.44 (d, 1H), 2.87 - 2.79 (m, 1H), 2.78 - 2.57 (m, 7H), 2.56 - 2.24 (m, 6H), 2.09 - 2.01 (m, 1H), 1.99 - 1.91 (m, 1H), 1.64 - 1.49 (m, 2H), 1.46 - 1.34 (m, 2H), 1.30 - 1.17 (m , 2H), 1.03 - 0.92 (m, 1H) 135 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.58 (dd, 2H), 7.55 - 7.45 (m, 1H), 7.34 (dd, 2H), 7.23 - 7.13 (m, 1H), 7.10 (d, 1H) ), 6.78 (d, 1H), 6.57 - 6.40 (m, 2H), 6.29 - 6.10 (m, 2H), 5.87 (d, 1H), 5.61 (ddd, 1H), 4.71 - 4.50 (m, 2H), 4.43 - 4.34 (m, 2H), 4.01 - 3.87 (m, 3H), 3.84 (s, 1H), 3.61 (s, 3H), 3.56 - 3.42 (m, 2H), 3.42 - 3.20 (m, 4H), 3.19 - 3.11 (m, 1H), 2.64 (s, 3H), 2.55 (t, 4H), 1.84 (d, 3H), 1.72 - 1.55 (m, 3H), 1.46 (d, 2H), 1.41 - 1.21 ( m, 4H), 1.16 (d, 3H), 0.89 (s, 1H). 145 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.55 (q, 1H), 7.41 (d, 1H), 7.36 (d, 1H), 7.22 (td, 1H), 7.12 (d, 1H), 6.81 ( d, 1H), 5.87 (d, 1H), 4.64 (d, 1H), 4.36 (d, 1H), 4.12 (s, 1H), 4.00 (s, 1H), 3.94 (s, 2H), 3.80 (s , 1H), 3.65 (s, 3H), 3.53 (d, 1H), 3.38 (q, 1H), 3.24 (d, 2H), 2.97 - 2.79 (m, 5H), 2.56 - 2.42 (m, 7H), 2.24 (d, 2H), 1.91 - 1.76 (m, 3H), 1.66 - 1.44 (m, 2H), 1.42 - 1.21 (m, 4H), 1.14 (d, 1H), 0.73 (s, 1H). 146 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.55 (q, 1H), 7.48 - 7.30 (m, 1H), 7.25 - 7.18 (m, 1H), 7.13 (s, 1H), 6.81 (s, 1H) ), 5.89 (d, 1H), 5.27 - 5.18 (m, 1H), 5.14 - 5.05 (m, 1H), 4.64 (d, 1H), 4.36 (d, 1H), 4.08 (s, 1H), 4.01 - 3.86 (m, 3H), 3.79 (s, 1H), 3.64 (s, 3H), 3.51 (d, 1H), 3.37 (s, 2H), 3.23 (d, 2H), 3.01 (s, 3H), 2.71 (s, 5H), 2.23 (d, 3H), 1.90 - 1.74 (m, 2H), 1.66 - 1.43 (m, 2H), 1.42 - 1.20 (m, 4H), 1.14 (s, 1H), 0.71 (s , 1H). 147 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 7.59 - 7.50 (m, 1H), 7.37 (dd, 2H), 7.26 - 7.16 (m, 1H), 7.12 (dd, 1H), 6.80 (d, 1H) ), 5.87 (d, 1H), 4.62 (d, 1H), 4.37 (dd, 1H), 4.24 (s, 1H), 4.11 (s, 1H), 3.93 (d, 2H), 3.78 (s, 1H) , 3.64 (d, 3H), 3.52 (d, 2H), 3.35 (q, 2H), 3.26 (d, 2H), 2.56 - 2.50 (m, 3H), 2.47 (d, 2H), 2.45 (d, 2H) ), 2.22 (d, 2H), 1.91 - 1.77 (m, 3H), 1.67 - 1.44 (m, 3H), 1.42 - 1.25 (m, 4H), 1.15 (s, 2H), 0.90 - 0.65 (m, 2H) ). 151 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.61 - 7.53 (m, 2H), 7.52 - 7.35 (m, 3H), 7.25 (d, 1H), 7.16-7.12 (m, 1H), 6.90 (d , 1H), 6.51 - 6.35 (m, 2H), 4.75 (d, 1H), 4.50 (d, 1H), 3.96-3.88 (m, 3H), 3.80 (s, 2H), 3.64 - 3.45 (m, 4H) ), 3.45 - 3.27 (m, 2H), 2.76 - 2.48 (m, 9H), 2.45-2.38 (m, 5H), 2.22 (d, 1H), 2.02 - 1.80 (m, 2H), 1.57 - 1.41 (m , 2H), 1.38 - 1.22 (m, 2H), 1.18-1.10 (m, 2H), 0.90-0.80 (m, 1H). 186 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.76 (d, 1H), 7.45 (dd, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.73 - 6.59 (m, 2H), 6.43 - 6.34 (m, 2H), 4.54 (d, 1H), 4.35 (d, 1H), 4.07 - 3.90 (m, 3H), 3.83 (s, 2H), 3.72 (s, 2H), 3.64 (d, 3H), 3.25 (s, 3H), 2.82 (dd, 2H), 2.67 - 2.56 (m, 2H), 2.45 (s, 3H), 2.36 - 2.28 (m, 2H), 2.25 - 2.13 (m, 7H) , 2.10 - 1.95 (m, 3H), 1.91 - 1.82 (m, 1H), 1.78 - 1.60 (m, 3H), 1.55 - 1.43 (m, 1H), 1.36 - 1.28 (m, 3H), 1.25 - 1.15 ( m, 2H), 0.77 - 0.64 (m, 1H) 188 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.70 - 7.63 (m, 2H), 7.55 - 7.37 (m, 3H), 7.16 (t, 1H), 6.93 (s, 1H), 6.77 (s, 1H) ), 6.59 (d, 1H), 4.68 (d, 1H), 4.41 (d, 1H), 4.18 (s, 2H), 4.10 - 3.95 (m, 5H), 3.74 (d, 2H), 3.64 (s, 3H), 3.53 (d, 2H), 3.42 (d, 1H), 3.26 - 3.21 (m, 1H), 2.63 - 2.35 (m, 12H), 2.22 (d, 1H), 1.93 - 1.83 (m, 2H) , 1.62 - 1.26 (m, 8H), 1.24 - 1.11 (m, 4H), 1.03 - 0.98 (m, 2H), 0.90 - 0.75 (m, 1H) 189 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.70 (dd, 1H), 7.59 - 7.39 (m, 4H), 7.22 - 7.17 (m, 2H), 6.91 (s, 1H), 6.58 (d, 1H) ), 4.77 (d, 1H), 4.54 (d, 1H), 4.13 - 4.07 (m, 1H), 4.03 - 3.95 (m, 3H), 3.87 - 3.75 (m, 1H), 3.64 (s, 3H), 3.55 - 3.48 (m, 2H), 3.37 - 3.32 (m, 1H), 3.10 (s, 3H), 2.91 (s, 3H), 2.78 - 2.53 (m, 10H), 2.47 - 2.37 (m, 2H), 2.31 - 2.25 (m, 1H), 2.02 - 1.86 (m, 2H), 1.58 - 1.45 (m, 2H), 1.43 - 1.35 (m, 2H), 1.25 - 1.13 (m, 4H), 1.02 - 0.98 (m , 2H), 0.95 - 0.83 (m, 1H) 190 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.60 (d, 2H), 7.56 - 7.40 (m, 3H), 7.15 (dd, 2H), 6.84 (s, 1H), 6.51 (d, 1H), 5.16 (d, 1H), 4.74 (d, 1H), 4.45 (d, 1H), 4.15 (s, 2H), 4.10 - 3.95 (m, 3H), 3.80 - 3.70 (m, 4H), 3.65 (s, 3H), 3.59 - 3.32 (m, 5H), 2.70 - 2.43 (m, 12H), 2.30 - 2.20 (m, 1H), 1.95 - 1.85 (m, 2H), 1.58 - 1.47 (m, 2H), 1.42 - 1.30 (m, 2H), 1.24 - 1.10 (m, 4H), 1.03 - 0.97 (m, 2H), 0.90 - 0.76 (m, 1H) 191 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.62 (dd, 2H), 7.46 - 7.26 (m, 3H), 7.06 (t, 1H), 6.85 (s, 1H), 6.70 (s, 1H), 6.60 - 6.47 (m, 1H), 4.58 (d, 1H), 4.31 (d, 1H), 4.10 (s, 2H), 3.98 (s, 2H), 3.92 (s, 2H), 3.54 (s, 3H) , 3.33 (d, 1H), 3.25 (d, 1H), 3.14 (d, 1H), 2.58 - 2.39 (m, 14H), 2.32 (dd, 3H), 2.10 (dd, 1H), 1.78 (t, 2H) ), 1.38 (d, 2H), 1.31 - 1.18 (m, 4H), 1.17 - 1.00 (m, 4H), 0.96 - 0.86 (m, 2H), 0.82 - 0.67 (m, 1H) 192 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.51 - 7.42 (m, 2H), 7.38 (d, 2H), 7.13 (d, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 4.61 (d, 1H), 4.40 (d, 1H), 4.22 (s, 2H), 4.09 (s, 2H), 4.02 - 3.95 (s, 1H), 3.61 (s, 3H), 3.20 - 3.15 (m, 7H), 3.10 -2.95 (m, 2H), 2.67 - 2.62 (m, 1H), 2.51 (s, 3H), 2.51 - 2.45 (m, 2H), 2.40 - 2.31 (m, 1H), 2.26 - 2.16 ( m, 3H), 2.15 - 2.05 (m, 2H), 2.05 - 2.03 (m, 1H), 1.95 - 1.85 (m, 1H), 1.83 - 1.75 (m, 1H), 1.55 - 1.45 (m, 1H), 1.37 - 1.35 (m, 1H), 1.32 - 1.26 (m, 2H), 1.23 - 1.17 (m, 1H), 0.84 - 0.74 (m, 1H) 193 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.54 (s, 1H), 7.48 (dd, 2H), 7.40 (d, 1H), 7.14 (t, 1H), 6.86 (d, 1H), 6.74 ( d, 1H), 4.65 (d, 1H), 4.39 (d, 1H), 4.16 (s, 2H), 4.03 (s, 2H), 3.99 (dd, 1H), 3.62 (s, 3H), 3.23 - 3.15 (m, 8H), 2.64 - 2.52 (m, 3H), 2.51 (s, 3H), 2.48 - 2.40 (m, 1H), 2.40 - 2.13 (m, 6H), 1.91 - 1.80 (m, 2H), 1.55 - 1.45 (m, 1H), 1.39 - 1.30 (m, 3H), 1.25 - 1.15 (m, 2H), 0.8 - 0.69 (m, 1H) 194 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.56 (d, 2H), 7.46 - 7.38 (m, 2H), 7.33 (d, 1H), 7.08 (d, 1H), 6.86 (s, 1H), 6.69 (s, 1H), 6.55 - 6.48 (m, 1H), 6.41 (d, 2H), 6.05 (d, 1H), 5.59 (t, 1H), 4.60 (d, 1H), 4.32 (d, 1H) , 3.94 (s, 2H), 3.90 (s, 1H), 3.81 (s, 2H), 3.71 - 3.68 (m, 1H), 3.63 - 3.58 (m, 2H), 3.54 (s, 3H), 3.35 - 3.28 (m, 4H), 2.98 (s, 2H), 2.55 - 2.41 (m, 8H), 2.33 - 2.24 (m, 3H), 2.20 - 2.12 (m, 1H), 1.85 - 1.75 (m, 2H), 1.45 - 1.35 (m, 1H), 1.32 - 1.25 (m, 3H), 1.13 - 1.05 (m, 3H), 0.75 - 065 (m, 1H) 196 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.76 (d, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 7.09 (s, 1H), 6.70 - 6.65 (m, 2H), 6.39 (dd, 2H), 4.60 - 4.49 (m, 2H), 4.32 (d, 1H), 4.20 (s, 1H), 3.98 (s, 2H), 3.84 (s, 2H), 3.74 (s, 2H) , 3.24 (s, 3H), 2.92 (d, 1H), 2.80 (d, 1H), 2.68 (s, 3H), 2.68 - 2.62 (m, 1H), 2.55 - 2.48 (m, 1H), 2.45 - 2.40 (m, 3H), 2.35 - 2.28 (m, 3H), 2.27 - 2.23 (m, 5H), 2.10 - 2.00 (m, 3H), 1.89 - 1.78 (m, 3H), 1.66 (d, 1H), 1.51 - 1.42 (m, 1H), 1.32 - 1.25 (m, 4H), 1.18 - 1.10 (m, 1H), 0.75 - 0.68 (m, 1H) 197 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.37 (s, 1H), 7.49 - 7.40 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.70 (d, 1H), 6.65 (s, 1H), 6.34 (s, 1H), 4.62 - 4.50 (m, 2H), 4.35 (d, 1H), 4.14 (s, 2H), 4.00 (s, 3H), 3.60 (s, 3H) , 3.10 (s, 3H), 2.97 - 2.90 (m, 1H), 2.94 (s, 3H), 2.82 (d, 1H), 2.67 - 2.58 (m, 2H), 2.45 (s, 3H), 2.39 - 2.32 (m, 2H), 2.25 - 2.15 (m, 1H), 2.12 - 1.99 (m, 3H), 1.82 - 1.72 (m, 2H), 1.72 - 1.65 (m, 1H), 1.50-1.46 (m, 1H) , 1.43 - 1.06 (m, 5H), 0.77 - 0.64 (m, 1H) 198 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.65 (d, 2H), 7.54 - 7.38 (m, 3H), 7.16 (d, 1H), 6.81 (d, 2H), 6.50 (d, 2H), 6.16 - 6.06 (m, 2H), 5.61 (dd, 1H), 4.66 (d, 1H), 4.40 (d, 1H), 4.02 (s, 2H), 4.02 - 3.95 (m, 1H), 3.90 (s, 2H), 3.63 (s, 3H), 3.53 (t, 2H), 3.33 (s, 3H), 3.26 - 3.09 (m, 3H), 2.61 (d, 1H), 2.54 (s, 3H), 2.44 (d , 2H), 2.36 - 2.27 (m, 3H), 2.23 - 2.16 (m, 1H), 1.90 - 1.81 (m, 2H), 1.55 - 1.51 (m, 2H), 1.37 - 1.34 (m, 3H), 1.25 - 1.13 (m, 2H), 0.82 - 0.75 (m, 1H) 199 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.84 - 7.79 (m, 1H), 7.54 - 7.41 (m, 2H), 7.37 (d, 1H), 7.11 (t, 1H), 6.76 (dd, 2H) ), 6.55 - 6.49 (m, 2H), 4.60 (d, 1H), 4.41 (d, 1H), 4.34 (s, 1H), 4.19 (s, 2H), 4.05 (s, 2H), 3.92 (s, 2H), 3.34 (s, 2H), 3.17 (s, 3H), 3.17 - 3.10 (m, 1H), 3.05 - 2.95 (m, 2H), 2.68 - 2.60 (m, 6H), 2.49 (s, 3H) , 2.48 - 2.40 (m, 1H), 2.40 - 2.30 (m, 1H), 2.29 - 2.21 (m, 1H), 2.20 - 2.10 (m, 3H), 2.09 - 2.00 (m, 2H), 1.95 - 1.87 ( m, 1H), 1.80 (d, 1H), 1.58 - 1.50 (m, 1H), 1.42 - 1.25 (m, 1H), 1.35 - 1.28 (m, 3H), 1.25 - 1.15 (m, 2H), 1.11 - 1.07 (m, 3H), 0.90 - 0.78 (m, 1H) 200 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.81 (d, 1H), 7.51 - 7.42 (m, 2H), 7.37 (d, 1H), 7.11 (t, 1H), 6.75 (dd, 2H), 6.58 - 6.44 (m, 2H), 4.60 (d, 1H), 4.40 (d, 1H), 4.35 - 4.30 (m, 1H), 4.19 - 4.15 (m, 2H), 4.04 (s, 2H), 3.91 ( s, 2H), 3.19 - 3.17 (m, 4H), 3.16 - 3.12 (m, 1H), 3.05 - 2.95 (m, 2H), 2.67 - 2.65 (m, 1H), 2.64 - 2.57 (m, 6H), 2.50 (s, 3H), 2.49 - 2.43 (m, 2H), 2.38 - 2.30 (m, 1H), 2.27 - 2.13 (m, 3H), 2.10 - 2.01 (m, 3H), 1.95 - 1.88 (m, 1H) ), 1.86 (s, 3H), 1.79 (d, 1H), 1.57 - 1.48 (m, 1H), 1.37 - 1.30 (m, 2H), 1.25 - 1.18 (m, 1H), 0.90 - 0.75 (m, 1H) ) 202 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.76 (d, 1H), 7.49 (dt, 3H), 7.11 (t, 1H), 6.67 (d, 1H), 6.63 (d, 2H), 6.44 ( d, 1H), 6.43 - 6.35 (m, 2H), 4.62 (d, 1H), 4.58 - 4.50 (m, 1H), 4.33 (d, 1H), 3.98 - 3.94 (m, 2H), 3.82 (s, 2H), 3.72 (s, 2H), 3.24 (s, 3H), 2.90 (dd, 1H), 2.72 (d, 2H), 2.64 - 2.55 (m, 1H), 2.48 (s, 3H), 2.33 - 2.26 (m, 2H), 2.23 (s, 6H), 2.10 - 1.95 (m, 4H), 1.81 - 1.73 (m, 1H), 1.69 - 1.58 (m, 2H), 1.55 - 1.48 (m, 3H), 1.48 - 1.43 (m, 1H), 1.36 - 1.27 (m, 1H), 1.20 - 1.11 (m, 2H), 0.62 - 0.53 (m, 1H) 203 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.77 (t, 1H), 7.51 - 7.42 (m, 2H), 7.36 (d, 1H), 7.15 - 7.07 (m, 1H), 6.91 - 6.56 (m , 3H), 6.44 - 6.37 (m, 1H), 6.33 - 6.26 (m, 1H), 6.17 - 6.00 (m, 1H), 5.84 - 5.69 (m, 1H), 5.03 (d, 2H), 4.46 (dd , 3H), 3.97 (dd, 3H), 3.81 (d, 2H), 3.60 (s, 3H), 3.15 (d, 2H), 3.09 (d, 3H), 3.02 (d, 2H), 2.87 (s, 1H), 2.74 (s, 1H), 2.66 - 2.56 (m, 1H), 2.46 (s, 3H), 2.36 (s, 2H), 2.25 (s, 1H), 2.05 (d, 3H), 1.86 (s , 3H), 1.71 (d, 1H), 1.48 (s, 1H), 1.37 - 1.25 (m, 4H), 0.84 - 0.64 (m, 1H) 204 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.49 (dt, 3H), 7.16 (t, 1H), 7.05 (s, 1H), 6.81 (s, 1H), 4.73 (d, 1H), 4.50 - 4.40 (m, 1H), 4.18 (d, 2H), 4.10 (s, 1H), 3.98 (s, 1H), 3.69 - 3.60 (m, 3H), 3.58 - 3.43 (m, 1H), 3.32 (s, 1H), 3.28 - 3.17 (m, 2H), 3.16 - 3.12 (m, 1H), 3.02 (d, 1H), 2.97(d, 3H), 2.70 (d, 1H), 2.66 (s, 3H), 2.65 - 2.50 (m, 4H), 2.47 - 2.43 (m, 1H), 2.30 - 2.18 (m, 3H), 2.16 - 2.02 (m, 2H), 1.90 - 1.75 (m, 3H), 1.60 - 1.43 (m, 3H), 1.39 - 1.28 (m, 6H), 1.27 - 1.06 (m, 4H), 0.90 - 0.73 (m, 1H) 206 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.56 - 7.38 (m, 3H), 7.18 - 7.16 (m, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 4.70 (d, 1H) ), 4.41 (d, 1H), 3.99 (d, 1H), 3.63 (s, 3H), 3.53 (s, 2H), 3.40 (d, 4H), 3.34 (d, 2H), 3.30 - 3.18 (m, 3H), 3.13 (dd, 1H), 2.87 (s, 3H), 2.60 (s, 1H), 2.58 (s, 3H), 2.48 (d, 3H), 2.40 - 2.31 (m, 2H), 2.30 - 2.17 (m, 2H), 2.07 - 2.19 (m, 1H), 1.94 - 1.75 (m, 3H), 1.53 - 1.38 (m, 2H), 1.37 - 1.26 (m, 3H), 1.25 - 1.14 (m, 2H) , 0.83 - 0.75 (m, 1H) 207 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.50 (s, 1H), 7.53 - 7.44 (m, 2H), 7.40 (d, 1H), 7.15 - 7.11 (m, 1H), 6.83 (s, 1H) ), 6.72 (s, 1H), 6.27 (s, 1H), 4.63 (d, 1H), 4.39 (d, 1H), 4.18 (s, 2H), 4.05 (s, 2H), 4.03 - 3.96 (m, 1H), 3.65 (s, 3H), 3.27 - 3.23 (m, 1H), 3.14 (s, 3H), 3.12 - 3.09 (m, 2H), 3.04 (s, 3H), 2.86 (s, 3H), 2.64 - 2.57 (m, 1H), 2.55 - 2.45 (m, 5H), 2.45 - 2.37 (m, 1H), 2.34 - 2.22 (m, 3H), 2.21 - 2.12 (m, 2H), 1.94 - 1.76 (m, 2H), 1.55 - 1.45 (m, 1H), 1.39 - 1.30 (m, 3H), 1.27 - 1.16 (m, 2H), 0.83 - 0.71 (m, 1H) 208 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.54 - 7.38 (m, 3H), 7.18 - 7.14 (m, 1H), 6.98 (s, 1H), 6.79 (s, 1H), 4.70 (d, 1H) ), 4.41 (d, 1H), 3.99 (s, 1H), 3.63 (s, 3H), 3.53 (s, 2H), 3.45 - 3.37 (m, 4H), 3.36 - 3.34 (m, 2H), 3.30 - 3.20 (m, 3H), 3.16 - 3.10 (m, 1H), 2.87 (s, 3H), 2.64 - 2.59 (m, 1H), 2.58 (s, 3H), 2.52 - 2.43 (m, 3H), 2.41 - 2.30 (m, 2H), 2.29 - 1.87 (m, 2H), 2.07 - 1.97 (m, 1H), 1.93 - 1.76 (m, 3H), 1.55 - 1.38 (m, 2H), 1.36 - 1.27 (m, 3H) ), 1.23 - 1.14 (m, 2H), 0.85 - 0.70 (m, 1H) 209 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.51 - 7.40 (m, 2H), 7.36 (d, 1H), 7.27 (s, 2H), 7.12 - 7.08 (m, 1H), 6.69 (d, 2H) ), 4.56 (d, 1H), 4.36 (d, 1H), 4.30 (s, 2H), 4.16 (s, 2H), 4.03 - 3.96 (m, 1H), 3.61 (s, 3H), 3.00 (s, 1H), 2.84 (s, 1H), 2.70 (s, 1H), 2.65 - 2.58 (m, 1H), 2.56 - 2.50 (m, 1H), 2.46 (s, 3H), 2.38 - 2.34 (m, 1H) , 2.33 - 2.19 (m, 8H), 2.08 - 1.98 (m, 3H), 1.93 - 1.78 (m, 3H), 1.70 (d, 1H), 1.54 - 1.43 (m, 1H), 1.39 - 1.23 (m, 4H), 1.20 - 1.08 (m, 3H), 1.02 - 0.93 (m, 2H), 0.78 - 0.67 (m, 1H) 210 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.44 (d, 2H), 7.35 (d, 1H), 7.31 (s, 2H), 7.09 (t, 1H), 6.72 - 6.60 (m, 2H), 4.55 (d, 1H), 4.35 (d, 1H), 4.30 (s, 2H), 4.16 (s, 2H), 4.04 - 3.95 (m, 1H), 3.60 (s, 3H), 2.99 (s, 3H) , 2.96 - 2.89 (m, 1H), 2.81 (d, 1H), 2.66 - 2.54 (m, 2H), 2.45 (s, 3H), 2.32 - 2.26 (m, 8H), 2.22 - 2.15 (m, 1H) , 2.04 - 1.93 (m, 3H), 1.90 - 1.82 (m, 1H), 1.80 - 1.62 (m, 3H), 1.53 - 1.42 (m, 1H), 1.38 - 1.16 (m, 5H), 0.77 - 0.66 ( m, 1H) 211 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.48 (dd, 3H), 7.13 (t, 3H), 6.80 (d, 2H), 4.66 (d, 1H), 4.39 (d, 1H), 4.32 ( s, 2H), 4.19 (s, 2H), 4.04 - 3.94 (m, 1H), 3.62 (s, 3H), 3.22 (dd, 2H), 2.65 - 2.57 (m, 1H), 2.56 - 2.45 (m, 7H), 2.38 - 2.31 (m, 1H), 2.30 - 2.18 (m, 10H), 1.94 - 1.80 (m, 2H), 1.56 - 1.47 (m, 1H), 1.40 - 1.31 (m, 3H), 1.24 - 1.15 (m, 2H), 0.90 - 0.67 (m, 1H) 212 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.80 (s, 1H), 8.69 (d, 1H), 7.92 (d, 1H), 7.71 (s, 1H), 7.52 - 7.49 (m, 1H), 7.47 - 7.35 (m, 5H), 7.08 (s, 2H), 6.96 (s, 1H), 6.52 (t, 1H), 5.74 (d, 1H), 5.51 (d, 1H), 4.85 - 4.82 (m, 1H), 4.65 - 4.58 (m, 1H), 4.13 (s, 2H), 4.08 - 4.03 (m, 1H), 4.00 (s, 2H), 3.49 (s, 3H), 3.15 - 3.10 (m, 1H) , 3.07 - 2.95 (m, 2H), 2.69 - 2.60 (m, 1H), 2.49 - 2.40 (m, 2H), 2.30 - 2.22 (m, 1H), 2.19 - 2.02 (m, 5H), 1.87 - 1.80 ( m, 1H), 1.73 - 1.64 (m, 1H), 1.53 - 1.47 (m, 1H), 1.42 - 1.36 (m, 2H), 1.22 - 1.06 (m, 3H), 0.90 - 0.80 (m, 1H) 213 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.69 - 8.65 (m, 1H), 8.18 - 8.05 (m, 2H), 7.83 -7.71 (m, 1H), 7.60 (d, 1H), 7.54 (d , 1H), 7.50 - 7.45 (m, 2H), 7.41 (d, 1H), 7.15 - 7.07 (m, 2H), 7.04 - 6.97 (m, 1H), 6.84 (dd, 1H), 6.55 (t, 1H) ), 6.08 (d, 1H), 5.57 (d, 1H), 4.91 - 4.80 (m, 2H), 4.69 (d, 1H), 4.18 - 4.12 (m, 2H), 4.07 (d, 1H), 4.01 ( s, 2H), 3.53 (s, 3H), 3.20 - 3.13 (m, 1H), 3.11 - 2.94 (m, 2H), 2.71 - 2.63 (m, 1H), 2.51 - 2.41 (m, 2H), 2.32 - 2.25 (m, 1H), 2.23 - 2.13 (m, 3H), 2.07 (d, 2H), 1.90 - 1.83 (m, 1H), 1.78 - 1.67 (m, 1H), 1.56 - 1.49 (m, 1H), 1.44 - 1.38 (m, 1H), 1.33 - 1.30 (m, 1H), 1.25 - 1.16 (m, 2H), 0.94 - 0.82 (m, 1H) 214 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 8.70 (d, 1H), 7.89 - 7.87 (m, 1H), 7.76 - 7.70 (m, 1H), 7.67 (dd, 1H), 7.62 (dd, 1H) ), 7.57 (dd, 1H), 7.49 - 7.44 (m, 2H), 7.40 (d, 1H), 7.14 - 7.08 (m, 2H), 7.02 - 6.97 (m, 1H), 6.90 (dd, 1H), 6.57 (t, 1H), 6.35 (d, 1H), 5.63 (d, 1H), 4.85 - 4.81 (m, 1H), 4.67 (d, 1H), 4.18 - 4.13 (m, 2H), 4.08 (d, 1H), 4.05 - 4.00 (m, 2H), 3.52 (s, 3H), 3.18 - 3.12 (m, 1H), 3.09 - 2.99 (m, 2H), 2.69 - 2.62 (m, 1H), 2.50 - 2.41 ( m, 2H), 2.34 - 2.26 (m, 1H), 2.25 - 2.12 (m, 4H), 2.10 - 2.02 (m, 1H), 1.91 - 1.81 (m, 1H), 1.76 - 1.67 (m, 1H), 1.56 - 1.48 (m, 1H), 1.44 - 1.36 (m, 2H), 1.27 - 1.12 (m, 3H), 0.95 - 1.83 (m, 1H) 215 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.72 (s, 1H), 7.48 - 7.42 (m, 3H), 7.39 (d, 2H), 7.13 - 7.04 (m, 2H), 6.98 (m, 1H) ), 6.76 - 6.60 (m, 1H), 6.55 (t, 1H), 6.24 - 6.14 (m, 1H), 5.73 (dd, 1H), 4.70 - 4.61 (m, 1H), 4.60 - 4.54 (m, 1H) ), 4.41 - 4.22 (m, 1H), 4.11 (s, 3H), 4.08 - 4.04 (m, 1H), 4.01 - 3.95 (m, 2H), 3.87 - 3.77 (m, 1H), 3.66 - 3.56 (m , 2H), 3.50 (s, 3H), 3.19 - 3.08 (m, 3H), 3.06 - 2.96 (m, 2H), 2.85 - 2.70 (m, 1H), 2.69 - 2.60 (m, 1H), 2.50 - 2.42 (m, 2H), 2.30 - 2.23 (m, 1H), 2.21 - 2.12 (m, 3H), 2.08 -2.03 (m, 1H), 1.88 - 1.82 (m, 1H), 1.74 - 1.67 (m, 1H) , 1.54 - 1.48 (m, 1H), 1.41 - 1.35 (m, 2H), 1.21 - 1.11 (m, 3H), 1.00 (d, 3H), 0.93 - 0.82 (m, 1H) 216 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.71 (s, 1H), 7.47 - 7.43 (m, 3H), 7.38 (dd, 2H), 7.08 (s, 2H), 6.97 (s, 1H), 6.74 - 6.61 (m, 1H), 6.55 (t, 1H), 6.19 (d, 1H), 5.73 (dd, 1H), 4.83 - 4.79 (m, 1H), 4.65 (d, 1H), 4.39 - 4.19 ( m, 1H), 4.15 - 4.06 (m, 4H), 3.98 (s, 2H), 3.65 - 3.60 (m, 2H), 3.52 (s, 3H), 3.18 - 2.89 (m, 6H), 2.83 - 2.62 ( m, 2H), 2.48 - 2.41 (m, 2H), 2.30 - 2.22 (m, 1H), 2.23 - 2.02 (m, 6H), 1.89 - 1.79 (m, 1H), 1.72 - 1.67 (m, 1H), 1.53 - 1.47 (m, 1H), 1.42 - 1.35 (m, 2H), 1.24 - 1.20 (m, 1H), 0.99 (d, 3H), 0.91 - 0.80 (m, 1H) 217 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.93 (s, 1H), 7.55-7.44 (m, 7H), 7.19-7.15 (m, 1H), 6.45-6.43 (m, 2H), 5.10-4.95 (m, 2H), 4.00 (s, 2H), 3.93-3.88 (m, 3H), 3.63-3.54 (m, 5H), 3.41 (d, 1H), 2.83-2.58 (m, 5H), 2.53-2.45 (m, 3H), 2.26-2.23 (m, 1H), 1.93-1.91 (m, 2H), 1.57-1.24 (m, 7H). 218 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.63 (s, 2H), 7.54-7.40 (m, 5H), 7.18-7.14 (m, 1H), 6.46-6.44 (m, 2H), 4.99-4.89 (m, 2H), 4.05-4.01 (m, 3H), 3.90 (s, 2H), 3.61-3.53 (m, 5H), 3.41 (d, 1H), 2.84-2.63 (m, 5H), 2.50-2.40 (m, 3H), 2.25-2.22 (m, 1H), 1.93-1.90 (m, 2H), 1.59-1.52 (m, 1H), 1.42-1.13 (m, 6H). 221 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.92 (s, 1H), 7.64 (d, 2H), 7.56-7.43 (m, 5H), 7.19-7.15 (m, 1H), 6.51-6.49 (m , 2H), 5.10-4.89 (m, 2H), 4.02 (s, 2H), 3.94-3.90 (m, 3H), 3.62-3.49 (m, 5H), 3.41-3.38 (m, 1H), 2.82-2.44 (m, 9H), 2.25-2.22 (m, 1H), 1.94-1.91 (m, 2H), 1.57-1.07 (m, 8H), 1.06-0.93 (m, 3H). 222 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.92 (s, 1H), 7.56-7.41 (m, 7H), 7.20-7.16 (m, 1H), 6.59 (t, 1H), 5.10-4.93 (m , 2H), 4.17 (s, 2H), 4.02 (s, 1H), 3.92-3.89 (m, 2H), 3.64-3.53 (m, 5H), 3.43-3.40 (m, 1H), 2.84-2.42 (m , 9H), 2.27-2.24 (m, 1H), 1.94-1.91 (m, 2H), 1.58-1.14 (m, 8H), 1.04-0.99 (m, 3H). 223 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.86 (s, 1H), 8.09 (s, 1H), 7.74 - 7.67 (m, 3H), 7.58 - 7.40 (m, 5H), 7.18 (t, 1H) ), 6.46 (d, 2H), 5.06 (d, 1H), 4.96 (d, 1H), 4.01 (s, 2H), 3.91 - 3.85 (m, 5H), 3.63 - 3.50 (m, 5H), 3.42 ( d, 1H), 2.81 (t, 1H), 2.76 - 2.66 (m, 2H), 2.65 - 2.58 (m, 2H), 2.48 - 2.38 (m, 2H), 2.25 (d, 1H), 2.02 - 1.95 ( m, 1H), 1.94 - 1.87 (m, 1H), 1.64 - 1.51 (m, 2H), 1.46 - 1.35 (m, 3H), 1.33 - 1.17 (m, 3H), 1.06 - 0.95 (m, 1H) 226 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.77 (s, 1H), 7.58 - 7.39 (m, 6H), 7.17 (t, 1H), 6.77 - 6.57 (m, 3H), 6.14 (d, 1H) ), 5.72 (dd, 1H), 5.08 - 5.03 (m, 2H), 4.25 - 4.03 (m, 4H), 4.01 - 3.88 (m, 2H), 3.65 - 3.51 (m, 5H), 3.41 (d, 2H) ), 2.81 (t, 1H), 2.73 - 2.60 (m, 4H), 2.54 - 2.40 (m, 3H), 2.25 (d, 1H), 2.01 - 1.81 (m, 4H), 1.63 - 1.48 (m, 3H) ), 1.47 - 1.33 (m, 4H), 1.32 - 1.15 (m, 4H), 1.04 - 0.94 (m, 1H) 227 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.73 (s, 1H), 7.57 - 7.38 (m, 6H), 7.17 (t, 1H), 6.76 - 6.43 (m, 3H), 6.25 - 6.13 (m , 1H), 5.76 - 5.62 (m, 1H), 5.05 (d, 1H), 4.95 (d, 1H), 4.26 - 4.05 (m, 4H), 3.99 - 3.87 (m, 1H), 3.87 - 3.76 (m , 1H), 3.67 - 3.50 (m, 5H), 3.47 - 3.38 (m, 2H), 2.88 - 2.60 (m, 5H), 2.54 - 2.36 (m, 3H), 2.25 (d, 1H), 2.09 - 1.88 (m, 4H), 1.87 - 1.52 (m, 5H), 1.51 - 1.11 (m, 8H), 1.08 - 0.95 (m, 1H) 229 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.41 (s, 1H), 8.91 (s, 1H), 8.46 (d, 1H), 8.19 (d, 1H), 8.12 (d, 1H), 7.65 - 7.38 (m, 5H), 7.20-7.15 (m, 1H), 6.64 (d, 1H), 5.08 (d, 1H), 4.94 (d, 1H), 4.68 (s, 2H), 4.56 (s, 2H) , 3.94-3.92 (m, 1H), 3.73 - 3.52 (m, 5H), 3.51 - 3.38 (m, 1H), 2.89 - 2.48 (m, 8H), 2.25 (d, 1H), 1.94-1.92 (m, 2H), 1.60 - 1.19 (m, 6H), 0.99-0.96 (m, 1H). 233 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.93 (s, 1H), 7.74 (d, 1H), 7.56-7.43 (m, 5H), 7.19-7.15 (m, 1H), 6.65 (s, 1H) ), 6.59 (dd, 1H), 5.48-5.33 (m, 1H), 5.10-4.94 (m, 2H), 4.74 (s, 2H), 4.63-4.41 (m, 4H), 4.10 (s, 2H), 3.97-3.90 (m, 3H), 3.65-3.50 (m, 5H), 3.43-3.40 (m, 1H), 2.84-2.50 (m, 9H), 2.29-2.23 (m, 1H), 1.97-1.90 (m , 2H), 1.60-1.14 (m, 8H), 1.08-0.95 (m, 3H). 234 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.93 (s, 1H), 7.83 (d, 1H), 7.56-7.43 (m, 5H), 7.19-7.15 (m, 1H), 6.63 (s, 1H) ), 6.57 (dd, 1H), 5.48-5.33 (m, 1H), 5.11-4.92 (m, 2H), 4.70 (s, 1H), 4.57-4.41 (m, 4H), 4.10 (s, 2H), 3.97-3.90 (m, 3H), 3.65-3.54 (m, 5H), 3.43-3.40 (m, 1H), 3.12 (s, 3H), 2.84-2.44 (m, 8H), 2.26-2.23 (m, 1H) ), 1.97-1.90 (m, 2H), 1.60-1.23 (m, 6H), 0.97-0.94 (m, 1H). 235 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.93 (s, 1H), 7.75 (d, 1H), 7.56-7.44 (m, 5H), 7.20-7.16 (m, 1H), 6.61 (d, 1H) ), 6.56 (dd, 1H), 5.10-4.95 (m, 2H), 4.73-4.69 (m, 2H), 4.21-4.07 (m, 6H), 3.97-3.92 (m, 3H), 3.64-3.54 (m , 5H), 3.43-3.40 (m, 1H), 2.84-2.50 (m, 9H), 2.27-2.23 (m, 1H), 1.96-1.92 (m, 2H), 1.57-1.15 (m, 11H), 1.08 -0.96 (m, 3H). 245 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.93 (s, 1H), 7.76 (d, 1H), 7.56-7.43 (m, 5H), 7.19-7.15 (m, 1H), 6.61-6.58 (m , 2H), 5.11-4.96 (m, 2H), 4.52 (s, 2H), 4.10 (s, 2H), 4.00-3.90 (m, 3H), 3.65-3.54 (m, 5H), 3.43-3.38 (m , 1H), 2.89 (s, 6H), 2.84-2.50 (m, 9H), 2.26-2.23 (m, 1H), 1.97-1.90 (m, 2H), 1.60-1.17 (m, 8H), 1.08-0.94 (m, 3H). 248 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.76 - 8.68 (m, 1H), 7.60 - 7.39 (m, 7H), 7.17 (t, 1H), 6.60 (t, 1H), 6.35 - 6.18 (m , 2H), 5.76 (dd, 1H), 5.04 (d, 1H), 4.92 (d, 1H), 4.49 (d, 2H), 4.27 (p, 1H), 4.23 - 4.14 (m, 3H), 4.07 ( s, 2H), 3.99 - 3.89 (m, 1H), 3.63 - 3.50 (m, 4H), 3.41 (d, 1H), 2.81 (t, 1H), 2.77 - 2.59 (m, 4H), 2.58 - 2.38 ( m, 3H), 2.25 (d, 1H), 2.01 - 1.85 (m, 2H), 1.64 - 1.49 (m, 2H), 1.48 - 1.33 (m, 3H), 1.33 - 1.16 (m, 3H), 1.09 - 0.94 (m, 1H) 250 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.97-8.93 (m, 2H), 7.75 (d, 1H), 7.66-7.62 (m, 1H), 7.56-7.43 (m, 6H), 7.19-7.15 (m, 1H), 6.56-6.52 (m, 2H), 5.72 (s, 2H), 5.10-4.92 (m, 2H), 4.07 (s, 2H), 3.94-3.90 (m, 3H), 3.65-3.53 (m, 5H), 3.42-3.39 (m, 1H), 2.83-2.49 (m, 9H), 2.26-2.22 (m, 1H), 1.97-1.90 (m, 2H), 1.60-1.14 (m, 8H) , 1.09-0.94 (m, 3H). 251 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.92 (s, 1H), 8.22 (s, 1H), 7.93 (d, 1H), 7.79 (s, 1H), 7.56-7.43 (m, 5H), 7.19-7.15 (m, 1H), 6.57-6.54 (m, 2H), 5.49-5.35 (m, 1H), 5.10-4.92 (m, 2H), 4.67-4.56 (m, 4H), 4.52-4.42 (m , 2H), 4.10 (s, 2H), 3.95-3.89 (m, 6H), 3.63-3.53 (m, 5H), 3.42-3.39 (m, 1H), 2.83-2.48 (m, 8H), 2.26-2.22 (m, 1H), 1.93-1.91 (m, 2H), 1.57-1.24 (m, 6H), 1.02-0.94 (m, 1H). 256 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 8.93 (s, 1H), 7.85-7.80 (dd, 2H), 7.63 - 7.32 (m, 4H), 7.22-7.18 (m, 1H), 6.72 (d , 1H), 5.15-4.96 (m, 2H), 4.57 - 4.21 (m, 4H), 4.01 - 3.89 (m, 1H), 3.77 - 3.52 (m, 5H), 3.44 (d, 1H), 3.10 (s , 3H), 2.82 - 2.61 (m, 5H), 2.58 - 2.47 (m, 2H), 2.34 - 2.15 (m, 2H), 1.99-1.92 (m, 2H), 1.66 - 1.09 (m, 9H), 1.07 - 0.76 (m, 3H). 257 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.01 (s, 1H), 7.66 - 7.51 (m, 3H), 7.40 - 7.25 (m, 2H), 7.09-7.04 (m, 1H), 6.50 (dd , 1H), 6.40 (d, 1H), 5.11-4.99 (m, 2H), 4.07 (s, 2H), 4.02 - 3.84 (m, 3H), 3.70 - 3.50 (m, 5H), 3.48 - 3.39 (m , 1H), 3.13 (s, 3H), 2.95 (s, 3H), 2.88 - 2.60 (m, 5H), 2.58 - 2.39 (m, 3H), 2.30 - 2.19 (m, 1H), 2.06 - 1.85 (m , 2H), 1.65-1.58 (m, 1H), 1.48-1.31 (m, 4H), 1.25 - 0.96 (m, 2H). 258 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.99 (s, 1H), 7.87 - 7.75 (m, 1H), 7.61-7.58 (m, 2H), 7.34-7.32 (m, 2H), 7.09-7.05 (m, 1H), 6.68 - 6.38 (m, 2H), 5.11-4.95 (m, 3H), 4.66-4.53 (m, 1H), 4.31 - 4.05 (m, 3H), 4.03 - 3.75 (m, 4H) , 3.70 - 3.36 (m, 8H), 2.99 - 2.61 (m, 5H), 2.59 - 2.36 (m, 3H), 2.26-2.19 (m, 1H), 2.07 - 1.89 (m, 2H), 1.67 - 1.03 ( m, 11H). 261 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.92 (s, 1H), 8.21 (s, 1H), 7.93 (d, 1H), 7.78 (s, 1H), 7.56-7.43 (m, 5H), 7.20-7.16 (m, 1H), 6.57-6.53 (m, 2H), 5.10-4.95 (m, 2H), 4.66-4.60 (m, 2H), 4.24-4.07 (m, 6H), 3.94-3.89 (m , 6H), 3.61-3.56 (m, 5H), 3.42-3.39 (m, 1H), 2.83-2.48 (m, 8H), 2.26-2.22 (m, 1H), 1.94-1.91 (m, 2H), 1.54 -1.25 (m, 9H), 1.02-0.96 (m, 1H). 262 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.91 (s, 1H), 7.84 (d, 1H), 7.56-7.44 (m, 5H), 7.20-7.16 (m, 1H), 6.60-6.56 (m , 2H), 5.10-4.94 (m, 2H), 4.69 (br, 2H), 4.21-3.92 (m, 9H), 3.65-3.56 (m, 5H), 3.43-3.40 (m, 1H), 3.11 (s , 3H), 2.84-2.49 (m, 8H), 2.26-2.23 (m, 1H), 1.94-1.91 (m, 2H), 1.58-1.25 (m, 9H), 1.02-0.94 (m, 1H). 263 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.81 (s, 1H), 7.64 (d, 2H), 7.56-7.43 (m, 5H), 7.20-7.16 (m, 1H), 6.51 (dd, 2H) ), 6.29 (d, 2H), 5.08-4.95 (m, 2H), 4.06 (s, 2H), 3.93-3.90 (m, 3H), 3.61-3.49 (m, 5H), 3.43-3.40 (m, 1H) ), 3.06 (s, 3H), 2.86-2.64 (m, 9H), 2.51-2.43 (m, 3H), 2.27-2.23 (m, 1H), 1.93-1.91 (m, 2H), 1.57-1.24 (m , 8H), 1.01-0.93 (m, 3H). 264 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.92 (s, 1H), 7.78 (d, 2H), 7.56-7.44 (m, 5H), 7.20-7.16 (m, 1H), 6.63-6.58 (m , 2H), 5.10-4.94 (m, 2H), 4.60 (s, 2H), 4.12-3.54 (m, 15H), 3.48-3.35 (m, 4H), 2.84-2.50 (m, 9H), 2.26-2.23 (m, 1H), 1.94-1.90 (m, 2H), 1.58-1.17 (m, 8H), 1.08-0.95 (m, 3H). 271 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 8.94 - 8.86 (m, 1H), 7.65 (d, 1H), 7.62 - 7.40 (m, 7H), 7.21 - 7.14 (m, 1H), 6.52 (d , 1H), 6.30 - 6.15 (m, 2H), 5.70 (dd, 1H), 5.11 - 5.03 (m, 1H), 4.99 - 4.92 (m, 1H), 4.41 - 4.33 (m, 1H), 4.08 - 4.00 (m, 3H), 3.96 - 3.86 (m, 2H), 3.69 - 3.59 (m, 3H), 3.59 - 3.46 (m, 6H), 3.42 (d, 1H), 3.09 - 2.97 (m, 1H), 2.87 - 2.76 (m, 1H), 2.74 - 2.61 (m, 3H), 2.50 (dt, 2H), 2.35 - 2.19 (m, 2H), 1.98 - 1.86 (m, 2H), 1.64 - 1.51 (m, 2H) , 1.49 - 1.32 (m, 4H), 1.29 - 1.18 (m, 2H), 1.06 - 0.94 (m, 1H) 284 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 (d, 2H), 7.53 (q, 1H), 7.49 - 7.40 (m, 2H), 7.39 (d, 1H), 7.19 (t, 1H), 7.04 (s, 1H), 6.50 (d, 2H), 4.76 (d, 1H), 4.03 (s, 2H), 3.99 - 3.86 (m, 3H), 3.73 - 3.52 (m, 6H), 3.50 - 3.42 ( m, 2H), 2.88 - 2.70 (m, 3H), 2.70 - 2.41 (m, 6H), 2.30 (d, 1H), 2.13 (d, 1H), 2.01 - 1.89 (m, 1H), 1.66 - 1.51 ( m, 2H), 1.53 - 1.25 (m, 10H), 1.22 - 1.11 (m, 3H), 1.03 - 0.95 (m, 2H). 285 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 (q, 1H), 7.49 - 7.36 (m, 5H), 7.19 (t, 1H), 7.04 (s, 1H), 6.45 (d, 2H), 4.77 (d, 1H), 4.01 (s, 2H), 3.97 - 3.82 (m, 3H), 3.72 - 3.53 (m, 6H), 3.51 - 3.42 (m, 1H), 2.89 - 2.69 (m, 3H), 2.69 - 2.57 (m, 3H), 2.53 - 2.38 (m, 2H), 2.30 (d, 1H), 2.12 (d, 1H), 2.02 - 1.87 (m, 1H), 1.64 - 1.51 (m, 1H), 1.50 - 1.26 (m, 10H), 1.24 - 1.01 (m, 3H). 286 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 (d, 2H), 7.49 - 7.40 (m, 2H), 7.39 (d, 1H), 7.19 (t, 1H), 7.03 (s, 1H), 6.48 (dd, 1H), 6.37 (d, 1H), 4.75 (d, 1H), 4.06 (s, 2H), 3.99 - 3.86 (m, 3H), 3.71 - 3.52 (m, 6H), 3.46 (d, 1H), 3.11 (s, 3H), 2.93 (s, 3H), 2.87 - 2.56 (m, 6H), 2.55 - 2.40 (m, 2H), 2.30 (d, 1H), 2.12 (d, 1H), 2.01 - 1.88 (m, 1H), 1.66 - 1.51 (m, 2H), 1.50 - 1.25 (m, 10H), 1.22 - 1.02 (m, 2H). 287 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 (q, 1H), 7.49 - 7.36 (m, 5H), 7.22 - 7.16 (m, 1H), 7.05 (s, 1H), 6.49 (d, 2H) ), 4.78 (d, 1H), 4.03 - 3.88 (m, 3H), 3.84 (s, 2H), 3.72 - 3.55 (m, 6H), 3.51 - 3.44 (m, 1H), 2.90 - 2.55 (m, 6H) ), 2.50 - 2.37 (m, 2H), 2.30 (d, 1H), 2.14 (d, 1H), 2.02 - 1.88 (m, 1H), 1.67 - 1.51 (m, 2H), 1.50 - 1.27 (m, 10H) ), 1.24 - 1.05 (m, 2H). 288 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.69 (d, 2H), 7.53 (q, 1H), 7.49 - 7.42 (m, 2H), 7.40 (d, 1H), 7.19 (t, 1H), 7.05 (s, 1H), 6.51 (d, 2H), 4.78 (d, 1H), 4.07 - 4.00 (m, 2H), 3.91 (d, 3H), 3.71 - 3.53 (m, 6H), 3.50 - 3.44 ( m, 1H), 3.01 (s, 3H), 2.87 - 2.56 (m, 6H), 2.52 - 2.39 (m, 2H), 2.29 (d, 1H), 2.14 (d, 1H), 2.01 - 1.89 (m, 1H), 1.67 - 1.52 (m, 2H), 1.52 - 1.25 (m, 10H), 1.23 - 1.05 (m, 2H). 299 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.77 (d, 1H), 7.60 (d, 1H), 7.48 (d, 1H), 7.43 - 7.32 (m, 3H), 7.01 (t, 1H), 6.44 - 6.37 (m, 2H), 6.29 (t, 1H), 4.96 (d, 1H), 4.27 - 4.16 (m, 1H), 3.99 (s, 2H), 3.85 (s, 2H), 3.80 (s, 2H), 3.44 (s, 3H), 3.30 - 3.29 (m, 2H), 3.23 (s, 3H), 2.91 (d, 2H), 2.83 - 2.70 (m, 2H), 2.41 - 2.21 (m, 9H) , 2.13 - 2.05 (m, 2H), 1.94 - 1.87 (m, 2H), 1.78 - 1.70 (m, 1H), 1.68 - 1.47 (m, 3H), 1.42 - 1.35 (m, 1H), 1.23 - 1.06 ( m, 2H), 0.93 0.87 (m, 1H), 0.85 - 0.73 (m, 1H) 306 ¹ H NMR (400 MHz, methanol- d ₄ ) 7.76 (d, 1H), 7.37-7.46 (m, 1H), 7.31-7.36 (m, 1H), 7.20-7.29 (m, 1H), 7.06-7.13 ( m, 1H), 6.41 (d, 1H), 6.37 (dd, 1H), 3.97 (s, 2H), 3.82-3.90 (m, 1H), 3.83 (s, 2H), 3.72 (s, 2H), 3.45 (s, 3H), 3.25 (s, 3H), 2.79-2.97 (m, 3H), 2.59-2.69 (m, 1H), 2.30-2.40 (m, 2H), 2.23 (s, 6H), 1.95-2.15 (m, 5H), 1.47-1.87 (m, 8H), 1.10-1.39 (m, 2H). 307 ¹ H NMR (400 MHz, methanol- d ₄ ) 7.77 (d, 1H), 7.34-7.42 (m, 1H), 7.22-7.28 (m, 1H), 7.16-7.22 (m, 1H), 6.95-7.03 ( m, 1H), 6.42 (d, 1H), 6.39 (dd, 1H), 4.03-4.10 (m, 1H), 3.99 (s, 2H), 3.86 (s, 2H), 3.73 (s, 2H), 3.54 (s, 3H), 3.18-3.28 (m, 2H), 3.25 (s, 3H), 2.86-2.98 (m, 2H), 2.63-2.72 (m, 1H), 2.66 (s, 1H), 2.34-2.47 (m, 3H), 2.24 (s, 6H), 1.90-2.12 (m, 4H), 1.64-1.84 (m, 4H), 1.17-1.58 (m, 7H). 310 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.92 (s, 1H), 7.60-7.43 (m, 7H), 7.20-7.14 (m, 2H), 5.11-4.97 (m, 2H), 3.92-3.90 (m, 1H), 3.64-3.55 (m, 5H), 3.45-3.42 (m, 1H), 3.20-3.17 (m, 2H), 3.11-3.09 (m, 2H), 2.83-2.76 (m, 1H) , 2.72-2.61 (m, 3H), 2.53-2.49 (m, 1H), 2.34-2.23 (m, 3H), 2.05-1.89 (m, 4H), 1.82-1.79 (m, 2H), 1.73-1.71 ( m, 2H), 1.58-1.16 (m, 8H), 1.06-0.99 (m, 3H). 319 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.91 (s, 1H), 7.76 (d, 1H), 7.56-7.43 (m, 5H), 7.20-7.09 (m, 3H), 5.48-5.34 (m , 1H), 5.11-4.89 (m, 2H), 4.74 (s, 2H), 4.58-4.42 (m, 4H), 3.93-3.91 (m, 1H), 3.66-3.38 (m, 10H), 2.83-2.66 (m, 4H), 2.53-2.51 (m, 1H), 2.35-2.27 (m, 3H), 2.09-2.01 (m, 2H), 1.96-1.92 (m, 2H), 1.77-1.74 (m, 2H) , 1.68-1.18 (m, 10H), 1.09-0.99 (m, 3H). 326 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 8.54 (s, 1H), 7.61 - 7.44 (m, 2H), 7.44 - 7.31 (m, 2H), 7.31 - 7.12 (m, 2H), 7.03 (t , 1H), 6.86 (dt, 1H), 6.57 (dt, 1H), 5.73 (d, 1H), 4.85 (d, 1H), 4.66 (d, 1H), 4.20 - 4.12 (m, 2H), 3.93 ( s, 1H), 3.57 (s, 2H), 3.54 - 3.38 (m, 2H), 3.29 (d, 1H), 3.09 (t, 2H), 3.00 (t, 2H), 2.88 (s, 2H), 2.49 (m, 7H), 2.15 - 2.00 (m, 5H), 1.85 (d, 2H), 1.80 - 1.64 (m, 4H), 1.59 - 1.43 (m, 2H), 1.42 - 1.27 (m, 2H), 1.27 - 1.07 (m, 2H), 0.83 (s, 1H). 327 ¹ H NMR (400 MHz, acetonitrile- d ₃ ) δ 8.43 (s, 1H), 7.54 (dd, 1H), 7.33 (q, 1H), 7.23 - 7.16 (m, 1H), 7.08 - 6.93 (m, 3H) ), 6.34 - 6.24 (m, 1H), 5.71 (dd, 1H), 3.91 (d, 1H), 3.73 (s, 2H), 3.57 (s, 2H), 3.53 - 3.35 (m, 3H), 2.94 ( t, 2H), 2.85 (q, 2H), 2.56 (m, 6H), 2.25 - 2.14 (m, 4H), 2.13 - 2.02 (m, 3H), 1.86 (d, 2H), 1.76 - 1.69 (m, 1H), 1.65 (t, 2H), 1.61 - 1.42 (m, 2H), 1.38 (q, 2H), 1.22 (dq, 2H), 1.07 (s, 1H). 341 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.65 (d, 2H), 7.53 (q, 1H), 7.49 - 7.43 (m, 1H), 7.41 (d, 1H), 7.23 - 7.14 (m, 2H) ), 7.06 (s, 1H), 6.52 (d, 2H), 6.29 - 6.14 (m, 2H), 5.70 (dd, 1H), 4.37 (t, 1H), 4.08 - 3.99 (m, 3H), 3.92 ( s, 2H), 3.68 - 3.54 (m, 6H), 3.53 - 3.45 (m, 3H), 3.03 (p, 2H), 2.90 - 2.53 (m, 7H), 2.52 - 2.41 (m, 2H), 2.29 ( d, 1H), 2.15 (d, 1H), 1.96 (d, 1H), 1.67 - 1.52 (m, 2H), 1.49 - 1.37 (m, 7H), 1.36 - 1.27 (m, 4H), 1.23 - 1.07 ( m, 3H). 343 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.33 - 7.25 (m, 3H), 7.22 (d, 1H), 7.16 (d, 1H), 6.96 - 6.90 (m, 1H), 4.31 (s, 2H) ), 4.18 (s, 2H), 4.00 - 3.90 (m, 1H), 3.56 (s, 2H), 3.47 (s, 3H), 3.17 - 3.00 (m, 4H), 2.98 - 2.75 (m, 3H), 2.60 - 2.50 (m, 2H), 2.48 - 2.34 (m, 3H), 2.30 (s, 6H), 2.15 - 2.06 (m, 2H), 2.05 - 1.88 (m, 4H), 1.87 - 1.76 (m, 1H) ), 1.74 - 1.62 (m, 2H), 1.60 - 1.47 (m, 3H), 1.44 - 1.30 (m, 3H), 1.18 - 1.09 (m, 5H), 1.01 - 0.94 (m, 2H). 344 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.52 - 7.41 (m, 3H), 7.36 (d, 1H), 7.16 - 7.07 (m, 1H), 6.85 (s, 1H), 6.72 (s, 1H) ), 6.51 (dd, 1H), 6.28 (d, 1H), 4.64 (d, 1H), 4.50 (d, 1H), 3.97 (s, 3H), 3.84 (s, 2H), 3.59 (s, 3H) , 3.29 - 3.20 (m, 2H), 3.18 - 3.09 (m, 2H), 3.07 (s, 3H), 2.81 (s, 3H), 2.70 -2.59 (m, 1H), 2.54 - 2.43 (m, 2H) , 2.42 - 2.30 (m, 2H), 2.28 - 2.17 (m, 3H), 2.15 - 2.06 (m, 1H), 1.94 - 1.82 (m, 2H), 1.57 - 1.46 (m, 1H), 1.39 (d, 3H), 1.36 - 1.30 (m, 3H), 1.26 (d, 3H), 1.24 - 1.18 (m, 2H), 0.96 - 0.83 (m, 1H). 345 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 (d, 1H), 7.50 - 7.41 (m, 2H), 7.38 (d, 1H), 7.17 - 7.10 (m, 1H), 6.97 (s, 1H) ), 6.79(s, 1H), 6.61 (d, 1H), 6.48 (dd, 1H), 4.70 (d, 1H), 4.54 (d, 1H), 4.08 - 4.02 (m, 4H), 4.01 - 3.95 ( m, 1H), 3.91 (s, 2H), 3.60 (s, 3H), 3.44 - 3.32 (m, 3H), 3.29 - 3.25 (s, 1H), 2.71 - 2.69 (m, 1H), 2.66 (s, 6H), 2.60 - 2.58 (m, 1H), 2.57 - 2.53 (m, 2H), 2.50 - 2.36 (m, 4H), 2.18 (d, 1H), 1.99 - 1.86 (m, 2H), 1.58 - 1.46 ( m, 1H), 1.42 (d, 3H), 1.40 - 1.31 (m, 3H), 1.29 (d, 3H), 1.25 - 1.18 (m, 2H), 1.05 - 0.87 (m, 1H). 346 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.41 - 7.31 (m, 1H), 7.25 - 7.14 (m, 2H), 7.12 (s, 2H), 7.04 - 6.93 (m, 1H), 4.32 (s , 2H), 4.20 (s, 2H), 3.95 - 3.63 (m, 3H), 3.47 (s, 3H), 3.40 - 3.32 (m, 2H), 3.29 - 3.06 (m, 4H), 2.62 - 2.49 (m , 5H), 2.45 - 2.35 (m, 1H), 2.32 - 2.28 (m, 2H), 2.26 (s, 6H), 2.17 - 2.02 (m, 2H), 1.88 - 1.74 (m, 2H), 1.72 - 1.50 (m, 5H), 1.48 - 1.40 (m, 1H), 1.37 - 1.25 (m, 2H), 1.19 (d, 3H). 347 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.38 - 7.29 (m, 3H), 7.25 - 7.13 (m, 2H), 6.97 (t, 1H), 4.33 (s, 2H), 4.20 (s, 2H) ), 4.01 - 3.83 (m, 1H), 3.76 - 3.55 (m, 2H), 3.48 (s, 3H), 3.29 - 3.17 (m, 4H), 3.15 - 3.03 (m, 2H), 2.99 (s, 3H) ), 2.59 - 2.44 (m, 4H), 2.42 - 2.33 (m, 1H), 2.31 (s, 6H), 2.28 - 2.17 (m, 3H), 2.15 - 1.97 (m, 2H), 1.91 - 1.81 (m , 1H), 1.80 - 1.70 (m, 1H), 1.68 - 1.47 (m, 5H), 1.46 - 1.37 (m, 1H), 1.35 - 1.23 (m, 2H), 1.17 (d, 3H). 348 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 - 7.38 (m, 2H), 7.34 (d, 1H), 7.12 - 7.05 (m, 3H), 6.77 (d, 1H), 6.67 (s, 1H) ), 4.59 (d, 1H), 4.47 (d, 1H), 4.28 (s, 2H), 4.14 (s, 2H), 4.03 - 3.92 (m, 1H), 3.61 (s, 3H), 3.28 - 3.20 ( m, 1H), 3.03 (d, 1H), 2.94 (d, 1H), 2.83 - 2.71 (m, 1H), 2.69 - 2.57 (m, 1H), 2.42 - 2.30 (m, 2H), 2.25 (s, 6H), 2.23 - 2.15 (m, 1H), 2.08 - 1.99 (m, 3H), 1.99 - 1.90 (m, 2H), 1.89 - 1.80 (m, 1H), 1.79 - 1.71 (m, 1H), 1.58 - 1.46 (m, 1H), 1.38 (d, 3H), 1.35 - 1.27 (m, 3H), 1.25 (d, 3H), 1.23 - 1.15 (m, 2H), 0.90 - 0.71 (m, 1H). 349 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.49 (d, 1H), 7.39 - 7.31 (m, 1H), 7.25 - 7.13 (m, 2H), 7.04 - 6.93 (m, 1H), 6.52 (d , 1H), 6.28 (d, 1H), 3.99 (s, 2H), 3.95 - 3.83 (m, 3H), 3.80 - 3.71 (m, 1H), 3.65 - 3.40 (m, 4H), 3.28 - 3.11 (m , 6H), 3.07 (s, 3H), 2.81 (s, 3H), 2.61 - 2.45 (m, 4H), 2.43 - 2.20 (m, 4H), 2.05 - 1.92 (m, 2H), 1.90 - 1.71 (m , 2H), 1.68 - 1.26 (m, 8H), 1.18 (d, 3H). 351 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.55 (d, 1H), 7.46 - 7.36 (m, 1H), 7.32 - 7.16 (m, 2H), 7.04 (td, 1H), 6.58 (d, 1H) ), 6.50 (dd, 1H), 4.54 (s, 2H), 4.12-4.08 (m, 3H), 3.96 (s, 2H), 3.90 - 3.78 (m, 2H), 3.76 - 3.36 (m, 10H), 3.01 (s, 3H), 2.82-2.76 (m, 1H), 2.69-2.64 (m, 3H), 2.56-2.50 (m, 1H), 2.47-2.41 (m, 2H), 2.34 - 1.78 (m, 5H) ), 1.74 - 1.16 (m, 8H). 352 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.09 (s, 1H), 7.73 - 7.67 (m, 3H), 7.57 - 7.38 (m, 3H), 7.19 (t, 2H), 7.05 (s, 1H) ), 6.46 (d, 2H), 4.01 (s, 2H), 3.95 - 3.86 (m, 5H), 3.68 - 3.52 (m, 6H), 3.46 (d, 1H), 2.88 - 2.55 (m, 7H), 2.50 - 2.37 (m, 2H), 2.29 (d, 1H), 2.13 (d, 1H), 1.99 - 1.90 (m, 1H), 1.63 - 1.53 (m, 2H), 1.49 - 1.27 (m, 12H), 1.18 - 1.11 (m, 1H). 353 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.46 (d, 2H), 7.43 - 7.34 (m, 1H), 7.28 - 7.18 (m, 2H), 7.03 (td, 1H), 6.46 (d, 2H) ), 4.16 - 4.06 (m, 3H), 4.02 (s, 2H), 3.91 (s, 2H), 3.87 - 3.79 (m, 2H), 3.64 - 3.57 (m, 1H), 3.54 - 3.40 (m, 5H) ), 2.79 (t, 1H), 2.71 - 2.60 (m, 3H), 2.56 - 2.47 (m, 1H), 2.38 (dd, 2H), 2.32 - 2.19 (m, 2H), 2.01 - 1.84 (m, 2H) ), 1.69 - 1.48 (m, 4H), 1.44 - 1.22 (m, 6H). 354 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 - 7.45 (m, 1H), 7.45 - 7.32 (m, 2H), 7.30 - 7.17 (m, 2H), 7.13 - 7.04 (m, 1H), 6.78 - 6.64 (m, 1H), 6.52 - 6.43 (m, 1H), 4.08 (s, 1H), 4.03 (s, 1H), 3.90 (s, 1H), 3.69 - 3.55 (m, 2H), 3.55 - 3.40 (m, 3H), 2.99 - 2.84 (m, 2H), 2.84 - 2.70 (m, 1H), 2.70 - 2.52 (m, 3H), 2.42 - 2.19 (m, 3H), 2.19 - 2.03 (m, 2H) , 2.03 - 1.90 (m, 2H), 1.76 - 1.47 (m, 4H), 1.42 - 1.20 (m, 2H). 355 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.76 (d, 1H), 7.43 (m, 2H), 7.34 (d, 1H), 7.09 (t, 1H), 6.43 - 6.33 (m, 3H), 4.60 - 4.55 (m, 1H), 4.47 (d, 1H), 4.28 (d, 1H), 4.02 - 3.96 (m, 3H), 3.84 (s, 2H), 3.72 (s, 2H), 3.59 (s, 3H), 3.24 (s, 3H), 2.92 (d, 1H), 2.83 (d, 1H), 2.66 - 2.58 (m, 2H), 2.40 (s, 3H), 2.37 - 2.31 (m, 2H), 2.24 (s, 6H), 2.20 - 2.16 (m, 1H), 2.07 - 2.05 (m, 1H), 2.04 - 2.02 (m, 1H), 1.99 (s, 3H), 1.76 - 1.69 (m, 2H), 1.51 - 1.45 (m, 1H), 1.33 - 1.29 (m, 5H), 1.20 - 1.15 (m, 1H), 0.93 - 0.86 (m, 1H), 0.84 - 0.75 (m, 1H). 356 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.56 - 7.40 (m, 3H), 7.37 (d, 1H), 7.16 - 7.08 (m, 1H), 6.88 (s, 1H), 6.74 (s, 2H) ), 6.54 - 6.40 (m, 1H), 4.66 (d, 1H), 4.53 (d, 1H), 4.08 (s, 2H), 4.04 - 3.93 (m, 3H), 3.87 (s, 2H), 3.59 ( s, 3H), 3.29 - 3.21 (m, 2H), 2.71 - 2.61 (m, 7H), 2.56 - 2.32 (m, 7H), 2.19 - 2.12 (m, 1H), 1.98 - 1.85 (m, 2H), 1.58 - 1.49 (m, 1H), 1.44 - 1.18 (m, 13H), 0.99 - 0.88 (m, 1H). 357 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.47 (d , 1H), 7.39 - 7.33 (m, 1H), 7.27 - 7.13 (m, 2H), 7.04 - 6.94 (m, 1H), 6.72 (s , 1H), 6.43 (d, 1H), 3.99 (s, 2H), 3.95 - 3.83 (m, 3H), 3.83 - 3.76 (m, 3H), 3.47 (s, 3H), 2.70 - 2.48 (m, 5H) ), 2.45 (s, 6H), 2.39 - 2.25 (m, 3H), 2.17 - 2.05 (m, 2H), 2.06 - 2.00 (m, 1H), 1.94 - 1.80 (m, 2H), 1.80 - 1.70 (m , 1H), 1.67 - 1.51 (m, 5H), 1.51 - 1.38 (m, 2H), 1.38 - 1.24 (m, 6H), 1.22 - 1.15 (m, 3H). 358 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.77 (d, 1H), 7.50 - 7.37 (m, 2H), 7.34 (d, 1H), 7.14 - 7.04 (m, 1H), 6.73 (d, 1H) ), 6.64 (s, 1H), 6.45 - 6.33 (m, 2H), 4.57 (d, 1H), 4.44 (d, 1H), 4.05 - 3.92 (m, 3H), 3.85 - 3.80 (m, 2H), 3.77 - 3.69 (m, 2H), 3.62 (s, 3H), 3.27 - 3.17 (m, 4H), 2.87 - 2.73 (m, 2H), 2.69 - 2.53 (m, 2H), 2.36 - 2.27 (m, 2H) ), 2.23 (s, 6H), 2.17 - 2.09 (m, 1H), 2.04 - 1.92 (m, 3H), 1.90 - 1.80 (m, 1H), 1.78 - 1.65 (m, 3H), 1.58 - 1.46 (m , 1H), 1.39 (d, 3H), 1.37 - 1.26 (m, 3H), 1.24 (d, 3H), 1.22 - 1.12 (m, 2H), 0.80 - 0.63 (m, 1H). 361 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.78 (d, 1H), 7.42 - 6.61 (m, 4H), 6.46 - 6.39 (m, 2H), 4.64 - 4.47 (m, 1H), 4.47 - 4.31 (m, 2H), 4.00 (s, 2H), 3.94 - 3.85 (m, 3H), 3.82 (s, 2H), 3.62 (s, 3H), 3.23 (s, 3H), 3.20 - 3.08 (m, 2H) ), 2.87 - 2.80 (m, 1H), 2.76 - 2.72 (m, 1H), 2.46 - 2.34 (m, 3H), 2.31 (s, 6H), 2.23 - 2.16 (m, 2H), 2.15 - 2.11 (m , 1H), 2.06 - 2.01 (m, 6H), 1.94 - 1.91 (m, 1H), 1.86 - 1.83 (m, 2H), 1.80 - 1.76 (m, 2H), 1.62 - 1.60 (m, 1H), 1.34 - 1.32 (m, 3H), 1.29 - 1.29 (m, 2H), 0.92 - 0.87 (m, 2H). 362 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.47 - 7.40 (m, 2H), 7.34 (d, 1H), 7.12 - 7.05 (m, 1H), 6.69 (s, 1H), 6.63 (s, 1H) ), 4.53 (d, 1H), 4.34 (d, 1H), 4.02 - 3.93 (m, 1H), 3.59 (s, 3H), 3.29 (s, 3H), 3.16 (s, 2H), 2.92 - 2.88 ( m, 4H), 2.81 - 2.75 (m, 1H), 2.64 - 2.58 (m, 1H), 2.57 - 2.50 (m, 1H), 2.43 (s, 3H), 2.23 - 2.16 (m, 3H), 1.96 - 1.93 (m, 7H), 1.90 - 1.84 (m, 2H), 1.77 - 1.64 (m, 3H), 1.52 - 1.44 (m, 1H), 1.35 - 1.28 (m, 3H), 1.26 - 1.18 (m, 2H) ), 0.77 - 0.64 (m, 1H). 363 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.84 (s, 1H), 7.57 - 7.44 (m, 4H), 7.40 (d, 1H), 7.17 (t, 1H), 7.10 (s, 1H), 6.45 (d, 2H), 5.01 (d, 2H), 4.01 (s, 2H), 3.89 (s, 2H), 3.83 - 3.70 (m, 1H), 3.59 (t, 1H), 3.56 - 3.43 (m, 5H), 2.92 - 2.70 (m, 3H), 2.64 (dd, 2H), 2.43 (dd, 2H), 2.39 - 2.30 (m, 1H), 2.20 (d, 1H), 2.07 (d, 1H), 2.01 - 1.89 (m, 1H), 1.67 - 1.56 (m, 1H), 1.48 - 1.35 (m, 4H), 1.32 (s, 9H), 1.28 - 1.16 (m, 2H). 364 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.59 - 7.51 (m, 2H), 7.50 - 7.40 (m, 3H), 7.34 (d, 1H), 7.24 - 7.17 (m, 1H), 6.99 (s , 1H), 6.53 (d, 1H), 4.59 (d, 1H), 4.26 (s, 2H), 4.12 (s, 2H), 4.02 - 3.91 (m, 1H), 3.69 - 3.52 (m, 5H), 3.42 (d, 1H), 2.80 (t, 1H), 2.75 - 2.56 (m, 8H), 2.46 (q, 2H), 2.32 (d, 1H), 2.03 (d, 1H), 1.99 - 1.87 (m, 1H), 1.64 - 1.47 (m, 2H), 1.46 - 1.33 (m, 2H), 1.32 - 1.13 (m, 3H), 1.03 - 0.87 (m, 1H). 366 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.64 (d, 1H), 7.59 (dd, 1H), 7.57 - 7.51 (m, 1H), 7.50 - 7.41 (m, 2H), 7.34 (d, 1H) ), 7.24 - 7.18 (m, 1H), 6.99 (s, 1H), 6.60 (d, 1H), 4.60 (d, 1H), 4.28 (s, 2H), 4.14 (s, 2H), 4.02 - 3.93 ( m, 1H), 3.69 - 3.55 (m, 5H), 3.42 (d, 1H), 2.87 - 2.56 (m, 11H), 2.47 (q, 2H), 2.32 (d, 1H), 2.04 (d, 1H) , 1.99 - 1.88 (m, 1H), 1.62 - 1.48 (m, 2H), 1.45 - 1.33 (m, 2H), 1.32 - 1.20 (m, 2H), 1.19 - 1.14 (m, 2H), 1.05 - 0.99 ( m, 2H), 0.99 - 0.89 (m, 1H). 367 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 - 7.27 (m, 4H), 7.10-7.08 (m, 1H), 6.03 (dd, 1H), 5.97 (d, 1H), 4.31 - 3.88 (m , 10H), 3.75 - 3.44 (m, 7H), 2.94 - 2.21 (m, 9H), 2.17 - 1.82 (m, 3H), 1.71-1.28 (m, 11H). 369 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 - 7.27 (m, 4H), 7.09-7.06 (m, 1H), 6.03 (dd, 1H), 5.97 (d, 1H), 4.16 - 3.90 (m , 8H), 3.65 - 3.42 (m, 6H), 3.24-3.20 (m, 1H), 2.85-2.79 (m, 1H), 2.73 - 2.57 (m, 3H), 2.51 - 2.18 (m, 6H), 2.10 - 1.83 (m, 4H), 1.69 - 1.19 (m, 10H). 372 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 8.04 - 7.88 (m, 4H), 7.69 (d, 2H), 7.55 - 7.28 (m, 3H), 7.14 - 7.01 (m, 1H), 6.84 - 6.53 (m, 2H), 6.52 - 6.36 (m, 2H), 4.71 - 4.52 (m, 2H), 4.35 (d, 1H), 4.05 - 3.90 (m, 3H), 3.81 (s, 2H), 3.60 (s , 3H), 2.92 (d, 1H), 2.81 (d, 1H), 2.68 - 2.56 (m, 2H), 2.44 (s, 3H), 2.37 - 2.27 (m, 2H), 2.24 - 2.15 (m, 1H) ), 2.08 - 1.97 (m, 3H), 1.93 - 1.82 (m, 1H), 1.81 - 1.64 (m, 3H), 1.54 - 1.44 (m, 1H), 1.34 - 1.21 (m, 4H), 0.80 - 0.64 (m, 1H). 373 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.49 - 7.29 (m, 4H), 7.14 - 7.05 (m, 1H), 7.74 - 7.57 (m, 2H), 6.32 (s, 1H), 4.56 (d , 1H), 4.35 (d, 1H), 4.11 (s, 2H), 3.98 (s, 3H), 3.60 (s, 3H), 3.10 (s, 3H), 2.97 - 2.89 (m, 4H), 2.82 ( d, 1H), 2.69 - 2.56 (m, 2H), 2.45 (s, 3H), 2.38 - 2.28 (m, 2H), 2.25 (s, 3H), 2.23 - 2.15 (m, 1H), 2.08 - 1.97 ( m, 3H), 1.90 - 1.83 (m, 1H), 1.80 - 1.64 (m, 3H), 1.53 - 1.44 (m, 1H), 1.38 - 1.18 (m, 5H), 0.76 - 0.62 (m, 1H). 374 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.48 - 7.40 (m, 3H), 7.36 (d, 1H), 7.12 - 7.06 (m, 1H), 6.70 - 6.62 (m, 2H), 6.48 - 6.45 (m, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.11 (s, 2H), 4.01 - 3.95 (m, 3H), 3.60 (s, 3H), 3.13 (s, 3H), 2.97 - 2.90 (m, 1H), 2.86 (s, 3H), 2.84 - 2.78 (m, 1H), 2.65 - 2.57 (m, 2H), 2.45 (s, 3H), 2.36 - 2.29 (m, 2H), 2.24 - 2.16 (m, 1H), 2.09 (s, 3H), 2.05 - 1.97 (m, 3H), 1.89 - 1.82 (m, 1H), 1.79 - 1.70 (m, 2H), 1.70 - 1.64 (m, 1H) ), 1.52 - 1.44 (m, 1H), 1.35 - 1.24 (m, 4H), 1.19 - 1.10 (m, 1H), 0.79 - 0.65 (m, 1H). 376 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 8.15 - 7.83 (m, 4H), 7.70 (d, 2H), 7.42 - 7.33 (m, 1H), 7.30 - 7.13 (m, 2H), 7.03 - 6.95 (m, 1H), 6.45 (d, 2H), 4.15 - 4.05 (m, 1H), 3.97 (s, 2H), 3.82 (s, 2H), 3.81 - 3.74 (m, 2H), 3.70 (s, 3H ), 3.56 (s, 3H), 3.05 - 2.80 (m, 2H), 2.71 - 2.59 (m, 1H), 255 - 2.42 (m, 1H), 2.40 - 2.30 (m, 2H), 2.09 - 2.03 (m , 2H), 2.00 - 1.90 (m, 2H), 1.89 - 1.81 (m, 1H), 1.81 - 1.71 (m, 2H), 1.70 - 1.62 (m, 1H), 1.57 - 1.47 (m, 2H), 1.43 - 1.33 (m, 3H), 1.28 - 1.14 (m, 2H). 377 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.73 (d, 1H), 7.48 - 7.40 (m, 2H), 7.36 (d, 1H), 7.13 - 7.06 (m, 1H), 6.72 - 6.63 (m , 2H), 6.39 (d, 1H), 4.56 (d, 1H), 4.35 (d, 1H), 4.13 (s, 2H), 4.03 - 3.97 (m, 3H), 3.60 (s, 3H), 3.11 ( s, 3H), 2.98 - 2.92 (m, 4H), 2.88 - 2.80 (m, 1H), 2.69 - 2.58 (m, 2H), 2.45 (s, 3H), 2.39 - 2.33 (m, 2H), 2.26 - 2.17 (m, 1H), 2.11 - 1.99 (m, 3H), 1.90 - 1.75 (m, 3H), 1.72 - 1.65 (m, 1H), 1.52 - 1.44 (m, 1H), 1.37 - 1.21 (m, 5H) ), 0.80 - 0.67 (m, 1H). 380 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.46 - 7.35 (m, 2H), 7.30 - 7.20 (m, 2H), 7.05 - 6.97 (m, 1H), 6.47 (d, 1H), 4.16 - 4.10 (m, 2H), 4.06 - 3.98 (m, 3H), 3.74 (s, 2H), 3.53 (s, 3H), 3.13 (s, 3H), 3.10 - 2.97 (m, 2H), 2.86 (s, 3H) ), 2.51 - 2.38 (m, 3H), 2.16 - 2.08 (m, 5H), 2.02 - 1.93 (m, 3H), 1.90 - 1.69 (m, 3H), 1.54 - 1.33 (m, 6H), 1.31 - 1.20 (m, 2H). 381 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.96 - 7.84 (m, 1H), 7.49 - 7.32 (m, 3H), 7.15 - 7.02 (m, 1H), 6.78 - 6.60 (m, 2H), 6.40 (d, 1H), 4.60 - 4.53 (m, 2H), 4.35 (d, 1H), 4.13 (s, 2H), 3.99 (s, 3H), 3.60 (s, 3H), 3.13 (s, 3H), 3.04 (s, 3H), 2.94 (d, 1H), 2.86 - 2.79 (m, 4H), 2.68 - 2.59 (m, 2H), 2.45 (s, 3H), 2.40 - 2.32 (m, 2H), 2.25 - 2.15 (m, 1H), 2.11 - 1.98 (m, 3H), 1.92 - 1.84 (m, 1H), 1.81 - 1.64 (m, 3H), 1.53 - 1.44 (m, 1H), 1.37 - 1.29 (m, 2H) ), 1.26 - 1.23 (m, 1H), 1.20 - 1.14 (m, 1H), 0.81 - 0.66 (m, 1H). 382 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.48 - 7.42 (m, 2H), 7.36 (d, 1H), 7.23 (s, 1H), 7.13 - 7.07 (m, 1H), 6.70 (s, 1H) ), 6.66 (s, 1H), 6.46 (s, 1H), 4.57 (s, 1H), 4.54 (s, 1H), 4.36 (d, 1H), 4.08 (s, 2H), 4.01 - 3.97 (m, 1H), 3.95 (s, 2H), 3.61 (s, 3H), 3.54 (s, 2H), 2.96 (d, 1H), 2.85 (d, 1H), 2.68 - 2.61 (m, 2H), 2.45 (s , 3H), 2.36 - 2.31 (m, 2H), 2.27 (s, 6H), 2.20 (s, 3H), 2.07 - 2.01 (m, 3H), 1.83 - 1.69 (m, 3H), 1.55 - 1.43 (m , 2H), 1.33 - 1.29 (m, 4H), 0.96 - 0.87 (m, 1H), 0.81 - 0.65 (s, 1H). 383 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 (d, 1H), 7.40 - 7.33 (m, 1H), 7.26 - 7.17 (m, 2H), 6.99 (t, 1H), 6.46 (dd, 1H) ), 6.35 (d, 1H), 4.04 - 3.97 (m, 3H), 3.86 (s, 2H), 3.73 (s, 2H), 3.51 (s, 3H), 3.35 - 3.32 (m, 1H), 3.11 ( s, 3H), 2.93 (s, 3H), 2.92 - 2.87 (m, 2H), 2.71 - 2.58 (m, 1H), 2.56 - 2.46 (m, 1H), 2.38 - 2.32 (m, 2H), 2.10 - 2.03 (m, 2H), 1.96 - 1.85 (m, 2H), 1.82 - 1.72 (m, 3H), 1.57 - 1.48 (m, 2H), 1.43 - 1.34 (m, 3H), 1.31 - 1.25 (m, 1H) ), 1.21 - 1.10 (m, 1H). 384 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.99 - 7.91 (m, 4H), 7.69 (d, 2H), 7.41 - 7.33 (m, 1H), 7.26 - 7.13 (m, 2H), 7.03 - 6.96 (m, 1H), 6.44 (d, 2H), 4.08 - 3.99 (m, 1H), 3.95 (s, 2H), 3.81 (s, 2H), 3.73 (s, 2H), 3.49 (s, 3H), 2.99 - 2.84 (m, 2H), 2.71 - 2.60 (m, 1H), 2.54 - 2.44 (m, 1H), 2.37 - 2.27 (m, 2H), 2.08 - 2.00 (m, 2H), 1.95 - 1.67 (m , 6H), 1.58 - 1.46 (m, 2H), 1.44 - 1.33 (m, 3H), 1.33 - 1.12 (m, 2H). 385 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.63 (d, 1H), 7.49 - 7.39 (m, 2H), 7.35 (d, 1H), 7.14 - 7.05 (m, 1H), 6.75 - 6.59 (m , 2H), 6.27 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.12 (s, 2H), 4.04 - 3.92 (m, 3H), 3.60 (s, 3H), 3.57 ( s, 2H), 2.92 (d, 1H), 2.81 (d, 1H), 2.66 - 2.57 (m, 2H), 2.47 (s, 3H), 2.38 - 2.33 (m, 2H), 2.32 (s, 6H) , 2.25 - 2.15 (m, 1H), 2.11 - 1.98 (m, 3H), 1.90 - 1.82 (m, 1H), 1.80 - 1.64 (m, 3H), 1.55 - 1.44 (m, 1H), 1.40 - 1.27 ( m, 3H), 1.26 - 1.15 (m, 2H), 0.85 - 0.65 (m, 1H). 386 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.46 - 7.39 (m, 3H), 7.33 (d, 1H), 7.11 - 7.04 (m, 1H), 6.74 (d, 1H), 6.65 (d, 1H) ), 6.48 - 6.44 (m, 1H), 4.56 (d, 1H), 4.45 (d, 1H), 4.11 (s, 2H), 4.01 - 3.95 (m, 3H), 3.58 (s, 3H), 3.26 - 3.20 (m, 1H), 3.13 (s, 3H), 2.92 (d, 1H), 2.87 - 2.81 (m, 4H), 2.68 - 2.59 (m, 2H), 2.36 - 2.28 (m, 2H), 2.22 - 2.13 (m, 1H), 2.09 (s, 3H), 2.05 - 1.94 (m, 3H), 1.89 - 1.82 (m, 1H), 1.80 - 1.68 (m, 3H), 1.54 - 1.44 (m, 1H), 1.39 - 1.31 (m, 5H), 1.27 - 1.17 (m, 6H), 0.84 - 0.71 (m, 1H). 387 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.36 (s, 1H), 8.10 - 7.97 (m, 2H), 7.71 (d, 2H), 7.62 (t, 1H), 7.48 - 7.40 (m, 2H) ), 7.38 - 7.33 (m, 1H), 7.15 - 7.04 (m, 1H), 6.68 (d, 2H), 6.44 (d, 2H), 4.61 - 4.51 (m, 1H), 4.40 - 4.31 (m, 1H) ), 4.03 - 3.91 (m, 3H), 3.85 - 3.78 (m, 2H), 3.60 (s, 3H), 3.01 - 2.93 (m, 1H), 2.89 - 2.81 (m, 1H), 2.70 - 2.58 (m , 2H), 2.45 (s, 3H), 2.37 - 2.30 (m, 2H), 2.28 - 2.18 (m, 1H), 2.10 - 1.99 (m, 3H), 1.88 - 1.76 (m, 3H), 1.72 - 1.64 (m, 1H), 1.53 - 1.45 (m, 1H), 1.38 - 1.30 (m, 2H), 1.28 - 1.17 (m, 3H), 0.80 - 0.63 (m, 1H). 388 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.49 - 7.40 (m, 2H), 7.36 (d, 1H), 7.27 (d, 1H), 7.13 - 7.05 (m, 1H), 6.74 - 6.61 (m , 2H), 6.23 (d, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.05 (s, 2H), 4.04 - 3.96 (m, 3H), 3.92 (s, 2H), 3.60 ( s, 3H), 2.96 (d, 1H), 2.84 (d, 1H), 2.70 - 2.58 (m, 2H), 2.45 (s, 3H), 2.36 - 2.29 (m, 2H), 2.25 - 2.17 (m, 1H), 2.10 (s, 3H), 2.07 - 1.98 (m, 3H), 1.88 - 1.68 (m, 4H), 1.53 - 1.45 (m, 1H), 1.40 (t, 3H), 1.36 - 1.28 (m, 3H), 1.25 - 1.14 (m, 2H), 0.82 - 0.64 (m, 1H). 389 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.49 - 7.39 (m, 2H), 7.36 - 7.27 (m, 2H), 7.14 - 7.02 (m, 1H), 6.76 (d, 1H), 6.67 (s , 1H), 6.17 (d, 1H), 4.53 (dd, 2H), 4.17 (s, 2H), 4.11 - 3.99 (m, 5H), 3.60 (s, 3H), 3.42 (s, 2H), 3.29 - 3.23 (m, 1H), 2.89 (dd, 2H), 2.70 - 2.55 (m, 2H), 2.37 - 2.27 (m, 2H), 2.17 (s, 6H), 2.05 - 1.91 (m, 3H), 1.89 - 1.81 (m, 1H), 1.78 - 1.66 (m, 3H), 1.53 - 1.45 (m, 1H), 1.47 - 1.37 (m, 7H), 1.36 - 1.22 (m, 9H). 390 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.52 - 7.39 (m, 2H), 7.36 (d, 2H), 7.12 - 7.05 (m, 1H), 6.75 - 6.58 (m, 2H), 6.47 - 6.40 (m, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.14 (s, 2H), 4.05 - 3.92 (m, 3H), 3.60 (s, 3H), 3.10 (s, 3H), 2.96 - 2.88 (m, 4H), 2.80 (d, 1H), 2.66 - 2.56 (m, 2H), 2.44 (s, 3H), 2.38 - 2.30 (m, 2H), 2.23 - 2.15 (m, 1H), 2.07 - 1.98 (m, 3H), 1.90 - 1.82 (m, 1H), 1.79 - 1.63 (m, 3H), 1.53 - 1.43 (m, 1H), 1.30 - 1.05 (m, 5H), 0.79 - 0.63 (m , 1H). 391 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.47 - 7.35 (m, 4H), 7.12 - 7.07 (m, 1H), 6.83 - 6.63 (m, 2H), 6.53 (t, 1H), 4.57 (d , 1H), 4.38 (d, 1H), 4.15 (s, 2H), 4.04 - 3.95 (m, 3H), 3.60 (s, 3H), 3.13 (s, 3H), 3.00 - 2.94 (m, 4H), 2.89 - 2.82 (m, 1H), 2.71 - 2.61 (m, 2H), 2.50 (s, 3H), 2.40 - 2.33 (m, 2H), 2.27 - 2.18 (m, 1H), 2.10 - 2.01 (m, 3H) ), 1.91 - 1.79 (m, 3H), 1.73 - 1.66 (m, 1H), 1.52 - 1.45 (m, 1H), 1.34 - 1.19 (m, 5H), 0.79 - 0.65 (m, 1H). 392 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.59 - 7.47 (m, 3H), 7.46 (d, 1H), 7.18 (t, 1H), 7.10 - 6.95 (m, 1H), 6.87 - 6.72 (m , 1H), 6.39 (d, 1H), 4.75 (d, 1H), 4.48 (d, 1H), 4.34 (q, 2H), 4.27 - 4.20 (m, 4H), 4.16 (s, 2H), 4.02 - 4.95 (m, 1H), 3.66 (s, 3H), 3.52 - 3.43 (m, 2H), 2.81 (s, 6H), 2.70 - 2.58 (m, 8H), 2.55 - 2.46 (m, 2H), 2.28 ( d, 1H), 1.95 - 1.83 (m, 2H), 1.57 - 1.45 (m, 5H), 1.42 - 1.32 (m, 2H), 1.31 - 1.26 (m, 2H), 1.24 - 1.12 (m, 2H), 0.95 - 0.86 (m, 1H). 393 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.58 (d, 1H), 7.48 - 7.40 (m, 2H), 7.36 (d, 1H), 7.13 - 7.07 (m, 1H), 6.73 - 6.61 (m , 2H), 6.02 (dd, 1H), 5.98 (d, 1H), 4.56 (d, 1H), 4.35 (d, 1H), 4.16 (q, 2H), 4.03 - 3.94 (m, 3H), 3.83 ( s, 2H), 3.60 (s, 3H), 3.13 (s, 3H), 2.98 - 2.92 (m, 1H), 2.87 - 2.80 (m, 1H), 2.68 - 2.59 (m, 2H), 2.45 (s, 3H), 2.37 - 2.31 (m, 2H), 2.21 - 2.16 (m, 1H), 2.07 - 2.01 (m, 3H), 1.88 - 1.77 (m, 3H), 1.71 - 1.66 (m, 1H), 1.45 ( t, 3H), 1.30 - 1.28 (m, 3H), 1.23 - 1.10 (m, 2H), 0.95 - 0.82 (m, 1H), 0.79 - 0.68 (m, 1H). 394 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.43 - 7.33 (m, 2H), 7.24 (dd, 2H), 7.04 - 6.96 (m, 1H), 6.55 (t, 1H), 4.17 (s, 2H) ), 4.12 - 4.07 (m, 1H), 4.03 (s, 2H), 3.85 - 3.76 (m, 2H), 3.67 (s, 3H), 3.51 (s, 3H), 3.15 (s, 3H), 2.97 ( s, 3H), 2.96 - 2.87 (m, 2H), 2.73 - 2.61 (m, 1H), 2.53 - 2.46 (m, 1H), 2.42 - 2.35 (m, 2H), 2.11 - 2.05 (m, 2H), 2.00 - 1.91 (m, 2H), 1.88 - 1.75 (m, 3H), 1.71 - 1.65 (m, 1H), 1.57 - 1.49 (m, 2H), 1.44 - 1.34 (m, 3H), 1.29 - 1.17 (m , 2H). 395 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 - 7.42 (m, 2H), 7.38 (d, 1H), 7.12 (m, 1H), 6.73 (d, 2H), 5.83 (d, 2H), 4.60 - 4.58 (m, 1H), 4.37 - 4.35 (m, 1H), 4.07 (q, 2H), 4.03 - 3.91 (m, 3H), 3.82 - 3.80 (m, 2H), 3.61 (s, 3H), 3.13 (m, 1H), 3.03 - 2.88 (m, 2H), 2.61 - 2.59 (m, 1H), 2.49 (s, 3H), 2.42 (m, 2H), 2.31 (s, 3H), 2.20 - 2.00 ( m, 5H), 1.94 - 1.81 (m, 1H), 1.77 - 1.73 (m, 1H), 1.54 - 1.46 (m, 1H), 1.40 (t, 3H), 1.38 - 1.25 (m, 4H), 1.23 - 1.08 (m, 2H), 0.85 - 0.62 (m, 1H). 396 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.49 - 7.41 (m, 2H), 7.40 - 7.31 (m, 2H), 7.18 - 7.05 (m, 1H), 6.87 - 6.61 (m, 2H), 6.21 (d, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.27 - 4.17 (m, 1H), 4.15 - 4.01 (m, 2H), 4.00 - 3.96 (m, 1H), 3.95 - 3.85 (m, 2H), 3.75 (dd, 1H), 3.60 (s, 3H), 3.08 (s, 3H), 2.92 - 2.78 (m, 5H), 2.69 - 2.56 (m, 2H), 2.45 (s, 3H) ), 2.38 - 2.28 (m, 2H), 2.25 - 2.14 (m, 1H), 2.09 - 1.95 (m, 3H), 1.90 - 1.84 (m, 1H), 1.82 - 1.63 (m, 2H), 1.56 - 1.43 (m, 1H), 1.41 - 1.27 (m, 6H), 1.27 - 1.16 (m, 3H), 0.80 - 0.62 (m, 1H). 397 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.53 - 7.43 (m, 2H), 7.39 (d, 1H), 7.16 - 7.09 (m, 1H), 6.85 - 6.67 (m, 2H), 5.80 (d , 1H), 5.72 (s, 1H), 4.62 (d, 1H), 4.38 (d, 1H), 4.11 (q, 2H), 4.05 - 3.97 (m, 3H), 3.87 (s, 2H), 3.62 ( s, 3H), 3.24 - 3.16 (m, 1H), 3.10 - 2.99 (m, 2H), 2.65 - 2.58 (m, 1H), 2.53 - 2.43 (m, 5H), 2.41 - 2.30 (m, 1H), 2.28 - 2.10 (m, 5H), 1.93 - 1.84 (m, 1H), 1.79 (d, 1H), 1.55 - 1.46 (m, 1H), 1.41 (t, 3H), 1.37 - 1.30 (m, 4H), 1.26 - 1.20 (m, 1H), 0.84 - 0.67 (m, 1H). 398 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.55 - 7.33 (m, 3H), 7.13 (t, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 6.07 (d, 1H), 5.85 (d, 1H), 4.63 (d, 1H), 4.38 (d, 1H), 4.11 (q, 2H), 4.06 - 3.94 (m, 3H), 3.88 (s, 2H), 3.62 (s, 3H) , 3.28 - 3.22 (m, 1H), 3.15 - 3.04 (m, 2H), 2.64 - 2.57 (m, 1H), 2.57 - 2.39 (m, 6H), 2.31 - 2.11 (m, 5H), 1.92 - 1.77 ( m, 2H), 1.55 - 1.46 (m, 1H), 1.42 - 1.29 (m, 6H), 1.26 - 1.13 (m, 2H), 0.85 - 0.68 (m, 1H). 399 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.73 - 7.63 (m, 3H), 7.61 - 7.51 (m, 2H), 7.48 - 7.39 (m, 2H), 7.37 - 7.28 (m, 2H), 7.09 (t, 1H), 6.67 (d, 2H), 6.44 (d, 2H), 4.58 - 4.51 (m, 2H), 4.35 (d, 1H), 4.02 - 3.92 (m, 3H), 3.82 (s, 2H) ), 3.60 (s, 3H), 2.92 (d, 1H), 2.81 (d, 1H), 2.67 - 2.56 (m, 2H), 2.45 (s, 3H), 2.37 - 2.27 (m, 2H), 2.24 - 2.15 (m, 1H), 2.06 - 1.97 (m, 3H), 1.92 - 1.83 (m, 1H), 1.81 - 1.60 (m, 3H), 1.53 - 1.42 (m, 1H), 1.33 - 1.26 (m, 4H) ), 0.78 - 0.62 (m, 1H). 400 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.59 - 7.50 (m, 2H), 7.50 - 7.40 (m, 2H), 7.21 - 7.14 (m, 1H), 7.05 (s, 1H), 6.82 (s , 1H), 5.91 - 5.85 (m, 1H), 4.73 (d, 1H), 4.46 - 4.34 (m, 3H), 4.12 (s, 2H), 4.05 - 3.95 (m, 3H), 3.65 (s, 3H) ), 3.53 - 3.39 (m, 2H), 3.30 - 3.24 (m, 1H), 2.65 - 2.60 (m, 4H), 2.60 - 2.52 (m, 4H), 2.52 - 2.42 (m, 3H), 2.32 - 2.21 (m, 1H), 1.94 - 1.82 (m, 2H), 1.57 - 1.45 (m, 2H), 1.42 - 1.37 (m, 1H), 1.37 - 1.34 (m, 3H), 1.34 - 1.28 (m, 1H) , 1.26 - 1.14 (m, 2H), 0.91 - 0.75 (m, 1H). 401 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 - 7.35 (m, 3H), 7.19 - 7.10 (m, 2H), 7.02 (d, 1H), 6.84 (s, 1H), 6.73 (s, 1H) ), 6.37 (d, 1H), 4.65 (d, 1H), 4.39 (d, 1H), 4.08 (s, 2H), 4.00 (q, 2H), 3.97 - 3.93 (m, 3H), 3.62 (s, 3H), 3.38 - 3.32 (m, 1H), 3.27 - 3.15 (m, 2H), 2.65 - 2.58 (m, 1H), 2.55 - 2.40 (m, 7H), 2.34 - 2.17 (m, 4H), 1.94 - 1.81 (m, 2H), 1.55 - 1.45 (m, 1H), 1.41 (t, 3H), 1.35 - 1.29 (m, 3H), 1.26 - 1.14 (m, 2H), 0.87 - 0.71 (m, 1H). 402 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 - 7.47 (m, 1H), 7.46 - 7.38 (m, 2H), 7.36 (d, 1H), 7.35 - 7.29 (m, 1H), 7.11 - 7.03 (m, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 6.49 (d, 1H), 4.55 (d, 1H), 4.45 (d, 1H), 4.04 - 3.95 (m, 2H), 3.91 - 3.84 (m, 2H), 3.78 - 3.70 (m, 1H), 3.64 - 3.55 (m, 3H), 3.26 - 3.19 (m, 1H), 3.07 (s, 3H), 2.95 - 2.90 (m, 1H) ), 2.89 (s, 3H), 2.85 - 2.78 (m, 1H), 2.69 - 2.55 (m, 2H), 2.35 - 2.26 (m, 2H), 2.21 - 2.11 (m, 1H), 2.04 - 1.93 (m , 3H), 1.90 - 1.82 (m, 1H), 1.79 - 1.68 (m, 3H), 1.53 - 1.45 (m, 1H), 1.37 (d, 3H), 1.35 - 1.28 (m, 3H), 1.24 (d , 3H), 1.22 - 1.14 (m, 2H), 0.85 - 0.68 (m, 1H). 403 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.52 - 7.48 (m, 1H), 7.45 (d, 2H), 7.39 - 7.33 (m, 2H), 7.13 - 7.07 (m, 1H), 6.72 - 6.63 (m, 2H), 6.50 (d, 1H), 4.55 (d, 1H), 4.36 (d, 1H), 4.05 - 3.96 (m, 2H), 3.88 (d, 2H), 3.79 - 3.73 (m, 1H) ), 3.60 (s, 3H), 3.08 (s, 3H), 2.95 (d, 1H), 2.89 (s, 3H), 2.83 (d, 1H), 2.68 - 2.59 (m, 2H), 2.45 (s, 3H), 2.35 - 2.33 (m, 2H), 2.24 - 2.18 (m, 1H), 2.08 - 1.99 (m, 3H), 1.88 - 1.66 (m, 4H), 1.52 - 1.45 (m, 1H), 1.36 - 1.19 (m, 5H), 0.78 - 0.67 (m, 1H). 404 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.51 - 7.44 (m, 2H), 7.40 (d, 1H), 7.20 - 7.12 (m, 2H), 6.82 (s, 1H), 6.72 (s, 1H) ), 6.21 (t, 1H), 4.63 (d, 1H), 4.39 (d, 1H), 4.24 (q, 2H), 4.12 (s, 2H), 3.99 (s, 3H), 3.62 (s, 3H) , 3.27 - 3.21 (m, 1H), 3.14 - 3.07 (m, 2H), 2.72 - 2.56 (m, 2H), 2.53 - 2.48 (m, 4H), 2.44 - 2.37 (m, 1H), 2.30 - 2.15 ( m, 5H), 1.98 - 1.68 (m, 3H), 1.54 - 1.48 (m, 1H), 1.39 - 1.34 (m, 5H), 1.24 - 1.12 (m, 2H), 0.84 - 0.73 (m, 1H). 405 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.50 - 7.40 (m, 2H), 7.40 - 7.29 (m, 2H), 7.09 (t, 1H), 6.76 - 6.58 (m, 2H), 6.27 (d , 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.21 (s, 2H), 4.14 (q, 2H), 4.07 (s, 2H), 4.03 - 3.93 (m, 1H), 3.64 ( s, 3H), 2.92 (d, 1H), 2.81 (d, 1H), 2.66 - 2.55 (m, 2H), 2.45 (s, 3H), 2.35 - 2.27 (m, 2H), 2.25 - 2.14 (m, 1H), 2.07 - 1.96 (m, 3H), 1.92 - 1.81 (m, 1H), 1.79 - 1.64 (m, 3H), 1.56 - 1.46 (m, 1H), 1.42 (t, 3H), 1.38 - 1.15 ( m, 5H), 0.82 - 0.64 (m, 1H). 406 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 - 7.41 (m, 3H), 7.35 (d, 1H), 7.09 (t, 1H), 6.73 - 6.61 (m, 2H), 6.53 (d, 1H) ), 4.54 (d, 1H), 4.35 (d, 1H), 4.30 - 4.22 (m, 2H), 4.13 (s, 2H), 4.05 - 3.91 (m, 1H), 3.60 (s, 3H), 3.12 ( s, 3H), 2.95 - 2.88 (m, 4H), 2.81 (d, 1H), 2.65 - 2.54 (m, 2H), 2.44 (s, 3H), 2.37 - 2.29 (m, 2H), 2.24 - 2.15 ( m, 1H), 2.08 - 1.97 (m, 3H), 1.91 - 1.83 (m, 1H), 1.78 - 1.65 (m, 3H), 1.51 - 1.43 (m, 1H), 1.38 - 1.27 (m, 3H), 1.25 - 1.15 (m, 2H), 0.82 - 0.65 (m, 1H). 407 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.73 (d, 1H), 7.44 - 7.31 (m, 1H), 7.26 - 7.21 (m, 2H), 6.98 (t, 1H), 6.49 (dd, 1H) ), 6.26 (d, 1H), 4.12 - 4.04 (m, 1H), 4.01 (s, 2H), 3.87 (s, 2H), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.09 (s, 3H), 3.04 (s, 3H), 2.96 - 2.86 (m, 2H), 2.84 (s, 3H), 2.72 - 2.61 (m, 1H), 2.51 - 2.42 (m, 1H) , 2.41 - 2.30 (m, 2H), 2.11 - 2.02 (m, 2H), 2.00 - 1.89 (m, 2H), 1.88 - 1.73 (m, 3H), 1.71 - 1.63 (m, 1H), 1.55 - 1.46 ( m, 2H), 1.45 - 1.33 (m, 3H), 1.28 - 1.15 (m, 2H). 408 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.73 - 7.63 (m, 3H), 7.61 - 7.51 (m, 2H), 7.40 - 7.27 (m, 2H), 7.24 - 7.12 (m, 2H), 7.09 (t, 1H), 6.44 (d, 2H), 4.15 - 4.05 (m, 1H), 3.98 (s, 2H), 3.85 (s, 2H), 3.78 (d, 2H), 3.66 (s, 3H), 3.49 (s, 3H), 3.15 - 3.03 (m, 2H), 2.51 - 2.40 (m, 3H), 2.20 - 1.95 (m, 6H), 1.88 - 1.78 (m, 1H), 1.76 - 1.68 (m, 1H) ), 1.56 - 1.45 (m, 3H), 1.42 - 1.35 (m, 2H), 1.32 - 1.15 (m, 3H). 409 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.49 (d, 1H), 7.47 - 7.40 (m, 2H), 7.39 - 7.33 (m, 1H), 7.12 - 7.05 (m, 1H), 6.70 (d , 1H), 6.67 - 6.62 (m, 1H), 6.02 - 5.97 (m, 2H), 4.58 - 4.52 (m, 1H), 4.39 - 4.31 (m, 1H), 4.16 (q, 2H), 4.03 - 3.94 (m, 3H), 3.82 (s, 2H), 3.60 (s, 3H), 2.97 - 2.90 (m, 2H), 2.85 - 2.79 (m, 1H), 2.67 - 2.59 (m, 2H), 2.45 (s , 3H), 2.36 - 2.30 (m, 2H), 2.21 - 2.17 (m, 1H), 2.10 - 1.98 (m, 4H), 1.91 - 1.83 (m, 1H), 1.77 - 1.73 (m, 1H), 1.71 - 1.65 (m, 1H), 1.46 (t, 3H), 1.34 - 1.31 (m, 3H), 1.28 - 1.22 (m, 2H), 1.13 - 1.08 (m, 2H), 0.99 - 0.93 (m, 2H) , 0.92 - 0.85 (m, 1H), 0.79 - 0.67 (m, 1H). 410 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.42 - 7.33 (m, 2H), 7.28 - 7.20 (m, 2H), 7.03 - 6.95 (m, 1H), 6.21 (d, 1H), 4.27 - 4.15 (m, 1H), 4.13 - 4.00 (m, 3H), 3.90 (t, 2H), 3.79 - 3.70 (m, 3H), 3.51 (s, 3H), 3.08 (s, 3H), 2.99 - 2.89 (m , 2H), 2.89 (s, 3H), 2.74 - 2.58 (m, 1H), 2.50 - 2.43 (m, 1H), 2.38 - 2.28 (m, 2H), 2.10 -2.00 (m, 2H), 1.96 - 1.68 (m, 6H), 1.57 - 1.46 (m, 2H), 1.45 - 1.35 (m, 3H), 1.31 (t, 3H), 1.29 - 1.25 (m, 1H), 1.24 - 1.13 (m, 1H). 411 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.12 (s, 1H), 7.74 (s, 1H), 7.53 (dd, 1H), 7.45 (dd, 1H), 7.38 - 7.31 (m, 1H), 7.28 - 7.20 (m, 2H), 7.01 - 6.94 (m, 1H), 6.51 (t, 1H), 4.11 - 4.05 (m, 3H), 3.96 - 3.92 (m, 2H), 3.88 (s, 3H), 3.79 - 3.73 (m, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 2.95 - 2.85 (m, 2H), 2.69 - 2.58 (m, 1H), 2.51 - 2.43 (m, 1H), 2.38 - 2.31 (m, 2H), 2.07 - 2.00 (m, 2H), 1.97 - 1.89 (m, 2H), 1.85 - 1.72 (m, 3H), 1.68 - 1.62 (m, 1H), 1.54 - 1.46 (m , 2H), 1.42 - 1.34 (m, 3H), 1.26 - 1.16 (m, 2H). 412 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.36 (s, 1H), 8.06 - 7.99 (m, 2H), 7.71 (d, 2H), 7.62 (t, 1H), 7.39 - 7.30 (m, 1H) ), 7.26 - 7.16 (m, 2H), 7.02 - 6.94 (m, 1H), 6.44 (d, 2H), 4.11 - 4.03 (m, 1H), 3.97 - 3.93 (m, 2H), 3.84 - 3.80 (m , 2H), 3.78 - 3.73 (m, 2H), 3.63 (s, 3H), 3.49 (s, 3H), 2.93 - 2.83 (m, 2H), 2.66 - 2.57 (m, 1H), 2.52 - 2.41 (m , 1H), 2.37 - 2.28 (m, 2H), 2.06 - 2.00 (m, 2H), 1.96 - 1.87 (m, 2H), 1.86 - 1.79 (m, 1H), 1.76 - 1.69 (m, 2H), 1.67 - 1.61 (m, 1H), 1.54 - 1.45 (m, 2H), 1.42 - 1.31 (m, 3H), 1.25 - 1.12 (m, 2H). 413 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 (d, 1H), 7.45 - 7.38 (m, 1H), 7.30 - 7.20 (m, 2H), 7.04 (t, 1H), 6.55 (d, 1H) ), 4.36 - 4.28 (m, 2H), 4.24 - 4.15 (m, 2H), 4.09 - 4.02 (m, 1H), 3.82 - 3.69 (m, 2H), 3.55 (s, 3H), 3.29 - 3.20 (m , 2H), 3.13 (s, 3H), 2.93 - 2.88 (m, 3H), 2.61 - 2.52 (m, 2H), 2.49 - 2.38 (m, 2H), 2.35 - 2.23 (m, 3H), 2.20 - 2.06 (m, 2H), 1.88 - 1.78 (m, 2H), 1.60 - 1.35 (m, 6H), 1.32 - 1.19 (m, 2H). 414 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.13 (s, 1H), 7.75 (s, 1H), 7.66 (d, 1H), 7.61 (dd, 1H), 7.50 - 7.41 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.72 - 6.61 (m, 2H), 6.53 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.19 (s, 2H) , 4.07 - 3.96 (m, 3H), 3.88 (s, 3H), 3.60 (s, 3H), 2.90 (d, 1H), 2.80 (d, 1H), 2.66 - 2.56 (m, 2H), 2.44 (s , 3H), 2.34 - 2.27 (m, 2H), 2.21 - 2.13 (m, 1H), 2.06 - 1.97 (m, 3H), 1.90 - 1.80 (m, 1H), 1.77 - 1.63 (m, 3H), 1.53 - 1.42 (m, 1H), 1.35 - 1.19 (m, 5H), 0.80 - 0.63 (m, 1H). 415 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.78 - 8.71 (m, 2H), 7.85 - 7.77 (m, 2H), 7.71 (d, 2H), 7.49 - 7.33 (m, 3H), 7.10 (t , 1H), 6.75 - 6.70 (m, 1H), 6.67 (s, 1H), 6.46 (d, 2H), 4.57 (d, 1H), 4.36 (d, 1H), 4.03 - 3.94 (m, 3H), 3.85 (s, 2H), 3.60 (s, 3H), 3.05 - 2.96 (m, 1H), 2.91 - 2.82 (m, 1H), 2.80 - 2.68 (m, 1H), 2.65 - 2.58 (m, 1H), 2.47 (s, 3H), 2.40 - 2.33 (m, 2H), 2.30 - 2.20 (m, 1H), 2.13 - 2.02 (m, 3H), 1.95 - 1.79 (m, 3H), 1.70 (d, 1H), 1.53 - 1.45 (m, 1H), 1.35 - 1.20 (m, 5H), 0.80 - 0.67 (m, 1H). 416 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 8.09 - 7.92 (m, 3H), 7.86 (d, 2H), 7.41 - 7.33 (m, 1H), 7.26 - 7.17 (m, 2H), 7.05 - 6.95 (m, 1H), 6.59 - 6.44 (m, 2H), 4.58 (s, 1H), 4.13 - 4.06 (m, 1H), 4.02 (s, 2H), 3.89 (s, 2H), 3.84 - 3.75 (m , 4H), 3.66 (s, 3H), 3.49 (s, 3H), 3.11 - 2.82 (m, 3H), 2.49 - 2.39 (m, 3H), 2.25 - 2.14 (m, 7H), 2.05 - 1.99 (m , 3H), 1.86 - 1.80 (m, 1H), 1.77 - 1.71 (m, 1H), 1.57 - 1.46 (m, 3H), 1.42 - 1.36 (m, 2H), 1.31 - 1.23 (m, 3H). 417 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.40 - 7.37 (m, 1H), 7.36 - 7.31 (m, 1H), 7.26 - 7.16 (m, 2H), 6.98 (t, 1H), 6.21 (d , 1H), 4.25 - 4.17 (m, 1H), 4.12 - 4.02 (m, 3H), 3.90 (t, 2H), 3.78 - 3.73 (m, 2H), 3.65 (s, 3H), 3.49 (s, 3H) ), 3.08 (s, 3H), 2.92 - 2.85 (m, 5H), 2.65 - 2.56 (m, 1H), 2.51 - 2.44 (m, 1H), 2.36 - 2.29 (m, 2H), 2.06 - 1.98 (m , 2H), 1.96 - 1.89 (m, 2H), 1.87 - 1.80 (m, 1H), 1.77 - 1.62 (m, 3H), 1.54 - 1.46 (m, 2H), 1.41 - 1.35 (m, 2H), 1.34 - 1.28 (m, 5H), 1.25 - 1.13 (m, 2H). 418 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.44 (d, 1H), 7.41 - 7.34 (m, 1H), 7.28 - 7.17 (m, 2H), 7.01 (t, 1H), 6.48 (d, 1H) ), 4.17 - 4.12 (m, 2H), 4.11 - 4.07 (m, 1H), 4.06 - 3.99 (m, 2H), 3.79 (s, 2H), 3.67 (s, 3H), 3.49 (s, 3H), 3.14 (s, 3H), 2.87 (s, 3H), 2.65 (s, 3H), 2.57 - 2.44 (m, 3H), 2.32 - 2.17 (m, 3H), 2.15 - 2.05 (m, 5H), 1.91 - 1.79 (m, 2H), 1.57 - 1.48 (m, 3H), 1.46 - 1.34 (m, 3H), 1.31 - 1.24 (m, 3H). 419 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.38 - 7.30 (m, 2H), 7.27 - 7.17 (m, 2H), 6.98 (t, 1H), 6.16 (d, 1H), 4.18 - 4.14 (m , 2H), 4.08 - 4.04 (m, 4H), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.41 (s, 2H), 2.91 (t, 2H), 2.68 - 2.59 (m, 1H), 2.53 - 2.44 (m, 1H), 2.39 - 2.33 (m, 2H), 2.17 (s, 6H), 2.08 - 2.02 (m, 2H), 1.99 - 1.90 (m, 2H), 1.87 - 1.72 (m, 3H), 1.70 - 1.63 (m, 1H), 1.55 - 1.47 (m, 2H), 1.42 (t, 3H), 1.39 - 1.34 (m, 2H), 1.34 - 1.27 (m, 2H) ), 1.26 - 1.16 (m, 2H). 420 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.48 (d, 1H), 7.39 - 7.30 (m, 1H), 7.28 - 7.16 (m, 2H), 7.02 - 6.93 (m, 1H), 6.57 - 6.49 (m, 1H), 4.31 - 4.24 (m, 2H), 4.18 - 4.11 (m, 2H), 4.11 - 4.03 (m, 1H), 3.76 (s, 2H), 3.65 (s, 3H), 3.64 - 3.55 (m, 1H), 3.49 (s, 3H), 3.12 (s, 3H), 2.97 - 2.87 (m, 5H), 2.66 (s, 1H), 2.52 - 2.43 (m, 1H), 2.36 (s, 2H ), 2.09 - 2.02 (m, 2H), 1.93 (d, 2H), 1.86 - 1.70 (m, 3H), 1.69 - 1.62 (m, 1H), 1.54 - 1.46 (m, 2H), 1.42 - 1.36 (m , 2H), 1.32 - 1.26 (m, 2H). 421 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.13 (s, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.61 (dd, 1H), 7.41 - 7.31 (m, 1H), 7.27 - 7.16 (m, 2H), 6.98 (t, 1H), 6.53 (d, 1H), 4.19 (s, 2H), 4.11 - 4.04 (m, 3H), 3.88 (s, 3H), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.00 - 2.85 (m, 2H), 2.74 - 2.61 (m, 1H), 2.53 - 2.42 (m, 1H), 2.39 - 2.31 (m, 2H), 2.10 - 2.01 (m, 2H), 1.98 - 1.90 (m, 2H), 1.87 - 1.72 (m, 3H), 1.67 (d, 1H), 1.55 - 1.45 (m 2H), 1.40 - 1.30 (m , 3H), 1.26 - 1.16 (m, 2H). 422 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.40 - 7.34 (m, 1H), 7.27 - 7.17 (m, 2H), 7.09 (s, 1H), 7.00 (t, 1H), 6.28 (s, 1H) ), 4.12 - 4.05 (m, 3H), 3.99 (s, 2H), 3.83 - 3.75 (m, 5H), 3.66 (s, 3H), 3.49 (s, 3H), 3.22 - 3.05 (m, 6H), 2.93 (s, 3H), 2.52 - 2.40 (m, 3H), 2.25 - 2.15 (m, 3H), 2.10 - 2.01 (m, 2H), 1.88 - 1.74 (m, 2H), 1.56 - 1.47 (m, 3H) ), 1.44 - 1.36 (m, 2H), 1.34 - 1.19 (m, 3H). 423 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.64 (d, 1H), 7.43 - 7.30 (m, 1H), 7.27 - 7.13 (m, 2H), 6.98 (t, 1H), 6.27 (d, 1H) ), 4.17 - 4.03 (m, 3H), 3.98 (s, 2H), 3.76 (s, 2H), 3.65 (s, 3H), 3.58 (s, 2H), 3.50 (s, 3H), 2.89 (t, 2H), 2.69 - 2.58 (m, 1H), 2.52 - 2.43 (m, 1H), 2.41 - 2.26 (m, 8H), 2.13 - 2.00 (m, 2H), 2.00 - 1.88 (m, 2H), 1.84 - 1.60 (m, 4H), 1.57 - 1.46 (m, 2H), 1.42 - 1.30 (m, 3H), 1.25 - 1.11 (m, 2H). 424 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.62 (d, 1H), 7.50 - 7.31 (m, 3H), 7.15 - 7.06 (m, 1H), 6.75 - 6.60 (m, 2H), 6.27 (d , 1H), 4.56 (d, 1H), 4.36 (d, 1H), 4.15 (s, 2H), 4.06 - 3.96 (m, 5H), 3.61 (s, 3H), 3.54 - 3.46 (m, 2H), 3.16 (s, 3H), 3.01 - 2.93 (m, 1H), 2.89 - 2.81 (m, 1H), 2.71 - 2.57 (m, 2H), 2.46 (s, 3H), 2.40 - 2.33 (m, 2H), 2.21 (s, 6H), 2.13 - 2.01 (m, 3H), 1.90 - 1.77 (m, 3H), 1.74 - 1.64 (m, 1H), 1.53 - 1.49 (m, 1H), 1.44 (t, 3H), 1.38 - 1.18 (m, 6H), 0.80 - 0.67 (m, 1H). 425 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.59 (d, 1H), 7.41 - 7.32 (m, 1H), 7.27 - 7.16 (m, 2H), 7.01 - 6.94 (m, 1H), 6.24 (d , 1H), 4.15 (s, 2H), 4.11 - 4.05 (m, 1H), 4.05 - 3.97 (m, 4H), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.41 (s, 2H), 3.15 (s, 3H), 2.96 - 2.85 (m, 2H), 2.69 - 2.60 (m, 1H), 2.52 - 2.43 (m, 1H), 2.41 - 2.32 (m, 2H), 2.14 (s, 6H), 2.09 - 2.02 (m, 2H), 1.97 - 1.89 (m, 2H), 1.85 - 1.64 (m, 4H), 1.55 - 1.47 (m, 2H), 1.46 - 1.35 (m, 6H) ), 1.27 - 1.16 (m, 2H). 426 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.73 (d, 1H), 7.40 - 7.33 (m, 1H), 7.28 - 7.18 (m, 2H), 7.00 (td, 1H), 6.48 (dd, 1H) ), 6.27 (d, 1H), 4.12 - 4.05 (m, 1H), 4.00 (s, 2H), 3.88 (s, 2H), 3.81 - 3.74 (m, 2H), 3.66 (s, 3H), 3.49 ( s, 3H), 3.24 - 3.11 (m, 3H), 3.06 (s, 3H), 2.86 (s, 3H), 2.54 - 2.45 (m, 3H), 2.26 - 2.18 (m, 3H), 2.13 - 2.04 ( m, 2H), 1.86 - 1.76 (m, 2H), 1.55 - 1.47 (m, 3H), 1.43 - 1.20 (m, 5H). 427 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.45 - 7.29 (m, 2H), 7.28 - 7.11 (m, 2H), 7.02 - 6.92 (m, 1H), 6.55 (d, 1H), 4.17 - 4.01 (m, 3H), 4.00 - 3.89 (m, 2H), 3.76 (s, 2H), 3.72 - 3.59 (m, 6H), 3.55 (s, 3H), 3.13 (s, 3H), 2.99 - 2.83 (m , 5H), 2.67 - 2.58 (m, 1H), 2.54 - 2.43 (m, 1H), 2.40 - 2.29 (m, 2H), 2.08 - 2.01 (m, 2H), 1.99 - 1.88 (m, 2H), 1.87 - 1.62 (m, 4H), 1.55 - 1.46 (m, 2H), 1.43 - 1.30 (m, 3H), 1.28 - 1.13 (m, 2H). 428 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.74 (d, 2H), 7.80 (d, 2H), 7.71 (d, 2H), 7.38 - 7.32 (m, 1H), 7.26 - 7.15 (m, 2H) ), 6.98 (t, 1H), 6.46 (d, 2H), 4.11 - 4.04 (m, 1H), 3.98 (s, 2H), 3.85 (s, 2H), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.04 - 2.87 (m, 2H), 2.82 - 2.63 (m, 1H), 2.51 - 2.44 (m, 1H), 2.42 - 2.31 (m, 2H), 2.13 - 2.04 ( m, 2H), 2.00 - 1.91 (m, 2H), 1.88 - 1.79 (m, 2H), 1.72 - 1.64 (m, 1H), 1.57 - 1.31 (m, 6H), 1.27 - 1.15 (m, 2H). 429 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.51 - 7.36 (m, 3H), 7.17 - 7.06 (m, 2H), 6.84 - 6.69 (m, 2H), 6.28 (s, 1H), 4.63 (d , 1H), 4.39 (d, 1H), 4.10 (s, 2H), 4.04 - 3.94 (m, 3H), 3.81 (s, 3H), 3.61 (s, 3H), 3.27 - 3.15 (m, 2H), 3.10 (s, 3H), 3.05 - 2.99 (m, 1H), 2.94 (s, 3H), 2.65 - 2.59 (m, 1H), 2.53 (s, 3H), 2.48 - 2.36 (m, 3H), 2.21 - 2.07 (m, 4H), 1.91 - 1.76 (m, 2H), 1.54 - 1.47 (m, 1H), 1.39 - 1.29 (m, 4H), 1.25 - 1.15 (m, 2H), 0.82 - 0.67 (m, 1H) ). 430 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.04 (s, 1H), 7.76 - 7.69 (m, 2H), 7.39 - 7.30 (m, 1H), 7.27 - 7.15 (m, 2H), 6.98 (t , 1H), 6.01 (dd, 1H), 5.88 (d, 1H), 4.12 - 4.01 (m, 3H), 3.94 (s, 2H), 3.89 (s, 3H), 3.81 (s, 2H), 3.75 ( s, 2H), 3.65 (s, 3H), 3.48 (d, 3H), 2.97 - 2.85 (m, 2H), 2.70 - 2.57 (m, 1H), 2.52 - 2.42 (m, 1H), 2.36 - 2.30 ( m, 2H), 2.09 - 2.00 (m, 2H), 1.98 - 1.88 (m, 2H), 1.86 - 1.72 (m, 3H), 1.69 - 1.62 (m, 1H), 1.54 - 1.45 (m, 2H), 1.41 - 1.38 (t, 3H), 1.30 - 1.27 (m, 3H), 1.22 - 1.18 (m, 1H), 0.95 - 0.85 (m, 1H). 431 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.40 - 7.31 (m, 2H), 7.28 - 7.16 (m, 2H), 6.98 (t, 1H), 6.50 (d, 1H), 4.18 - 4.05 (m , 3H), 4.02 - 3.86 (m, 3H), 3.83 - 3.72 (m, 3H), 3.65 (s, 3H), 3.48 (s, 3H), 3.11 (s, 3H), 3.01 - 2.88 (m, 5H) ), 2.69 (s, 1H), 2.52 - 2.46 (m, 1H), 2.43 - 2.33 (m, 2H), 2.12 - 2.03 (m, 2H), 2.02 - 1.90 (m, 2H), 1.89 - 1.74 (m , 3H), 1.74 - 1.64 (m, 1H), 1.50 - 1.46 (m, 2H), 1.46 - 1.33 (m, 3H), 1.30 - 1.20 (m, 5H). 432 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.50 - 7.30 (m, 4H), 7.12 - 7.09 (m, 1H), 6.71 - 6.66 (m, 2H), 6.50 (d, 1H), 4.65 - 4.52 (m, 3H), 4.37 - 4.34 (m, 1H), 4.08 (q, 2H), 3.98 - 3.86 (m, 4H), 3.79 - 3.60 (m, 1H), 3.60 (s, 3H), 3.13 (s , 3H), 2.98 - 2.93 (m, 1H), 2.92 - 2.89 (m, 4H), 2.78 - 2.57 (m, 2H), 2.46 (s, 3H), 2.39 - 2.35 (m, 2H), 2.24 - 2.18 (m, 1H), 2.08 - 2.01 (m, 4H), 1.90 - 1.81 (m, 3H), 1.62 - 1.47 (m, 4H), 1.28 - 1.25 (m, 3H), 0.75 - 0.72 (s, 1H) . 433 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.74 (d, 1H), 7.54 - 7.45 (m, 2H), 7.41 (d, 1H), 7.15 (t, 1H), 6.87 - 6.65 (m, 2H) ), 6.48 (dd, 1H), 6.27 (d, 1H), 4.66 (d, 1H), 4.40 (d, 1H), 4.03 - 3.97 (m, 3H), 3.88 (s, 2H), 3.63 (s, 3H), 3.27 - 3.22 (m, 1H), 3.21 - 3.16 (m, 1H), 3.06 (s, 3H), 2.86 (s, 3H), 2.64 - 2.58 (m, 1H), 2.58 - 2.48 (m, 6H), 2.46 - 2.40 (m, 1H), 2.35 - 2.27 (m, 3H), 2.23 - 2.17 (m, 1H), 1.92 - 1.82 (m, 2H), 1.55 - 1.46 (m, 1H), 1.38 - 1.30 (m, 4H), 1.24 - 1.13 (m, 2H), 0.85 - 0.71 (m, 1H). 434 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.12 (s, 1H), 7.74 (s, 1H), 7.53 (dd, 1H), 7.48 - 7.41 (m, 3H), 7.35 (d, 1H), 7.13 - 7.05 (m, 1H), 6.70 (d, 1H), 6.65 (d, 1H), 6.51 (t, 1H), 4.59 - 4.52 (m, 1H), 4.39 - 4.31 (m, 1H), 4.10 - 4.05 (m, 2H), 4.02 - 3.95 (m, 1H), 3.95 - 3.92 (m, 2H), 3.88 (s, 3H), 3.60 (s, 3H), 2.97 - 2.89 (m, 1H), 2.85 - 2.78 (m, 1H), 2.66 - 2.58 (m, 2H), 2.45 (s, 3H), 2.36 - 2.30 (m, 2H), 2.25 - 2.16 (m, 1H), 2.07 - 1.98 (m, 3H), 1.91 - 1.83 (m, 1H), 1.81 - 1.65 (m, 3H), 1.54 - 1.45 (m, 1H), 1.36 - 1.18 (m, 5H), 0.78 - 0.65 (m, 1H). 435 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.41 - 7.29 (m, 1H), 7.29 - 7.15 (m, 2H), 7.04 - 6.93 (m, 1H), 6.00 - 5.95 (m, 1H), 5.96 - 5.90 (m, 1H), 4.12 - 4.04 (m, 1H), 4.01 (s, 2H), 3.92 - 3.85 (m, 5H), 3.80 - 3.73 (m, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.08 (s, 3H), 2.97 - 2.87 (m, 5H), 2.74 - 2.61 (m, 1H), 2.53 - 2.43 (m, 1H), 2.42 - 2.32 (m, 2H), 2.13 - 2.05 (m, 2H), 2.00 - 1.89 (m, 2H), 1.81 (s, 3H), 1.71 - 1.62 (m, 1H), 1.56 - 1.47 (m, 2H), 1.44 - 1.34 (m, 3H) , 1.26 - 1.16 (m, 2H). 436 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 - 7.41 (m, 2H), 7.40 - 7.32 (m, 2H), 7.14 - 7.05 (m, 1H), 6.79 (s, 1H), 6.71 (s , 1H), 6.51 (d, 1H), 4.60 (d, 1H), 4.39 (d, 1H), 4.13 - 4.05 (m, 2H), 4.01 - 3.91 (m, 3H), 3.67 - 3.59 (m, 6H) ), 3.13 (s, 3H), 3.09 - 3.01 (m, 1H), 2.95 - 2.87 (m, 4H), 2.85 - 2.72 (m, 1H), 2.67 - 2.60 (m, 1H), 2.52 (s, 3H) ), 2.43 - 2.35 (m, 2H), 2.33 - 2.24 (m, 1H), 2.12 - 2.02 (m, 3H), 1.90 - 1.86 (m, 1H), 1.78 - 1.70 (m, 1H), 1.53 - 1.45 (m, 1H), 1.34 - 1.23 (m, 7H), 0.81 - 0.69 (m, 1H). 437 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.01 (s, 2H), 7.68 (d, 1H), 7.62 (dd, 1H), 7.48 - 7.40 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.71 - 6.62 (m, 2H), 6.53 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.19 (s, 2H), 4.07 - 3.96 (m, 3H), 3.60 (s, 3H), 2.91 (d, 1H), 2.80 (d, 1H), 2.65 - 2.56 (m, 2H), 2.44 (s, 3H), 2.34 - 2.27 (m, 2H), 2.22 - 2.14 (m, 1H), 2.07 - 1.97 (m, 3H), 1.89 - 1.81 (m, 1H), 1.77 - 1.64 (m, 3H), 1.52 - 1.45 (m, 1H), 1.33 - 1.28 (m, 3H), 1.25 - 1.18 (m, 2H), 0.78 - 0.62 (m, 1H). 438 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.19 (s, 1H), 7.77 (s, 1H), 7.68 (d, 1H), 7.62 (dd, 1H), 7.51 - 7.41 (m, 2H), 7.36 (d, 1H), 7.14 - 7.07 (m, 1H), 6.76 - 6.63 (m, 2H), 6.53 (d, 1H), 4.61 - 4.53 (m, 1H), 4.35 (d, 1H), 4.21 - 4.15 (m, 4H), 4.09 - 3.96 (m, 3H), 3.60 (s, 3H), 2.95 (d, 1H), 2.84 (d, 1H), 2.71 - 2.59 (m, 2H), 2.46 (s, 3H), 2.37 - 2.30 (m, 2H), 2.26 - 2.16 (m, 1H), 2.10 - 1.99 (m, 3H), 1.91 - 1.75 (m, 3H), 1.73 - 1.64 (m, 1H), 1.54 - 1.46 (m, 1H), 1.43 (t, 3H), 1.36 - 1.18 (m, 5H), 0.77 - 0.59 (m, 1H). 439 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.04 (s, 1H), 7.76 - 7.67 (m, 2H), 7.51 - 7.43 (m, 2H), 7.43 - 7.32 (m, 1H), 7.12 (t , 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.02 (dd, 1H), 5.89 (d, 1H), 4.62 (d, 1H), 4.38 (d, 1H), 4.06 (q, 2H), 4.02 - 3.93 (m, 3H), 3.89 (s, 3H), 3.84 (s, 2H), 3.61 (s, 3H), 3.24 - 3.15 (m, 1H), 3.10 - 2.94 (m, 2H) , 2.66 - 2.57 (m, 1H), 2.55 - 2.48 (m, 3H), 2.48 - 2.42 (m, 2H), 2.27 - 2.08 (m, 5H), 1.94 - 1.84 (m, 1H), 1.79 (d, 1H), 1.56 - 1.47 (m, 1H), 1.40 (t, 3H), 1.36 - 1.32 (m, 2H), 1.31 - 1.28 (m, 2H), 1.24 - 1.13 (m, 2H), 0.83 - 0.69 ( m, 1H). 440 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.66 (d, 1H), 7.39 - 7.31 (m, 1H), 7.26 - 7.16 (m, 2H), 6.98 (t, 1H), 6.28 (d, 1H) ), 4.17 - 4.12 (m, 1H), 4.10 - 4.02 (m, 3H), 3.91 (q, 2H), 3.79 - 3.73 (m, 3H), 3.65 (s, 3H), 3.49 (s, 3H), 3.14 (s, 3H), 3.11 (s, 3H), 2.92 (s, 3H), 2.91 - 2.83 (m, 2H), 2.65 - 2.56 (m, 1H), 2.51 - 2.44 (m, 1H), 2.37 - 2.29 (m, 2H), 2.05 - 1.99 (m, 2H), 1.97 - 1.89 (m, 2H), 1.86 - 1.79 (m, 1H), 1.75 - 1.67 (m, 2H), 1.54 - 1.47 (m, 2H) ), 1.41 - 1.35 (m, 3H), 1.33 (t, 3H), 1.30 - 1.28 (m, 1H), 1.26 - 1.15 (m, 2H). 441 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.53 (d, 1H), 7.48 - 7.41 (m, 2H), 7.38 - 7.32 (m, 1H), 7.14 - 7.05 (m, 1H), 6.71 - 6.62 (m, 2H), 6.32 - 6.26 (m, 1H), 4.55 (d, 1H), 4.35 (d, 1H), 4.04 (s, 2H), 4.03 - 3.97 (m, 3H), 3.91 (s, 2H ), 3.60 (s, 3H), 3.16 (s, 3H), 2.93 (d, 1H), 2.82 (d, 1H), 2.66 - 2.59 (m, 2H), 2.45 (s, 3H), 2.35 - 2.29 ( m, 2H), 2.20 - 2.17 (m, 1H), 2.15 - 2.12 (m, 3H), 2.05 - 1.99 (m, 3H), 1.89 - 1.83 (m, 1H), 1.80 - 1.71 (m, 2H), 1.69 - 1.64 (m, 1H), 1.52 - 1.47 (m, 1H), 1.42 (t, 3H), 1.35 - 1.31 (m, 3H), 1.27 - 1.23 (m, 1H), 1.20 - 1.15 (m, 1H) ), 0.78 - 0.68 (m, 1H). 442 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.67 (d, 1H), 7.51 - 7.42 (m, 2H), 7.38 (d, 1H), 7.11 (t, 1H), 6.77 (s, 1H), 6.69 (s, 1H), 6.29 (d, 1H), 4.60 (d, 1H), 4.38 (d, 1H), 4.18 - 4.10 (m, 1H), 4.09 - 4.02 (m, 2H), 4.02 - 3.96 ( m, 1H), 3.96 - 3.89 (m, 2H), 3.80 - 3.76 (m, 1H), 3.61 (s, 3H), 3.14 (s, 3H), 3.11 (s, 3H), 2.99 (d, 1H) , 2.92 (s, 4H), 2.67 - 2.59 (m, 1H), 2.49 (s, 3H), 2.45 - 2.38 (m, 2H), 2.37 - 2.28 (m, 1H), 2.19 - 2.00 (m, 5H) , 1.92 - 1.83 (m, 1H), 1.83 - 1.70 (m, 1H), 1.54 - 1.45 (m, 1H), 1.40 - 1.34 (m, 2H), 1.33 (t, 3H), 1.31 - 1.28 (m, 2H), 1.26 - 1.16 (m, 2H), 0.83 - 0.68 (m, 1H). 443 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.21 (s, 1H), 7.77 (s, 1H), 7.68 (d, 1H), 7.65 - 7.60 (m, 1H), 7.47 - 7.40 (m, 2H) ), 7.38 - 7.31 (m, 1H), 7.13 - 7.03 (m, 1H), 6.66 (d, 2H), 6.52 (d, 1H), 4.59 - 4.50 (m, 2H), 4.41 - 4.30 (m, 1H) ), 4.22 - 4.15 (m, 2H), 4.07 - 3.95 (m, 3H), 3.60 (s, 3H), 2.93 - 2.84 (m, 1H), 2.82 - 2.76 (m, 1H), 2.66 - 2.55 (m , 2H), 2.44 (s, 3H), 2.35 - 2.27 (m, 2H), 2.22 - 2.14 (m, 1H), 2.05 - 1.96 (m, 3H), 1.90 - 1.82 (m, 1H), 1.77 - 1.63 (m, 3H), 1.48 - 1.44 (m, 6H), 1.38 - 1.26 (m, 4H), 1.25 -1.16 (m, 2H), 0.79 - 0.63 (m, 1H). 444 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.56 (d, 1H), 7.50 - 7.41 (m, 2H), 7.36 - 7.34 (m, 1H), 7.11 - 7.09 (m, 1H), 6.76 - 6.60 (m, 2H), 6.05 - 5.90 (m, 2H), 4.55 (d, 1H), 4.35 (d, 1H), 4.18 (q, 2H), 4.03 - 3.89 (m, 3H), 3.79 - 3.81(m , 2H), 3.60 (s, 3H), 2.94 (m, 1H), 2.82 - 2.80 (m, 1H), 2.68 - 2.59 (m, 2H), 2.45 (s, 3H), 2.37 - 2.28 (m, 2H) ), 2.21 - 2.19 (m, 1H), 2.09 - 1.97 (m, 3H), 1.86 - 1.84 (m, 1H), 1.73 - 1.70 (m, 3H), 1.48 - 1.43 (m, 1H), 1.45 (t , 3H), 1.33 - 1.30 (m, 3H), 1.22 - 1.19 (m, 2H), 0.74 - 0.72 (m, 1H). 445 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.53 (d, 1H), 7.35 (dd, 1H), 7.30 - 7.20 (m, 2H), 6.98 (t, 1H), 6.29 (d, 1H), 4.11 - 4.06 (m, 1H), 4.05 (s, 2H), 4.00 (q, 2H), 3.92 (s, 2H), 3.76 (s, 2H), 3.65 (s, 3H), 3.50 (s, 3H) , 3.16 (s, 3H), 2.94 - 2.85 (m, 2H), 2.66 - 2.59 (m, 1H), 2.50 - 2.45 (m, 1H), 2.38 - 2.31 (m, 2H), 2.19 (t, 1H) , 2.13 (s, 3H), 2.05 - 2.01 (m, 3H), 1.96 - 1.89 (m, 2H), 1.85 - 1.79 (m, 1H), 1.75 - 1.72 (m, 1H), 1.64 - 1.59 (m, 1H), 1.54 - 1.47 (m, 2H), 1.41 (t, 3H), 1.38 - 1.34 (m, 3H), 1.22 - 1.18 (m, 1H). 446 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.09 (s, 1H), 7.77 - 7.75 (m, 2H), 7.47 - 7.40 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H) ), 6.70 - 6.62 (m, 2H), 6.56 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.24 (s, 2H), 4.09 (s, 2H), 4.02 - 3.97 ( m, 1H), 3.88 (s, 3H), 3.60 (s, 3H), 3.09 (s, 3H), 2.91 (d, 1H), 2.80 (s, 3H), 2.79 - 2.75 (m, 1H), 2.65 - 2.58 (m, 2H), 2.44 (s, 3H), 2.35 - 2.28 (m, 2H), 2.25 - 2.17 (m, 1H), 2.10 - 1.92 (m, 3H), 1.88 - 1.79 (m, 1H) , 1.78 - 1.64 (m, 3H), 1.53 - 1.43 (m, 1H), 1.39 - 1.17 (m, 5H), 0.76 - 0.68 (m, 1H). 447 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.96 (d, 1H), 7.53 - 7.35 (m, 3H), 7.15 - 7.13 (m, 1H), 6.87 (s, 1H), 6.74 (s, 1H) ), 6.42 (d, 1H), 4.68 - 4.60 (m, 3H), 4.42 - 4.38 (m, 1H), 4.20 (s, 2H), 4.13 - 3.93 (m, 3H), 3.67 - 3.65 (m, 3H) ), 3.41 - 3.38 (m, 1H), 3.32 (s, 3H), 3.25 - 3.21 (m, 1H), 2.72 - 2.51 (m, 6H), 2.49 - 2.40 (m, 4H), 2.39 - 2.28 (m , 1H), 2.20 - 2.17 (m, 1H), 1.95 - 1.82 (m, 2H), 1.55 - 1.43 (m, 2H), 1.42 - 1.28 (m, 3H), 1.26 - 1.15 (m, 2H), 0.94 - 0.78 (m, 1H). 448 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.61 (d, 1H), 7.79 - 7.70 (m, 3H), 7.66 (dd, 1H), 7.43 - 7.34 (m, 1H), 7.28 - 7.17 (m , 2H), 7.02 (td, 1H), 6.49 (d, 2H), 4.09 (q, 1H), 4.04 (s, 2H), 3.92 (s, 2H), 3.88 - 3.76 (m, 2H), 3.67 ( s, 3H), 3.64 - 3.55 (m, 1H), 3.47 (s, 5H), 2.77 (t, 1H), 2.70 - 2.58 (m, 6H), 2.55 - 2.46 (m, 1H), 2.39 (dd, 2H), 2.31 - 2.17 (m, 2H), 1.95 (d, 1H), 1.92 - 1.81 (m, 1H), 1.70 - 1.27 (m, 7H). 449 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.63 (d, 1H), 8.54 (s, 1H), 7.93 (d, 1H), 7.68 (d, 2H), 7.43 - 7.35 (m, 1H), 7.28 - 7.17 (m, 2H), 7.02 (td, 1H), 6.49 (d, 2H), 4.13 - 4.06 (m, 1H), 4.05 (s, 2H), 3.93 (s, 2H), 3.88 - 3.76 ( m, 2H), 3.67 (s, 3H), 3.63 - 3.55 (m, 1H), 3.54 - 3.40 (m, 5H), 2.77 (t, 1H), 2.69 - 2.59 (m, 3H), 2.55 - 2.37 ( m, 6H), 2.31 - 2.17 (m, 2H), 1.95 (d, 1H), 1.91 - 1.81 (m, 1H), 1.70 - 1.28 (m, 7H). 450 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.10 (s, 1H), 7.77 (s, 1H), 7.66 (d, 1H), 7.55 - 7.37 (m, 3H), 7.20 - 7.13 (d, 1H) ), 6.84 (s, 1H), 6.72 (s, 1H), 6.56 (t, 1H), 4.62 (d, 1H), 4.41 (d, 1H), 4.14 (s, 2H), 4.02 (s, 2H) , 4.01 - 3.95 (m, 1H), 3.88 (s, 3H), 3.61 (s, 3H), 3.25 - 3.18 (m, 1H), 3.10 (s, 3H), 3.09 - 3.00 (m, 2H), 2.87 (s, 3H), 2.67 - 2.61 (m, 1H), 2.55 - 2.43 (m, 5H), 2.42 - 2.35 (m, 1H), 2.30 - 2.10 (m, 5H), 1.90 - 1.82 (m, 2H) , 1.53 - 1.49 (s, 1H), 1.38 - 1.32 (m, 3H), 1.30 - 1.10 (m, 2H), 0.90 - 0.81 (m, 1H). 451 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.93 (d, 1H), 7.38 - 7.31 (m, 1H), 7.27 - 7.15 (m, 2H), 7.01 - 6.94 (m, 1H), 6.32 - 6.25 (m, 1H), 4.12 (s, 2H), 4.09 - 4.02 (m, 1H), 3.98 (s, 2H), 3.83 - 3.74 (m, 4H), 3.65 (s, 3H), 3.49 (s, 3H) ), 3.26 (s, 3H), 2.96 - 2.84 (m, 2H), 2.69 - 2.59 (m, 1H), 2.53 - 2.44 (m, 1H), 2.42 - 2.33 (m, 2H), 2.28 (s, 6H) ), 2.10 - 2.02 (m, 2H), 1.99 - 1.89 (m, 2H), 1.88 - 1.80 (m, 1H), 1.80 - 1.71 (m, 2H), 1.69 - 1.62 (m, 1H), 1.55 - 1.46 (m, 2H), 1.43 - 1.32 (m, 3H), 1.28 - 1.16 (m, 2H). 452 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.93 (d, 1H), 7.50 - 7.40 (m, 2H), 7.39 - 7.31 (m, 1H), 7.13 - 7.05 (m, 1H), 6.71 - 6.61 (m, 2H), 6.29 (d, 1H), 4.59 - 4.50 (m, 1H), 4.42 - 4.31 (m, 1H), 4.11 (s, 2H), 4.04 - 3.98 (m, 1H), 3.97 (s , 2H), 3.79 (s, 2H), 3.60 (s, 3H), 3.26 (s, 3H), 2.95 - 2.88 (m, 1H), 2.85 - 2.78 (m, 1H), 2.66 - 2.58 (m, 2H) ), 2.45 (s, 3H), 2.36 - 2.30 (m, 2H), 2.27 (s, 6H), 2.23 - 2.14 (m, 1H), 2.10 - 1.98 (m, 3H), 1.92 - 1.82 (m, 1H) ), 1.80 - 1.64 (m, 3H), 1.54 - 1.44 (m, 1H), 1.42 - 1.26 (m, 3H), 1.25 - 1.14 (m, 2H), 0.80 - 0.63 (m, 1H). 455 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.49 - 7.40 (m, 3H), 7.36 (d, 1H), 7.09 (t, 1H), 6.71 - 6.61 (m, 2H), 6.46 (d, 1H) ), 4.55 (d, 1H), 4.35 (d, 1H), 4.10 (s, 2H), 4.01 - 3.87 (m, 3H), 3.60 (s, 3H), 3.13 (s, 3H), 2.94 (d, 1H), 2.87 (s, 3H), 2.83 (d, 1H), 2.66 - 2.53 (m, 3H), 2.45 (s, 3H), 2.41 - 2.31 (m, 3H), 2.24 - 2.16 (m, 1H) , 2.11 - 1.92 (m, 3H), 1.90 - 1.82 (m, 1H), 1.78 - 1.68 (m, 3H), 1.53 - 1.44 (m, 1H), 1.35 - 1.17 (m, 5H), 1.09 (t, 3H), 0.80 - 0.67 (m, 1H). 456 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.43 (d, 1H), 7.34 - 7.25 (m, 3H), 6.93 (t, 1H), 6.47 (d, 1H), 4.12 (s, 2H), 4.01 - 3.96 (m, 3H), 3.55 (s, 3H), 3.13 (s, 3H), 3.00 - 2.85(m, 4H), 2.87 (s, 3H), 2.63 - 2.51 (m, 2H), 2.37 - 2.31 (m, 2H), 2.16 (s, 6H), 2.09 (s, 3H), 2.05 - 1.82 (m, 4H), 1.75 - 1.65 (m, 5H), 1.60 - 1.33 (m, 5H), 1.25 - 1.21 (m, 1H). 459 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.59 - 7.51 (m, 1H), 7.50 - 7.40 (m, 3H), 7.34 (s, 1H), 7.21 (t, 1H), 6.99 (s, 1H) ), 6.49 (d, 1H), 4.80 - 4.75 (m, 1H), 4.65 - 4.54 (m, 1H), 4.20 - 4.15 (m, 2H), 4.03 (s, 2H), 3.96 (s, 1H), 3.64 - 3.54 (m, 2H), 3.41 (d, 1H), 3.14 (s, 3H), 2.86 (s, 3H), 2.72 (s, 3H), 2.70 - 2.60 (m, 5H), 2.51 - 2.41 ( m, 2H), 2.31 (d, 1H), 2.09 (s, 3H), 2.08 - 2.00 (m, 1H), 1.94 - 1.89 (m, 1H), 1.63 - 1.51 (m, 2H), 1.33 - 1.27 ( m, 4H), 1.22 (s, 1H), 1.01 - 0.91 (m, 1H). 471 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 (d, 1H), 7.40 - 7.31 (m, 1H), 7.28 - 7.15 (m, 2H), 7.02 - 6.95 (m, 1H), 6.44 (d , 1H), 4.49 (s, 2H), 4.19 (s, 2H), 4.12 - 4.01 (m, 3H), 3.76 (s, 2H), 3.66 (s, 3H), 3.50 (s, 3H), 3.15 ( s, 3H), 2.95 - 2.84 (m, 2H), 2.70 - 2.59 (m, 1H), 2.53 - 2.44 (m, 1H), 2.43 - 2.34 (m, 2H), 2.10 - 2.03 (m, 2H), 2.00 - 1.89 (m, 2H), 1.88 - 1.80 (m, 1H), 1.79 - 1.70 (m, 2H), 1.69 - 1.63 (m, 1H), 1.57 - 1.46 (m, 2H), 1.45 - 1.34 (m , 3H), 1.27 - 1.14 (m, 2H). 472 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.53 (d, 1H), 7.48 - 7.41 (m, 2H), 7.40 - 7.33 (m, 1H), 7.12 - 7.06 (m, 1H), 6.72 - 6.62 (m, 2H), 6.46 (d, 1H), 4.58 - 4.53 (m, 1H), 4.51 (s, 2H), 4.39 - 4.33 (m, 1H), 4.18 (s, 2H), 4.05 (s, 2H) ), 4.03 - 3.96 (m, 1H), 3.61 (s, 3H), 3.16 (s, 3H), 2.95 - 2.90 (m, 1H), 2.85 - 2.78 (m, 1H), 2.66 - 2.59 (m, 2H) ), 2.45 (s, 3H), 2.39 - 2.33 (m, 2H), 2.24 - 2.17 (m, 1H), 2.10 - 2.00 (m, 3H), 1.89 - 1.83 (m, 1H), 1.79 - 1.71 (m , 2H), 1.70 - 1.65 (m, 1H), 1.53 - 1.47 (m, 1H), 1.40 - 1.31 (m, 3H), 1.25 - 1.15 (m, 2H), 0.78 - 0.66 (m, 1H). 474 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.24 (s, 1H), 8.05 - 7.95 (m, 1H), 7.83 (s, 1H), 7.49 - 7.41 (m, 2H), 7.39 - 7.33 (m , 1H), 7.14 - 7.05 (m, 1H), 6.67 (d, 2H), 6.53 - 6.45 (m, 1H), 4.57 - 4.54 (m, 1H), 4.48 (s, 2H), 4.38 - 4.32 (m , 1H), 4.17 (s, 2H), 4.04 (s, 2H), 4.01 - 3.97 (m, 1H), 3.87 (s, 3H), 3.60 (s, 3H), 3.11 (s, 3H), 2.94 - 2.90 (m, 1H), 2.84 - 2.79 (m, 1H), 2.66 - 2.59 (m, 2H), 2.45 (s, 3H), 2.38 - 2.32 (m, 2H), 2.20 - 2.17 (m, 1H), 2.07 - 2.01 (m, 3H), 1.91 - 1.85 (m, 1H), 1.78 - 1.68 (m, 3H), 1.61 - 1.55 (m, 1H), 1.38 - 1.33 (m, 3H), 1.23 - 1.13 (m , 2H), 0.77 - 0.67 (m, 1H). 475 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.30 (s, 1H), 8.09 - 8.04 (m, 1H), 7.89 (s, 1H), 7.50 - 7.40 (m, 2H), 7.39 - 7.31 (m , 1H), 7.13 - 7.05 (m, 1H), 6.72 - 6.62 (m, 3H), 4.55 (d, 1H), 4.49 - 4.33 (m, 3H), 4.28 - 4.10 (m, 2H), 4.03 - 3.96 (m, 1H), 3.89 (s, 3H), 3.64 (s, 3H), 3.02 (s, 3H), 2.95 - 2.89 (m, 1H), 2.84 - 2.78 (m, 1H), 2.66 - 2.56 (m , 2H), 2.45 (s, 3H), 2.37 - 2.30 (m, 2H), 2.23 - 2.15 (m, 1H), 2.09 - 1.98 (m, 3H), 1.91 - 1.83 (m, 1H), 1.78 - 1.63 (m, 3H), 1.53 - 1.44 (m, 1H), 1.43 - 1.28 (m, 3H), 1.24 - 1.13 (m, 2H), 0.82 - 0.66 (m, 1H). 476 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.62 (d, 1H), 7.54 - 7.47 (m, 2H), 7.44 (d, 1H), 7.19 - 7.14 (m, 1H), 7.02 (s, 1H) ), 6.81 (s, 1H), 6.42 (d, 1H), 4.73 (d, 1H), 4.58 (s, 2H), 4.51 - 4.41 (m, 3H), 4.17 (s, 2H), 4.07 (s, 2H), 3.99 - 3.93 (m, 1H), 3.64 (s, 3H), 3.50 - 3.41 (m, 1H), 3.28 - 3.22 (m, 1H), 3.05 (s, 3H), 2.92 (s, 3H) , 2.66 (s, 3H), 2.60 - 2.55 (m, 3H), 2.50 - 2.47 (m, 1H), 2.27 (d, 1H), 2.02 - 1.80 (m, 3H), 1.64 - 1.46 (m, 3H) , 1.41 - 1.30 (m, 5H), 1.23 - 1.15 (m, 2H), 0.93 - 0.87 (m, 1H). 477 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.56 (d, 1H), 7.52 - 7.45 (m, 2H), 7.43 - 7.38 (m, 1H), 7.18 - 7.12 (m, 1H), 6.88 (s , 1H), 6.75 (s, 1H), 6.55 - 6.42 (m, 1H), 4.72 - 4.60 (m, 2H), 4.46 (s, 2H), 4.43 - 4.37 (m, 1H), 4.22 (s, 2H ), 4.09 (s, 2H), 4.03 - 3.97 (m, 1H), 3.63 (s, 3H), 3.21 - 3.09 (m, 2H), 2.64 - 2.57 (m, 2H), 2.54 (s, 3H), 2.35 - 2.25 (m, 3H), 2.25 - 2.13 (m, 2H), 2.09 - 1.96 (m, 1H), 1.95 - 1.72 (m, 3H), 1.55 - 1.49 (m, 1H), 1.43 - 1.35 (m , 2H), 1.28 - 1.11 (m, 3H), 0.84 - 0.70 (m, 1H). 478 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.11 (s, 1H), 7.71 (s, 1H), 7.63 (d, 1H), 7.48 - 7.40 (m, 2H), 7.39 - 7.32 (m, 1H) ), 7.09 (t, 1H), 6.72 - 6.60 (m, 2H), 6.31 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.05 (s, 4H), 4.00 - 3.95 ( m, 1H), 3.91 (d, 4H), 3.88 (s, 3H), 3.60 (s, 3H), 2.94 - 2.88 (m, 1H), 2.82 -2.77 (m, 1H), 2.65 - 2.58 (m, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.34 - 2.28 (m, 2H), 2.21 - 2.17 (m, 1H), 2.05 - 2.00 (m, 3H), 1.89 - 1.82 (m, 1H), 1.76 - 1.68 (m, 2H), 1.64 - 1.59(m, 1H), 1.51 - 1.45 (m, 1H), 1.35 - 1.31 (m, 4H), 1.19 - 1.14 (m, 1H), 0.77 - 0.65 (m, 1H). 479 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.89 - 7.82 (m, 1H), 7.49 - 7.40 (m, 2H), 7.40 - 7.32 (m, 1H), 7.13 - 7.06 (m, 1H), 6.74 - 6.61 (m, 2H), 6.54 - 6.44 (m, 1H), 4.59 - 4.52 (m, 3H), 4.39 - 4.32 (m, 1H), 4.19 (s, 2H), 4.06 (s, 2H), 4.03 - 3.96 (m, 1H), 3.61 (s, 3H), 3.42 (s, 3H), 3.15 (s, 3H), 2.96 - 2.90 (m, 1H), 2.85 - 2.78 (m, 1H), 2.68 - 2.60 (m, 2H), 2.45 (s, 3H), 2.40 - 2.33 (m, 2H), 2.23 - 2.17 (m, 1H), 2.09 - 1.99 (m, 3H), 1.92 - 1.85 (m, 1H), 1.78 - 1.64 (m, 3H), 1.54 - 1.47 (m, 1H), 1.37 - 1.31 (m, 3H), 1.25 - 1.15 (m, 2H), 0.78 - 0.64 (m, 1H). 480 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.96 - 7.89 (m, 1H), 7.51 - 7.42 (m, 2H), 7.38 - 7.33 (m, 1H), 7.14 - 7.06 (m, 1H), 6.73 - 6.64 (m, 3H), 4.60 - 4.53 (m, 3H), 4.40 - 4.33 (m, 2H), 4.27 - 4.20 (m, 1H), 4.02 - 3.96 (m, 1H), 3.61 (s, 3H) , 3.38 (s, 3H), 3.06 (s, 3H), 2.97 - 2.91 (m, 1H), 2.81 - 2.78 (m, 1H), 2.67 - 2.59 (m, 2H), 2.45 (s, 3H), 2.38 - 2.32 (m, 2H), 2.22 - 2.16 (m, 1H), 2.09 - 2.00 (m, 3H), 1.90 - 1.84 (m, 1H), 1.80 - 1.66 (m, 3H), 1.53 - 1.46 (m, 1H), 1.38 - 1.32 (m, 3H), 1.24 - 1.13 (m, 2H), 0.79 - 0.66 (m, 1H). 481 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 - 7.46 (m, 2H), 7.35 (d, 2H), 7.13 - 7.10 (m, 1H), 6.71 (d, 1H), 6.66 (s, 1H) ), 6.26 (d, 1H), 4.56 (d, 1H), 4.36 (d, 1H), 4.08 (s, 2H), 4.03 (s, 2H), 4.00 (s, 3H), 3.94 (s, 2H) , 3.60 (s, 3H), 2.98 (d, 1H), 2.90 - 2.80 (m, 2H), 2.70 - 2.60 (m, 2H), 2.46 (s, 3H), 2.38 - 2.30 (m, 2H), 2.29 - 2.20 (m, 1H), 2.11 - 1.97 (m, 3H), 1.80 - 1.78 (m, 3H), 1.69 (m, 1H), 1.52 - 1.47 (m, 1H), 1.35 - 1.24 (m, 5H) , 1.20 (d, 6H), 0.80 - 0.72 (m, 1H). 487 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.50 - 7.39 (m, 3H), 7.36 - 7.25 (m, 1H), 7.13 - 7.03 (m, 1H), 6.06 (dd, 1H), 6.02 - 5.97 (m, 1H), 4.76 - 4.62 (m, 1H), 4.16 - 4.09 (m, 1H), 4.06 (s, 1H), 3.99 - 3.86 (m, 3H), 3.80 - 3.69 (m, 2H), 3.69 - 3.62 (m, 4H), 3.62 - 3.53 (m, 2H), 3.53 - 3.42 (m, 2H), 2.89 - 2.75 (m, 1H), 2.75 - 2.53 (m, 4H), 2.53 - 2.39 (m, 3H), 2.39 - 2.14 (m, 2H), 2.11 - 1.99 (m, 1H), 1.90 (s, 4H), 1.60 - 1.45 (m, 2H), 1.45 - 1.33 (m, 9H). 490 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.48 - 7.30 (m, 6H), 6.99 (t, 1H), 6.41 (d, 2H), 5.98 (s, 1H), 4.14 - 3.99 (m, 1H) ), 3.95 (s, 2H), 3.80 (s, 2H), 3.49 (s, 3H), 3.43 - 3.38 (m, 1H), 3.30 - 3.26 (m, 2H), 2.93 - 2.75 (m, 2H), 2.72 - 2.58 (m, 2H), 2.36 - 2.27 (m, 2H), 2.09 - 1.99 (m, 3H), 1.93 - 1.85 (m, 1H), 1.81 - 1.69 (m, 3H), 1.61 - 1.53 (m , 1H), 1.47 - 1.42 (m, 1H), 1.33 - 1.28 (m, 2H), 1.24 - 1.15 (m, 2H), 1.10 - 1.03 (m, 1H). 493 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.47 - 7.35 (m, 2H), 7.30 - 7.20 (m, 2H), 7.01 (t, 1H), 6.50 (d, 1H), 4.21 - 4.13 (m , 2H), 4.12 - 4.01 (m, 3H), 3.86 - 3.75 (m, 2H), 3.60 - 3.50 (m, 1H), 3.49 (s, 3H), 3.46 - 3.40 (s, 1H), 3.15 (s , 3H), 2.88 (s, 3H), 2.81 - 2.72 (m, 1H), 2.67 - 2.55 (m, 3H), 2.53 - 2.45 (m, 3H), 2.30 - 2.14 (m, 2H), 2.10 (s , 3H), 1.93 - 1.85 (m, 2H), 1.75 - 1.63 (m, 1H), 1.58 - 1.37 (m, 5H), 1.31 - 1.22 (m, 2H). 494 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.55 (d, 1H), 7.46 - 7.32 (m, 3H), 7.07-7.02 (m, 1H), 6.51 (dd, 1H), 6.40 (d, 1H) ), 4.24 - 3.92 (m, 7H), 3.86 - 3.34 (m, 10H), 3.13 (s, 3H), 2.95 (s, 3H), 2.86-2.80 (m, 3H), 2.70-2.62 (m, 4H) ), 2.50 - 2.21 (m, 4H), 2.10 - 1.86 (m, 2H), 1.72 - 1.20 (m, 7H). 497 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.52 (d, 1H), 7.47 - 7.30 (m, 3H), 7.12 - 6.96 (m, 1H), 6.63 - 6.48 (m, 1H), 6.31 (d , 1H), 4.32 - 3.80 (m, 8H), 3.80 - 3.44 (m, 9H), 3.09 (s, 3H), 2.87-2.85 (m, 6H), 2.70-2.62 (m, 4H), 2.50 - 2.20 (m, 4H), 2.12 - 1.84 (m, 2H), 1.71 - 1.20 (m, 7H). 498 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.43 (d, 1H), 7.40 - 7.31 (m, 3H), 6.98 (t, 1H), 6.47 (d, 1H), 4.13 - 4.09 (d, 3H) ), 4.04 - 3.97 (m, 3H), 3.71 (s, 3H), 3.55 (s, 3H), 3.13 (s, 3H), 2.96 - 2.89 (m, 2H), 2.87 (s, 3H), 2.77 ( s, 3H), 2.70 - 2.61 (m, 2H), 2.39 - 2.31 (m, 2H), 2.09 (s, 3H), 2.07 - 2.00 (m, 3H), 1.95 - 1.90 (m, 1H), 1.81 - 1.71 (m, 3H), 1.60 - 1.46 (m, 3H), 1.33 - 1.29 (m, 5H), 1.24 - 1.16 (m, 1H). 505 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.49 - 7.39 (m, 2H), 7.35 (d, 1H), 7.20 (s, 1H), 7.12 - 7.05 (m, 1H), 6.73 - 6.60 (m , 2H), 4.54 (d, 1H), 4.41 - 4.29 (m, 3H), 4.18 (s, 2H), 4.05 - 3.94 (m, 1H), 3.63 (s, 3H), 3.12 (s, 3H), 2.94 - 2.78 (m, 5H), 2.67 - 2.55 (m, 2H), 2.44 (s, 3H), 2.33 - 2.27 (m, 5H), 2.23 - 2.15 (m, 1H), 2.09 (s, 3H), 2.03 - 1.93 (m, 3H), 1.89 - 1.82 (m, 1H), 1.78 - 1.64 (m, 3H), 1.53 - 1.45 (m, 1H), 1.36 - 1.16 (m, 5H), 0.80 - 0.64 (m , 1H). 506 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.41 - 7.32 (m, 1H), 7.28 - 7.16 (m, 3H), 7.03 - 6.95 (m, 1H), 4.34 (s, 2H), 4.21 (s , 2H), 4.12 - 4.05 (m, 1H), 3.82 - 3.74 (m, 2H), 3.66 (s, 3H), 3.49 (s, 3H), 3.18 - 3.02 (m, 5H), 2.86 (s, 3H) ), 2.51 - 2.38 (m, 3H), 2.29 (s, 3H), 2.13 - 2.01 (m, 7H), 1.86 - 1.72 (m, 2H), 1.55 - 1.37 (m, 5H), 1.35 - 1.20 (m , 5H). 508 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 - 7.42 (m, 2H), 7.36 (d, 1H), 7.21 (d, 1H), 7.14 - 7.07 (m, 1H), 6.73 (s, 1H) ), 6.67 (s, 1H), 4.57 (d, 1H), 4.41 - 4.30 (m, 3H), 4.20 (s, 2H), 4.04 - 3.94 (m, 1H), 3.60 (s, 3H), 3.57 ( s, 2H), 3.09 - 2.96 (m, 1H), 2.95 - 2.85 (m, 1H), 2.81 - 2.71 (m, 1H), 2.70 - 2.49 (m, 2H), 2.46 (s, 3H), 2.42 - 2.34 (m, 2H), 2.28 (s, 6H), 2.25 - 2.14 (m, 1H), 2.11 - 2.01 (m, 3H), 1.95 - 1.78 (m, 3H), 1.77 - 1.67 (m, 1H), 1.64 - 1.44 (m, 2H), 1.40 - 1.34 (m, 2H), 1.00 - 0.86 (m, 1H), 0.80 - 0.59 (m, 1H). 509 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.58 (d, 2H), 7.44 (m, 2H), 7.36 (d, 1H), 7.09 (t, 1H), 6.67 (dd, 2H), 6.49 ( d, 2H), 4.55 (d, 1H), 4.35 (d, 1H), 4.03 - 3.92 (m, 5H), 3.85 (s, 2H), 3.60 (s, 3H), 3.33 (m, 3H), 3.24 - 3.18 (m, 1H), 2.93 (d, 1H), 2.82 (d, 1H), 2.62 (m, 2H), 2.45 (s, 3H), 2.34 (m, 2H), 2.20 (t, 1H), 2.11 - 1.98 (m, 3H), 1.79 (m, 4H), 1.65 (m, 3H), 1.54 - 1.44 (m, 1H), 1.38 - 1.17 (m, 5H), 0.75 - 0.70 (m, 1H). 511 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.67 (s, 2H), 7.62 (dd, 1H), 7.47 - 7.40 (m, 2H), 7.35 (d, 1H), 7.14 - 7.05 (m, 1H) ), 6.73 - 6.62 (m, 3H), 6.53 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.20 (s, 2H), 4.06 (s, 2H), 4.02 - 3.95 ( m, 1H), 3.91 (s, 3H), 3.60 (s, 3H), 2.91 (d, 1H), 2.80 (d, 1H), 2.66 - 2.56 (m, 2H), 2.44 (s, 3H), 2.35 - 2.28 (m, 2H), 2.21 - 2.16 (m, 1H), 2.09 - 1.95 (m, 4H), 1.90 - 1.82 (m, 1H), 1.78 - 1.52 (m, 4H), 1.52 - 1.42 (m, 1H), 1.26 - 1.12 (m, 3H), 0.79 - 0.62 (m, 1H). 512 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.78 (d, 1H), 7.65 - 7.49 (m, 3H), 7.38 - 7.30 (m, 2H), 7.27 - 7.16 (m, 2H), 6.98 (t , 1H), 6.05 (dd, 1H), 5.82 (d, 1H), 4.65 - 4.61 (m, 1H), 4.12 - 4.04 (m, 1H), 3.99 - 3.91 (m, 4H), 3.82 (s, 2H ), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 2.95 - 2.82 (m, 2H), 2.72 - 2.59 (m, 1H), 2.51 - 2.43 (m, 1H), 2.39 - 2.29 (m, 2H), 2.08 - 2.01 (m, 2H), 1.97 - 1.88 (m, 2H), 1.85 - 1.70 (m, 3H), 1.69 - 1.62 (m, 1H), 1.54 - 1.46 (m , 2H), 1.42 - 1.32 (m, 3H), 1.26 (t, 3H), 1.21 - 1.16 (m, 1H). 513 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.78 (d, 1H), 7.68 - 7.61 (m, 1H), 7.61 - 7.56 (m, 1H), 7.56 - 7.49 (m, 1H), 7.48 - 7.40 (m, 2H), 7.39 - 7.27 (m, 2H), 7.14 - 7.04 (m, 1H), 6.76 - 6.57 (m, 2H), 6.05 (dd, 1H), 5.82 (d, 1H), 4.63 - 4.50 (m, 2H), 4.35 (d, 1H), 4.03 - 3.91 (m, 5H), 3.81 (s, 2H), 3.60 (s, 3H), 2.94 (d, 1H), 2.83 (d, 1H), 2.68 - 2.58 (m, 2H), 2.45 (s, 3H), 2.36 - 2.29 (m, 2H), 2.22 - 2.17 (m, 1H), 2.07 - 2.00 (m, 3H), 1.87 - 1.65 (m, 4H) ), 1.52 - 1.44 (m, 1H), 1.30 - 1.28 (m, 3H), 1.25 (t, 3H), 1.23 - 1.18 (m, 1H), 0.78 - 0.64 (m, 1H). 514 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.82 - 7.73 (m, 2H), 7.71 - 7.65 (m, 1H), 7.57 - 7.49 (m, 1H), 7.48 - 7.39 (m, 2H), 7.38 - 7.29 (m, 2H), 7.13 - 7.05 (m, 1H), 6.74 - 6.59 (m, 2H), 6.51 - 6.44 (m, 1H), 6.21 - 6.17 (m, 1H), 4.61 - 4.50 (m, 1H), 4.41 - 4.29 (m, 1H), 4.03 - 3.94 (m, 3H), 3.84 (s, 2H), 3.59 (s, 3H), 3.09 (s, 3H), 2.97 - 2.89 (m, 1H) , 2.83 (s, 3H), 2.82 - 2.76 (m, 1H), 2.66 - 2.57 (m, 2H), 2.45 (s, 3H), 2.36 - 2.29 (m, 2H), 2.24 - 2.15 (m, 1H) , 2.08 - 1.98 (m, 3H), 1.90 - 1.82 (m, 1H), 1.79 - 1.63 (m, 3H), 1.54 - 1.45 (m, 1H), 1.38 - 1.25 (m, 3H), 1.25 - 1.15 ( m, 2H), 0.78 - 0.60 (m, 1H). 515 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.81 - 7.72 (m, 2H), 7.71 - 7.66 (m, 1H), 7.57 - 7.49 (m, 1H), 7.38 - 7.29 (m, 2H), 7.25 - 7.15 (m, 2H), 7.01 - 6.94 (m, 1H), 6.51 - 6.44 (m, 1H), 6.22 - 6.14 (m, 1H), 4.11 - 4.02 (m, 1H), 3.99 (s, 2H) , 3.85 (s, 2H), 3.78 - 3.72 (m, 2H), 3.64 (s, 3H), 3.49 (s, 3H), 3.09 (s, 3H), 2.93 - 2.84 (m, 2H), 2.83 (s , 3H), 2.67 - 2.57 (m, 1H), 2.52 - 2.43 (m, 1H), 2.38 - 2.29 (m, 2H), 2.10 - 1.98 (m, 2H), 1.96 - 1.88 (m, 2H), 1.87 - 1.80 (m, 1H), 1.76 - 1.61 (m, 3H), 1.52 - 1.43 (m, 2H), 1.41 - 1.29 (m, 3H), 1.26 - 1.14 (m, 2H). 516 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.39 - 7.31 (m, 1H), 7.26 - 7.15 (m, 2H), 6.98 (t, 1H), 6.16 (s, 1H), 4.19 (s, 2H) ), 4.06 (s, 2H), 3.79 - 3.73 (m, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.10 (s, 3H), 2.98 - 2.88 (m, 5H), 2.75 - 2.59 (m, 1H), 2.50 - 2.43 (m, 1H), 2.40 - 2.32 (m, 2H), 2.16 (d, 3H), 2.09 - 2.01 (m, 2H), 1.99 - 1.90 (m, 2H), 1.88 - 1.72 (m, 3H), 1.67 (d, 1H), 1.55 - 1.47 (m, 2H), 1.45 - 1.28 (m, 4H), 1.26 - 1.15 (m, 2H). 517 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.48 - 7.41 (m, 2H), 7.36 (d, 1H), 7.13 - 7.07 (m, 1H), 6.76 - 6.63 (m, 2H), 6.16 (s , 1H), 4.56 (d, 1H), 4.35 (d, 1H), 4.18 (s, 2H), 4.05 (s, 2H), 4.02 - 3.92 (m, 1H), 3.60 (s, 3H), 3.11 - 3.08 (m, 3H), 2.95 - 2.93 (m, 4H), 2.85 - 2.80 (m, 1H), 2.67 - 2.57 (m, 2H), 2.45 (s, 3H), 2.38 - 2.30 (m, 2H), 2.21 - 2.13 (m, 4H), 2.07 - 1.99 (m, 4H), 1.87 - 1.73 (m, 3H), 1.70 - 1.56 (m, 2H), 1.51 - 1.45 (m, 1H), 1.25 - 1.12 (m , 3H), 0.77 - 0.65 (m, 1H). 520 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.73 (s, 1H), 7.63 - 7.55 (m, 2H), 7.48 - 7.39 (m, 2H), 7.35 (d, 1H), 7.13 - 7.06 (m , 1H), 6.71 - 6.61 (m, 2H), 6.52 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.18 (s, 2H), 4.04 (s, 2H), 4.02 - 3.96 (m, 1H), 3.76 (s, 3H), 3.60 (s, 3H), 2.93 - 2.86 (m, 1H), 2.83 - 2.75 (m, 1H), 2.65 - 2.55 (m, 2H), 2.44 ( s, 3H), 2.41 (s, 3H), 2.35 - 2.28 (m, 2H), 2.23 - 2.13 (m, 1H), 2.04 - 1.97 (m, 3H), 1.91 - 1.82 (m, 1H), 1.77 - 1.61 (m, 3H), 1.54 - 1.44 (m, 1H), 1.37 - 1.27 (m, 3H), 1.25 - 1.16 (m, 2H), 0.80 - 0.64 (m, 1H). 521 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.63 - 7.51 (m, 2H), 7.49 - 7.40 (m, 2H), 7.35 (d, 1H), 7.09 (t, 1H), 6.74 - 6.61 (m , 2H), 6.53 (d, 1H), 4.54 (d, 1H), 4.35 (d, 1H), 4.18 (s, 2H), 4.09 - 3.93 (m, 3H), 3.70 (s, 3H), 3.63 ( s, 3H), 2.93 (d, 1H), 2.80 (d, 1H), 2.70 - 2.56 (m, 2H), 2.48 (s, 3H), 2.43 (s, 3H), 2.35 - 2.25 (m, 5H) , 2.19 (t, 1H), 2.12 - 1.96 (m, 3H), 1.89 - 1.83 (m, 1H), 1.78 - 1.62 (m, 3H), 1.52 - 1.46 (m, 1H), 1.38 - 1.18 (m, 5H), 0.77 - 0.70 (m, 1H). 526 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.44 - 7.33 (m, 1H), 7.29 - 7.20 (m, 2H), 7.02 - 6.95 (m, 1H), 6.24 (d, 1H), 4.18 (s , 2H), 4.13 - 4.05 (m, 3H), 3.76 (s, 2H), 3.65 (s, 3H), 3.49 (s, 3H), 3.12 (s, 3H), 3.00 - 2.96 (m, 1H), 2.89 (s, 3H), 2.70 - 2.64 (m, 1H), 2.49 - 2.46 (m, 1H), 2.40 - 2.35 (m, 2H), 2.14 - 2.02 (m, 5H), 1.99 - 1.85 (m, 2H) ), 1.83 - 1.75 (m, 3H), 1.69 - 1.65 (m, 1H), 1.52 - 1.48 (m, 2H), 1.48 - 1.32 (m, 3H), 1.29 - 1.21 (m, 3H). 538 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.76 (d, 1H), 7.55 (q, 1H), 7.51 - 7.41 (m, 2H), 7.32 (d, 1H), 7.20 (t, 1H), 6.97 (s, 1H), 6.56 (dd, 1H), 6.31 (d, 1H), 4.57 (d, 1H), 4.16 (s, 2H), 4.02 (s, 2H), 4.00 - 3.94 (m, 1H) , 3.70 - 3.53 (m, 5H), 3.41 (d, 1H), 3.04 (s, 3H), 2.82 (s, 3H), 2.79 - 2.59 (m, 8H), 2.53 (q, 2H), 2.32 (d , 1H), 2.01 (d, 1H), 1.98 - 1.87 (m, 1H), 1.65 - 1.49 (m, 2H), 1.45 - 1.33 (m, 2H), 1.32 - 1.16 (m, 3H), 1.02 - 0.86 (m, 1H). 539 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.73 (d, 2H), 7.59 - 7.51 (m, 1H), 7.51 - 7.41 (m, 2H), 7.33 (s, 1H), 7.21 (t, 1H) ), 6.98 (s, 1H), 6.54 (d, 2H), 4.58 (d, 1H), 4.13 (s, 2H), 4.00 (s, 3H), 3.69 - 3.53 (m, 5H), 3.42 (d, 1H), 2.87 - 2.59 (m, 9H), 2.52 (q, 2H), 2.32 (d, 1H), 2.02 (d, 1H), 1.99 - 1.88 (m, 1H), 1.65 - 1.49 (m, 2H) , 1.46 - 1.16 (m, 5H), 1.03 - 0.89 (m, 1H). 542 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.81 (d, 2H), 7.58 - 7.51 (m, 1H), 7.50 - 7.41 (m, 2H), 7.33 (d, 1H), 7.21 (t, 1H) ), 6.98 (s, 1H), 6.53 (d, 2H), 4.58 (d, 1H), 4.10 (s, 2H), 3.96 (s, 3H), 3.69 - 3.57 (m, 5H), 3.42 (d, 1H), 2.89 - 2.60 (m, 9H), 2.50 (q, 2H), 2.32 (d, 1H), 2.03 (d, 1H), 1.99 - 1.87 (m, 1H), 1.62 - 1.50 (m, 2H) , 1.47 - 1.17 (m, 5H), 1.03 - 0.89 (m, 1H). 543 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.53 (d, 1H), 7.41 - 7.35 (m, 1H), 7.29 - 7.22 (m, 2H), 7.05 - 6.95 (m, 1H), 6.64 (d , 1H), 4.13 - 4.05 (m, 3H), 3.99 (s, 2H), 3.82 - 3.73 (m, 2H), 3.67 (s, 3H), 3.53 - 3.45 (m, 5H), 3.28 - 3.18 (m , 2H), 3.12 (s, 3H), 2.92 - 2.85 (m, 2H), 2.64 - 2.40 (m, 4H), 2.33 - 2.18 (m, 3H), 2.15 - 2.08 (m, 2H), 1.88 - 1.70 (m, 2H), 1.60 - 1.40 (m, 4H), 1.40 - 1.28 (m, 3H), 1.26 - 1.22 (m, 1H). 545 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.90 (d, 1H), 7.53 - 7.42 (m, 2H), 7.39 (d, 1H), 7.12 (t, 1H), 6.85 (s, 1H), 6.74 (s, 1H), 6.61 (d, 1H), 4.60 (d, 1H), 4.42 (d, 1H), 4.08 (s, 2H), 4.02 - 3.92 (m, 3H), 3.61 (s, 3H) , 3.54 - 3.47 (m, 5H), 3.15 (s, 3H), 3.08 - 2.95 (m, 2H), 2.85 - 2.81 (m, 2H), 2.68 - 2.60 (m, 1H), 2.56 (s, 3H) , 2.50 - 2.42 (m, 2H), 2.40 - 2.32 (m, 1H), 2.27 - 2.15 (m, 3H), 2.10 - 2.03 (m, 2H), 1.95 - 1.85 (m, 1H), 1.79 (d, 1H), 1.55 - 1.45 (m, 1H), 1.40 - 1.27 (m, 4H), 1.25 - 1.10 (m, 2H), 0.82 - 0.70 (m, 1H). 546 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.53 (d, 1H), 7.49 - 7.41 (m, 2H), 7.35 (d, 1H), 7.18 - 7.09 (m, 1H), 6.69 (s, 1H) ), 6.68 - 6.58 (m, 2H), 4.53 (d, 1H), 4.35 (d, 1H), 4.07 (s, 2H), 4.01 - 3.98 (m, 1H), 3.97 (s, 2H), 3.60 ( s, 3H), 3.40 - 3.33 (m, 2H), 2.92 (d, 1H), 2.89 - 2.75 (m, 3H), 2.65 - 2.58 (m, 2H), 2.45 (s, 3H), 2.40 - 2.30 ( m, 2H), 2.24 - 2.15 (m, 1H), 2.10 - 1.97 (m, 3H), 1.89 - 1.78 (m, 1H), 1.77 - 1.65 (m, 3H), 1.51 - 1.47 (m, 1H), 1.38 - 1.18 (m, 5H), 0.73 - 0.69 (m, 1H). 547 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.49 - 7.40 (m, 3H), 7.36 (d, 1H), 7.13 - 7.06 (m, 1H), 6.71 - 6.65 (m, 2H), 6.42 (d , 1H), 4.64 (s, 2H), 4.55 (d, 1H), 4.36 (d, 1H), 4.12 (s, 2H), 4.02 - 3.96 (m, 1H), 3.97 (s, 2H), 3.64 ( s, 3H), 3.51 (s, 2H), 3.10 (s, 3H), 2.93 (d, 1H), 2.83 (d, 1H), 2.69 - 2.59 (m, 2H), 2.45 (s, 3H), 2.38 - 2.31 (m, 2H), 2.25 - 2.17 (m, 1H), 2.09 - 1.99 (m, 3H), 1.91 - 1.84 (m, 1H), 1.81 - 1.64 (m, 3H), 1.53 - 1.45 (m, 1H), 1.41 - 1.25 (m, 4H), 1.20 - 1.14 (m, 1H), 0.82 - 0.67(m, 1H). 548 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.27 (s, 1H), 8.02 (d, 1H), 7.89 (s, 1H), 7.53 - 7.40 (m, 3H), 7.15 (t, 1H), 6.97 (s, 1H), 6.79 (s, 1H), 6.61 (d, 1H), 4.70 (d, 1H), 4.44 (d, 1H), 4.07 (s, 2H), 4.01 - 3.94 (m, 3H) , 3.90 (s, 3H), 3.62 (s, 3H), 3.52 - 3.45 (m, 2H), 3.41 - 3.36 (m, 1H), 3.26 - 3.20 (m, 1H), 3.14 (s, 3H), 2.82 - 2.75 (m, 2H), 2.65 (s, 6H), 2.57 - 2.47 (m, 3H), 2.42 - 2.30 (m, 2H), 2.22 - 2.15 (m, 1H), 1.93 - 1.82 (m, 2H) , 1.55 - 1.47 (m, 1H), 1.40 - 1.27 (m, 4H), 1.22 - 1.02 (m, 2H), 0.85 - 0.72 (m, 1H). 549 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.52 - 7.47 (m, 3H), 7.13 (t, 1H), 6.90 (t, 1H), 6.81 (s, 1H), 6.72 (s, 1H), 6.56 (d, 1H), 6.22 (d, 1H), 4.61 (d, 1H), 4.38 (d, 1H), 4.02 - 3.98 (m, 1H), 3.98 (s, 2H), 3.86 (s, 2H) , 3.62 (s, 3H), 3.17 - 3.08 (m, 2H), 2.64 - 2.58 (m, 1H), 2.53 - 2.46 (m, 5H), 2.22 - 2.16 (m, 3H), 2.07- 2.03 (m, 2H), 1.91 - 1.81 (m, 2H), 1.63 - 1.57 (m, 2H), 1.53 - 1.47 (m, 1H), 1.29 - 1.18 (m, 5H), 0.81 - 0.69 (m, 1H). 550 ¹ H NMR (400 MHz, methanol - d ₄ ) δ 7.50 - 7.42 (m, 3H), 7.37 (d, 1H), 7.10 (t, 1H), 6.73 - 6.64 (m, 2H), 6.30 (d, 1H) ), 4.95 - 4.88 (m, 2H), 4.73 (d, 2H), 4.57 (d, 1H), 4.36 (d, 1H), 4.13 (s, 2H), 3.99 (d, 3H), 3.61 (s, 3H), 3.03 - 2.96 (m, 1H), 2.92 - 2.88 (s, 1H), 2.78 - 2.68 (m, 1H), 2.68 - 2.60 (m, 1H), 2.46 (s, 3H), 2.40 - 2.33 ( m, 2H), 2.29 - 2.21 (m, 1H), 2.17 (d, 3H), 2.15 - 2.03 (m, 3H), 1.89 - 1.60 (m, 3H), 1.70 - 1.60 (m, 1H), 1.53 - 1.45 (m, 1H), 1.33 - 1.24 (m, 4H), 1.21 - 1.14 (m, 1H), 0.77 - 0.67 (m, 1H). 553 ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.49 - 7.44 (m, 1H), 7.43 - 7.31 (m, 2H), 7.17 - 7.00 (m, 3H), 6.70 (dd, 1H), 6.48 - 6.43 (m, 1H), 4.08 (s, 1H), 4.02 (s, 1H), 3.89 (s, 1H), 3.67 - 3.54 (m, 3H), 3.54 - 3.39 (m, 2H), 2.94 (d, 1H) ), 2.83 (d, 1H), 2.78 - 2.60 (m, 2H), 2.60 - 2.47 (m, 1H), 2.40 - 2.19 (m, 3H), 2.09 - 1.91 (m, 3H), 1.59 - 1.36 (m , 5H), 1.36 - 1.16 (m, 4H). Example 39 Menin binding affinity

combined analysis 1

Binding affinity of representative compounds of the invention was determined using a fluorescence polarization (FP) competitive binding assay. FAM-labeled fluorescent probes were designed and synthesized based on the MLL1 peptide (FAM-MM2). The equilibrium dissociation constant (K) of FAM-MM2 for menin protein was determined from protein saturation experiments by monitoring the total fluorescence polarization of mixtures consisting of fluorescent probes at fixed concentrations and protein with increasing concentrations until complete saturation. _d ) value. Serial dilutions of protein were mixed with FAM-MM2 in assay buffer (PBS with 0.02% bovine gamma-globulin and 4% DMSO. 0.01% Triton X-100 was added immediately before analysis) to a final volume of 200 μl volume. The final FAM-MM2 concentration was 2 nM. The plates were incubated at room temperature for 30 minutes with gentle shaking to ensure equilibrium. Excitation at 485 nm and emission at 530 nm in Microfluor 1 96-well black v-bottom dishes (Thermo Scientific, Waltham, MA) using an Infinite M-1000 plate reader (Tecan US, Research Triangle Park, NC) Under the wavelength, the FP value in the micro-polarization unit (mP) was measured. The _Kd value for FAM-MM2 was determined to be 1.4 nM, which was calculated by fitting a sigmoidal dose-dependent increase in FP as a function of protein concentration using Graphpad Prism 6.0 software (Graphpad Software, San Diego, CA).

_IC50s of representative compounds of the invention were determined in competitive binding experiments. See Table 5. A mixture of 5 μl of DMSO containing the test compound and 195 μl of assay buffer containing the pre-incubated protein/probe complex solution was added to an assay dish incubated for 30 minutes at room temperature with gentle shaking. The final concentration of menin protein was 4 nM and the final probe concentration was 2 nM. A negative control containing only the protein/probe complex (equivalent to 0% inhibition) and a positive control containing no probe alone (equivalent to 100% inhibition) were included in each assay plate. FP values were measured as described above. _IC50 values were determined by nonlinear regression fitting of competition curves.

combined analysis 2 and 3

Compound binding potency was also measured against recombinant menin protein by a fluorescence-based polarized ligand shift assay using one of the two probes 36 or 37, as described in Zhou (2013), with the following modifications . See Zhou et al., Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin Mixed Lineage Leukemia 1 (MLL1) Protein Interaction -Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction.), J. Med. Chem., 2013; 56(3): 1113-23. All mixtures were prepared as 10 mM stock solutions in DMSO.

For compound analysis using probe 36 (Binding Assay 2), in a solution containing 100 mM potassium phosphate (pH 7.5), 100 μg/ml bovine gamma globulin, 0.02% sodium azide, 0.005% Triton X-100 and 2 Binding studies were performed in % DMSO buffer. A 10-point dose-response curve of compounds was added to the wells first, followed by a buffer solution containing 90 nM recombinant menin protein and 6 nM probe 36. The system was allowed to equilibrate at room temperature for 60 minutes in the dark, and then the FP signal was read at Ex480/Em530. The FP signal data were fitted to a four parameter dose equation to allow extraction of IC50 data.

For compound assays using probe 37 (binding assay 3), assay buffer was 100 mM potassium phosphate 7.5, 100 μg/ml bovine gamma globulin, 0.01% triton x 100, 5% DMSO. A 10-point dose-response curve of compounds was added to the wells first, followed by assay buffer containing 4 nM recombinant menin protein and 4 nM probe 37. The system was allowed to equilibrate for one hour at room temperature in the dark, and then the FP signal was read at Ex480/Em530. The FP signal data were fitted to a four parameter dose response equation to allow extraction of IC50 data.

Particular compounds disclosed herein were tested in the aforementioned binding assays and their IC50s were determined according to the following scores: (A) less than 50 nM, (B) between 50 nM and 100 nM, (C) greater than 100 nM, and ( NT) was not tested, as shown in Table 5 below. table 5 Compound number Binding Analysis 1 Binding Analysis 2 combined analysis 1 A B A NT 2 A A NT 3 A NT NT 4 A NT A 5 A NT A 6 A A A 7 A NT A 8 A NT NT 9 NT A A 10 NT A A 11 NT A B A 12 A NT NT 13 A NT NT 14 A A A 15 A NT NT 16 A NT NT 17 A A A 18 A NT NT 19 A A A 20 A NT NT twenty one A NT NT twenty two A NT NT twenty three NT NT NT twenty four A NT NT 25 A NT NT 26 A NT NT 27 A NT NT 28 A NT NT 29 A NT NT 30 A NT NT 31 NT A A 32 A NT NT 33 A NT NT 34 A NT NT 35 A NT NT 36 A NT NT 37 A NT NT 38 A NT A 39 A NT A 40 NT A A 41 A NT NT 42 B NT NT 43 A NT NT 44 A NT NT 45 A NT A 46 A NT NT 47 A NT NT 48 A NT NT 49 A NT NT 50 A NT NT 51 A NT NT 52 A NT NT 53 A NT NT 54 A NT NT 55 A NT NT 56 A NT NT 57 A NT NT 58 A NT NT 59 A NT NT 60 A NT NT 61 A NT NT 62 A NT A 63 A NT NT 64 A NT NT 65 A NT NT 66 A NT NT 67 A NT NT 68 A NT NT 69 A NT NT 70 A NT NT 71 A NT NT 72 A NT NT 73 A A NT 74 A NT NT 75 A B A NT 76 A A NT 77 A A NT 78 A NT NT 79 A NT NT 80 A NT NT 81 A NT NT 82 A A NT 83 A B NT 84 A A NT 85 A NT NT 86 A NT NT 87 A B NT 88 A B NT 89 A A A 90 A NT NT 91 NT NT NT 92 A NT NT 93 NT NT NT 94 A A A 95 A NT A 96 A NT A 97 A NT A 98 A NT NT 99 A NT NT 100 A A A 101 A A A 102 A A A 103 A A A 104 A A A 105 A A NT 106 A A A 107 A NT NT 108 A A A 110 A A A 111 A A NT 112 A NT NT 113 A NT NT 114 A NT NT 115 A NT NT 116 A A A 117 A NT NT 118 A NT NT 119 A NT NT 120 A NT NT 121 A NT NT 122 A NT NT 123 A NT NT 124 A A A 125 NT NT NT 126 A NT NT 127 A NT NT 128 A NT NT 129 A NT NT 130 A NT NT 131 A NT NT 132 A NT NT 133 A NT NT 134 A NT NT 135 A NT NT 136 A NT NT 137 A C A 138 A NT NT 139 NT NT NT 140 NT NT NT 141 A NT NT 142 B NT NT 143 A NT NT 144 A NT NT 145 B NT NT 146 A NT NT 147 C NT NT 148 C NT NT 149 A NT NT 150 B NT NT 151 A NT NT 152 A NT NT 153 A NT NT 154 B NT NT 155 B NT NT 156 C NT NT 157 B NT NT 158 A NT NT 159 A NT NT 160 A NT NT 161 B NT NT 162 A NT NT 163 A NT NT 164 A NT NT 165 A NT NT 166 A NT NT 167 A NT NT 168 A NT NT 169 B NT NT 170 A NT NT 171 A NT NT 172 A NT NT 173 A NT NT 174 A NT NT 175 A NT NT 176 A NT NT 177 A NT NT 178 A NT NT 179 A NT NT 180 A NT NT 181 A NT NT 182 A NT NT 183 C NT NT 184 A NT A 185 A NT NT 186 NT A A 187 NT A A 188 NT A A 189 NT A A 190 NT A NT 191 NT A A 192 NT B A 193 NT A A 194 NT A A 195 NT A A 196 NT A A 197 NT A A 198 NT A A 199 NT A A 200 NT A A 201 NT A A 202 NT A A 203 NT A A 204 NT C B 205 NT A A 206 NT A A 207 NT A A 208 NT B A 209 NT A A 210 NT B A 211 NT B A 212 NT A NT 213 NT A A 214 NT A A 215 NT B NT 216 NT A NT 217 A A NT 218 A A NT 219 A B NT 220 A A NT 221 A NT NT 222 A A NT 223 A A NT 224 A NT NT 225 A NT NT 226 A NT NT 227 A NT NT 228 A NT NT 229 A NT NT 230 A NT NT 231 A NT NT 232 A NT NT 233 A C B NT 234 A A NT 235 A A NT 236 C A NT 237 NT NT NT 238 NT NT NT 239 A B NT 240 A B NT 241 A NT NT 242 A NT NT 243 A NT NT 244 A NT NT 245 A A NT 246 A NT NT 247 A NT NT 248 A NT NT 249 A NT NT 250 A NT NT 251 A NT NT 252 A NT NT 253 A NT NT 254 A NT NT 255 A NT NT 256 A NT NT 257 A A NT 258 A B NT 259 NT NT NT 260 NT NT NT 261 A A NT 262 A A NT 263 A A NT 264 A NT NT 265 A NT NT 266 A NT NT 267 A NT NT 268 A NT NT 269 A NT NT 270 A NT NT 271 A NT NT 272 A NT NT 273 A NT NT 274 A NT NT 275 A NT NT 276 A NT NT 277 A NT NT 278 A NT NT 279 A NT NT 280 A NT NT 281 A NT NT 282 A NT NT 283 A NT NT 284 A A A 285 A A A 286 A NT NT 287 A NT NT 288 A NT NT 289 A NT A 290 A NT NT 291 A NT NT 292 A NT NT 293 A NT NT 294 A NT A 295 A NT NT 296 A NT NT 297 A NT NT 298 A NT NT 299 NT A A 300 NT A A 301 A NT NT 302 A NT NT 303 A NT NT 304 A NT NT 305 A NT NT 306 NT A A 307 NT A A 308 A NT NT 309 A A NT 310 A NT NT 311 A A NT 312 A NT NT 313 A NT NT 314 A NT NT 315 A NT NT 316 A NT NT 317 A NT NT 318 A NT NT 319 A NT NT 320 A NT NT 321 A NT NT 322 A NT NT 323 A NT NT 324 A NT NT 325 A NT NT 326 A NT NT 327 A NT NT 328 A NT NT 329 A NT NT 330 NT NT NT 331 A NT NT 332 A NT NT 333 A NT NT 334 A NT NT 335 A NT NT 336 A NT NT 337 A NT NT 338 A NT A 339 NT NT NT 340 NT NT A 341 A NT A 342 A NT NT 343 NT A A 344 NT A A 345 NT A A 346 NT A A 347 NT A A 348 NT A A 349 NT A A 350 A NT A 351 A NT NT 352 A NT A 353 A NT NT 354 A NT A 355 NT NT A 356 NT NT A 357 NT NT A 358 NT NT A 359 A NT A 360 A NT NT 361 NT NT A 362 NT NT A 363 A NT A 364 A NT A 365 A NT A 366 A NT A 367 A NT A 368 A NT A 369 A NT A 370 A NT A 371 A NT A 372 NT NT A 373 NT NT A 374 NT NT A 375 NT NT A 376 NT NT A 377 NT NT A 378 NT NT A 379 NT NT A 380 NT NT A 381 NT NT A 382 NT NT A 383 NT NT A 384 NT NT A 385 NT NT A 386 NT NT A 387 NT NT A 388 NT NT A 389 NT NT A 390 NT NT A 391 NT NT A 392 NT NT A 393 NT NT A 394 NT NT A 395 NT NT A 396 NT NT A 397 NT NT A 398 NT NT A 399 NT NT A 400 NT NT A 401 NT NT A 402 NT NT A 403 NT NT A 404 NT NT A 405 NT NT A 406 NT NT A 407 NT NT A 408 NT NT A 409 NT NT A 410 NT NT A 411 NT NT A 412 NT NT A 413 NT NT A 414 NT NT A 415 NT NT A 416 NT NT A 417 NT NT A 418 NT NT A 419 NT NT A 420 NT NT A 421 NT NT A 422 NT NT A 423 NT NT A 424 NT NT A 425 NT NT A 426 NT NT A 427 NT NT A 428 NT NT A 429 NT NT A 430 NT NT A 431 NT NT A 432 NT NT A 433 NT NT A 434 NT NT A 435 NT NT C 436 NT NT A 437 NT NT A 438 NT NT A 439 NT NT A 440 NT NT A 441 NT NT A 442 NT NT A 443 NT NT A 444 NT NT A 445 NT NT A 446 NT NT A 447 NT NT B 448 A NT NT 449 A NT NT 450 NT NT A 451 NT NT A 452 NT NT A 453 A NT NT 454 A NT NT 455 NT NT A 456 NT NT A 457 A NT NT 458 A NT NT 459 NT NT A 460 A NT NT 461 A NT NT 462 C NT NT 463 NT NT NT 464 NT NT NT 465 A NT A 466 A NT A 467 A NT A 468 A NT A 469 A NT NT 470 A NT NT 471 NT NT A 472 NT NT A 474 NT NT A 475 NT NT A 476 NT NT A 477 NT NT A 478 NT NT A 479 NT NT A 480 NT NT A 481 NT NT A 482 A NT NT 483 A NT A 484 A NT A 485 A NT A 486 A NT A 487 A NT A 488 NT NT A 489 NT NT A 490 NT NT A 491 A NT NT 492 A NT NT 493 NT NT A 494 A NT NT 495 A NT NT 496 A NT NT 497 A NT NT 498 NT NT A 499 A NT NT 500 A NT NT 501 A NT NT 502 A NT A 503 A NT A 504 A NT A 505 NT NT A 506 NT NT A 507 NT NT A 508 NT NT A 509 NT NT A 510 NT NT A 511 NT NT A 512 NT NT A 513 NT NT A 514 NT NT A 515 NT NT A 516 NT NT A 517 NT NT A 518 NT NT A 519 NT NT A 520 NT NT A 521 NT NT A 522 A NT NT 523 A NT NT 524 A NT NT 525 A NT NT 526 NT NT A 527 A NT NT 528 A NT NT 529 A NT NT 530 A NT NT 531 A NT NT 532 NT NT NT 533 A NT NT 534 A NT NT 535 A NT NT 536 A NT NT 537 A NT NT 538 A NT NT 539 A NT NT 540 A NT NT 541 A NT NT 542 A NT NT 543 NT NT A 544 NT NT A 545 NT NT A 546 NT NT A 547 NT NT A 548 NT NT A 549 NT NT A 550 NT NT A 551 NT NT A 552 NT NT A 553 A NT A Example 40 Cell Growth Inhibition

program 1

The effect of representative compounds of the invention on cell viability was determined in a 4-day or 7-day proliferation assay. Cells were maintained in appropriate medium with 10% FBS at 37°C in an atmosphere of 5% _CO2 .

Cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, cat. no. 3595) at a density of 2,000 to 3,000 cells/well in 100 μl of medium. Compounds were serially diluted in appropriate media and 100 μl of diluted compound was added to appropriate wells of cell culture plates. Following compound addition, cells were incubated for 4 or 7 days at 37°C in an atmosphere of 5% CO ₂ . In the 7-day assay, WST (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-di Sulfophenyl)-2H-tetrazolium monosodium salt) Cell Count-8 Kit (Dojindo Molecular Technologies, Inc., Rockville, MD) was used to determine cell viability. In the 4 day assay, cell viability was determined using CellTiter-Glo® Luminescent Cell Viability Reagent according to the manufacturer's instructions.

Cell viability reagents were added to each well at a final concentration of 10% (v/v), and the plates were then incubated at 37°C for 1 to 2 hours for color development. Absorbance at 450 nm was measured using a SPECTRAmax PLUS disk reader (Molecular Devices, Sunnyvale, CA). Readings were normalized to DMSO-treated cells and analyzed by nonlinear regression (fit with variable slope, least squares, and four parameters without constraints) using GraphPad Prism 5 software (GraphPad Software, La Jolla, CA). S-type) analysis to calculate the half maximal inhibitory concentration ( _IC50 ).

Particular compounds disclosed herein were tested in the aforementioned assays and were determined to inhibit cell proliferation with _IC50s according to the following scores: (A) less than 100 nM, (B) between 100 nM and 500 nM, (C) at 500 nM and 1 µM, (D) was greater than 1 µM, (E) was not fitted, and (NT) was not tested, as shown in Table 6 below.

program 2

The effect of representative compounds of the invention on cell viability was determined in a 4-day or 7-day proliferation assay. Cells were maintained in appropriate medium with 10% FBS at 37°C in an atmosphere of 5% _CO2 .

Cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, Cat. No. 3903) at a density of 4,000 to 7,500 cells/well in 50 μl of medium. Compounds were serially diluted in appropriate media and 50 μl of diluted compound was added to appropriate wells of cell culture plates. Following compound addition, cells were incubated for 4 or 7 days at 37°C in an atmosphere of 5% CO ₂ . Cell viability was determined using CellTiter-Glo® Luminescent Cell Viability Reagent according to the manufacturer's instructions.

CellTiter-Glo® Luminescent Cell Viability Reagent was added to each well and incubated on an orbital shaker for 10 minutes at room temperature. Luminescence signals were measured using an EnSpire® disc reader (PerkinElmer, Waltham, MA). Readings were normalized to DMSO-treated cells and analyzed by nonlinear regression (fit with variable slope, least squares, and four parameters without constraints) using GraphPad Prism 5 software (GraphPad Software, La Jolla, CA). S-type) analysis to calculate the half maximal inhibitory concentration ( _IC50 ).

， 或其醫藥學上可接受之鹽，其中： 各R^a 獨立地選自由H及C₁ -C₄ 烷基組成之群； 各R^b 獨立地選自由H及C₁ -C₄ 烷基組成之群； R^c 選自由H及鹵基組成之群； 各R^d 獨立地選自由鹵基組成之群； p、q、r及s獨立地為1或2； 各n獨立地為0、1或2； Q選自由以下組成之群：-N(H)C(=O)OR、-N(R)C(=O)OR、-N(H)C(=O)R、-N(H)C(O)NHR、-N(H)C(O)NR₂ 、-OC(=O)NR₂ 、

； V選自由以下組成之群：-CH₂ OH、-CH₂ OMe、-CH₂ OEt、-CH₂ NH₂ 、-CH₂ NHMe、-CH₂ NMe₂ 、-CN、-CO₂ Me、-CO₂ Et、-CH₂ NHCO₂ Me、-CH₂ NHCO₂ Et、-CH₂ NHCO₂ iPr、-CH₂ N(H)CONH₂ 、-CO₂ H、-CONH₂ 、-CONHMe、-CONMe₂ 、-CONHEt、-CONEt₂ 、_- CON(Me)(Et)、-CON(CD₃ )₂ 、-CON(Me)(CD₃ )、-CON(Et)(CD₃ )、-CON(i-Pr)(CD₃ )、-CH₂ NHCONHCH₂ CF₃ 、-CH₂ NHCONHiPr、-CH₂ NHCONHMe、-CH₂ NHCONHEt、

； 各R^f 獨立地選自由以下組成之群：H、C₁ -C₄ 烷基、OH、C₁ -C₄ 烷氧基及F； 各R^g 獨立地選自由以下組成之群：H、C₁ -C₄ 烷基及NH₂ ； 各R獨立地為C₁ -C₄ 烷基、C₁ -C₄ 鹵烷基或CD₃ ； T選自由以下組成之群：-C₁ -C₄ 烷基、-SO₂ C₁ -C₄ 烷基、-SO₂ -環烷基、-C(O)C₁ -C₄ 烷基、-C(O)芳基、

其中 R⁴ 為氫或C₁ -C₄ 烷基； m為1或2； J為氰基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、芳基磺醯基、雜芳基磺醯基、雜環磺醯基、雜環烷基磺醯基及甲醯胺基； v為0或1； R⁶ 為鹵基、鹵烷基、-C₁ -C₄ 烷基、-C(O)C₁ -C₄ 烷基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、芳基磺醯基、雜芳基磺醯基、雜環磺醯基、雜環烷基磺醯基、甲醯胺基、甲磺酸酯基或三級丁氧基羰基； 各R⁷ 獨立地選自由以下組成之群：氰基、鹵基、鹵烷基、-C₁ -C₄ 烷基、-C(O)C₁ -C₄ 烷基、-OH、磺醯胺基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、芳基磺醯基、雜芳基磺醯基、雜環磺醯基、雜環烷基磺醯基或甲醯胺基； R^8a 及R^8b 獨立地選自由以下組成之群：氫、鹵基、-C₁ -C₄ 烷基、-C₁ -C₄ 烷氧基、-CH₂ OC₁ -C₄ 烷基、-CH₂ SO₂ C₁ -C₄ 烷基及R^a1 ； Z為氫、C₁ -C₄ 烷基、-C(O)C₁ -C₄ 烷基、-OH、-CN、-CF₃ 、-NO₂ 、鹵基、-NHSO₂ Me、-NHCOMe、-CONH₂ 、-CONH(C₁ -C₄ 烷基)、胺基、磺醯胺基、烷基磺醯基及環烷基磺醯基； R^a1 為-CN、烷氧基烷基、烷基磺醯基、(胺基)烷基、甲醯胺基、視情況經取代之雜芳基、(雜芳基)烷基、-NR₄ C(O)C₁ -C₄ 烷基、-OCH₂ CH=CH-烷基磺醯基及(雜環基)烷基； X選自由以下組成之群：-C₁ -C₄ 烷基、-C₁ -C₄ 烯基、-NH₂ 、-NHC₁ -C₄ 烷基、-NH(C₁ -C₄ 烷基)₂ 、(胺基)烷基及-CH₂ CH₂ NR₄ Y-Z² ；

，其中 t及u獨立地為0、1、2或3； Y為不存在或為-C(=O)-、-SO₂ -、-C(=O)NH-、-C(=O)N(Me)-； Z² 選自由以下組成之群：-C(R^14a )=C(R^14b )(R^14c )、-C≡CR^14d 、鹵烷基及R^a2 R^9a 及R^9b 各自獨立地選自由以下組成之群：烯基、炔基、-CN、-C₁ -C₄ 烷基、鹵基、(胺基)烷基及-C(R^14a )=C(R^14b )(R^14c )； 各Q¹ 獨立地選自由-CH₂ -及-C(=O)-組成之群 R¹⁰ 選自由以下組成之群：氫、-C₁ -C₄ 烷基、-NHCOMe、-NHSO₂ Me、-CN、鹵基、-OCH₂ CH=CH-R^a3 、-CH₂ CH₂ CH=CH-R^a3 ； R¹¹ 為-NHCOC(R^14a )=C(R^14b )(R^14c )、甲醯胺基、-C(O)NHCH₂ Ra⁵ 、-C(O)NHCH₂ C≡CR^a6 或-CH₂ CH₂ CH=CH-R^a3 ； R¹² 選自由以下組成之群：烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基及甲醯胺基； R¹³ 為氫或C₁ -C₄ 烷基； R^14a 、R^14b 、R^14c 及R^14d 各自獨立地選自由以下組成之群：氫、鹵基、C₁ -C₄ 烷基、(胺基)烷基及R^a3 ； R^a2 為-N(R¹⁵ )CH₂ CH=CH-R^a3 或-CH=CHCH₂ R^a4 ； R^a3 選自由以下組成之群：烷氧基羰基、烷基磺醯基、環烷基磺醯基及甲醯胺基； R^a4 為視情況經取代之雜環基； R^a5 選自由氰基及(胺基)烷基組成之群； R^a6 為氫或甲醯胺基； R¹⁵ 為氫或C₁ -C₄ 烷基；且 各W獨立地選自由-CH-或-N-組成之群。 態樣2.    如態樣1之化合物，其具有式X' ：

， 或其醫藥學上可接受之鹽。 態樣3.    如態樣1之化合物，其具有式XI' ：

， 或其醫藥學上可接受之鹽。 態樣4.    如態樣1至3中任一者之化合物或其醫藥學上可接受之鹽，其中： 各R^a 獨立地選自由H及C₁ -C₄ 烷基組成之群； 各R^b 獨立地選自由H及C₁ -C₄ 烷基組成之群； R^c 選自由H及鹵基組成之群； Q選自由以下組成之群：-NHCO₂ Me、-NHCONHMe、-CHCOEt、-NHCOEt、-NHCOMe、

； V選自由以下組成之群：

， 其中各R^f 獨立地選自由以下組成之群：H、Me、Et、iPr、OH及

，其中各R^g 獨立地選自由以下組成之群：H、Me、Et、iPr及NH₂ 。 態樣5.    如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中： Q選自由以下組成之群：-NHCO₂ Me、

； V為

，其中各R^f 獨立地選自由以下組成之群：H、Me、Et、iPr及OH。 態樣6.    如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中： Q選自由以下組成之群：-NHCO₂ Me、

； V為

，其中各R^g 獨立地選自由以下組成之群：H、Me、Et、iPr及NH₂ 。 態樣7.    如態樣1至4中任一者之化合物或其醫藥學上可接受之鹽，其中Q為-NHCO₂ Me。 態樣8.    如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中R^c 為鹵基。 態樣9.    如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中R^c 為氟。 態樣10.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中R^8a 及R^8b 中之至少一者為鹵基。 態樣11.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中R^8a 及R^8b 中之至少一者為氟。 態樣12.   如態樣1至2中任一者之化合物或其醫藥學上可接受之鹽，其中p、q、r及s為1。 態樣13.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中一個R^g 為C₁ -C₄ 烷基。 態樣14.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中一個R^g 為甲基。 態樣15.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中各R^g 為氫。 態樣16.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中T為T-1、T-2或T-31。 態樣17.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中T為T-1。 態樣18.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中T為T-2。 態樣19.   如態樣1至7中任一者之化合物或其醫藥學上可接受之鹽，其中T為T-31。 態樣20.   如態樣17之化合物或其醫藥學上可接受之鹽，其中X為-CH₃ 、X-1、X-11或X-12。 態樣21.   如態樣17之化合物，其中X為-CH₃ 。 態樣22.   如態樣17之化合物，其中X為X-1。 態樣23.   如態樣17之化合物，其中X為X-11。 態樣24.   如態樣17之化合物，其中X為X-12。 態樣25.   如態樣1之化合物，其中該化合物為表1之化合物中之任一者或多者或其醫藥學上可接受之鹽。 態樣26.   一種醫藥組合物，其包含如態樣1至25中任一者之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑。 態樣27.   一種治療患者之方法，該方法包含向該患者投與治療有效量之如態樣1至25中任一者之化合物或其醫藥學上可接受之鹽，其中該患者患有癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。 態樣28.   如態樣27之方法，其中該患者患有癌症。 態樣29.   如態樣28之方法，其中該癌症為表2之癌症中之任一者或多者。 態樣30.   如態樣28之方法，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。 態樣31.   如態樣27至30中任一者之方法，其進一步包含投與治療有效量之適用於治療該疾病或病狀之第二治療劑。 態樣32.   如態樣26之醫藥組合物，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。 態樣33.   如態樣32之醫藥組合物，其用於治療癌症。 態樣34.   如態樣33之醫藥組合物，其中該癌症為表2之癌症中之任一者或多者。 態樣35.   如態樣33之醫藥組合物，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。 態樣36.   如態樣1至25中任一者之化合物或其醫藥學上可接受之鹽，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。 態樣37.   如態樣36之化合物，其用於治療癌症。 態樣38.   如態樣37之化合物，其中該癌症為表2之癌症中之任一者或多者。 態樣39.   如態樣37之化合物，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。 態樣40.   一種如態樣1至25中任一者之化合物或其醫藥學上可接受之鹽的用途，其係用於製造用以治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染之藥劑。 態樣41.   如態樣40之用途，其用於治療癌症。 態樣42.   如態樣41之用途，其中該癌症為表2之癌症中之任一者或多者。 態樣43.   如態樣41之用途，其中該癌症係選自由以下組成之群：急性淋巴球性白血病、急性單核細胞性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合譜系白血病。Particular compounds disclosed herein were tested in the aforementioned assays and determined as ICs according to the following scores₅₀ Inhibits cell proliferation: (A) less than 100 nM, (B) between 100 nM and 500 nM, (C) between 501 nM and 1 µM, (D) greater than 1 µM, (E) no fit, and (NT) not tested, as shown in Table 6 below. Table 6 Compound number Program 1 MV4-11 Program 2 MV4-11 Program 1 MOLM13 Program 2 MOLM13 1 A B A C 2 A A A B 3 B NT B NT 4 A A B B 5 A B B B 6 A A A B 7 A A A B 8 B NT B NT 9 NT A NT B 10 NT A NT A 11 NT A NT A 12 A NT B NT 13 A NT B NT 14 A A B B 15 A NT A NT 16 A NT B NT 17 A A A A 18 A NT B NT 19 A A A B 20 A NT B NT twenty one A NT A NT twenty two A NT B NT twenty three A NT B NT twenty four A NT B NT 25 A NT A NT 26 A NT A NT 27 A NT A NT 28 A NT B NT 29 B NT B NT 30 A NT A NT 31 NT A NT B 32 A NT B NT 33 A NT B NT 34 A NT B NT 35 A NT B NT 36 A NT A NT 37 A NT A NT 38 A A A B 39 A A A A 40 NT A NT A 41 B NT B NT 42 E NT E NT 43 A NT B NT 44 A NT B NT 45 A A A B 46 A NT A NT 47 A NT A NT 48 A NT A NT 49 A NT A NT 50 A NT A NT 51 A NT A NT 52 A NT A NT 53 A NT A NT 54 A NT B NT 55 E NT E NT 56 E NT E NT 57 D NT C NT 58 A NT A NT 59 C NT C NT 60 C NT C NT 61 A NT A NT 62 A A A B 63 A NT A NT 64 B NT B NT 65 A NT A NT 66 A NT A NT 67 A NT A NT 68 A NT B NT 69 B NT B NT 70 A NT A NT 71 A NT B NT 72 A NT C NT 73 A B B C 74 A NT C NT 75 A A A B 76 A A A B 77 A A A B 78 C NT E NT 79 A NT B NT 80 NT NT A NT 81 A NT A NT 82 A A A B 83 A B A E 84 A A A B 85 E NT E NT 86 A NT A NT 87 A A A B 88 A A A B 89 A A A C 90 E NT E NT 91 NT NT NT NT 92 A NT A NT 93 NT NT NT NT 94 A A A A 95 A A A B 96 A A A C 97 A A A B 98 A NT A NT 99 A NT B NT 100 A A A A 101 A A A A 102 A A A A 103 A A A B 104 A A A A 105 B B C E 106 A A A B 107 A NT B NT 108 C E E E 110 A A B B 111 C E E E 112 A A A B 113 A NT A NT 114 A NT A NT 115 A NT B NT 116 A A A A 117 A NT A NT 118 A NT A NT 119 A NT A NT 120 A NT A NT 121 A NT A NT 122 A NT A NT 123 A NT A NT 124 A A A A 125 NT NT NT NT 126 A NT B NT 127 A NT A NT 128 A NT B NT 129 A NT A NT 130 A NT B NT 131 A NT A NT 132 A NT B NT 133 A NT A NT 134 A NT B NT 135 A NT A NT 136 E NT E NT 137 D NT E NT 138 E NT E NT 139 NT NT NT NT 140 NT NT NT NT 141 E NT D NT 142 E NT E NT 143 E NT E NT 144 E NT E NT 145 E NT E NT 146 E NT E NT 147 E NT E NT 148 E NT E NT 149 E NT E NT 150 E NT E NT 151 A NT A NT 152 D NT D NT 153 E NT E NT 154 E NT E NT 155 E NT E NT 156 E NT E NT 157 E NT E NT 158 E NT E NT 159 E NT E NT 160 E NT E NT 161 E NT E NT 162 E NT E NT 163 A NT A NT 164 C NT C NT 165 E NT E NT 166 E NT E NT 167 E NT E NT 168 E NT E NT 169 E NT E NT 170 E NT E NT 171 E NT E NT 172 E NT E NT 173 E NT E NT 174 E NT E NT 175 E NT E NT 176 E NT E NT 177 E NT E NT 178 E NT E NT 179 E NT E NT 180 A NT A NT 181 A NT A NT 182 A NT A NT 183 E NT D NT 184 A A B A 185 B NT B NT 186 NT A NT A 187 NT B NT B 188 NT A NT B 189 NT E NT E 190 NT A NT B 191 NT B NT B 192 NT E NT E 193 NT B NT E 194 NT A NT A 195 NT B NT C 196 NT A NT B 197 NT A NT B 198 NT A NT B 199 NT A NT B 200 NT B NT B 201 NT A NT B 202 NT B NT E 203 NT B NT E 204 NT E NT E 205 NT A NT A 206 NT E NT E 207 NT C NT E 208 NT E NT E 209 NT A NT B 210 NT B NT E 211 NT B A NT C B 212 NT A NT B 213 NT A NT B 214 NT A NT B 215 NT B NT C 216 NT A NT B 217 A A A B 218 A B A C 219 A A A B 220 A A A B 221 A NT A NT 222 A A A B 223 A A A B 224 A NT A NT 225 A NT A NT 226 A NT B NT 227 A NT B NT 228 B NT B NT 229 A NT B NT 230 B NT D NT 231 A NT A NT 232 A NT B NT 233 A A A B 234 A A A B 235 A A A B 236 E A E B 237 NT NT NT NT 238 NT NT NT NT 239 C A E B 240 B B B C 241 A NT A NT 242 A NT A NT 243 B NT C NT 244 B NT C NT 245 A A A A B 246 A NT B NT 247 A NT B NT 248 A NT A NT 249 A NT A NT 250 A NT B NT 251 A NT A NT 252 A NT A NT 253 A NT B NT 254 A NT A NT 255 B NT D NT 256 B NT E NT 257 A A A B 258 A B A B 259 NT NT NT NT 260 NT NT NT NT 261 A A B B 262 A A B B 263 A A B B 264 A NT B NT 265 A NT A NT 266 A NT B NT 267 A NT B NT 268 A NT A NT 269 A NT B NT 270 A NT C NT 271 A NT B NT 272 A NT B NT 273 A NT B NT 274 A NT A NT 275 A NT B NT 276 B NT B NT 277 B NT B NT 278 A NT A NT 279 A NT A NT 280 A NT A NT 281 A NT B NT 282 A NT A NT 283 A NT A NT 284 A A A A 285 A A A A 286 A NT A NT 287 A NT B NT 288 A NT A NT 289 A A A A 290 A NT A NT 291 A NT B NT 292 A NT A NT 293 A NT A NT 294 A A A A 295 A NT B NT 296 A NT B NT 297 B NT E NT 298 C NT D NT 299 NT A NT B 300 NT A NT B 301 C NT D NT 302 C NT C NT 303 C NT C NT 304 B NT B NT 305 B NT B NT 306 NT B NT B 307 NT A NT A 308 A NT B NT 309 A A A C 310 A NT B NT 311 A B A E 312 B NT B NT 313 B NT B NT 314 A NT B NT 315 A NT B NT 316 A NT A NT 317 B NT C NT 318 A NT C NT 319 A NT A NT 320 B NT B NT 321 B NT C NT 322 A NT A NT 323 A NT B NT 324 B NT B NT 325 B NT C NT 326 A NT B NT 327 B NT C NT 328 E NT E NT 329 B NT B NT 330 NT NT NT NT 331 B NT C NT 332 A NT B NT 333 B NT B NT 334 B NT C NT 335 B NT B NT 336 B NT B NT 337 A NT A NT 338 A A A B 339 NT NT NT NT 340 NT C NT E 341 A A A A 342 B NT C NT 343 NT B NT E 344 NT A NT A 345 NT A NT A 346 NT B NT C 347 NT C NT E 348 NT B NT B 349 NT A NT B 350 A A B B 351 A NT A NT 352 A A A B 353 A NT B NT 354 A A A B 355 NT B NT B 356 NT A NT A 357 NT C NT C 358 NT A NT A 359 A A A A 360 B NT C NT 361 NT A NT B 362 NT E NT E 363 A A A B 364 A A B B 365 B B C D 366 A A B B 367 A A A A 368 A A A A 369 A A A B 370 A A A B 371 A A A A 372 NT A NT A 373 NT A NT B 374 NT A NT B 375 NT E NT E 376 NT A NT B 377 NT A NT B 378 NT E NT E 379 NT E NT E 380 NT B NT E 381 NT B NT E 382 NT A NT A 383 NT A NT B 384 NT A NT B 385 NT A NT A 386 NT A NT B 387 NT A NT B 388 NT A NT A 389 NT A NT A 390 NT A NT A 391 NT A NT B 392 NT A NT A 393 NT A NT B 394 NT A NT B 395 NT B NT B 396 NT B NT E 397 NT A NT A 398 NT B NT B 399 NT A NT B 400 NT A NT A 401 NT B NT E 402 NT E NT E 403 NT E NT E 404 NT A NT A 405 NT A NT B 406 NT A NT B 407 NT B NT D 408 NT A NT B 409 NT A NT B 410 NT E NT E 411 NT A NT B 412 NT A NT B 413 NT A NT E 414 NT A NT A 415 NT A NT B 416 NT B NT C 417 NT B NT E 418 NT B NT B 419 NT A NT B 420 NT A NT B 421 NT A NT A 422 NT B NT E 423 NT A NT A 424 NT A NT B 425 NT A NT C 426 NT C NT E 427 NT B NT E 428 NT A NT B 429 NT A NT B 430 NT B NT C 431 NT B NT E 432 NT B NT D 433 NT B NT D 434 NT A NT A 435 NT E NT E 436 NT A NT B 437 NT A NT A 438 NT A NT A 439 NT A NT B 440 NT E NT E 441 NT A NT B 442 NT C NT E 443 NT A NT B 444 NT A NT C 445 NT B NT C 446 NT A NT B 447 NT E NT E 448 B NT B NT 449 B NT B NT 450 NT A NT C 451 NT A NT B 452 NT A NT A 453 A NT A NT 454 E NT E NT 455 NT A NT B 456 NT A NT A 457 A NT A NT 458 A A A B 459 NT A NT B 460 E NT E NT 461 D NT C NT 462 D NT E NT 463 NT NT NT NT 464 NT NT NT NT 465 A A A B 466 A A A A 467 A A A B 468 A A A A 469 B NT B NT 470 A NT A NT 471 NT B NT E 472 NT B NT E 474 NT E NT E 475 NT B NT E 476 NT A NT B 477 NT E NT E 478 NT A NT B 479 NT E NT E 480 NT B NT E 481 NT A NT A 482 B NT B NT 483 A A A B 484 A A A A 485 A A A B 486 A A A B 487 A A A B 488 NT A NT A 489 NT A NT B 490 NT B NT B 491 A NT A NT 492 A NT A NT 493 NT A NT C 494 A NT A NT 495 A NT C NT 496 A NT A NT 497 A NT B NT 498 NT A NT A 499 A NT A NT 500 A NT A NT 501 D NT E NT 502 A A A B 503 A A B B 504 A B E B 505 NT A NT B 506 NT B NT E 507 NT A NT A 508 NT A NT A 509 NT A NT B 510 NT A NT B 511 NT B NT E 512 NT B NT B 513 NT A NT B 514 NT A NT A 515 NT A NT B 516 NT B NT B 517 NT A NT B 518 NT A NT A 519 NT A NT B 520 NT A NT A 521 NT A NT A 522 B NT B NT 523 B NT B NT 524 B NT B NT 525 D NT C NT 526 NT A NT C 527 A NT A NT 528 B NT C NT 529 B NT B NT 530 B NT C NT 531 A NT B NT 532 NT NT NT NT 533 A NT A NT 534 B NT B NT 535 A NT A NT 536 A NT A NT 537 A NT A NT 538 A NT A NT 539 A NT A NT 540 A NT A NT 541 B NT E NT 542 A NT A NT 543 NT A NT B 544 NT A NT C 545 NT B NT E 546 NT C NT E 547 NT A NT B 548 NT C NT E 549 NT E NT E 550 NT B NT E 551 NT A NT B 552 NT A NT A 553 E NT E NT appearance Aspect 1. A compound having the formulaI ,

, or a pharmaceutically acceptable salt thereof, wherein: each R^a independently selected from H and C₁ -C₄ A group consisting of alkyl groups; each R^b independently selected from H and C₁ -C₄ A group consisting of alkyl groups; R^c is selected from the group consisting of H and halo; each R^d independently selected from the group consisting of halogen groups; p, q, r and s are independently 1 or 2; each n is independently 0, 1 or 2; Q is selected from the group consisting of: -N(H)C(=O)OR, -N(R)C(=O)OR, -N(H)C(=O)R, -N(H)C (O)NHR, -N(H)C(O)NR₂ , -OC(=O)NR₂ ,

; V is selected from the group consisting of: -CH₂ OH, -CH₂ OMe, -CH₂ OEt, -CH₂ NH₂ , -CH₂ NHMe, -CH₂ NMe₂ , -CN, -CO₂ Me, -CO₂ Et, -CH₂ NHCO₂ Me, -CH₂ NHCO₂ Et, -CH₂ NHCO₂ iPr, -CH₂ N(H)CONH₂ , -CO₂ H, -CONH₂ , -CONHMe, -CONMe₂ , -CONHEt, -CONEt₂ ,_- CON(Me)(Et), -CON(CD₃ )₂ , -CON(Me)(CD₃ ), -CON(Et)(CD₃ ), -CON(i-Pr)(CD₃ ), -CH₂ NHCONHCH₂ CF₃ , -CH₂ NHCONHiPr, -CH₂ NHCONHMe, -CH₂ NHCONHEt,

; each R^f Independently selected from the group consisting of: H, C₁ -C₄ Alkyl, OH, C₁ -C₄ alkoxy and F; each R^g Independently selected from the group consisting of: H, C₁ -C₄ Alkyl and NH₂ ; Each R is independently C₁ -C₄ Alkyl, C₁ -C₄ haloalkyl or CD₃ ; T is selected from the group consisting of: -C₁ -C₄ Alkyl, -SO₂ C₁ -C₄ Alkyl, -SO₂ -Cycloalkyl, -C(O)C₁ -C₄ Alkyl, -C(O)aryl,

in R⁴ as hydrogen or C₁ -C₄ alkyl; m is 1 or 2; J is cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocycloalkylsulfonyl group and formamide group; v is 0 or 1; R⁶ is halo, haloalkyl, -C₁ -C₄ Alkyl, -C(O)C₁ -C₄ Alkyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate or tertiary butoxycarbonyl; each R⁷ independently selected from the group consisting of: cyano, halo, haloalkyl, -C₁ -C₄ Alkyl, -C(O)C₁ -C₄ Alkyl, -OH, Sulfonamido, Alkyl Sulfonyl, Haloalkyl Sulfonyl, Cycloalkyl Sulfonyl, Aryl Sulfonyl, Heteroaryl Sulfonyl, Heterocyclic Sulfonyl, Heterocycloalkylsulfonyl or carboxamido; R^8a and R^8b independently selected from the group consisting of: hydrogen, halo, -C₁ -C₄ Alkyl, -C₁ -C₄ Alkoxy, -CH₂ OC₁ -C₄ Alkyl, -CH₂ SO₂ C₁ -C₄ Alkyl and R^a1 ; Z is hydrogen, C₁ -C₄ Alkyl, -C(O)C₁ -C₄ Alkyl, -OH, -CN, -CF₃ , -NO₂ , halogen, -NHSO₂ Me, -NHCOMe, -CONH₂ , -CONH(C₁ -C₄ alkyl), amine, sulfonamido, alkylsulfonamido and cycloalkylsulfonamido; R^a1 is -CN, alkoxyalkyl, alkylsulfonyl, (amino)alkyl, carboxamido, optionally substituted heteroaryl, (heteroaryl)alkyl, -NR₄ C(O)C₁ -C₄ Alkyl, -OCH₂ CH=CH-alkylsulfonyl and (heterocyclyl)alkyl; X is selected from the group consisting of: -C₁ -C₄ Alkyl, -C₁ -C₄ Alkenyl, -NH₂ , -NHC₁ -C₄ Alkyl, -NH(C₁ -C₄ alkyl)₂ , (amino) alkyl and -CH₂ CH₂ NR₄ Y-Z² ;

,in t and u are independently 0, 1, 2 or 3; Y is absent or -C(=O)-, -SO₂ -, -C(=O)NH-, -C(=O)N(Me)-; Z² Selected from the group consisting of: -C(R^14a )=C(R^14b )(R^14c ), -C≡CR^14d , haloalkyl and R^a2 R^9a and R^9b Each independently selected from the group consisting of: alkenyl, alkynyl, -CN, -C₁ -C₄ Alkyl, halo, (amino)alkyl and -C(R^14a )=C(R^14b )(R^14c ); each Q¹ Independently selected from -CH₂ - and -C(=O)- R¹⁰ Selected from the group consisting of: hydrogen, -C₁ -C₄ Alkyl, -NHCOMe, -NHSO₂ Me, -CN, halo, -OCH₂ CH=CH-R^a3 , -CH₂ CH₂ CH=CH-R^a3 ; R¹¹ for -NHCOC(R^14a )=C(R^14b )(R^14c ), formamide, -C(O)NHCH₂ Ra⁵ , -C(O)NHCH₂ C≡CR^a6 or -CH₂ CH₂ CH=CH-R^a3 ; R¹² selected from the group consisting of alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl and carboxamido; R¹³ as hydrogen or C₁ -C₄ alkyl; R^14a , R^14b , R^14c and R^14d each independently selected from the group consisting of: hydrogen, halo, C₁ -C₄ Alkyl, (amino)alkyl and R^a3 ; R^a2 for -N(R¹⁵ )CH₂ CH=CH-R^a3 or -CH=CHCH₂ R^a4 ; R^a3 selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl, and carboxamido; R^a4 is optionally substituted heterocyclyl; R^a5 is selected from the group consisting of cyano and (amino)alkyl; R^a6 is hydrogen or formamide; R¹⁵ as hydrogen or C₁ -C₄ alkyl; and Each W is independently selected from the group consisting of -CH- or -N-. Aspect 2. The compound of Aspect 1, which has the formulaX' :

, or its pharmaceutically acceptable salt. Aspect 3. The compound of Aspect 1, which has the formulaXI' :

, or its pharmaceutically acceptable salt. Aspect 4. The compound of any one of Aspects 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: each R^a independently selected from H and C₁ -C₄ A group consisting of alkyl groups; each R^b independently selected from H and C₁ -C₄ A group consisting of alkyl groups; R^c is selected from the group consisting of H and halo; Q is selected from the group consisting of: -NHCO₂ Me, -NHCONHMe, -CHCOEt, -NHCOEt, -NHCOMe,

; V is selected from the group consisting of:

, where each R^f Independently selected from the group consisting of H, Me, Et, iPr, OH and

, where each R^g Independently selected from the group consisting of: H, Me, Et, iPr and NH₂ . Aspect 5. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: Q is selected from the group consisting of: -NHCO₂ Me,

; V is

, where each R^f Independently selected from the group consisting of H, Me, Et, iPr, and OH. Aspect 6. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: Q is selected from the group consisting of: -NHCO₂ Me,

; V is

, where each R^g Independently selected from the group consisting of: H, Me, Et, iPr and NH₂ . Aspect 7. The compound of any one of Aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q is -NHCO₂ Me. Aspect 8. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R^c is a halogen group. Aspect 9. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R^c is fluorine. Aspect 10. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R^8a and R^8b At least one of them is a halogen group. Aspect 11. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R^8a and R^8b At least one of them is fluorine. Aspect 12. The compound of any one of Aspects 1 to 2, or a pharmaceutically acceptable salt thereof, wherein p, q, r, and s are 1. Aspect 13. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein one R^g for C₁ -C₄ alkyl. Aspect 14. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein one R^g is methyl. Aspect 15. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each R^g for hydrogen. Aspect 16. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-1, T-2, or T-31. Aspect 17. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-1. Aspect 18. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-2. Aspect 19. The compound of any one of Aspects 1 to 7, or a pharmaceutically acceptable salt thereof, wherein T is T-31. Aspect 20. The compound of aspect 17 or a pharmaceutically acceptable salt thereof, wherein X is -CH₃ , X-1, X-11 or X-12. Aspect 21. The compound of Aspect 17, wherein X is -CH₃ . Aspect 22. The compound of Aspect 17, wherein X is X-1. Aspect 23. The compound of Aspect 17, wherein X is X-11. Aspect 24. The compound of Aspect 17, wherein X is X-12. Aspect 25. The compound of Aspect 1, wherein the compound is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt thereof. Aspect 26. A pharmaceutical composition comprising the compound of any one of Aspects 1 to 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Aspect 27. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the patient has cancer , chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections. Aspect 28. The method of Aspect 27, wherein the patient has cancer. Aspect 29. The method of Aspect 28, wherein the cancer is any one or more of the cancers of Table 2. Aspect 30. The method of Aspect 28, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia. Aspect 31. The method of any one of Aspects 27-30, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating the disease or condition. Aspect 32. The pharmaceutical composition of Aspect 26, for use in the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections. Aspect 33. The pharmaceutical composition of Aspect 32, for use in the treatment of cancer. Aspect 34. The pharmaceutical composition of Aspect 33, wherein the cancer is any one or more of the cancers of Table 2. Aspect 35. The pharmaceutical composition of Aspect 33, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia leukemia and mixed lineage leukemia. Aspect 36. The compound of any one of Aspects 1 to 25, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections . Aspect 37. The compound of Aspect 36, for use in the treatment of cancer. Aspect 38. The compound of Aspect 37, wherein the cancer is any one or more of the cancers of Table 2. Aspect 39. The compound of Aspect 37, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia. Aspect 40. Use of a compound according to any one of Aspects 1 to 25, or a pharmaceutically acceptable salt thereof, in the manufacture of a compound for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, hyperplasia Medications for sexually transmitted diseases, sepsis or viral infections. Aspect 41. The use of Aspect 40, for the treatment of cancer. Aspect 42. The use of Aspect 41, wherein the cancer is any one or more of the cancers of Table 2. Aspect 43. The use of Aspect 41, wherein the cancer is selected from the group consisting of: acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia.

Now that the methods, compounds, and compositions of matter provided herein are fully described, those skilled in the art will understand that without affecting the scope of the methods, compounds, and compositions provided herein or in any of the examples The methods, compounds and compositions of matter can be performed within a broad and equivalent range of conditions, formulations and other parameters.

All patents, patent applications, and publications cited herein are incorporated by reference in their entirety.

Claims (47)

A compound having formula I ,

, or a pharmaceutically acceptable salt thereof, wherein: each R ^a is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl; each R ^b is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl R ^c is selected from the group consisting of hydrogen and halo; each R ^d is independently selected from the group consisting of halo; p, q, r and s are independently 1 or 2; each n is independently 0, 1 or 2; Q is selected from the group consisting of: -N(H)C(=O)OR, -N(R)C(=O)OR, -N(H)C(=O)R, -N( H)C(O)NHR, -N(H)C(O)NR ₂ , -OC(=O)NR ₂ ,

; V is selected from the group consisting of: _-CH2OH , _-CH2OMe , _-CH2OEt , _-CH2NH2 , _-CH2NHMe , _-CH2NMe2 , cyano, _{- (} C=O) H, -CO ₂ Me, -CO ₂ Et, -CH ₂ NR ¹ CO ₂ Me, -CH ₂ NR ¹ CO ₂ CD ₃ , -CH ₂ NR ¹ CO ₂ Et, -CH ₂ NR ¹ CO ₂ iPr, - CH ₂ NR ¹ CONH ₂ , -CO ₂ H, -CONH ₂ , -CONHMe, -CONMe ₂ , -CONHEt, -CONEt ₂ , -CON(Me)(Et), -CON(CD ₃ ) ₂ , -CON( Me)( _CD3 ), -CON(Et)( _CD3 ), -CON ₍ i-Pr)( _{CD3 )} , _{-CH2NHCONHCH2CF3} , _{-CH2NHCONHiPr} , _-CH2NHCONHMe , _-CH2 NHCONHEt,

; each R ^{f is} independently selected from the group consisting of: hydrogen, C ₁ -C ₄ alkyl, hydroxy, C ₁ -C ₄ alkoxy, and halo; each R ^g is independently selected from the group consisting of: hydrogen , C ₁ -C ₄ alkyl and NH ₂ ; each R is independently C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or CD ₃ ; each R ¹ is independently hydrogen or C ₁ -C ₄ alkyl; each R2 is independently _C1 ^- _C4 alkyl or C3 _{- C6} cycloalkyl; each k is independently 0, 1, 2, 3 or 4; T is selected from the group consisting of:- C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylsulfonyl, cycloalkylsulfonyl, -C ₁ -C ₄ alkylcarbonyl, arylcarbonyl,

, wherein R ⁴ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkylcarbonyl, heterocyclyl and haloalkyl; each m is independently 1 or 2; J is hydrogen, cyano, alkyl Sulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocycloalkylsulfonyl and carboxamido; v is 0 or 1; R ⁶ is hydrogen, haloalkyl, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkyl Sulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocycloalkylsulfonyl, carboxamido, mesylate or tertiary butoxycarbonyl; R ⁷ is independently selected from the group consisting of hydrogen, cyano, halo, haloalkyl, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkylcarbonyl, hydroxy, sulfonamido, alkane ylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, heterocycloalkylsulfonyl, or carboxamido ; R ^8a , R ^8b , R ^8c and R ^8d are independently selected from the group consisting of hydrogen, halo, carboxyl, hydroxyl, -C ₁ -C ₄ alkoxycarbonyl, -C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkoxy, haloalkyl, haloalkoxy, -CH ₂ SO ₂ C ₁ -C ₄ alkyl, sulfonamido and R ^a1 ; Z is hydrogen, C ₁ -C ₄ Alkyl, -C ₁ -C ₄ alkylcarbonyl, hydroxyl, cyano, haloalkyl, -NO ₂ , halo, -NR ¹ SO ₂ (C ₁ -C ₄ alkyl), -NR ¹ SO ₂ ( C ₂ -C ₆ alkenyl), -NR ¹ CO(C ₁ -C ₄ alkyl), -CONH ₂ , -CONH(C ₁ -C ₄ alkyl), -CON(C ₁ -C ₄ alkyl) ₂ , -S(=O)(=NR ¹ )CF ₃ , S(=O)(=NR ¹ )(C ₁ -C ₄ alkyl), amino, sulfonamido, alkylsulfonamido, Haloalkylsulfonyl and cycloalkylsulfonyl; R ^a1 is cyano, alkoxyalkyl, aralkoxy, alkylsulfonyl, (amino)alkyl, formamido, sulfur amide, optionally substituted heteroaryl, (heteroaryl)alkyl, -NR13C(O) _{C1 -} C4alkyl, ^-OCH2CH = _CH -alkylsulfonyl, -O (C ₁ -C ₄ alkyl) O(C ₁ -C ₄ alkyl), -C ₂ -C ₆ alkenyl, heterocyclyloxy, aminocarbonyloxy and (heterocyclyl) alkyl; X selected Free from the group consisting of: -C ₁ -C ₄ alkyl, -C ₂ -C ₄ alkenyl, -NH ₂ , -NHC ₁ -C ₄ alkyl, -N(C ₁ -C ₄ alkyl) ₂ , (Amino) alkyl and -CH ₂ CH ₂ NR ¹ YZ ² ;

, where t and u are independently 0, 1, 2, or 3; Y is absent or is -C(=O)-, -SO ₂ -, -C(=O)NH-, -C(=O) N(Me)-; Z ² is selected from the group consisting of -C(R ^14a )=C(R ^14b )(R ^14c ), -C≡CR ^14d , alkyl, alkoxy, haloalkyl and R ^a2 R ^9a and R ^9b are each independently selected from the group consisting of alkenyl, alkynyl, cyano, -C ₁ -C ₄ alkyl, halo, (amino)alkyl and -C(R ^14a ) =C(R ^14b )(R ^14c ); each Q ¹ is independently selected from the group consisting of -CH ₂ - and -C(=O)- R ¹⁰ is selected from the group consisting of: hydrogen, -C ₁ -C ₄ Alkyl, -NR ¹³ CO (C ₁ -C ₄ alkyl), -NR ¹³ SO ₂ (C ₁ -C ₄ alkyl), cyano, halo, -OCH ₂ CH=CH-R ^a3 , -CH ₂ CH ₂ CH=CH-R ^a3 ; R ¹¹ is halogen, -NR ¹³ COC(R ^14a )=C(R ^14b )(R ^14c ), formamide, -C(O)NR ¹³ CH ₂ R ^a5 , -C(O)NR ¹³ CH ₂ CH=CH-R ^a3 , -C(O)NR ¹³ CH ₂ C≡CR ^a6 or -CH ₂ CH ₂ CH=CH-R ^a3 ; R ¹² is selected from the following compositions The group: alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl and carboxamido; R ¹³ is hydrogen or C ₁ -C ₄ alkyl; R ^14a , R ^14b , R ^14c and R ^14d are each independently selected from the group consisting of hydrogen, halo, C ₁ -C ₄ alkyl, (amino)alkyl and R ^a3 ; R ^a2 is -N(R ¹⁵ )CH ₂ CH=CH- R ^a3 or -CH=CHCH ₂ R ^a4 ; R ^a3 is selected from the group consisting of alkoxycarbonyl, alkylsulfonyl, cycloalkylsulfonyl and carboxamido; R ^a4 is optionally substituted R ^a5 is selected from the group consisting of cyano and (amino) alkyl; R ^a6 is hydrogen or carboxamido; R ¹⁵ is hydrogen or C ₁ -C ₄ alkyl; and each W is independently Selected from the group consisting of -CH- or -N-. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: each R ^a is hydrogen; each R ^b is hydrogen; R ^c is selected from the group consisting of hydrogen and halo; Q is selected from the group consisting of: -NHCO ₂ Me, -NHCONHMe, -CHCOEt, -NHCOEt, -NHCOMe,

; V is selected from the group consisting of:

, wherein each R ^{f is} independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, hydroxyl and

, wherein each R ^g is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and _NH2 . The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein p, q, r and s are 1. The compound of claim 1 having formula XII , XIII , XIV , XV or XVI :

, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein T is T-1, T-2, T-3, T-29 or T-32. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein T is T-1 or T-2. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein T is T-14, T-15, T-16, T-17, T-18, T-19, T -24, T-25, T-26, T-31 or T-36. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein Z is cyano, haloalkyl, alkylsulfonyl or cycloalkylsulfonyl. The compound of claim 1 having formula XI :

, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein: Q is selected from the group consisting of: -NHCO ₂ Me,

; V is

, where each R ^{f is} independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and hydroxyl. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein: Q is selected from the group consisting of: -NHCO ₂ Me,

; V is

, wherein each R ^g is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and _NH2 . The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein Q is -NHCO ₂ Me. The compound of claim 1 having formula XVIII :

, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R ^c is halo. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R ^c is fluorine. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein at least one of R ^8a and R ^8b is halo. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein at least one of R ^8a and R ^8b is fluorine. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein X is X-1, X-10, X-16, X-17, X-18, X-19 or X -20. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein X is X-2 or X-3. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein X is X-5 or X-21. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein X is X-11 or X-12. The compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein one R ^g is C ₁ -C ₄ alkyl. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein one R ^g is methyl. The compound of claim 1 having formula XXIV or XXX :

, or a pharmaceutically acceptable salt thereof. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein X is -CH ₃ , -NH ₂ , X-1, X-2, X-3, X-5, X-16 or X-18 ; Z is cyano, haloalkyl, alkylsulfonyl or cycloalkylsulfonyl; and R ^8b is hydrogen, -CH ₂ NMe ₂ , -C(O)NMe ₂ , -C ₁ -C ₄ alkane oxy, -CH ₂ OC ₁ -C ₄ alkyl,

. The compound of claim 1 having formula XXVI or XLII :

, or a pharmaceutically acceptable salt thereof. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R ^8b is -CH ₂ NMe ₂ , -C(O)NMe ₂ , -C ₁ -C _4alkoxy , -CH ₂ OC ₁ - C ₄ alkyl,

; X is X-1, X-2, X-3, X-5, X-6, X-11, X-12, X-13, X-14, X-16, X-18, X-19 , X-20, X-21, X-22, or X-23; and Z is cyano, haloalkyl, alkylsulfonyl, or cycloalkylsulfonyl. The compound of any one of claims 1 to 8 and 24 to 27 or a pharmaceutically acceptable salt thereof, wherein Z is cyano, -CF ₃ , methylsulfonyl or cyclopropylsulfonyl. The compound of claim 1, wherein the compound is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein the patient suffers from cancer, chronic autologous Immune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections. The method of claim 31, wherein the patient has cancer. The method of claim 32, wherein the cancer is any one or more of the cancers of Table 2. The method of claim 32, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia . The method of any one of claims 31 to 34, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating the disease or condition. The pharmaceutical composition of claim 30 for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections. The pharmaceutical composition of claim 36 for use in the treatment of cancer. The pharmaceutical composition of claim 37, wherein the cancer is any one or more of the cancers of Table 2. The pharmaceutical composition of claim 37, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed leukemia. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections. The compound of claim 40 for use in the treatment of cancer. The compound of claim 41, wherein the cancer is any one or more of the cancers of Table 2. The compound of claim 41, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and mixed lineage leukemia . Use of a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the manufacture of a compound for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections. The use of claim 44 for the treatment of cancer. The use of claim 45, wherein the cancer is any one or more of the cancers of Table 2. The use of claim 45, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia and mixed lineage leukemia .