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AU2018306606B2 - Compounds and methods for the targeted degradation of Androgen Receptor - Google Patents

Compounds and methods for the targeted degradation of Androgen Receptor Download PDF

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AU2018306606B2
AU2018306606B2 AU2018306606A AU2018306606A AU2018306606B2 AU 2018306606 B2 AU2018306606 B2 AU 2018306606B2 AU 2018306606 A AU2018306606 A AU 2018306606A AU 2018306606 A AU2018306606 A AU 2018306606A AU 2018306606 B2 AU2018306606 B2 AU 2018306606B2
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AU2018306606A1 (en
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Michael Berlin
Xin Chen
Andrew P. Crew
Craig M. Crews
Hanqing Dong
Yimin Qian
Lawrence Snyder
Jing Wang
Kurt Zimmermann
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Arvinas Operations Inc
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Arvinas Operations Inc
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Abstract

The present disclosure relates to bifunctional compounds, which find utility to degrade (and inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.

Description

COMPO[JNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR CROSS-REFERENCE TO RELATED APPLICATIONS
[001] The present disclosure is an International Patent Application claiming priority to U.S. Patent Application Serial No. 15/663,273, which is a Continuation-In-Part of U.S. Nonprovisional Application Serial No. 15/002,303, filed 20 January 2016, which claims the benefit of, and priority to, U.S. Provisional Patent Application Serial No. 62/105,210, filed 20 Januaryy 2015 and entitled: Compounds and Methods for the Targeted Degradation of the Androgen Receptor, all of which are incorporated herein by reference in their entireties.
BACKGROUND
[0021 1. Field of the Discovery. The present description relates to bifunctional compounds, which are useful for the modifying the ubiquitination and subsequent degradation of target polypeptides and proteins, in particular, androgen receptor. In certain aspects, the compounds comprise a Von Hippel-Lindau (V-L) binding moiety, which binds to the ViL E3 ubiquitin ligase, a target protein binding moiety, which binds to the target protein (e.g., androgen receptor), and optionally a linker moiety which links the VHiL binding moiety and target protein binding moiety.These compounds work in such way that the target protein/polypeptide is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein (e.g., androgen receptor).
[0031 2. Background Information. Androgen Receptor (AR) belongs to a nuclear hormone receptor family that is activated by androgens, such as testosterone and dihydrotestosterone (Pharmnacol.Rev. 2006, 58(4), 782-97; VTam. Horm. 1999, 55:309-52.). In the absence of androgens, AR is bound by Heat Shock Protein 90 (Hsp90) in the cytosol. When an androgen binds AR, its conformation changes to release AR from Hsp90 and to expose the Nuclear Localization Signal (NLS). The latter enables AR to translocate into the nucleus where AR acts as a transcription factor to promote gene expression responsible for male sexual characteristics (Endocr. Rev. 1987, 8(1):1-28;Mo. Endocrinol. 2002, 16(10), 2181-7). AR deficiency leads to Androgen Insensitivity Syndrome, formerly termed testicular feminization.
I
[0041 While AR is responsible for development of male sexual characteristics, it is also a well-documented oncogene in certain forms cancers including prostate cancers (Endocr. Rev. 2004, 25(2), 276-308). A commonly measured target gene of AR activity is the secreted Prostate Specific Antigen (PSA) protein. The current treatment regimen for prostate cancer involves inhibiting the androgen-AR axis by two methods. The first approach relies on reduction of androgens, while the second strategy aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12,823-824). Despite the development of effective targeted therapies, most patients develop resistance and the disease progresses. An alternative approach for the treatment of prostate cancer involves eliminating the AR protein. Because AR is a critical driver of tumorigenesis in many forms of prostate cancers, its elimination should lead to therapeutically benefical response.
[005] There exists an ongoing need in the art for effective treatments for diseases and conditions that are related to aberrant AR regulation or activity, such as, for example, cancer, prostate cancer, and IKennedy's Disease.
SUMMARY
[0061 The present disclosure describes compounds, including compositions comprising the same, which function to recruit endogenous proteins to an E3 ubiquitin ligase, e.g., Von Hippel-Lindau (VHL) E3 ubiquitin ligase, for ubiquitination and subsequent degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination and degradation of androgen receptor (AR). In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition including cancer, e.g., prostate cancer, and Kennedy's Disease.
[007] Thus, in one aspect, the disclosure provides compounds which function to recruit endogenous proteins, e.g., AR proteins, to E3 Ubiquitin Ligase for ubiquintination and degradation. In certain embodiments, the compounds have the following general structure:
[0081 ABM - L-ULM (I), 1009] wherein ABM is an AR binding moiety, ULM is an E3 ligase binding moiety, e.g., a VHL E3 ligase binding moiety (VLM), and L is a bond or a linker moiety which links the
ABM and ULM. As such, in certain embodiments, the description provides compounds having the following general structure:
[0101 ABM - L-VLM (II),
[011] wherein ABM is an AR binding moiety, VLM is a VHL E3 ligase binding moiety and L is a bond or a linkermoiety which links the ABM and VLM. In certain embodiments, the VLM comprises a hydroxyl prolyl moiety.
[0121 In certain embodiments, the ULM is a moiety specific for an E3 ubiquitin ligase such as, e.g., cereblon, mouse double minute 2 homolog (Mdm2), or inhibitor of apoptosis (IA), wherein the ULM moiety is coupled to an ABM as described herein.
[013] It will be understood that the general structures are exemplary and the respective moieties can be arranged spatially in any desired order or configuration, e.g. ULM-L-ABM and VLM-L-ABM respectively.
[014] In another aspect, the description provides AR binding moieties (ABM). In an additional embodiment, the description provides compounds having the following general structure: ABM-L, wherein ABM is an AR binding moiety as described herein, and L is a chemical linker moiety, or optionally a bond. In certain embodiments, the ABM and/or L are coupled to a ULM as described herein.
[0151 In any of the aspects or embodiments described herein, the ABM is selected from followingstructures:
- R22 Ro
-- N Y! W - W
ABM-a ABM-b
W' ----N' 2 W SRb Y2
A[3M-c andA l)-d wherein W 1 is aryl or heteroaryl, independently substituted by I or more halo, hydroxyl. nitro, CN, C CH, CF 3, C- 6 alkyl (linear, branched, optionally substituted by I or more halo, C1 6 alkoxyl), Cpn alkoxyl (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2 _ 6 alkynyl; Y, Y 2 are each independently NR, 0, S; Y,Y 4 ,Y 5are each independently a bond, 0, NR, CRYR, C=,C=S,SO, S02; Q is a 3-6 membered alicyclic oraromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 RQ, each R is independently H, OH, C16 alkyl (linear, branched, optionally substituted by I or more halo, C 1-6 alkoxyl), or.2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); 1 2 a Y V 2 R, R R, RRR, RE are each independently H, OH, C- alkyl (linear, branched, optionally substituted by I or more halo, C1- alkoxyl), or R ,R together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; W2 is a bond, C1 6 alkyl, alicyclic (e.g., C1-6 alicyclic), heterocyclic, ary, heteroaryl, bicyclic, biaryl, biheteroaryl, biheterocyclic, each optionally substituted by 1, 2 or 3 R"2; and each R"Wis independently H, halo, C 1 6alkyl (optionally substituted by I or more F),
OC 1 3alkyl (optionally substituted by I or more F), OH, NH 2, NR R, <CN.
[0161 In any of the aspects or embodiments described herein, the ABM can comprise or consist of a structure as set forth herein, in particular in any of the ABMs as provided in Examples 1-870.
[017] In certain embodiments, the JLM (derivatized or configured to be linked or coupled to an ABM via a linker (as indicated by the dashed line)) has the structure,
N 11R
R1 wherein, W3 is optionally substituted aryl, optionally substituted heteroaryl, or R, each R9 and Rio is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl or haloalkyl; or R 9 , RIO, and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R- is optionally substituted heterocyclic, optionally substituted alkoxy, optionally
RO
substituted heteroaryl, optionally substituted aryl or
RI, is H or optionally substituted alkyl; R 13 is H, optionally substituted alkyl, optionally substituted alkycarbonyl, optionally substituted (cycloalkyi)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R14a, R14, is each independently H, haloalkyl, or optionally substituted alkyl; W 5 is aphenyl or a 5-10 membered heteroaryl, R 1.5is H, halogen, CN, OH, NO 2, N R14aR14, OR a,4 CONR aR1 4 4 NR1 4 aCOR1 4b, b,
SO 2 NRi4R4h, NR4a SO2R 14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or wherein RI is H, halo, optionally substituted C3 6 cycloalkyl, optionally substituted C1 _-alkyl, optionally substituted C 1 alkenyl, or C1_haloalkyl;Xa is S or 0; each R1isis independently halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2, .3, or 4; each R 1 isis independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linked; and p is 0, 1. 2, 3, or 4. 10181 In another embodiments, the L has the structure
HO.
N'N 0
R.
wherein: R 9 is H; RI( is isopropyl, tert-butyl, sec-butyl, cyclopentyl or cyclohexyl;
R11 is; Rp is H;
R3 is -, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arvicarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted arylalkyl;
Ra is -, haloalkyl, methyl, ethyl, isopropyl, cyclopropyl, or C-C6 alkyli(linear, branched, optionally substituted), each optionally substituted with I or more halo, hydroxyl, nitro, CN, CBC6 alkyl (linear, branched, optionally substituted), or C-C alkoxyl (linear, branched, optionally substituted); and
Ris is wherein R1 7 is H, halo, optionally substituted C 3 .cycloalkyl, optionally substituted C1_6 alkvl, optionally substituted C1_ 6 alkenyl, and C 1haloalkyl; 6 and Xa is S or 0.
[0191 In certain embodiments, an androgen receptor binding moiety has a structure of
wherein: W is aryl orheteroaryl, independently substituted by1 or more halo, CF3 , hydroxyl, nitro, CN, C-CH, C16 alkyl (linear, branched, optionally substituted by I or more halo, C6 alkoxyl), C 1 - alkoxyl (linear, branched, optionally substituted by I or more halo), C2)6 alkenyl, C2_6 alkynyl; Y Y are each independently NR'. O, S; YY 4 , Y are each independently a bond, 0, NRy,CRYRC-R , C=o S, SO, SO 2 ; Qis a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 RQ, each R~is independently H,1-1 OHC6 alkyl (linear, branched, optionally substituted by I or more halo, C 6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);
R ,R are each independently H, OH,C-6 alkyl (linear, branched, optionally substituted by I or more halo, C1 6 alkoxyl);
W 2 is a bond, C 6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl, bicyclic, biaryl,
biheteroaryl,or biheterocyclic, each optionally substituted by 1, 2 or 3 Rw; and each Rw is independently [, halo, C 1 6 alkyl (optionally substituted by I or more F), OC Yl Y2 3alkyl (optionally substituted by Ior more F) OH. NH2, NR R , CN. 10201 In certain additional embodiments, the compounds comprise a plurality of E3 ligase binding moieties and/or a plurality of ABMs.
[0211 In certain embodiments, the linker group (L) comprises a chemical structural unit represented by the formula:
-Ag -- q
wherein q is an integer greater than 1; and A is independently selected from the group consisting of a bond. CR'R1, O, S. SO, SO2,NR3, SO 2 NRL, SONR3,CONR3, NRL 3 CONRI, NR--SO2NRt,CO,CR=CR[z, I'1 L2 Ii Lr 13 C-C. SiR R P(0)R P(O)OR NR"C(=NCN)NR!, NR C(=NCN), NR'C(=CNO2)NR', C 3 1Icycloalkyl optionally substituted with 0-6 R and/or RL groups, C3_heteocyclyl optionally substituted with 0-6 R' and/or RL groups, aryl optionally substituted with 0-6 R and/or R groups, heteroaryl optionally substituted with 0-6 R and/or RL2groups; LI L2 L3 L/A L5 wherein R R ,R R and R are each, independently, selected from the group consisting of H, halo, CIsalkyl, OCsalkyl, SCsalkyl, NHCpsalkyl, N(C-salkyl)2 , C ucycloalkyl, aryl, heteroaryl, C3 _1 heterocyclyl, OCscycloalkyl, SCIscycloalkyl, NHC scycloalkyl, N(C1 .scycloalkyl) 2 , N(Cjgcvcloalkyi)(C 8 alkyl), OH, NHL, SH, SO 2 C 8 alkyl, P(O)(OC> 8 alkyl)(Ci-salkyl), P(O)(OC -salkyl)2, CC-C -salkyl, CCH,CH-=CH(C 1 8 alkyl), C(C1 .salkyl)=CH(C 1 salkyl), C(C isalkyl)=C(C isalkyl)2. Si(OH) 3 , Si(C -galkyl)3, Si(OH)(C salkyl)2, COC-salkyl, COH, halogen, CN, CF 3 , CHF2 , CH 2F, NO2, SF,, SO 2NHC!salkyl, SO 2N(Csalkyl) 2, SONHC-aakySON(Csalky) 2 CONHCsalkyl, CON(Csalkyl) 2 ,
N(Csalkyl)CONI-I(C-salkyl), N(Csalkyl)CON(Csalkyl)2, NHCONH(C -salkyl), NHCON(Ci-salkyl) 2 ,NHCONH 2 . N(C1 salkvl)SO2NH(Cisalkyl),N(Casalkyl)SO 2N(C
salkyl) 2 , NH SO2NH(C.salkyl), N- SON(C.salkyl) 2, and NH SO 2 NH 2 ; and wherein when q is greater than 1, R or R Leach, independentlycanbelinkedto another A group to form cycloalkyl and/or heterocyclyl moeity that can be further substituted with 0-4 R Lgroups.
[0221 In certain embodiments, the description provides a bifunctional compound having a structure selected from the group consisting of Examples 1-870, a salt, a polymorph, and a prodrug thereof.
[0231 In another aspect, the description provides compositions comprising compounds as described herein, and a pharmaceutically acceptable carrier. In certain embodiments, the compositions are therapeutic or pharmaceutical compositions comprising an effective amount of a compound as described herein and a pharmaceutally acceptable carrier. In certain embodiments, the therapeutic or pharmaceutical compositions comprise an additional biologically active agent, e.g., an agent effective for the treatment of cancer.
[0241 In any of the aspects or embodiments described herein, the therapeutic compositions comprising compounds described herein can be in any suitable dosage form, e.g. solid, or liquid, and configured to be delivered by any suitable route, e.g., oral, parenteral, intravenous, intraperitoneal, subcutaneous, intramuscular, etc., and in any desired unit dosage form. For example, in certain embodimetns, the therapeutic composition as described herein is configured to be administered or consumed by a subject one or more times over a descired time
period, e.g., day, week, month, etc.
[025] In another aspect, the disclosure provides methods of modulating protein ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal, or human patient, the method comprising administering an effective amount of a compound as described herein or a composition comprising an effective amount of the same to a subject, wherein the compound or composition comprising the same is effective in modulating protein ubquitination and degration of the protiein inthe subject. In certain embodiments, the protein is androgen receptor (AR).
[0261 In another aspect, the disclosure provides methods of modulating AR protein ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal, or human patient, the method comprising administering an effective amount of a compound as described herein or a composition comprising an effective amount of the same to a subject, wherein the compound or composition comprising the same is effective in modulating AR protein ubquitination and degration of the protiein in the subject.
[027] In another aspect, the disclosure provides methods of treating or ameliorating a symptom of a disease related to AR activity in a subject, e.g., a cell, atissue, mammal, or human patient, the method comprising administering an effective amount of a compound as described herein or a composition comprising an effective amount of the same to a subject in need thereof, wherein the compound or composition comprising the same is effective in treating or ameliorating a symptom of a disease related to AR activity in the subject. In certain embodiments, the disease to be treated is cancer, e.g., prostate cancer, or Kennedy's Disease. In a preferred embodiment, the subject is a human.
[0281 In another aspect, the disclosure provides methods for identifying the effects of the degradation of proteins of interest in a biological system using compounds according to the present invention.
[0291 In another aspect, the description provides kits comprising compounds or compositions as described herein. The kit may be promoted, distributed, or sold as a unit for performing the methods of the present invention. In addition, the kits of the present invention may preferably contain instructions which describe a suitable use. Such kits can be conveniently used, e.g., in clinical settings, to treat patients exhibiting symptoms of, e.g., cancer or Kennedy's Disease.
[0301 Where applicable or not specifically disclaimed, any one of the embodiments described herein are contemplated to be able to combine with any other one or more embodiments, even though the embodiments are described under different aspects of the invention. As such, the preceding general areas of utility are given by way of example only and are not intended to be limiting on the scope of the present disclosure and appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present invention will be appreciated by one of ordinary skill in the art in light of the instant claims, description, and examples. For example, the various aspects and embodiments of the invention may be utilized in numerous combinations, all of which are expressly contemplated by the present description. These additional advantages objects and embodiments are expressly included within the scope of the present invention. The publications and other materials used herein to illuminate the background of the invention, and in particular cases, to provide additional details respecting the practice, are incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS 10311 The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating an embodiment of the invention and are not to be construed as limiting the invention. Further objects, features and advantages of the invention will become apparent from the following detailed description taken in conjunction with the accompanying figures showing illustrative embodiments of the invention, in which:
[0321 Figure IA and Figure 1B.Illustration of general principle for PROTAC function. Figure IA: Exemplary PROTACs comprise an androgen receptor targeting moiety (ABM; darklv shaded rectangle), a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (VLM; lightly shaded triangle), and a linker moiety (L; black line) coupling or tethering the ABM to the VLM (as described herein, L can be absent or a bond or a chemical linker moiety). Figure 1B Illustrates the functional use of the PROTACs as described herein. Briefly, the VLM recognizes and binds to Von Hippel-Lindau (VHL) E3 ubiquitin ligase, and the ABM binds and recruits androgen receptor and brings it into close proximity to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin conjugating protein, and either alone or via the E2 protein catalyzes attachment of ubiquitin (dark circles')to a lysine on the target protein via an isopeptide bond. The poly-ubiquitinated protein (far right) is then targeted for degration by the proteosomal machinery of the cell.
[0331 Figure 2. Apoptosis in VCaP cells. VCaP cells were cultured in Charcoal Stripped Serum containing media supplemented with 0.1 nM R1881 for 48 hrs. The degree of apoptosis was ascertained with CaspaseGlo assay (Promega). These results demonstrated that PROTACs are much more potent in inducing apoptosis than an AR antagonist enzalutamide. Further, the degree of AR degradation correlates with their ability to induce apoptosis in VCaP cells.
[0341 Figure 3. Anti-proliferation in LNCaP F876L. Anti-proliferation in LNCaP F876L cells observed with treatment with Example I as compared to enzaluamide. LNCaP cells transduced with AR F876L construct were cultured in Charcoal Stripped Serum containing media.
[0351 Figure 4. PSA suppression in LNCaP F876L. LNCaP cells transduced with AR F876L construct were cultured in Charcoal Stripped Serum containing media supplemented with 0.1 nM R1881 for 7 days. The results demonstrated that AR PROTAC is able to suppress the transcriptional activity of AR in F876L containing cells.
[0361 Figure 5. Prostate involution in C57B6 mouse model. 12-week old male C57BL/6 mice were treated with AR PROTAC Example 163 and its inactive epimer analog Compound A which is unable to bind to VHL E3 ligase. Enzalutamide (PO, QD. 30 mpk), Example 163 (IP, QD, I and 3 mpk) and Compound A (IP, QD, 1 and3 mpk) were administered for 10 days, upon which the prostates were isolated and weighed. These results demonstrated that
II the ability of PROTAC Example 163 to degrade AR leads to significant prostate involution in mice at very low doses.
[037] Figure 6. Tumor growth inhibition in VCaP xenograft model. VCaP cells were implanted into CB17 scid mice subcutaneously. Once the tumors were palpable, the mice were castrated, leading to temporary tumor stasis. Upon regrowth of tumors, the mice were dosed with enzalutamide (PO, QD, 30 mpk) or AR PROTAC Example 163 (IP, QD, at 30, 10 and 3 mpk) as indicated. Tumor growth inhibition was observed in all treatment arms.
[038] Figure 7A and Figure 7B. AR degradation of PROTAC is E3 Hiase dependent. Figure 7A: AR PROTAC Example I was added to LNCaP cells at indicated concentrations for 24 hours in the presence or absence of 10 uM VHL E3 ligase ligand compound B. Figure 7B: LNCaP cells were treated with AR PROTAC Example I and its inactive epimer analog compound C which is unable to bind to VHL E3 ligase."
DETAILED DESCRIPTION
[039] The following is a detailed description provided to aid those skilled in the art in practicing the present invention. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, figures and other references mentioned herein are expressly incorporated by reference in their entirety.
[0401 The present description relates to the surprising and unexpected discovery that an E3 ubiquitin ligase protein can ubiquitinate a target protein, in particular androgen receptor, once the E3 ubiquitin ligase protein and the target protein are brought into proximity by a chimeric construct (e.g., PROTAC) as described herein, in which a moiety that binds the E3 ubiquitin ligase protein is coupled, e.g., covalently, to a moiety that bind the androgen receptortarget protein. Accordingly, the present description provides compounds, compositions comprising the same. and associated methods of use for ubiquitination and degradation of a chosen target protein, e.g., androgen receptor (See Figure IA and Figure 1B).
[041] The present description is related in certain aspects to U.S. Patent Publication 2014/0356322AI, which is incorporated herein by reference in its entirety for all purposes.
[042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the invention.
[043] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms in which case each carbon atom number falling within the range is provided), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
[044] The following terms are used to describe the present invention. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present invention.
[045] The articles "a" and "an" as used herein and in the appended claims are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.
[046] The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); inyet another embodiment, to both A and B (optionally including other elements); etc.
[047] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one. but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e.."one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."
[048] The term "about" and the like, as used herein, in association with numeric values or ranges, reflects the fact that there is a certain level of variation that is recognized and tolerated in the art due to practical and/or theoretical limitations. For example, minor variation is tolerated due to inherent variances in the manner in which certain devices operate and/or measurements are taken. In accordance with the above, the phrase "about" is normally used to encompass values within the standard deviation or standard error.
[0491 In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having." "containing," "involving," "holding." "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
[050] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
[051] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise.
[10521 The terms "co-administration" and "co-administering" or "combination therapy" can refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time. In certain preferred aspects, one or more of the present compounds described herein, are coadministered in combination with at least one additional bioactive agent. especially including an anticancer agent. In particularly preferred aspects, the co-administration of compounds results in synergistic activity and/or therapy, including anticancer activity.
[1053] The term "effective" can mean, but is in no way limited to, that amount/dose of the active pharmaceutical ingredient, which, when used in the context of its intended use, effectuates or is sufficient to prevent, inhibit the occurrence, ameliorate, delay or treat (alleviate a symptom to some extent, preferably all) the symptoms of a condition, disorder or disease state in a subject in need of such treatment or receiving such treatment. The term effective subsumes all other effective amount or effective concentration terms, e.g., "effective amount/dose," "pharmaceutically effective amount/dose" or "therapeutically effective amount/dose," which are otherwise described or used in the present application.
[054] The effective amount depends on the type and severity of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration., concurrent medication, and other factors which those skilled in the medical arts will recognize. The exact amount can be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3. 1992); Lloyd. The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The
Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams
& Wilkins).
[055] The term "pharmacological composition," "therapeutic composition," "therapeutic formulation" or "pharmaceutically acceptable formulation" can mean, but is in no way limited to, a composition or formulation that allows for the effective distribution of an agent provided by the invention, which is in a form suitable for administration to the physical location most suitable for their desired activity, e.g., systemic administration.
[0561 The term "pharmaceutically acceptable" or "pharmacologically acceptable" can mean, but is in no way limited to, entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. 1057] The tern "pharmaceutically acceptable carrier" or"pharmacologically acceptable carrier" can mean, but is in no way limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
[0581 The term "systemic administration" refers to a route of administration that is, e.g., enteral or parenteral, and results in the systemic distribution of an agent leading to systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example.pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect. Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful.
[059] The term "local administration" refers to a route of administration in which the agent is delivered to a site that is apposite or proximal, e.g., within about 10 cm, to the site of the lesion or disease. 1060] The term "compound", as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other steroisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof where applicable, in context. Within its use in context. the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds. The term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described.
[0611 ft is understood by those of ordinary skill that molecules which are described
herein are stable compounds as generally described hereunder. When the bond is shown, both a double bond and single bond are represented within the context of the compound shown.
[062] As used herein, "derivatives" can mean compositions formed from the native compounds either directly, by modification, or by partial substitution. As used herein, "analogs" can mean compositions that have a structure similar to, but not identical to, the native compound.
[0631 The term "Ubiquitin Ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. By way of example, Von Hippel-Lindau E3 Ubiquitin Ligase or VCB E3 Ubiquitin Ligase is protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to mono-ubiquitination, in which only a single ubiquitin is added by the ubiquitin ligase to a substrate molecule. Mono-ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin. Further complicating matters, different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
[0641 The term "subject" is used throughout the specification to describe a cell, tissue, or animal, preferably a mammal, e.g., a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc. In general, in the present invention, the term patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.
[0651 Compounds
[0661 In one aspect, the present invention provides compounds useful for regulating protein activity. The composition comprises a ubiquitin pathway protein binding moiety (preferably for an E3 ubiquitin ligase. alone or in complex with an E2 ubiquitin conjugating enzyme which is responsible for the transfer of ubiquitin to targeted proteins) according to a defined chemical structure and a protein targeting moiety which are linked or coupled together, preferably through a linker, wherein the ubiquitin pathway protein binding moiety recognizes an ubiquitin pathway protein and the targeting moiety recognizes a target protein (e.g., androgen receptor). Such compounds may be referred to herein as PROTAC compounds or PROTACs.
[0671 In one aspect, the description provides AR binding moieties (ABM). In certain embodiments, the compounds having the following general structure: ABM-L, wherein ABM is an AR binding moiety as described herein, and L is a chemical linker moiety. e.g., a linker as described herein, or optionally a bond. In certain embodiments, the ABM and/or L are coupled to a ULM as described herein below.
[0681 In another aspect, the disclosure provides compounds which function to recruit androgen receptor (AR) proteins to E3 Ubiquitin Ligase for ubiquintination and degradation. In certain embodiments, the compounds have the following general structure:
[0691 ABM -L-ULM (),
[0701 wherein ULM is an E3 ligase binding moiety. ABM is an AR binding moiety, which binds to an AR protein and L is a bond or a chemical liner moiety which links the A3M and ULM.
[0711 In certain embodiments, the ULM is a moiety specific for an E3 ubiquitin ligase such as, e.g., Von Hippel-Lindau E3 ubiquitin ligase (VHL), cereblon, mouse double minutes homolog (Mdm2), or inhibitor of apoptosis (IAP), wherein the ULM moiety is coupled to an ABM as described herein.
[0721 Without being bound by any particular theory, it is hypothesized that due at least in part to the proximity of AR and the E3 ubiquitin ligase, the AR is ubiquitinated by the ubiquitin ligase and degraded. In certain embodiments, the ABM is chemically linked or coupled directly to the ULM group. In certain additional embodiments, the AIM is chemically linked or coupled to the ULM via a chemical linker moiety. In additional embodiments, the description provides compounds having the following general structure:
[073] ABM -L-VLM (II),
[0741 wherein ABM is an AR binding moiety and VLM is a Von Hippel-Lindau E3 Ubiquitin Ligase (VHL) binding moiety,and L is a bond or a chemical linker moiety which links the ABM and VLM. The ULM or VLM group and ABM group may be covalently linked to the linker group through any covalent bond which is appropriate and stable to the chemistry of the linker.
[075] In certain embodiments, the ULM or VLM comprises a hydroxyprolyl moiety. The hydroxyl prolyl moiety has been shown to be important for binding and recruiting of the VHL protein.
[0761 It will be understood that the general structures are exemplary and the respective moieties can be arranged in any desired order or configuration, e.g., ULM-L-ABM, and VLM-L ABM respectively. In certain additional embodiments, the compounds comprise a plurality of E3 ligase binding moieties and/or a plurality of ABMs.
[0771 In certain embodiments, ABM alone, without forming ABM-L-ULM, provides desired properties in regulating protein activity.
[0781 In any of the aspects or embodiments of compounds described herein, unless indicated otherwise, the compounds are intended to encompass pharmaceuically acceptable salts, enantiomers, stercoisomers, solvates or polymorphs thereof.
[079] Exemplarv ULMs
[080] In certain embodiments of the compounds as described herein, theULM comprises a chemical structure selected from the group ULM-a:
W3 jaRP
X2
ULM-a wherein: a dashed line indicates the attachment of at least one ABM, another ULM or VLM (i.e., LULM' or VLM'), or a chemical linker moiety coupling at least one ABM, a ULM' or VLM' to the other end of the linker; 1 2V3 N; y X , X are each independently a bond, 0, NRY3, CR R- , C=0, C=S, SO, SO 2 ; R, are each independently H, linear or branched C1 6 alkyl, optionally substituted byI or more halo, optionally substituted Cs6 alkoxyl (e.g., optionally substituted with 0-3 R groups); RP is 0. 1, 2, or 3, groups, each independently selected from H, halo, -OH, C1 3 alkyl, C=O;
W3 is an optionally substituted -T-N(aRR), ---T-Aryl, an optionally substituted -T Heteroaryl, an optionally substituted -T-Heterocycle, an optionally substituted -NR -T Aryl, an optionally substituted -NRT-1-Heteroaryl or an optionally substituted -NR-iT Heterocycle, where T is covalently bonded to X: each R I, RRibis independently 1-1, a C 1 -Ce alkyl group (linear, branched, optionally substituted by I or more halo. -OH), RC=, R3 C=S, R3 S0. R"SO2, N(R 3 R 4 )C=O. 4 )C=S, N(R Y R N(RR Y 4 )SO, N(R13 R 4 )SO 2; W4 is an optionally substituted -NR -T-Aryl, anoptionallysubstiuted-NR--T-Heteroaryl grouporanoptionally substituted-NR-T-Heterocycle,wherein -NR iscovalently bonded to X R is H or CH 3, preferably H; and is an optionally substituted-(CH 2 )n-group. wherein each one of themethylene groups may be optionally substituted with one or two substituentspreferably selected from halogen, a C1 -C alkyl group (linear, branched. optionally substituted by I or more halogen, -OH) or the sidechain of an amino acid as otherwise described herein, preferably methyl, which may be optionally substituted; and n is 0 to 6, often 0, 1., or 3, preferably 0.
[0811 Alternatively, Tmay also be a -(CH O),- 2 group, a-(OC 2 )n-group, a (CH 2CH 2O)n- group, a -(OCH 2CH 2)n- group, each of which groups is optionally substituted; and
[0821 Alternatively, T is an optionally substituted -(CH 2 )i- group, wherein each one of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, an amino acid sidechain as otherwise described herein or a C-C6 alkyl group (linear, branched, optionally substituted by 1 or more halo, -OH), preferably one or two methyl groups, which may be optionally substituted; and n is 0 to 6. often 0, 1, 2 or 3, preferably 0 or 1.
[083] Alternatively, T may also be a -(CH 20)- group,a-(OCH 2 )-groupa
(C1 2 CH2 O),- group, a -(OCI-1 2CH2 )n- group, all of which groups are optionally substituted.
[084] In any of the embodiments described herein., W and/or W can be attached to a linker moiety as described herein.
[085] In certain embodiments, aryl groups for W include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or naphthyl group is optionally substituted with a linker group to which is attached a ABIM group (including a ULM' group) and/or a halogen (preferably F or Cl). an amine, monoalkyl- or dialkyl amine (preferably, dimethylamine), an amido group (preferably a -(CH)m-NR 1C(O)R 2 groupwhereinmR 1 andR 2 are the same as for R), a halogen(often F or CD), OH, C3, CF 3, OMe, OCF3, NO2, CN or a
S(O)2Rs group (Rs is a a C-C 6 alkyl group, an optionally substituted aryl, heteroaryl or heterocycle group or a -(CI 2 )mNRR 2 group), each of which may be substituted in ortho-, meta and/or para- positions of the phenyl ring, preferably para-), or an Ar (preferably phenyl), heteroaryl or heterocycle. Preferably said substituent phenyl group is an optionally substituted phenyl group (i.e., the substituent phenyl group itself is preferably substituted with at least one of F. Cl, OH, SH, COOH, CH 3 , CF3 . OMe. OCF3, NO2 , CN or a linker group to which is attached a ABM group (including a ULM' group), wherein the substitution occurs in ortho-, meta- and/or para- positions of the phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted including as described above, an optionally substituted heteroaryl (preferably an optionally substituted isoxazole including a methylsubstituted isoxazole, an optionally substituted oxazole including a methylsubstituted oxazole, an optionally substituted thiazole including a methyl substituted thiazole, an optionally substituted pyrrole including a methylsubstituted pyrrole, an optionally substituted imidazole including a methylimidazole. a benzylimidazole or methoxybenzylimidazole, an oximidazole or methyloximidazole, an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methylsubstituted triazole group, a pyridine group, including a halo (preferably, F) or methylsubstitutedpyridine group or an oxapyridine group (wherein the pyridine group is linked to the phenyl group by an oxygen) or an optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline oxane or thiane. Each of the aryl, heteroaryl or heterocyclic groups may be optionally substituted with a linker group to which is attached a ABM group (including a ULM' group). 10861 In certain embodiments, heteroaryl groups for W include an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2. 3 or 4-azaindolizine) an optionally substituted benzimidazole, benzodiazole, benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl substituted), an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably methyl and/or thiol substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably a 1,2,3-triazole substituted with a methyl group, a triisopropylsilyl group, an optionally substituted -(CH2)m-O-C-C6 alkyl group or an optionally substituted -(CH2 )m-C(O)-O-C 1 -C alkyl group), an optionally substituted pyridine
(2-, 3, or 4-pyridine) or a group according to the chemical structure: ' Sc 0 RHET O - RHET N N RE RURE
0
RHEr H T IN- 5 N
0 0
RHET H T
wherein: Sc'is CHR NRU or 0; RHisIH, CNNOhalo(preferably C or F), optionally substitutedC1 -C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3 ), optionally substituted O(C-C 6alkl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C-C-Ra wherein Ra is H or a C1 -C6 alkyl group (preferably C-C 3 alkyl); Rss is H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C1 -C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted -C(O)(C 1 -C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); RURE is C-C6 alkyl (preferably H or C1 -C 3 alkyl) or a -C(O)(t-C 6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine. tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted; and yc is N or C-Ryc, wherein Ryc is -, OH, CN, NO2, halo (preferably C or F), optionally substituted C 1 C 6alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3 ), optionally substituted O(C-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C--C-Ra wherein Ra is H or a C-C6 alkyl group (preferably CIC3 alkyl). Each of said heteroaryl groups may be optionally substituted with a linker group to which is attached a ABM group (including a ULM' group). 10871 In additional embodiments, heterocycle groups for W' include tetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane and thiane, each of which groups may be optionally substituted or a group according to the chemical structure:
RPRP1 RPRO1 RPRO 2
SRPRO N-(CH 2)n
0 0
RPRO 0 RR
N-(CH or N(CH2)
o group,
wherein: RPRO is H, optionally substituted C-C. alkyl or an optionally substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole. thiazole. isothiazole. imidazole. diazole. oximidazole,pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C--C 3 alkyl group, preferably methyl or a halo group, preferably F or C), benzofuran, indole, indolizine, azaindolizine;
RPRO and RPRO2 are each independently H, an optionally subsituted C--C 3 alkyl group or together form a keto group, and each n is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), wherein each of said Heteocycle groups may be optionally substituted with a linker group to which is attached a ABM group (including a ULM' group) or a pharmaceutically acceptable salt, stercoisomer, solvate or
polymorph thereof.
[0881 In certain embodiments, W 3 substituents for use in the present invention also include specifically (and without limitation to the specific compound disclosed) the W 3 substituents whichare found in the identified compounds disclosed herein (which includes the specific compounds which are disclosed in the present specification, and the figures which are attached hereto). Each of these W3 substituents may be used in conjunction with any number of W 4 substituents, which are also disclosed herein.
[089] In certain embodiments, Aryl groups for W 4 include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl group is optionally substituted with a linker group to which is attached an ABM group (including a ULM' group). a halogen (preferably F or Cl), an amine,monoalkyl- or dialkyl amine (preferably, dimethylamine), F, Cl, OH, COOH, C-C 6 alkyl, preferably CH 3, CF3, OMe, OCF3, NO2 , or CN group (each of which may be substituted in ortho-, meta- and/or para- positions of the phenyl ring, preferably para-), an optionally substituted phenyl group (the phenyl group itself is preferably substituted with a linker group attached to a ABM group, including a ULM' group), and/or at least one of F, Cl,
0H, COOH, CH3, CF3 , OMe, OCF3, NO 2 ,or CN group (in ortho-, meta- and/or para- positions of the phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole including a methylsubstituted isoxazole, an optionally substituted oxazole including a methylsubstituted oxazole, an optionally substituted thiazole including a methyl substituted thiazole, an optionally substituted isothiazole including a methyl substituted isothiazole, an optionally substituted pyrrole including a methylsubstituted pyrrole, an optionally substituted imidazole including a methylimidazole, an optionally substituted benzimidazole or methoxybenzylimidazole, an optionally substituted oximidazole or methyloximidazole, an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methylsubstituted triazole group, an optionally substituted pyridine group, including a halo
(preferably, F) or methylsubstitutedpyridine group or an oxapyridine group (wherein the pyridine group is linked to the phenyl group by an oxygen), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), an optionally substituted quinoline, an optionally substituted group according to the chemical structure:
SSc RHET O - RHET N R RHET o 0 N
R-J!ET N R HETiC FoC or N
S'~~ ~R isCRRNUE R PROI r0 R Z02 R PRO
0
wherein: Sc is CHR 5 NR JIor 0; Rn s f, CNNOhalo (prefrablyCorF), optionally substituted C-C 6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF), optionally substituted O(C-C 6alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C-C-Ra wherein Ra is H or a C-C6 alkyl group (preferably CC3 alkyl); Rss is H, CN, NO 2 , halo (preferably F or CA), optionally substituted CC6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halogroups), optionally substituted 0-(C-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up
to three halo groups) or an optionally substituted -C()(C-C6 alkyl) (preferably
substituted with one or two hydroxyl groups or up to threehalo groups); R UJRE C6 alkyl (preferably H or C-C 3 alkyl) or a -C(O)(I-C 6 alkyl) each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted phenyl group, an optionally substituted heteroaryl, or an optionally substituted heterocycle, preferably for example piperidine, morpholine, pyrrolidine. tetrahydrofuran); RPR 0 is H, optionally substituted C 1 -C 6 alkyl or an optionally substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran. thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a CIC alkyl group. preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine; llPRO! and RPRO2 are each independently H, an optionally subsituted CtC3 alkyl group or together form a keto group; and each n is independently 0, 1, 2, 3, 4, 5 or 6 (preferably 0 or 1), or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine. piperazine or morpholine (each of which groups when substituted, are preferably substituted with a methyl or halo (F, Br, Cl). each of which groups may be optionally substituted with a linker group to which is attached a AIM group (including a ULM' group).
RPROl PR2 RPRO
-N-(CH2)n
[0901 In certain preferred aspects, 0 is a
RPRO /o N-(CH2)nr .1 or R PRO
N-(CH 2 )n
[091] 0 or group,
[092] wherein RPR and n are the same as above.
[0931 In certain embodiments, heteroaryl groups for W4 include an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole, an optionally substituted indolizine, an optionally substituted azaindolizine, an optionally substituted benzofuran, including an optionally substituted benzofuran, an optionally substituted isoxazole, an opionally substituted thiazole, an optionally substituted isothiazole, an optionally substituted thiophene, an optionally substituted pyridine (2-, 3, or 4-pyridine), an optionally substituted imidazole, an optionally substituted pyrrole, an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted oxirnidazole, or a group according to the chemical structure: - Sc SC 0 HET O - R HET N N
0
RIET H ET N N N
0 0
RHET N or RHET
N Y
wherein: ss U'RE Sc is CHR NR or 0:
RHETis -, CN, NO 2 , halo (preferably CA or F), optionally substituted CeC 6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3 ), optionally substituted O(C-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group-C--C --Ra wherein Ra is -ora C-C6 alkyl group (preferably C-C 3 alkyl); Rss is H, NO2, halo (preferably F or Cl), optionally substituted C-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C-C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted -C(O)(C-C6 alkyl) (preferably
substituted with one or two hydroxyl groups or up to three halo groups); RURE is H. a C-C6 alkyl(preferably H orC-C3 alkyl) or a -C(O)(C-C 6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and Yc is N or C R' , wherein RYc is H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C-C 6alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. C13), optionally substituted O(CC6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -CC-Ra wherein Ra is H or a CIC6 alkyl group (preferably C-C3 alkyl). each of which groups may be optionally substituted with a linker group to which is attached a ABM group (including a ULM' group).
[0941 In certain embodiments, heterocycle groups for W 4 include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine, oxane or thiane, each of which groups may be optionally substituted, or a group according to the chemical structure:
R PRo2 R PRO 2 R RR HET - N-(CH2)n RN
o or 0
RPRO -(CH 2)0 RPRO N-(CH2),l or /
N-(CH2)n preferably, a 0 or group, wherein: RPR is H, optionally substituted CC6 alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group; PROJI PP02 R and R are each independently -, an optionally subsituted C-C 3 alkyl group or together form a keto group and each n is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1) each of which groups may be optionally substituted with a linker group to which is attached a ABM group (including a ULM' group) In additional embodiments, W' substituents for use in the present invention also include specifically (and without limitation to the specific compound disclosed) the
W 4 substituents which are found in the identified compounds disclosed herein (which includes the specific compounds which are disclosed in the present specification, and the figures which are attached hereto).Each of these W4 substituents may be used in conjunction with any number of W3 substituents whichare also disclosed herein.
[0951 In certain additional embodiments, ULM-a, is optionally substituted by 1-3 R groups in the pyrrolidine moiety. Each RPis independently H. halo, -OHCI-3 alkyl.
[0961 In any of the embodiments described herein, the W3, W4 can independently be covalently coupled to a linker which is attached one or more ABM groups.
[0971 In certain embodiments, ULM is a group (derivatized or configured to be linked or coupled to an ABM via a linker (as indicated by the dashed line) according to the chemical structure:
HO, H R 14a N 'R14b
W3 O w5
(R 1 0o R15
[098] wherein, W` is optionally substituted aryl, optionally substituted heteroaryl, or Rg 1-+R10 R1 1
[0991 each R 9 and RIO is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; or R 9, RIO, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
[0100] R, is optionally substituted heterocyclic, optionally substituted alkoxy, optionally 0
-N,' -N2- substituted heteroaryl, optionally substituted aryl, R13 )p or
0 -N4-(R3 N
[01011 R12 isH or optionally substituted alkyl;
[0102] R13is H. optionally substituted alkyl, optionally substituted alkylcarbonyl,
optionally substituted (cycIoalkyl)aikylcarbonyi, optionally substituted aralkylcarbonvl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
[01031 R14a, R14b, is each independently H, haloalkyl, or optionally substituted alkyl;
[0104] W- is a phenyl or a 5-10 membered heteroaryl, 101051 R- 5 is H, halogen, CN, OH, NO 2, NR4aR 4 b, OR] 4 a, CONR14R1 4,.NR 4 aCOR14b, S0 2 NR14.R14b, NR14aSO2R14, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted cycloalkyl; optionally substituted cycloheteroalkyl;
[0106] each R 1 6 is independently halo, optionally substituted alkyl, haloalkyl, hydroxy, optionally substituted alkoxy, or haloalkoxy;
[0107] ois0,1,2,3,or4;
[01081 each Ris is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; and 101091 p is 0, 1, 2, 3, or 4. R 17
N
[0110] In certain embodiments, R 15 is whereinR 1 7 isH,halooptionallyI, substituted C 3 _6cycloalkyl, optionally substituted C16alkyl, optionally substitutedC'1 6 alkenyl, and Ci-.haloalkyl; and
[0111] Xa is S or O.
[0112] In certain embodiments, RP is selected from the group methyl, ethyl, isopropyl, and cyclopropyl.
[0113] In certain additional embodiments, R 15 is selected from the group consisting of:
F C1 Br/
N N N S S Sg4 SS
F3 C
/NN'N 7 N
/ ; / ;5 n N
O O
[0114] In certain embodiments, R 1 1 is selected from the group consisting of: 0 0 F00
-N-N [-N F -N Br
0
[-N ;-N ON N Br -N
o 0
-N N -N -N 0
F ; ON; CN
-N -NOMe - N OMe CI;
0
-N -N CI -N OMe ;and 'N
[0115] In certain embodiments, the ULM (derivatized or configured to be linked or coupled to an ABM via a linker (as indicated by the dashed line)) has the structure:
HO, H N-"A R14a N R9 0 0
R1 5
[01161 wherein
[0117] R 9 is H;
[0118] Ro is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;
,R12 I-N,
[01191 RII is R13;
[0120] RA is H;
[1)121] R13 is 1, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
[01221 R14a is H, haloalkyl, methyl, ethyl, isopropyl, cyclopropyl, or C1C6 alkyl (linear, branched. optionally substitued), each optionally substituted with I or more halo, hydroxyl, nitro, CN, C-C 6 alkyl (linear, branched, optionally substituted), or -C.6 alkoxyl (linear, branched, optionally substituted);and
[0123] R15 is wherein R17 is H, halo, optionally substituted C3-6cycloalkyl, optionally substituted CI-6alkyl, optionally substituted CI-6alkenyl, orC1-6haloalkyl; and Xa is S or O. 10124] In certain embodiments, the ULM or VLM is selected from the group consisting of:
HO HO Ho NH NH
/N NH - NH H I-NH -NH HO HO H N- NH NH N NH
0 0 iNH 0
-- NH
HO i ~ HO Ho ~I
N NH N1~H NH
W-NH -- NH --- NH 0
N HO HO N rN N NH N NH N- H -NH O-NH O
OHOH
N NN HO ON -0 'N S H OHN H 0HN NH N NH/ OH 0~ 0 0 NC OS
N ;and N
attached to the linker moiety at the position indicated.
[0125] In certain embodiments the ULM is selected from the group consisting of:
(2S,4R)-I-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyithiazol-5 yl)benzvl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4
hydroxy-N-(4-(thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2SR)-1-((S)-2-amino-33 dimethylbutanovl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-vl)phenvi)ethvl)pyrrolidine-2 carboxamide; (2S,4R)-I-((S)-2-amino-3,3-dimethlvbutanoyl)-4-hydroxy-N-(4-(oxazol-5 yl)benzyl)pyrroidine-2-carboxamide hydrochloride; (2S,4R)-1-((S)-2-amino-3,3 dimethyilbutanoyl.)-4-hydroxy-N--(4.-(4-methyloxazol-.5--yl)benzyl)pyrrolidine-2.-carboxamide;
(2S,4R)-I-((S)-2-amino-3,3-dirnethlvbutanoyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2 carboxamide hydrochloride; (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-(4-cyanobenzyl) 4-hydroxypyiTolidine-2-carboxamide hydrochloride; (2S,4R)-1-((S)-2-amino-3-methylbutanoyl) 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzvl)pyrrolidine-2-carboxamide hydrochloride; (2S,4R)-I-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(thiazol-5-y)benzyl)pyrroidine-2 carboxamide hydrochloride; (2S,4R)-I-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4 methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride; (2S,4R)-1-((S)-2-amino 3,3-dimethylibutanoyl)-4-hydroxy-N-(4-(I-methyl-1H-pyrazol-5-yl)benzyl)pyrrolidine-2 carboxamide hydrochloride; (2S,4R)-4-tert-butoxy-N-(2-hydroxy-4-(4-methylithiazol-5 yl)benzyl)-1-((S)-3-methyl--2-(i-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2--carboxamide; (2S,4R)-4-tert-butoxy-1-((S)-2-(6-fluoro-I-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(2 hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-tert-butoxy-1 ((S)-2-(7-cyano-1-oxoisoindolin-2-yl)-3-rnethylbutanoyl)-N-(2-hydroxy-4-(4-methylthiazol-5 yl)benzyl)pvrrolidine-2-carboxamide; and (2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4 hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride.
[0126] Exemplarv Linkers
[01271 In certain embodiments, the compounds as described herein include one or more ABM chemically linked or coupled to one or more ULMs or VLMs via a chemical linker (L). In certain embodiments, the linker group L is a group comprises one or more covalently connected structural units of A (e.g. -A1 ..A,- ), wherein A 1is coupled to an ABM moiety, and q is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.
[0128] In certain embodiments, e. g., wherein q is greater than 2. A, is a group which is connected to a ULMorVLMmoiety, and A1 and A, are connected via structural units of A (number of such structural units of A: q-2).
[01291 In certain embodiments, e. g., wherein q is 2, A, is a group which is connected to A 1 and to a ULM or VLM moiety. 10130] In certain embodiments, e. g., wherein q is 1, the structure of the linker group L is -A 1-, and A1 is a group which is connected to a ULM or VLM moiety and an ABM moiety.
[0131] In additional embodiments, q is an integer from Ito 100, 1 to 90, 1 to 80, 1 to 70, I to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or I to 10.
[0132] In certain embodiments, A1 to A. are, each independently, a bond, CRLR , OS. SO, SO2, NR , SO 2 NRL, SONR, CONRL, NR'CONR', NR SO2 NR', CO, CR =CR', C-C, SiRt R ,P(O)RJ',P(O)ORI,NR5C(=NCN)NR.NRC(=NCN), NR'C(=CNO 2 )NR ,-C 3 _jcycloalkyl optionally substituted with 0-6 R and/or RL2 groups , C3. L. 12 1 1heteocyclyl optionally substituted with 0-6 R and/or R- groups, aryl optionally substituted L- L2 L with 0-6 R and/orR groups, heteroaryl optionally substituted with 0-6 R and/or R , groups. wherein RL or R 12, each independently, can be linked to other A groups to formcycloalkyl and/or heterocyclyl moeity which can be further substituted with 0-4 RL 5 groups;
[0133] wherein RU, RI, RL,R andR' are, each independently, H, halo, Csalkyl, OCi-salkyl, SC<salkyl, NHCaiky, .N(Csalkyl) 2, C 3 _JIcycloalkyl, aryl heteroaryl, C3_
i1 heterocyclyl, OC>scycloalkyl, SCIscycloalkyl, NHCsscycloalkyl, N(C-scycloalkyl) 2 , N(C> scycloalkyl)(CIsalkyl), OH, NH2 ,SH, S 2 Csalkyl P(O)(OC-salkyl)(Csailkyl), P(O)(OC gaikyl) 2, CC-C>sakyl, CCH, C-H=CH(Cpsalkyl), C(Csalkvl)=CI(Cpsalkyl), C(C saikyl)=C(C salkyl)2, Si(OH) 3, Si(CJ-salkyl) 3 , Si(OH)(Cjsalkvl)2, COCi-salkyl, CO 2H. halogen, CN, CF3, CHF 2, CH 2F, NO2 , SFS, SO 2 NHCgakvl, S02N(Cgalkvl)2, SONICA1 salkyl, SON(C salkvl)2, CONHCsalkyl, CON(Casalkyl)2, N(CIsalkyl)CONH(C salkyl), N(C salkyl)CON(C galkyl), NI-CONH(Cpsalkyl), NHCON(Cgalkv)2, NHCONH2, N(Caaky)SO 2 NH(Cpsaikyl), N(C-salkyl) S0 2 N(Cjsalkyl) 2, NH SO 2NH(Ctsalkvl) NH SO 2 N(Csalkyl)2 NH S0 2 NH 2
. 101341 In certain embodiments, the linker (L) is selected from the group consisting of:
\0 o
OH 0
0 0
0 ^ o O O
37 0
0 K% O H 0
H 0 0 0
0~ 0
0 0
0, 0 0
00
NN (N
'1N. 0
00 N 0
N 0.
- 0 0
N..-N N N NN
0
9 N N N NN O N
N N
00
N, O O
00
HO 00 NN N~
N '-N N 0
;0 -- ; 0
N N N -N N -N N N \ -1-N N-- N- -A -N N-- N-N1 and \
101351 In additional embodiments, the linker (L) comprises a structure selected from, but
not limited to the structure shown below, wherein a dashed line indicates the attachment point to
the ABM or ULM moieties:
WLWL
wherein:
W' 1and W )are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally
substituted with RQ, each RQ is independently a H. halo, OH, CN, CF 3 , NH 2. carboxyl,
C1-C 6 alkyl (linear, branched, optionally substituted), C 1 -C6 alkoxy (linear, branched, optionally substituted), or 2 RQ groups taken together with the atom they are attached to,
form a 4-8 membered ring system containing 0-4 heteroatoms;
Y" is each independently a bond, C 1-C 6 alkyl (linear, branched, optionally substituted) and
optionally one or more C atoms are replaced with 0: or C-C6 alkoxy (linear, branched,
optionally substituted); and
n is 0-10.
[01361 In additional embodiments, the linker (L) comprises a structure selected from, but
not limited to the structure shown below, wherein a dashed line indicates the attachment point to
the ABM or ULM moieties:
.y1 (R 0 )o0 s (Y i)0-2 WL2 W QnL
wherein:
W and WI are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1-6 alkyl (linear,
branched, optionally substituted), C-C6 alkoxy (linear, branched, optionally substituted),
bicyclic, biaryl, biheteroaryl,or biheterocyclic, each optionally substituted with RQ, each
R is independently a H, halo, OH, CN, CF 3 NH 2 , carboxyl, hydroxyl, nitro, C - CH,
C 2- 6 alkenyl. C 2 6 alkynyl, C-C alkyl (linear, branched, optionally substituted). C-C6 alkoxy (linear, branched, optionally substituted), C 3 alkyl (optionally substituted by I
or more F), OH, NH 2, NR- 1!Ry, CN, or 2 R groups taken together with the atom they
are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
Y" is each independently a bond, NR', O, S, NR1, CR RY 2 , C=O, C=S, SO, So -C6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with 0; C-C6 alkoxy (linear, branched, optionally substituted); QL is a 3-6 membered aliCyclic or aromatic ring with 0-4 heteroatoms, biheterocyclic, or bicyclic, optionally bridged, optionally substituted with 0-6 RQ, each RQ is independently H, C 1 6 alkyl (linear, branched, optionally substituted by I or more halo, C 1_6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R', RY areeach independently H,OH C16 alkyl (linear, branched, optionally substituted by 1 or more halo, C 16_ alkoxyl), or R R2 together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; and n is 0-10.
[0137] In additional embodiments, the linker group is optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units, between about I and about 50 ethylene glycol units, between I and about 25 ethylene glycol units, between about I and 10 ethylene glycol units, between I and about 8 ethylene glycol units and I and 6 ethylene glycol units, between 2 and 4 ethylene glycol units,or optionally substituted alkyl groups interdispersed with optionally substituted, O, N, S, P or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. In certain embodiments, the linker may be asymmetric or symmetrical.
[01381 In certain aspects the description provides a PROTAC compound in which the linker is cleavable in vivo into a functional E3 ligase binding moiety. and target protein binding moiety. In this regard, and without being bound by any particular theory, it is hypothesized that such a configuration can potentiate the beneficial effects of the degradation activity of the intact PROTAC molecule. Thus, in certain embodiments, the linker is configured or "tuned" to have the desired kinetics of cleavage into functional component molecules or active metabolites. In certain embodiments, the enzyme responsible for cleavage of the linker is a liver enzyme, such as, e.g. oxidases, peroxidase, reductases, transferases, dehydrogenases, peroxidases. In certain embodiments, the enzyme is at least one of cytochrome P450 oxidase, e.g.. CYP3A4, Flavin containing ionooxygenase, alcohol dehydrogenase, aldehyde dehydrogenase, monoamine oxidase, peroxidase. glutathione S-transferase, cytochrome P450 reductase, sulfotransferase, methyltransferase, N-acetyltransferase, glucuronosyltransferase, transpeptidase, or combination thereof.
[01391 Exemplary Androgen Binding Moieties (ABMs)
[01401 In another aspect, the description provides AR binding moieties (ABM), which in certain aspects and embodiments are coupled to a linker and/or aLLM as described herein.
[0141] In any of the compounds described herein, the ABM comprises a chemical moiety that binds to the androgen receptor (AR). Various androgen receptor binding compounds have been described in literature, including various androgen derivatives such as testosterone, dihydrotestosterone, and metribolone (also known as methyltrienolone or R1881), and non steroidal compounds such as bicalutamide, enzalutamide. Those of ordinary skill in the art would appreciate that these androgen receptor binding compounds could be potentially used as an ABM moiety in a PROTAC compound. Such literature includes, but not limited to, G. F. Allan et. al, NMuclear Receptor Signaling, 2003 1, e009; R. H. Bradbury et. al. Bioorganic & Medicinal Chernisty Leitters, 20115442-5445; C. Guo et. al, Bioorganic Medicinal Chernistry Letters, 0122572-2578; P. K. Poutiainen et. al, . Med. Che. 2012, 55, 6316 - 6327 A. Pepe et. al. J Med. Chem. 2013, 56, 8280 - 8297; M. E. Jung et al, J.Ale. Chein. 2010, 53, 2779-2796, which are incorporated by reference herein.
[01421 In certain embodiments, the ABM comprises a structure selected from, but not limited to the structures shown below, wherein a dashed line indicates the attachment point of linker moiety:
Y2 R R2
W N I N_ Y1 -
ABM-a
WI
ABM-b
Y1 y3 R
' 1 -- N R 2 y'
ABM-c ;and
wherein:
W1 is aryl or heteroaryl, independently substituted by 1 or more halo, hydroxyl, nitro, CF3
, CN, C--CH, Cp- alkyl (linear, branched, optionally substituted by Ior more halo, C-6
alkoxyl), C]- alkoxyl (linear, branched, optionally substituted by I or more halo), C2-6
alkenyl, C 2 _6 alkynyl; Y, Y are each independently NR . 0, S; Y, Y4 , Yare each independently a bond, 0, NRy, CRY'R .,C S,SO,SO 2 ; Qis a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally substituted
with 0-6 RQ, each RQ is independently H, OI, C16 alkyl (linear, branched, optionally substituted by I or more halo, C- alkoxyl), or 2 RQ groups taken together with the atom
they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms'); R , R , Ra, e, Ry R' are each independently H, OH, Cs alkyl (linear, branched,
optionally substituted by I or more halo. C-6 alkoxv), or R , R2 together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms;
W2 is a bond, C 10alkyl, alicyclic, heterocyclic. aryl. heteroaryl, bicyclic, biaryl. biheteroaryl, 2 or biheterocyclic, each optionally substituted by 1, 2 or 3 R ; and
each R is independently H. halo, OH, NH 2 , C 1 6 alkyl (optionally substituted by I or more
F),OC 1 3 alkyl (optionally substituted by I or more F), NR iR , or CN.
[0143] In certain embodiments described herein, the ABM comprises a structure shown
below, wherein a dashed line indicates the point of attachment to a linker moiety:
Y3 (Y 3)0- ww 5
ABM-d' wherein: WI isaryl orheteroaryl, each optionally substituted by 1 or more halo, hydroxyl, nitro, CN, CF3 , C1-6 alkyl (linear, branched, optionally substituted by I or more halo, C-6 alkoxyl), or C- alkoxyl (linear, branched, optionally substituted by I or more halo); each Y isindependently a bond, 0, NR2, CR'R", or each RQ is independently H. OH. C> 6 alkyl (linear, branched, optionally substituted by I or more halo, C -6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R , R- are each independently H,1-H, or C- 6 alkyl (linear, branched. optionally substituted by 1 or more halo, C1_6 alkoxyl); W 2 is a bond, Co, alkyl, aryl, heteroaryl, alicyclic, heterocyclic, bicyclic, biaryl, biheteroaryl, biheterocyclic, each optionally substituted by 1 2or 3 Rw2; and eachR R is independentlyHOHNH2,CRR ,halo, C alkyl (optionally substituted byI or more F), OC- 3 alkyl (optionally substituted by I or more F).
[0144] In any of the embodiments described herein, the W2 is covalently coupled to one or more ULM or VLMgroups, or a linker to which is attached one or more JLM or VLM groups as described herein.
(R234(R23)-3 (R23)o R 22 R22
[01451 In certain embodiments, W, is \=/ or -N wherein each R 2 2 is independently halo, optionally substituted alkyl, haloalkyl, cyano, or nitro; and each R23 is independently H, halo, optionally substituted alkyl, haloalkyl, cyano, or nitro.
[01461 In certain additional embodiments, W1 is selected from the group consisting of:
CF 3 OF3 F C1
C1 OMe F 1 C1 CF 3 - ~ \/ CN~
N F NC NC and 1-6 N-b
[01471 In certain embodiments, ABM is selected from the group consisting of:
0 0
N -
S ~' F3 S FC F o F 0 o0 NC N'+ NCF N NCNN - kN N FCS jCF
0 F 00
N-C4 N ------ NCN
o F i 0 0 0 0
oC- /
NC-r N NC '-NK Ne ~NN F F
eN = 45
00 0 N
N/ N NCN F3C S O 'A, F11 F I 0 0
NC /\---N N
F3 C s 0~
0
NNCN N 3 y
F~F
0, -,
NH NH
~~' N NN NA NA, H; H
46'r~
NNH
< - ~NH~ C, NH
CF3 ~ ~NA 0A H
HN NH N- N lCl CF 3
F ~ N KN
FSF F F )'a
00
N I NH--w NH 0 Fy 17 N CI6 O<;N
0 'NH0 NN 0 N CC CI
0- -NH 0'< NH 0'< N
Cl Ca CI0 NC NC NC
O-- NH 0- NH _H
NC NC; I
01III. NH 1 H
C-- 0 CI\
/ 01111... NH Cul..NH I
NI;i
AC NH
CI-I C111 \ / /C.
NCand NC
[0148 In certain embodimentsthe ABM comprisesthecstructure:
wherein: W 1 is aryl or heteroaryl, independently substitutedby Ior more halo, hydroxyl, nitro. CF 3 ,
CN,&C-H, Cj--akyl (linear, branched optionally substituted by Ior more haloCI-6 aikoxl), CIp6alkoxyl (linear, branched, optionally substituted by Ior more halo), C 6
aikenyl. C 2 -6aikynyl; 4 Yare each independently abond, 0, NR y, CR X', N(0,SSOO:
Q is a 4 membered alicyclic ring with 0-2 heteroatoms, optionally substituted with 0-6 RQ, each R is independently 11, C 1 alkyl (linear, branched, optionally substituted by 1 or more halo, C1_6 alkoxyl), or2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R, R Y2 are each independently H, OH, C. alkyl (linear, branched, optionally substituted by I or more halo, C16 alkoxyl); W2 is a bond, C6 alkyl, alcyclic (e.g., C 6 alicyclic),heterocyclic, aryl, heteroaryl, bicyclic, biheterocyclic, biaryl, or biheteroaryl each optionally substituted by 1 2 or 3 R; and each R', is independently H, halo, C- 6 alkyl (optionally substituted by I or more F), OC yJ Y 3alkyl (optionally substituted by Ior more F), OH NH 2 , NR R!, CN.
[0149] In an additional aspect, the description provides an androgen receptor bindingcompound comprising a structure of:
wherein: W1 is aryl or heteroaryl, independently substituted by 1 or more halo, hydroxyl, nitro, CN, CF3 , CECH, C-6alkyl (linear, branched, optionally substituted by I or more halo, C 1 alkoxyl), C1 -6 alkoxyl (linear, branched, optionally substituted by I or more halo), C2 6- alkenyl, C 2 -6 alkynyl; Y, Y2 are each independently NR, 0, S; YY 4, Y are each independently a bond, 0, NRY, CR'RY, C=O, C=S, SO. S02; Q is a.3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 R, each RQ is independently H, OH, C1-6 alkyl (linear, branched, optionally substituted by I or more halo, C 1 6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R',RY 2 are each independently- 01-, C1 alkyl (linear, branched, optionally substituted by 1 or more halo, C1_6 alkoxyl); 2 W is a bond, C6 alkyl, alicyclic, heterocyclic, aryl,heteroaryl, bicyclic, biheterocyclic, W2 biaryl, biheteroaryl, each optionally substituted by 1, 2 or 3 ; and each R2is independently H,halo, C 6 alkyl (optionally substituted by 1 or more F), OC1_
3alkyl (optionally substituted by I or more F),011, NH 2 , NRR, CN.
[0150] In certain embodimetns, the androgen receptor binding compound of ABM-e is selected from the group consisting of: trans-2-Ciloro-4-[3-amino-2,2,4,4-tetrametiylcyclobutoxyibenzonitrile; cis-2-Chiloro-4-[3-amino-2,2,4,4-tetramethvlcyclobutoxv]benzonitrile; trans 6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylpyridazine-3 carboxamide; trans tert-Butyl N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate; trans 4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2.2,4,4-tetramethylcyclobutyl]benzamide; trans 5-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2.2,4,4-tetramethylcyclobutyl]pyrazine-2 carboxamide; trans 2-Amino-N-[3-(3-chlioro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylipyrimidine-5 carboxamide; 4-Methoxy-N-[(1r.3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethyilcyclobutyl]benzamide; trans I-(2 -Hydroxyethyl) -N-[3-(3-chioro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl] I1H-pyrazole-4-carboxamide; trans 6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylpyridine-3 carboxamide; trans 4-[(5-Hydroxypentyl)amino] -N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4
tetrametihyicyclobutyl]benzamide; trans tert-Butyl 2-({5-[(4-{[3-(3-chiloro-4-cyanophenoxy)-2,2,4,4 tetramethvlcyclobutyl]carbamoI}phenyl)aminopentyl}oxv)acetate; trans-2-Chloro-4-[3-amino-2,2.4,4-tetramethylcyclobutoxy]benzonitrile; tert-butyl trans-(3-(3-chloro-4-cyanophenoxy)-2,2-dimethylcyclobutyl)carbamate; and tert-butyl cis-(3-(3-chloro-4-cyanophenoxy)-2,2-dimethylcyclobutyl)carbamate.
[0151] The term "hydrocarbyl" shall mean a compound which contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.
[0152] The term alkyll" shall mean within its context a linear, branch-chained or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a C-Co,more preferably a C-C6
. alternatively a C-C 3 alkyl group, which may be optionally substituted. Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopen tylethyl, cyclohexylethyl and cyclohexyl, among others. In certain preferred embodiments. compounds according to the present invention which may be used to covalently bind to dehalogenase enzymes. These compounds generally contain a side chain (often linked through a polyethylene glycol group) which terminates in an alkyl group which has a halogen substituent (often chlorine or bromine) on its distil end which results in covalent binding of the compound containing such a moiety to the protein.
[0153] The term "Alkenyl" refers to linear, branch-chained or cyclic C 2 -C1 0 (preferably
C 2-C) hydrocarbon radicals containing at least one C=C bond.
[01541 The term "Alkynyl" refers to linear, branch-chained or cyclic C2-C10 (preferably
C 2-C 6) hydrocarbon radicals containing at least one C--C bond.
[01551 The term "alkylene" when used, refers to a -(CH2)group (n is an integer generally from 0-6), which may be optionally substituted. When substituted, the alkylene group preferably is substituted on one or more of the methylene groups with a C-C6 alkyl group (including a cyclopropyl group or a t-butyl group), more preferably a methyl group, but may also be substituted with one or more halo groups, preferably from I to 3 halo groups or one or two hydroxyl groups, 0-(CCs alkyl) groups or amino acid sidechains as otherwise disclosed herein. In certain embodiments, an alkylene group may be substituted with a urethane or alkoxy group (or other group) which is further substituted with a polyethylene glycol chain (of from I to 10, preferably I to 6, often I to 4 ethylene glycol units) to which is substituted (preferably, but not exclusively on the distal end of the polyethylene glycol chain) an alkyl chain substituted with a single halogen group, preferably a chlorine group. In still other embodiments, the alkylene (often, a methylene) group, may be substituted with an amino acid sidechain group such as a sidechain group of a natural or unnatural amino acid, for example, alanine, -alanine, arginine, asparagine, aspartic acid, cysteine. cystine, glutamic acid, glutamine glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.
[0156] The term "unsubstituted" shall mean substituted only with hydrogen atoms. A range of carbon atoms which includes CO means that carbon is absent and is replaced with1-1. Thus, a range of carbon atoms which is Co-C 6 includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for Co, H stands in place of carbon. The term "substituted" or"optionally substituted" shall mean independently (i.e., where more than substituent occurs, each substituent is independent of another substituent) one or more substituents (independently up to five substitutents preferably up to three substituents, often I or 2 substituents on a moiety in a compound according to the present invention and may include substituents which themselves may be further substituted) at a carbon (or nitrogen) position anywhere on a molecule within context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (C--N), nitro (NO 2), halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group such as a trifluoromethyl), an alkyl group (preferably, C-C 1 0 ,more preferably, C--C 6), aryl (especially phenyl and substituted phenyl for example benzyl or benzoyl), alkoxy group (preferably, C-C. alkyl or aryl, including phenyl and substituted phenyl), thioether (C-C 6 alkyl or aryl), acyl (preferably, C-C 6 acyl), ester or thioester (preferably. C-Cf alkyl or aryl) including alkylene ester (such that attachment is on the alkylene group, rather than at the ester function which is preferably substituted with a
C-C 6 alkyl or aryl group), preferably, C-C 6 alkyl or aryl, halogen (preferably, F or CI), amine
(including a five- or six-membered cyclic alkylene amine, further including a CI-C6 alkyl amine or a C--C dialkyl amine which alkyl groups may be substituted with one or two hydroxyl groups) or an optionally substituted -N(Co-Ce alkyl)C(O)(O-C-C6 alkyl) group (which may be optionally substituted with a polyethylene glycol chain to which is further bound an alkyl group containing a single halogen, preferably chlorine substituent), hydrazine, amido, which is preferably substituted with one or two C-C6 alkyl groups (including a carboxamide which is optionally substituted with one or two C-C6 alkyl groups). alkanol (preferably, C-C6 alkyl or aryl), or alkanoic acid (preferably, C-C 6 alkyl or aryl). Substituents according to the present invention may include, for example -SiRR 2R 3groups wherein each of R 1 and R2 is as otherwise described herein and R 3 is H or a C-C6 alkyl group, preferably RI, R2, R. in this context is a C
C 3 alkyl group (including an isopropyl or t-butyl group). Each of the above-described groups may be linked directly to the substituted moiety or alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteraryl moiety) through an optionally substituted ---(CH 2 )m- or alternatively an optionally substituted -(OCH 2)m-,
(OCH2CH2)m-or --(CH 2CH2 O)m- group, which may be substituted with any one or more of the above-described substituents. Alkylene groups -(CH2)m- or -(C- 2 )- groups or other chains such as ethylene glycol chains, as identified above, may be substituted anywhere on the chain. Preferred substitutents on alkylene groups include halogenor C-C6 (preferably C-C3 ) alkyl groups, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (0-C-C. groups), up to three halo groups (preferably F). or a sideshain of an amino acid as otherwise described herein and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two Co-C alkyl substitutents, which groups) may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C
C 6 alkyl groups, preferably C-C 4 alkyl group, most often methyl or O-methyl groups or a sidechain of an amino acid as otherwise described herein. In the present invention, a moiety in a molecule may be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present invention moieties which are substituted are substituted with one or two substituents. 101-571 The term "substituted" (each substituent being independent of any other substituent) shall also mean within its context ofuse C-C6 alkyl, C-C6 alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, C!-C 6 ester (oxyester or carbonylester), C 1 -C 6 keto, urethane -O-C(O)-NRIR2 or -N(R 1)-C(0)-O-R 1, nitro, cyano and amine (especiallyincluding aC-Calkylene-NR 1 R 2 ,amono- or di- C-C6 alkyl substituted amines which may be optionally substituted with one or two hydroxyl groups). Each of these groups contain unless otherwise indicated, within context, between I and 6 carbon atoms. In certain embodiments, preferred substituents will include for example, -NH-, -N-C(O)-, -0-, =0, -(CH 2)- (here,m and n are in context, 1. 2, 3, 4, 5 or 6), -S-, -S(O)-, SO 2 -or ---NH-C(O)-NH-, (C12 ).0-, -(C-1 2 ),S1, l-(CH2)nCOOH, CC-C 6 alkyl, -(CI- 2 ) 1O-(C 1 1-C 6 alkyl), -(CH2 ),C()-(C-C
alkyl), -(CH 2 ),OC(0)-(C-C 6 alkyl), -(CH 2 )aC(0)O-(C 1-C 6 alkyl),-(CH2)nNHC(O)-R 1 , (C1-2)C(0)-NRjR 2, -(OCH2) 1H, -(C-12O)CO0H, C-C 6 alkyl, -(OC1 2 )iO-(C 1 -C6 alkyl), (CH2 O)C()-(C-C 6 alkyl), -(OCH2 )nNHC(0)-R, -(CH 20)nC(O)-NR 1R 2, -S(O) 2 -Rs, -S(O)-Rs (Rs is C-C 6 alkyl or a ---(CH2)m-NRIR 2 group). NO 2, CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context of the use of the substituent. R1 and R2 are each, within context, H or a C-C 6 alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" shall also mean, within the chemical context of the compound defined and substituent used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein. Alkylene groups may also be substituted as otherwise disclosed herein, preferably with optionally substituted C-C 6 alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl is preferred. thus providing a chiral center), a sidechain of an amino acid group as otherwise described herein, an amido group as described hereinabove, or a urethane group O-C(O)-NR1 R 2 group wherein R 1 and R 2 are as otherwise described herein, although numerous other groups may also be used as substituents. Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents and preferably with I or 2 substituents. It is noted that in instances where, in a compound at a particular position of the molecule substitution is required (principally, because of valency), but no substitution is indicated, then that substituent is construed or understood to be H, unless the context of the substitution suggests otherwise.
[0158] The term "aryl" or "aromatic", in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or condensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound to the compound according to the present invention at any available stable position on the ring(s) or as otherwise indicated in the chemical structure presented. Other examples of aryl groups, in context, may include heterocyclic aromatic ring systems "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic) such as imidazole, furyl, pyrrole, furanyl. thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc.. among others. which may be optionally substituted as described above. Among the heteroaryl groups which may be mentioned include nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline,quinolizinephthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline. phenacene, oxadiazole, benzimidazole, pyrrolopyridinepyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles comprising 2 or more hetero atoms selected from among nitrogen, sulfur and oxygen, such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole. furazan. phenoxazine, pyrazoloxazole, imidazothiazole. thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, among others, all of which may be optionally substituted.
[01591 The term "substituted aryl" refers to anaromatic carbocyclic group comprised of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic, wherein the ring(s) are substituted with one or more substituents. For example, an aryl group can comprise a substituent(s) selected from: -(CH 2)_O,-(CH)-O-(CC)alkyl,-(C 2)n--O-(CH 2)
(C-Cs~alkyl, -(CH2)-C(O)(Co-C6) alkyl, -(CH2),-C(O)O(Co-C6)alkyl, -(CH2)n--OC(O(o
C6 )alkyl, amine, mono- or di-(C-C,6 alkvl) amine wherein the alkyl group on the amine is optionally substituted with I or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups,
OH, COOH, CC6 alkyl, preferably CH 3 ,CF 3,OMe,OCFNOorCNgroup(eachofwhich may be substituted in ortho-., meta- and/or para- positions of the phenyl ring, preferably para-), an optionally substituted phenyl group (the phenyl group itself is preferably substituted with a linker group attached to a ABM group, including a ULM group), and/or at least one of F, Cl, OH, COO-, CH 3, CF3 , OMe, OCF 3, N02, or CN group (in ortho-, meta- and/or para- positions of the phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole including a methylsubstituted isoxazole, an optionally substituted oxazole including a methylsubstituted oxazole, an optionally substituted thiazole including a methyl substituted thiazole. an optionally substituted isothiazole including a methyl substituted isothiazole, an optionally substituted pyrrole including a methylsubstituted pyrrole, an optionally substituted imidazole including a methylimidazole, an optionally substituted benzimidazole or methoxybenzylimidazole, an optionally substituted oximidazole or methyloximidazole, an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group. including a methylsubstituted triazole group, an optionally substituted pyridine group, including a halo (preferably, F) or methylsubstitutedpyridine group or an oxapyridine group (where the pyridine group is linked to the phenyl group by an oxygen), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), an optionally substituted quinoline, and combinations thereof.
[01601 "Carboxyl" denotes the group -C(O)OR, wherein R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.
[01611 The term "heteroaryl"or"hetaryl" can mean but is in no way limited to an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3 or 4-azaindolizine) an optionally substituted benzimidazole, benzodiazole, benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl substituted), an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably methyl and/or thiol substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably a 1,2,3-triazole substituted with a methyl group, a triisopropylsilyl group, an optionally substituted -(CH 2 )m,-O
CI-C alkyl group or an optionally substituted -(Ci-C(O al up)anoptionally substituted pyridine (2-, 3, or 4-pyridine) or a group according to the chemical structure:
RHET O HET I ~N KN 4; RURE RURE R 0
RRHET HET N N
0 0
RHET Or pHET
N Yc
wherein:
Sc is CHRs NRRE or 0; RHETis H, CN, NO 2 , halo (preferably Ci or F), optionally substituted C-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF 3 ),
optionally substituted O(C-C 6 alkyl) (preferably substituted with one or two hydroxyl
groups or up to three halo groups) or an optionally substituted acetylenic group -C-C-Ra
wherein Ra is H or a C-C6 alkyl group (preferably CC 3 alkyl); Rss is H, CN. NO2, halo (preferably F or Cl), optionally substituted CIC6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally
substituted O-(C-C 6alkyl) (preferably substituted with one or two hydroxyl groups or up
to three halo groups) or an optionally substituted -C()(C-C6 alkyl) (preferably
substituted with one or two hydroxyl groups or up to three halo groups);
URE is H, a CI-C alkyl (preferably H or C-C 3 alkyl) or a -C(O)(C-C 6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three
halogen, preferably fluorine groups, or an optionally substituted heterocycle, for example
piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,
piperazine. each of which is optionally substituted, and
Yc is N or C-Ryc, wherein RYc is H, OH, CN, NO 2 , halo (preferably CI or F), optionally substituted C--C 6alkyl (preferably substituted with one or two hydroxyl groups or up to
three halo groups (e.g. CF 3). optionally substituted O(C-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -CEC-Ra wherein Ra is H or a CI-C 6 alkyl group (preferably C-C 3 alkyl).
[01621 The terms "arylkyl" and "heteroarylalkyl" refer to groups that comprise both aryl or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems according to the above definitions.
[0163] The term "arylalkyl" as used herein refers to an aryl group as defined above appended to an alkyl group defined above. The arylalkyl group is attached to the parent moiety through an alkyl group wherein the alkyl group is one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above. 101641 The term "heterocycle" refers to a cyclic group which contains at least one heteroatom, i.e., 0, N or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, the heteroaryl moieties are subsumed under the definition of heterocycle, depending on the context of its use. Exemplary heterocyclics include: azetidinyl, benzimidazolvi, 1,4- benzodioxanyl, 1,3 benzodioxolyl, benzoxazolyi, benzothiazoyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, I,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyi, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N methylpiperazinyl, piperidiny, phthalimide, succinirmide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, thiane among others.
[0165] Heterocyclic groups can be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy. oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thiokeo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO heteroaryl,- SO2-alkyl,- S02-substituted alkyl,- SO2-aryl, oxo (=0), and -SO2-heteroaryl.
Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogenheterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which any of the heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolylquinolyl, isoquinolyl, tetrahydroquinolyl. and the like).
[0166] The term "cycloalkyl" can mean but is in no way limited to univalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes, as defied herein, e.g., saturated monocyclic hydrocarbon groups having from three to twenty carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "substituted cycloalkyl" can mean but is in no way limited to a monocyclic or polycyclic alkyl group and being substituted by one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent groups have meanings which are identical with definitions of the corresponding groups as defined in this legend. 101-671 "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, 0, S or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, 0, S or P and ithe group is containing one or more substituents selected from the group consisting of halogen., alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend. 101681 Exemplarv AR-PROTAC Compounds
[0169] As described above, in certain aspects, the description provides bifuctional PROTAC compounds comprising at least one ABM group, a linker, and at least one ULM (or
VLM) group as described herein.
[01701 In certain embodiments, the compound is selected from the group consisting of compounds 1-864 (as described in Tables 2-30), and salts and polymorphs thereof.
[0171] In certain embodiments, the compound is selected from the group consisting of:
0
N -N H S N O N'\1O
NH O NC-- -N O F F F F--O
NH NOHN 0
i-S ON NH N \ H 'OH;
N O NC- N N 0 2 N- N FC S N S F3 C
0
0 S sO 0--N N OH
N N ;'OH HOH
O ~H
NY 00 NH NH
0S N`
CN F ON OH OH
0 y~N 0 N
NN \N- N
i\ '
& N CN
0 S0 0 0
F N F
0~N
CF, CF ON - N
- OH ) - OH HN- N; Y ~ NNo~HN Nl ( 0 0~ -~ HO-Z
N -KN -N, 'N N
1,OH r6Nj
0 N HN
o K 0 i
S I b
r~K
NN
eFF
F~lK F
0 0K2
N N N F H 0 NH
02 N CF:3
N <\ NNh
NN /\FNN" N O
CN 'NC~
NC - S F 3C 01) NC- " y N-- WX0--\-o
FC) HN
\0 N H
N-~
- NH NO
F N~ N F0--, ,[\Cl
HN-~ N-- ~ f
WO 2019/023553
F 3C N
0
o ~ N 0
Na - N--- OH -
FF NN O N N-,N
WA HO "'0-N H-'
N-NI NC--N \ \-O IIN HN / -NH ')OH N NC
0, \-o
HN HN
N=N---
00 'II 00 N- 4 ~~HN H'NI N.-/
0-.
IiZ I.\ SiN>7<,!, ,
N0 HHNFN
\ /< ss 0 N -NH 'OH-N
N~--/65
NN
HN j N--0 H
-NH.) N,, WN-N \-NNN NN
FHN =0\ N~N 0 11 -- "-
00
,N N~ --
- -N-N
0
F- -0
HN N-S H
~ NN0 N
." H"-NH "OH;
0. 0,
N N
'0 >0o \ FC F
HN HN
0 0---( 00.. yQ N
~N~N
SIN- _N
0
N \ ~ N---\z
00
N> N
F F0 HO>b -0
00
WE NHN 0~ -NN \lh
Nl/
N~N F r
F 0--0
/ 0 r H/
N HN HN
0 NN
"OH --NIH "'H
0 0
0 ~~J~ 0 NC N ~ F F3 C F F
00
N~-S HN~ N ~ HN
00
F~C 0 NCNC
0
0 H/ H N 0 A 0 NH ,
S, - OH
N- 0
0F- N N
N C>
0 0-
0 ,0 JH\-0H
0 NH 0 NH ^Yl
NN
%j- '-N~ cI
0H N- 0-N0
HH NN
N~/~ U F~)N
F Z\: F
j-NH 0 NH
N-- N-,
0.y FSC F3' NN N C' S NHc 0
2 o 0 Ko N~S HN H HN~
NsH
NN
K0 N-N 0 DO H 10H
FF NNN HNN
0' N 0 NHH
S S-
F F4
C) H /N N - N N-'N
0 F-- F F
F -- F0
0 OiH N N H
0 NH 0
N4 N '
N, -NN
0 F- -- F -0 F NH O
F F N HNN F- F S O
HN4
_~~~~ N S-o,~~
H NH
F7
0 NC
NC--/ NC/ NC /
F~ s n,
0N 0
o NH 0
NHH NH
0 NH
-N\-<" I S N' -ij
3 S N N F½
<0 0 0
HN
0)Q~OH
N. \F'- N C/ F
\4' NH ~ ~ -S NH
N OH\ No
0 ;N6 H
0 0 LN I H F - 0.
0 N~h 0<-
HNA- ), .........
NC~ N
HOH 0
N0 ~N HN OH -~ NH
N N -NN
HN 0
j N "eN N' H HN 0
N
0 0i NHQ\
NI N*" NN
cl '.' 75
OH
00 Nr. N N ~ 0
N Cl
S
N ;and HO OH HN 0 N,, N N N
S N
[0172] In another embodiment, the present invention provides a library of compounds.
The library comprises more than one compound wherein each compound has a formula of ABM
L-ULM. wherein ULM is a ubiquitin pathway protein binding moiety (preferably, an E3 ubiquitin ligase moiety as otherwise disclosed herein), e.g., a VLM, and ABM is an AR protein
binding moiety, wherein ABM is coupled (preferably, through a linker moiety) to ULM, and
wherein the ubiquitin pathway protein binding moiety recognizes an ubiquitin pathway protein,
in particular, an E3 ubiquitin ligase.
10173] The present description includes, where applicable, the compositions comprising
the pharmaceutically acceptable salts, in particular, acid or base addition salts of compounds of
the present invention.
[01741 The term pharmaceuticallyy acceptable salt" is used throughout the specification
to describe, where applicable, a salt form of one or more of the compounds described herein
which are presented to increase the solubility of the compound in the gastic juices of the patient's
gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds.
Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of the phosphates according to the present invention.
[0175] The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds useful in this invention are those which form non toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)] salts, among numerous others.
[0176] Pharmaceutically acceptable base addition salts may also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives according to the present invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (eg., potassium and sodium) and alkaline earth metal cations (eg, calcium, zinc and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, among others.
[01771 Compositions
[0178] In another aspect, the description provides compositions comprising compounds as described herein, including salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the compositions are therapeutic or pharmaceutical compositions comprising an effective amount of a compound as described herein and a pharmaceutally acceptable carrier.
[0179] The amount of compound in a pharmaceutical composition of the instant invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease treated, the particular mode of administration. Generally, an amount between 0.1 mg/kg and 1000 mg/kg bodyweight/day of active ingredients is administered dependent upon potency of the agent. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED5. Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. 101801 The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate., disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose. polyacrylates, waxes, polyethylene-poiyoxypropylene-block polymers, polyethylene glycol and wool fat.
[0181] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient/patient per day. A typical topical dosage will range from 0.01-5% wt/wt in a suitable carrier.
[0182] The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than 1mg, I mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dosage of about 25-250 mg is often convenient.
[0183] The active ingredient is preferably administered to achieve peak- plasma concentrations of the active compound of about 0.00001-30 mM. preferably about 0.1-30 IM. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.
[01841 The concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
[0185] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS). 101861 In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, bioconpatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
[01871 Liposomal suspensions may also be phannaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface ofthe container. An aqueous solution of the active compound are then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
[0188] Modes of Adminstration
[0189] In any of the aspects or embodiments described herein, the therapeutic compositions comprising compounds described herein can be in any suitable dosage form configured to be delivered by any suitable route. For example, the compounds can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, rectally, nasally, buccally, vaginally or via an implanted reservoir or by aerosol form.
[0190] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intrapentoneally or intravenously.
[0191] The compounds as described herein may be administered in single or divided doses by the oral, parenteral or topical routes. Administration of the active compound may range from continuous (intravenous drip) to several oral administrations per day (for example, Q.LD.) and may include oral, topical, parenteral. intramuscular, intravenous, sub-cutaneous, transdermal (which may include a penetration enhancement agent), buccal, sublingual and suppository administration, among other routes of administration. Enteric coated oral tablets may also be used to enhance bioavailability of the compounds from an oral route of administration. The most effective dosage form will depend upon the pharmacokinetics of the particular agent chosen as well as the severity of disease in the patient.
[01921 Administration of compounds as sprays, mists, or aerosols for intra-nasal, intra tracheal orpulmonary administration may also be used. Compounds as described herein maybe administered in immediate release, intermediate release or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of compound at an injection site.
[0193] Sterile injectable forms of the compositions as described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
[01941 The pharmaceutical compositions as described herein may be orally administered in any orally acceptable dosage form including, but not limited to. capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials are included as part of the composition.
[01951 The tablets, pills, capsules, troches and the like can contain any of the following ingredients. or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid. Primogel. or corn starch; a lubricant such as magnesium stearate or Sterotes: a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
[01961 The active compound or pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
[01971 Alternatively, the pharmaceutical compositions as described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[01981 The pharmaceutical compositions of this invention may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-acceptable transdermal patches may also be used. Fortopical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. In certain preferred aspects of the invention, the compounds may be coated onto a stent which is to be surgically implanted into a patient in order to inhibit or reduce the likelihood of occlusion occurring in the stent in the patient.
[01991 Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octydodecanol, benzyl alcohol and water.
[02001 For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, p-I adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
[02011 The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption pronioters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[0202] Solutions or suspensions used for parenteral, intradernal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
[02031 It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight. general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.
[0204] A patient or subject in need of therapy using compounds as described herein can be treated by administering to the patient (subject) an effective amount of the compound including pharmaceutically acceptable salts, solvates or polymorphs, thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known agents.
[0205] Co-administration 102061 Disease states of conditions which may be treated using compounds or compositions according to the present description include, but not limited to. for example, cancer (e.g., prostate cancer), and Kennedy's disease. In certain embodiments, the therapeutic or pharmaceutical compositions comprise an effective amount of an additional biologically or bioactive active agent, e.g., an agent effective forthe treatment of cancer, that is co-administered.
[0207] The term "coadministration" or "combination therapy" shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time. Although compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided that effective concentrations of all coadministered compounds or compositions are found in the subject at a given time. In certain preferred aspects of the present invention, one or more of the present compounds described above, are coadministered in combination with at least one additional bioactive agent, especially including an anticancer agent. In particularly preferred aspects of the invention, the co administration of compounds results in synergistic therapeutic, including anticancer therapy.
[02081 In another aspect, the description provides a composition comprising an effective amount of two or more of the PROTAC compounds as described herein, and a pharmaceutically acceptable carrier. In certain embodiments, the composition further comprises an effective or synergistic amount of another bioactive agent that is not a PROTAC compound.
[02091 Pharmaceutical compositions comprising combinations of an effective amount of at least one bifunctional compound according to the present invention, and one or more of the compounds otherwise described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, represents a further aspect of the present invention.
[0210] The tern "bioactive agent" is used to describe an agent, other than the PROTAC compounds described herein, which is used in combination with the present compounds as an agent with biological activity to assist in effecting an intended therapy, inhibition and/or prevention/prophylaxis for which the present compounds are used. Preferred bioactive agents for use herein include those agents which have pharmacological activity similar to that for which the present compounds are used or administered and include for example, anti-cancer agents.
[02111 The term "additional anti-cancer agent" is used to describe an anti-cancer agent, which may be combined with PROTAC compounds according to the present description to treat cancer. These agents include, for exarnple, everolinus, trabectedin, abraxane, TLK 286, AV 299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, an androgen receptor inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-I modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody. a P13 kinase inhibitors, an AKT inhibitor, a JAK/STATinhibitor, a checkpoint-I or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, arirubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 11, 131--TM-601, ALT-I10, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102. talampanel, atrasentan. Xr 311, romidepsin, ADS-100380, sunitinib,5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-4-[2-(2-amino-4,7 dihydro-4-oxo- H -- pyrrolo[2,3-- d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremnifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC 1CI1, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)- indolylj-quinolone, vatalanib, AG 013736, AVE-0005, the acetate salt of [D- Ser(Bu t ) 6,Azgly 10 ] (pyro-Glu-His-Trp-Ser-Tvr D-Ser(Bu t)-Leu-Arg-Pro- Azgly-NH 2 acetate [C5 9H84 NisOi 4 -(C 2H 40 2)x wherein x = I to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, regestrol acetate, raloxifene, bicalutarnide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272. erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SUI1248, sorafenib. KRN951 , aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine. chlorambucil, cisplatin, cladribine, clodronate cvproterone, cytarabine, dacarbazine, dactinornycin, daunorubicin, diethylstilbestrol. epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine. 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291 , squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftiox,gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS- 247550, BMS-310705, droloxifene, 4 hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant acolbifene, lasofoxifene, idoxifene, TSE-424, HMR- 3339, ZK186619, topotecan, PTK787/71 222584, VX-745, PD 184352. rapamycin, 40-0-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RADO01, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony stimulating factor, histrelin, pegylated interferon alfa--2a, interferon alfa-2a, pegylated interferon alfa-2b. interferon alfa-2b. azacitidine. PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2. megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine. bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina asparaginase, strontium 89, casopitant, netupitant, an NK--1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methyIprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetronpegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.
[0212] Methods of Treatment
[02131 In another aspect, the disclosure provides methods of modulating protein ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal, or human patient, the method comprising administering an effective amount of a PROTAC compound as described herein or a composition comprising an effective amount of the same to a subject, wherein the compound or composition comprising the same is effective in modulating protein ubquitination and degration of the protein in the subject. In certain embodiments, the protein is androgen receptor (AR). 102141 In certain embodiments, the description provides a method for regulating protein activity of the androgen receptor in a patient in need comprising administering to said patient an amount of a compound as described herein to a patient.
[0215] In still additional embodiments, the description provides a method of treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for said disease state or condition, said method comprising administering to said patient an effective amount of a compound as described herein to said patient in order to regulate said protein activity in said patient. In certain embodiments, the protein is AR.
[0216] The terms "treat". "treating", and "treatment", etc., as used herein, refer to any action providing a benefit to a patient for which the present compounds may be administered, including the treatment of any disease state or condition which is modulated through the protein to which the present compounds bind. Disease states or conditions, including cancer, which may be treated using compounds according to the present invention are set forth hereinabove.
[0217] In another aspect, the disclosure provides methods of modulating AR protein ubiquitination and degradation in a subject, e.g., a cell, a tissue, mammal, or human patient, the method comprising administering an effective amount of a compound as described herein or a composition comprising an effective amount of the same to a subject, wherein the compound or composition comprising the same is effective in modulating AR protein ubquitination and degration of the protein in the subject.
[02181 In another aspect, the disclosure provides methods of treating or ameliorating a symptom of a disease related to AR activity in a subject, e.g., a cell, a tissue, mammal, or human patient, the method comprising administering an effective amount of a compound as described herein or a composition comprising an effective amount of the same to a subject in need thereof, wherein the compound or composition comprising the same is effective in treating or ameliorating a symptom of a disease related to AR activity in the subject.
[0219] In certain embodiments, the disease or disorder is asthma, multiple sclerosis, cancer, prostate cancer, Kenney's disease, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot---Marie---Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, I-laemochromatosis, I-aemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria. Polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease, Turner syndrome. The method according to claim 48 wherein said cancer is squamous-cell carcinoma., basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas,
prostate, and stomach; leukemias; benign and malignant lymphoma, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; mycloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer. cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms'tumoror teratocarcinomas. In certain embodiments, the disease to be treated is cancer, e.g., prostate cancer, or Kennedy's Disease. In a preferred embodiment, the subject is a human.
[0220] In another aspect, the disclosure provides methods of treating or ameliorating a symptom of a disease related to AR activity in a subject, e.g., a cell, a tissue, mammal, or human patient, the method comprising administering an effective amount of a compound as described herein or a composition comprising an effective amount of the same and an effective or synergistic amount of another bioactive agent to a subject in need thereof, wherein the composition comprising the same is effective in treating or ameliorating a symptom of a disease related to AR activity in the subject. In certain embodiments, the disease to be treated is cancer, e.g., prostate cancer, or Kennedy's Disease. In a preferred embodiment, the subject is a human. In certain additional embodiments, the additional bioactive agent is an anti-cancer agent.
[0221] In alternative aspects, the present invention relates to a method for treating a disease state by degrading a protein or polypeptide through which a disease state or condition is modulated comprising administering to said patient or subject an effective amount of at least one compound as described hereinabove, optionally in combination with an additional bioactive agent. The method according to the present invention may be used to treat a large number of disease states or conditions including cancer. by virtue of the administration of effective amounts of at least one compound described herein.
[0222] In another aspect, the disclosure provides methods for identifying the effects of the degradation of proteins of interest in a biological system using compounds according to the
present invention.
[0223] Kits 102241 In another aspect, the description provides kits comprising compounds or compositions as described herein. The kit may be promoted, distributed, or sold as a unit for performing the methods of the present invention. In addition, the kits of the present invention may preferably contain instructions which describe a suitable use. Such kits can be conveniently used, e.g., in clinical settings, to treat patients exhibiting symptoms of, e.g., cancer or Kennedy's Disease.
[0225] EXAMPLES
[02261 General Chemistry - Analysis and Synthesis
[0227] Unless otherwise noted, all materials/reagents were obtained from commercial suppliers and used without further purification. Reactions were monitored by LC-MS and/or thin layer chromatography (TLC) on silica gel 60 F254 (0.2mm) pre-coated aluminum foil or glass backed and visualized using UV light. Flash chromatography (alternatively called "ISCO chromatography") was performed using an ISCO CombiFiash RF 75 PSI or equivalent with RediSep normal-phase silica gel cartridges. Preparative TLC was performed on Whatman LK6F Silica Gel 60A size 20x20 cm plates with a thickness of 1000 pm or equivalent.
[0228] HNMR (300 or 400 MHz) and CNMR (100.6 MHz) spectra were recorded on Bruker spectrometers at room temperature with TMS or the residual solvent peak as the internal standard. The line positions or multiples are given in (6) and the coupling constants (/) are given
as absolute values in Hertz (Hz). The multiplicities in HNMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened).
[02291 Preparative HPLC purifications were performed on a Waters* UV-Directed Purification System equipped with 2545 Binary Gradient Module, 2767 Sample Manager and 2489 UV/Visible Detector, controlled by MvassLnx V4.1 software. All purification work was completed using the following columns: Atlantis Prep T3 OBD Column, SunFire Prep C18 OBD Column and XBridge Prep Phenyl OBD Column. The mobile phases were water (with 0.1%TFA or 0.01% NH 4HCO 3 ) and acetonitrile; all reagents used were of HPLC grade. The flow rate was 30ml/min. After the columns, a 1:1000 LC packings flow splitter allowed transfer of a small portion of the eluent into the UV detector. The electrospray source was set at 3.0 kV capillary voltage. 30 V conevoltage, 110°C source temperature. 350°C desolvation temperature, 600L/h desolvation gas flow, and 60L/h cone gas flow. For the analyzer, the multiplier was set at 550 for preparative tune method. 10230] Analytical LC-MS data was collected on a Shimadzu LCMS-2020 with a mobile phase of 0.05%TFA in Acetonitrile (A) and 0.05%TFA in HPLC grade water (B); 0.1% FA in Acetonitrile (A) and 0.1% FA in HPLC grade water (B); Acetonitrile (A) and 5 mM ammonium bicarbonate in HPLC grade water (B).
[0231] Shimadzu LCMS-2020 equipped with LC-20AD or 30AD pumps, SPD-M2OA PDA and Alltech 3300 ELSD. The system uses the following conditions for 2.0 min, 2.6 min, 3 min, 3.6 min, 5 min or 5.6 min run time.
[0232] 2.0 minute run: Kinetex XB-C 18 100A column, 2.6 um, 3.Ox 50 mm. The flow rate is 1.5 mL/min, the run time is 2.0 min, and the gradient profiles are 0.01 min 10% A, 1.10 min 100% A, 1.60 min 100% A, 1.70 min 10% A, 2.00 min 10% A.
[02331 2.6 minute run: Shim-pack VP-ODS column, 2.2 pm,3.x 50 mm. The flow rate is 1.5 mL/min, the run time is 2.6 min, and the gradient profiles are 0.01 min 5% A, 1.20 min 100% A, 2.20 min 100% A, 2.30 min 5% A, 2.60mim 5% A.
[0234] 3.0 minute run: ACE UltraCore Super C18 column, 2.5 p.m, 3.0x 50 mm.The flow rate is 1.5 mL/min, the run time is 3.0 min, and the gradient profiles are 0.01 min 10% A, 2.00 min 95% A, 2.60 min 95% A, 2.70 min 10% A, 3.00 min 10% A.
[0235] 3.6 minute run: Shim-pack VP-ODS column, 2.2 jm, 3.Ox 50 mm. The flow rate is 1.5 mL/min, the run time is 3.6 min, and the gradient profiles are 0.01 min 5% A, 2.20 min 100% A, 3.20 min 100% A, 3.30 min 5% A, 3.60 min 5% A.
[0236] 5.0 minute run: ACE UltraCore Super C18 column, 2.5 m, 3.Ox 50 mm. The flow rate is 1.5 mL/min, the run time is 5.0 min, and the gradient profiles are 0.01 min 10% A, 4.00 min 60% A, 4.70 min 60% A, 4.80 min 10% A, 5.00 min 10% A.
[0237] 5.6 minute run: Shim-pack VP-ODS column,2.2 pm, 3.Ox 50 mm. The flow rate is 1.5 mL/min. the run time is 5.6 min, and the gradient profiles are 0.01 min 5% A, 3.00 min 50% A, 5.00 min 50% A, 5.20 mim 5% A, 5.60 min 5% A
[0238] Alternatively, analytical LC-MS data was collected on Agilent infinity 1260 LC, Agilent 6230 TOF mass spectrometer. The analysis is conducted on a Poroshell 120 EC Cl8 column (50mm x 3.0mm internal diameter 2.7am packing diameter) at 45C.
[0239] The solvents employed are:
[0240] A = 0.1% v/v solution of formic acid in water.
[0241] B = 0.1% v/v solution of formic acid in acetonitrile. 102421 The gradient employed are as follows: 102431 Table 1. Exemplary Column Gradients. Time Flow Rate %A %JB (minutes) (mL/min)
0 1 95 5 0.5 1 95 5 3.0 1 1 99 4.0 1 1 99 4.1 1 95 5
4.5 1 95 5 102441
102451 The Vdetection is an averaged signal from wavelength of 210nm to 350nm and mass spectra are recorded on a mass spectrometer using positive modeelectrospray ionization.
[02461 Unless otherwise noted, all compounds were prepared with LC-MS purity >95%.
[0247] Chemical Synthesis 10248] A PROTAC of ABM-L-UL.M, or their pharmaceutically acceptable salts, polymorphic forms, prodrugs, solvate forms and isotope containing derivatives thereof, may be prepared by the general approaches described below (scheme 3-4). together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art. 10249] Scheme 3: 2 RG
ULM RG4 3 A - - intermedi eL [ BM -- RG ______-- AB ULM Stage 1 Stage 2
Scheme 3
[0250] Scheme 4: RG 2 RG 3 RG 2 ABM RG' ----------- RG intermediate L U 4 -- A \1 U UM RG LKL/1LJ% 2 L UL Stage 1 Stage 2
Scheme 4
[0251] More specifically, The compounds of the Formula I or their pharmaceutically acceptable salts, may be prepared by the general approaches described below (scheme 5-6), together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
[0252] Scheme 5:
RG 2 3 C RG
nterid ate L NN
1 RG Intermediate A
4 RP RG r/-~
( W R
Intermediate V -N r --------- -------------------- L Stage Y
Formula I
Scheme 5
10253] Scheme 6: RG2 Rr RORG3 RG
X x2 . Intermediate LX! NX
Stage intermediate V
1 Y, R R2
N
J\W YN2 RG22 RR
IntermediateA N E
y N X2 Stage 2 W3-. W4 Formula I
Scheme 6
[0254] In schemes 3-6, L, ABM, ULM groups, W, W2,2 W,3 W X X , .R 1 , R22 and R are as define above. RG RG2, RGand RG are moieties with suitable reacting groups that would be necessary to enable the synthetic chemistry to connect intermediate A, intermediate L and intermediate V together into PROTAC compounds of Formula I via covalent bond formation chemistries. These chemistries, depends on specific reacting groups, include but not limited to, amide formation, ester formation, carbamate formation, urea formation, ether formation, amine formation and various C-C, C=C bond formation. The stage I and stage 2 transformations in scheme 5 and scheme 6 may involve 1 or multiple synthetic steps. These are routine methods known in the art such as those methods disclosed in standard reference books such as the Compendium ofOrganicSYnthetic Methods. Vol. I-VI (Wiley-Interscience); or the Comprehensive Orgnic Transfbrnations,by R.C. Larock (Wiley-Interscience). Unless otherwise indicated, the substituents in the schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill. 10255] In certain examples, for the chemistry described in schemes 3-6, RG' is a moiety with a suitable nucleophile such as -OH and RG2 is a moiety with a suitable leaving group such as halogen, -OMs, or -OTs. In a typical procedure, a RG' containing intermediate is reacted with a RG 2 containing intermediate in a suitable solvent. Suitable solvents include, but are not limited to. water. ethers such as THF, glyme. and the like; chlorinated solvents such as DCM, 1,2 dichloroethane (DCE) or CHCI3 and the like, toluene, benzene and the like, DMF, DMSO, MeCN. If desired, mixtures of these solvents are used. A base may be added to the reaction to facilitate the reaction. Suitable bases include, but are not limited to, Cs2CO 3, K 2CO 3 , and the like. The above process may be carried out at temperatures between about -78 °C and about 150 °C. Preferably, the reaction is carried out between about 20 °C and about 120 °C. 102561 In another example, chemistry described in in schemes 3-6, RG 3 is a moiety contains a ---COOH group and RG 4 is a moiety contains a suitable amine group. In a typical procedure, a RG' containing intermediate is reacted with a RG4 containing intermediate in a suitable solvent in the presence of a suitable amide coupling reagent. Suitable solvents include, but are not limited to, water, ethers such as THF, glyme, and the like; chlorinated solvents such as DCM, 1,2--dichloroethane (DCE) or CHCl3 and the like, toluene, benzene and the like, DMF, DMSO, MeCN. If desired, mixtures of these solvents are used. In this case, the preferred solvents are DMF or DCM. A suitable amide coupling reagent include, but are not limited to, DCC, EDC, HATU, HBTU, PyBOP and the like. A base is often added to the reaction. Suitable bases include, but are not limited to,TEA, DIPEA, and the like. The above process may be carried out at temperatures between about -78 °C and about 150 °C. Preferably, the reaction is carried out between about 0 °C and about 100 °C.
[0257] Although not explicitly shown in schemes 3-6, a chemist of ordinary skill would realize that during any of the synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T.W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons (1981); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons (1991). and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference in their entireties.
[0258] When a general or exemplary synthetic procedure is referred to, one skilled in the art can readily determine the appropriate reagents, if not indicated, extrapolating from the general or exemplary procedures. Some of the general procedures are given as examples for preparing specific compounds. One skilled in the art can readily adapt such procedures to the synthesis of other compounds. Representation of an unsubstituted position in structures shown or referred to in the general procedures is for convenience and does not preclude substitution as described elsewhere herein. For specific groups that can be present, either as R groups in the general procedures or as optional substituents not shown, refer to the descriptions in the remainder of this document, including the claims, summary and detailed description. 102591 The process to produce compounds of the present invention ispreferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can also be used.
[0260] The compounds of Formulae 11-IV (below), or their pharmaceutically acceptable salts, may be prepared by the methods similar to chemistry illustrated above for synthesis of compounds of Formula I (scheme 3-6), together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art:
1 1 R R /-4"P
Formula~;n X
R R d
2 1 2 P a Rbaan
Formula IV
4
[0261] For compounds of FormuleI-IV, L, ABM, ULM groups,.W ,W, W,W ,X X2 2 Ra R R R, R R R areasdefineabove.
[0262] In certain embodiments, ABM compounds are active without forming bifunctional compounds of formularHI-IV.
[02631 Synthesis of ABM Moieties
[0264] ABM-1:2-chloro-4-(3-(4-hydroxypheny)-4,4-dimethy-5-oxo-2 Ste N 3 thioxoimnidazolidin-1-yl)benzoniitrile H
Step NC Step2 OH
A D
[0265] ^B-1
[0266] Step:Synthesis of 2-chioro-4-isothiocyanatobenzonitrile(B).
[02671 Toa stirred solutionof4-amino-2-chlorobenzonitrie(A,1g,6.55mmoi)in dichloromethane (9 mL) was added sodium bicarbonate(2.21 g,26.31 mmol) and water (9 mL). Therereslting mixture was cooled to0 °C, towhich thiophosgene (817 mg, 7.11rmmol) was added in drop wise in 30min at0 °C. The resulting mixture was then warmed up toroom temperaure andstirred atroom temperature for 1hour. The reaction mixture was diluted with dichoromethane(0 mL),washedwithbrine(50mLx2),driedoveranhydroussodiumsulfate and then concentrated under reduced pressure to give a crude residue. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v: v = 1: 30)) to give desired product (yield: 71%) HNMR (400 MHz, CDCi 3 ): 67.69 (d, J= 8.0 Hz, IH), 7.38(s,
1H), 7 28 (m, 1H);
[02681 Step 2: Synthesis of 2-chlioro-4-[3-(4-hydroxyphenyl)-5-imino-4, 4-dimethyl-2 sulfanylideneimidazolidin-1-yl]benzonitrile (D).
[0269] To a stirred solution of2-chlioro-4-isothiocyanatobenzonitrile (B, 399 mg, 2.05 mmol) in toluene (5 mL) was added 2-[(4-hydroxyphenyl)amino]-2-methylpropanenitrile (C, 300 mg, 1.70 mmnol) and 4-diethylaminopyridine (312 mg, 2.55 nmol). The resulting solution was then heated in an oil bath to 100 °C and stirred at the same temperature for 16h. LC-MS indicated formation of the desired product. The reaction mixture was concentrated under vacuum to give a crude reside which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v =1:1)) to give desired product (yield: 48%) as a brown solid. LC MS (ES'): i/ 370.95 [MIH], i =0.74 min (2.0 minute run);
[0270] Step 3: Synthesis of2-chloro-4-[3-(4-hydroxyphenil)-4,4-dimethyl-5-oxo- 2 sulfanylideneimidazolidin-1-yl]benzonitrile (ABM-1).
[0271] To a stirred solution of 2-chloro-4-[3-(4-hydroxyphenyil)-5-imino-4, 4-dimethyl -sulfanIylideneimidazolidin-1m-benzonitrile (D, 300 mg, 0.81 mmol) in methanol (6 ml) was added aqueous hydrogen chloride (2N, 3.0 mL). The resulting solution was then heated in an oil bath to 100 °C and stirred at the same temperature for 2h. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (60 mL x 3), washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give titled product (yield: 93%) as a yellow solid, which was used for the next step without any further purifications. LC-MS (ES'): inz 372.00 [MH+], R =0.97 min (2.0 minute run).
[02721 Unless otherwise noted, the following intermediates and their analogs (for examples, but not limited to, analogs with substitutions such as halogens) were synthesized according to similar procedures described above for the synthesis of ABM-1, by utilizing corresponding starting materials and reagents.
[0273] ABM-2: 2-fluoro-4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2 thioxoimidazolidin-1-yl)benzonitrile:
F 0
NC- N
s OH ABM-2
10274]1 ABM-3: 4-(3-(4-hydroxvpheny)-4,4-dinetivi-5-oxo-2-thioxoi-nidazolidi-1 yI)-2-(trifluiorornethyl)benzouiitrile: F 30C 0%
NC-N
1::OH ABM-3
102751 ABM-4: 5-(3-(4-hydroxypheny)A,4-dinetly-5-oxo-2-thioxoiniidazolidii-1 yI)-3-(trifluoromethyl)picolinonitrile: F'jC 0
NC /\N
ABM-4
[02761 ABM-5: 4-(3-(4-hydroxypheny)-4,4-dirnethy-5-oxo-2-thioxoinidazoidiw-1 yI.)-2-mnethoxybenzoiiitrile:
NC-N
OH ABM-5
[0277] ABM-6: 4-(3-(4-hydroxyphenyI)-4,4-dimethy1-5-oxo-2-thixoimidazolidin-1 yI)-2-methylbenzonitrile: 0
NC-N s ABM-6
1-02781 ABM-7: 3-chloro-5-(3-(4-hydroxypheny)-4,4-dinethy-5-oxo-2 thioxoirnidazolidin-1-yI)picolinonitrile:
CI NC-N
ABM-7
diazaspiro[4.5Idecan-3-yi)-2-(trifluoromethyl)benzonitrile: F3 C 0)
) ABM-8
[0280] ABM-9: 4=(1-(4-hydroxyphenyl)-8-methyl4-oxo-2-thioxo-1,3,8 triazaspiro-4.5Id&can-3-yI.)-2-(trifiiorondhtvl)beiizonitrile:
0 N
NC- /N
ABM-9 0H
[02811 ABM-10: 4-5- (4-hwdroxp ien I) -8-oxo-6-thioxo-5,7-d iazaspiro3.I octa -7 yI)=2-(trifluoromrethyI)beiitztnitrile F3 C
NC- y
ABM-10
102821 ABM- 1: 5-(5-(4-hydroxypheiriy1)-8-toxo-64hkiixo-5,7-.diazaspiro434]owtan-7
FC NC- - N
ABM-1 I
[0283] ABMV-12: 4-(4-(3-(4-evano-3-(trifluoromethyI,)phenyI)-5,5-dirnethy-4-oxo-2 thioxoimidazolidin-1-yI)plhenyl)hutanioic acid:
F
N:: - . N~
ABM-1 2
"
[0284] ABMV-13: 2-chloro-4-(3-(4'-hydroxybiphenyl-4-yI)-4,4-dirnethyl-5-oxo-2 thioxoimidazolidin-1-yI)benzonitrike:
/N"
ABM-13 ~ O
1[02851 ABM-14:4-(3-(4'-hydroxybiphenyl-4-l)-4,4-dinethyl-5-oxo-2 thioxoirnidazolidin-1-yI)-2-(trifluorornethyl)beuizonitrile:
FC 0
NC-C y~N
ABMI4OH.
[0286] ABM-15: 5-(3-(4'-hydroxybipheyl-4-yl-4,-dimethyl-5-Jxo-2 t~iioxonidazoidin-I -vi)-3- (triflurone thyI1)picolinon i ril e: F3 C, 0
NC-< N
ABM-15I OH
[0287] ABM-16: 4-(,3-(3-fluoro-4-hydroxypheiiv1)-4,4-dimethyl-5-oxo-2 thioxoimidazolidin-1-yI)-2-(trifluoroniethyl)benzoiiitrile. F3 C
NC /\-N N F N- N
SOH ABM-16
[02881 ABM-17: 1-(4-Iiydroxyphetyl)-5,.5-dimethyI-3-(4-nitro-3 (trifluorornethyl)phenyl)-2-thioxoimidazolidin-4-one:
0 2 N-/\ s ABM-17
[0289] ABMV-18: 4(3-(3,5-difluoro-4-hydroxypheny1)-4,4-dirnethyl-5-oxo-2 thioxoiridazolidiii-1-vi)-2-(trifliioroi-netliyl)beiizoiiitrile: F3 C 0
NC FN
O ABM-18
102901 ABM-19:4-(3-(4-hydrxyphenl)-4,4-dinethyl-2,5-dioxoinidazolidii-1-yI)-2 (trifluoromethyI,)benzonitrile: F.3C 0
ABM-19
[0291] ABM-20: 4-(3-(6-hydrxypyridi--3y)=4,4-dirnethyl-5--oxo-2 thioxoiridazolidiii-1-vI)-2-(trifliioroinetliyl)beirizoiiitrile: F3 C 0
NC )N: N OH ABM-20
[0292] ABMV-21: 2-chloro-4-(3-(3-fltioro-4-hydroxvphenyl)-4,4-dirnethyl-5-oxo-2 thioxoimidazolidin-1-yI)benzonitrike:
NC-\ N s OH ABM-21
[02931 ABM-22: 4-(3-3fluor-4-hyvdroxypheity1)-4,4-dirnethyI-5-oxo-2 thioxoimidazolidin-I-yi)-2-methoxybenzonitrile:
MeO, 04
NCW-N
ABM-22
[0294] ABMV-23: 5-(3-(3-fluoro-4-hydroxyphenyl)4,4-dimethy-5-x-2 thioxoiridazolidiii-1-vI)-3-(trifliioroi-netlyl)picoliiioiiitrile: F3 C 0
NC- N F N s tOH ABM-23
[02951 AB M -(-2ur-'hdovihiy-l-.4dime-f-5-rto-2 thioxoimidazolidin-1-yI)-3-(trifluoroniethyl)picoliiionitrile:
NC- , N yN><S
ABM-24I OH
[-0296]1 ABM-25. 4-(4,4-dirnethyl-5-oxo-3-(4-(piperidin-4-y)phenl)-2 thioxoirnidazolidiii-1-yI-2-(trifluiorornethyl)benzonitrile: F3 C
NC--N N
ABM-25
10297]1 ABM-26: tranis- 2-Chloro-4-[3-amino-2,2,4,4 tetrarnethylcyclobutoxylbenzonitrile.
[02981 ABM'-27: cis-2-Clhloro-4413-arniino-2,2,4,4 tetrarnetlhylcyclobutoxylbenzonitrile
102" cV oNH2
N
[0299] AB.M-28: trans 6-Amino-N-13-(3-cioro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]pyridazine-3-carboxanide
103001 ABM-29: trans tert-Buty N-[3-(3-chloro-4-yanopheoxy)-2,2,4,4 tetramethylcyclobutylicarbamate.
0' -NH
c /
1
[0301] ABM-30: trans 4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutylibenzamide
[0302] Step 1: Synthesis oftert-butyl (4-((trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carbanoyl)phenyil)carbamate.
[0303] A suspension of 4-((tert-butoxycarbonyi)amino)benzoic acid (1.50 g, 6.34 mmol) in methylene dichloride (40 mL)was charged with N,N-diisopropylethylamine (3.30 mL, 19.0 mmol), followed by4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride (2.0 g, 6.34 mmol). The mixture was stirred for several minutes and then charged with HATU (2.41 g,6.34 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The mixture was diluted with methylene dichloride (40 mL), washed with aqueous IN HC (2 x), saturated aqueous sodium bicarbonate (2 x), brine, and dried over anhydrous Na 2SO. The crude product was used in next step;
[0304] Step 2: Synthesis of trans 4-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]benzamide.
[0305] 4M HCi in Dioxane (1.38 mL, 40.0 mmol) was added to a pre-mixed solution of tert-butyl (4-((trans-3- (3-chloro-4-cyanophenoxv)-2,2,4,4 tetramethylcyclobutyl)carbamoyl)phenyl)carbamate (2.00 g, 4.01 mmol) in MeOH (2 mL) and left to stir at room temperature for 1 hour till completion. The reaction mixture was concentrated in vacuo to a solid, which was dissolved with 5% MeOH in DCM. The organic layer was washed with sodium bicarbonate (2 x), filtered through a Biotage Universal Phase Separator and then concentrated in vacuo to a solid. The crude product was recrystallized from EtOH/Heptanes to afford the desired product as a white solid, 1.2g, 75%yield. 11 NMR (400 MHz, METHANOL-d4) 6 7.72 (d, J = 8.80 Hz, 1H), 7.61 (d, J = 8.61 Hz, .2H), 7.13 (d, J = 2.35 Hz, 1H), 6.98 (dd, J = 2.45, 8.71 Hz, 1H), 6.69 (d, J = 8.61 Hz, 2H). 4.28 (s, 1H), 4.12 (s, 1H), 1.27 (s, 61), 1.22 (s, 61). LC-MS (ES+): mz 398.16/400.15 [MHW].
[0306] Unless otherwise noted, the following intermediates and their analogs (for examples, but not limited to, analogs with substitutions such as halogens) were synthesized according to similar procedures described above for the synthesis of ABM-30, by utilizing coresponding starting materials and reagents.
[0307] ABM-31: trans 5-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]pyrazine-2-carboxamide
[0308] ABM-32: trans 2-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]pyrimidine-5-carboxamid
[0309] ABM-33: 4-Methoxy-N-[(r,3r)-3-(3-chloro-4-yanophenoxy)-2,2,4,4 tetramethylcyclobutyl]benzamide
[0310] ABM-34: trans 1-(2-Hydroxyethyl)-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]-IH-pyrazole-4-carboxamide
[0311] ABM-35: trans 6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]pyridine-3-carboxamide.
N''
[0312] ABM-36: trans 4-[(5-Hydroxypetyl)amino]-N-[3-(3-chloro-4 eyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide
[0313] ABM-37: trans tert-Butyl 2-({5-(4-(13-(3-cliloro-4-yanophenoxy)-2,2,4,4 tetramethylcyelobutyl]carbanioyl}phenyl)aniinopentyl}oxy)acetate
N,. .'
[0314] ABM-38: tert-butyl trans-(3-(3-chloro-4-cyanophenoxy)-2,2 dimethylcyclobutyl)carbamate] and ABM-39: tert-butyl cis-(3-(3-chloro-4-cyanophenoxy) 2,2-dimethylevelobutyl)carbamate.
Br tBuOK, THF - O' CI O NH 2OH.HCI
A B TEA,MeCN C OBn NaOAc,EtOH r.t,1.5 hours
OH BocHN N - Boc2OTHFi h - Pd/C, H' NaOH,60C OBn 2 hours OBn F OBn G D E
Cl O ~NHBoc Co -NHBoc.
NC K CI NaH,DMF 0NC NC ABM-38 ABM-39
[0315] Step 1: Synthesis of ((vinyloxy)methyl)benzene (B).
[03161 To a stirred solution of potassium tert-butanolate (A) (23 g, 205 mmol) in tetrahydrofuran (120 ml) was added ((2-bromoethoxy)methyi)benzene (30 g, 140 mmol) in tetrahydrofuran (70 ml) at 0°C. The resulting mixture was allowed to wan to room temperature and stirred for 3 hours. TLC showed the reaction was complete. The mixture was partitioned between anhydrous dichloromethane (300 ml) and water (100 ml). The organic layer was collected, washed with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude ((vinyloxy)methyl)benzene (14.8 g, yield 80%) as colorless oil. 11- NMR (400 [z, CDCl 3): 6 4.09 (dd,J= 2.0, 6.8 Iz, 1H), 4.29-4.33 (in, 1), 4.77 (s, 2H), 6.54-6.60 (in. IH), 7.28-7.39 (m, 5H). Chemical Formula: C9 H10 0; Molecular Weight: 134.18.
[0317] Step 2: Synthesis of 3-.(benzyloxy)-2,2-dimethylcyclobutanone (C). 10318] To a stirred solution of benzyl vinyl ether (2 g, 15.2mmol) and triethylamine (13 ml, 9.2 mmol) in anhydrous acetonitrile (6 ml) was added slowly a solution of isobutyryl chloride (0.8 ml, 7.6 mmol) in dry acetonitrile (3 ml) at reflux. The resulting mixture was refluxed for 0.5 hour. TLC showed the reaction was complete. The reaction mixture was allowed to cool to room temperature and partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (20 ml x 2).
The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude residue which was purified by silica gel flash chromatography (eluted with 5-10% ethyl acetate in hexane) to afford 3- (benzyloxy)-22-dimethylcyclobutanone (1.5 g, yield 50%) as colorless oil. 111 NMR (400 Hz,
CDCl 3): 6 1.19 (s, 311), 1.26 (s, 3H), 3.08-3.24 (, 2H),3.96-3.99 (in, 1H), 4.55 (s, 2H), 7.29 7.39(m,5H). Chemical Formula: C 3 H 6 0 2; Molecular Weight: 204.26.
[03191 Step 3: Synthesis of 3-(benzyloxy)-2,2-dimethylcyclobutanone oxime (D)
[0320] To a solution of hydroxylamine hydrochloride (3.0g, 44.1 mmol) in ethanol (100 ml) was added 3-(benzyloxy)-2,2-dimethylcyclobutanone (7.5 g, 36.7 imol) and sodium acetate trihydrate (6.5 g, 47.7 mmol). The resulting mixture was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up in ethyl acetate (80 ml) and water (50 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 3-(benzyloxy)-22-dimethyilcyclobutanone oxime (8.3 g, crude) as colorless oil which was used in next step without further purification. LCMS: (ES): m/z 220.2 [M+H] t . tR = 2.550 min.
[03211 Step 4: Synthesis of3-(benzyloxv)-2,2?-dimethyiclyclobutanamine (E)
[0322] To a solution of 3-(benzyiloxy)-2,2-dimethylcyclobutanone oxime (8.3 g, crude) in tetrahydrofuran (75 ml) was added Ni/Al alloy (13.3 g 155mmol) under nitrogen atmosphere. The suspension was stirred at 60°C for 30 minutes. To the resulting mixture was added aqueous sodium hydroxide solution (6.9 g in 75 ml water, 172 mmol) dropwise to keep the mixture refluxing. After addition, the mixture was refluxed for another 2 hours. TLC showed the reaction was complete. The solid was removed through filtration and the filter cake was washed with tetrahydrofuran (10 ml x 2). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (75 ml).The combined organic layers were washed with brine (50 ml) and dried over sodium sulfate and concentrated togive 3-(benzyloxy)-2,2 dimethylcyclobutanamine (6.3 g, crude) as colorless oil. The crude product was used in next step without further purification. HNMR shows it was a mixture of trans/cisisomers (ratio:cis: trans: 1:1). LC_MS: (ES'): n/z 206.3 [M+H]. tR = 1.675 min. HNMR (400MH z, CDCl): Tans isomer: 6 1.01 (s, 3H), 1 11 (s, 3H), 2.22-2.28 (m. 1H), 2.44-2.53 (m, I H), 3.11-3.14 (in.
1H), 3.73-3.75 (m, 11), 4.39-4.74 (m, 211), 7.25-7.36 (i, 5H). Cis isomer: 6 1.02 (s, 3H), 1.11 (s, 3H), 1.57-1.62 (m, 1H), 1.80-1.86 (m, 1H), 2.58-2.65 (m, 1111), 3.41-3.45 (m, 11-), 4.39-4.74 (m, 2H). 7.25-7.36 (m, 5H). Chemical Formula: CnHNO: Molecular Weight: 205.30. 103231 Step 5: Synthesis of tert-butyl (3-(benzyloxy)-2,2-dimethylcyclobutyl)carbamate (F).
[03241 To a stirred solution of3-(benzyloxy)-2,2-dimethyleyclobutanamine (6.3g, crude) in tetrahydrofuran(70 ml) was added di-tert-butyl dicarbonate (7 ml, 30.7 mmol) slowly at room temperature. The reaction mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The volatiles were removed under reduced pressure to give a crude residue which was purified by silica gel flash chromatography elutedd with 5-10% ethyl acetate in hexane) to afford tert-butyl (3-(benzyloxy)-2,2-dimethycyclobutyl)carbam ate (6.0g, yield 53% over 3 steps) as colorless oil. LCMS: (ES"): m/z 306.2 [M+H]t . ta = 3.167 min. 103251 Step 6: Synthesis of tert-butyl (3-hydroxy-2,2-dimethycyelobuty)carbamate (G).
[03261 A mixture of tert-butyl (3-(benzyloxy)-2,2-dirnethylcyclobutyl)carbamate (6.3 g, 20.6 mmol) and palladium on carbon (10%, 700 mg) in methanol (10 iml) was stirred at room temperature overnight under hydrogen atmosphere (hydrogen balloon). TLC showed the reaction was complete. Palladium on carbon was removed through filtration and the filter cake was washed with methanol (25 ml x 2). The combined filtrates were concentrated under reduced pressure to afford tert-butyl (3-hydroxy-2,2-dirnethylcyclobutyl)carbamate (4.5 g, yield 95%) as white solid. HNMR shows it was a mixture of trans/cisisomers (ratio: ~ 1:1). HNMR (400MHz, CD30D): Tans isomer: 6 0.95 (s, 31), 1.08 (s, 31), 1.45 (s, 911), 2.07-2.19 (m, I1), 2.43-2.50 (m, 1H). 3.61-3.65 (i, 1H), 3.82-3.85 (m, 1H). C/s isomer: 6 0.91 (s, 3H). 1.13 (s, 3H), 1.45 (s, 9H), 1.72-1.79 (m. 11).2.43-2.50 (m, 111), 3.35-3.38 (m, 1H), 3.69-3.73 (m, 11). Chemical Formula: C .I- 2 1NO 3 ; Molecular Weight: 215.29.
[0327] Step 7: Synthesis of tert-butyl trans-(3- (3-chloro-4-cyanophenoxy)-2,2 dimethlvcyclobutvl)carbamate (ABM-38) and tert-butyl cis-(3-(3-chlioro-4-cyanophenoxy)-2,2 dimethylcyclobutyl)carbamate (ABM-39).
[03281 To a stirred solution of tert-butyl (3-hydroxy-2,2-dimethylcyclobutyil)carbamate (280 mg, 1.29 mmol) in N,N-dimethyfornamide (6 ml) was added sodium hydride (60% in mineral oil, 103 ing, 2.58 nmol) at 0°C. The mixture was stirred at 0°C for 0.5 hour, followed by addition of 2-Chloro-4-fluorobenzonitrile (200 mg, 1.29 mmol); the resulting mixture was stirred at 0°C for 1 hour. TLC showed the reaction was complete. The reaction mixture was quenched with water (3 ml) at 0°C and extracted with ethyl acetate (5 ml x 3). The combined organic layers were washed with brine (15 nl), dried over anhydrous sodium sulfae, and concentrated under reduced pressure to afford a crude residue which was purified by silica gel flash column chromatography (eluted with 20% tert-Butyl methyl ether in hexane) to afford ABM-38 (110 mg, yield 26%) as white solid and ABM-39 (120 mg, yield 26%) as white solid. ABM-38: LCMS: (ES'): m/z 351.2 [M+H]*. tR = 3.222 min. 1HNMR (400MHz. CDCls):6 1.15 (s, 3H), 1.18 (s, 3H), 1.45 (s, 91-1), 2.17-2.24 (m, i1), 2.39-2.46 (in, 111), 3.96-4.07 (n, 1),4.29-4.32 (m,1H). 4.59-4.67 (m, IH), 6.75 (dd,J=2.4,8.8 Hz, 1H), 6.89 (d,J= 2.0 Hz, IH), 7.54 (d,,J=
8.8 Hz, 11-). Chemical Formula: C 8 1-23CIN 2 O3; Molecular Weight: 350.84. ABM-39: LCMS: (ES-'): m/z 351.2 [M+H]*. tR =.3.173 min. IHNMR (400MHz, CDCik): 6 1.03 (s, 3H), 1.32 (s, 3H), 1.45 (s, 9H), 1.80-1.87 (m IH),2.79-2.86 (m, 1H), 3.64-3.72 (m, 1H), 4.16-4.20 (m, 1H). 4.57-4.59 (in, 1H), 6.77 (dd, J= 2.0, 8.8 Hz, H), 6.89 (d = 24 H-z, I H), 7.54 (d,J= 8.4 lz, 1H). Chemical Formula: CsH 23C1N 2 03 : Molecular Weight: 350.84.
[0329] The experimental procedure used to make ABM-30, may be used to synthesize the free amine, which is used for further coupling.
[03301 Synthesis of ULM Moieties
[0331] ULM-1: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4 inetiylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
NC C ~. H2 N N N
FrF NC NBrNC ------- -- H2N, Pd(OA c) 2, KOAc S Step 2 E Step 1 G H
HON OH HO -N
c H HO, 0 N I . N HCI N) N HATU, D!FA. DMF 60C Sp HO----
HCI K Step 3
N NN H) HO
OHc HH
HATIU/ DIEA 0 0Step
BOC'NH M HC NH ULM-1
[0332] Step 1: Synthesis of 4-(4-methyl-13-thiazol-5-yl)benzonitrile (G)
[03331 To a stirred solution of 4-bromobenzonitrile (E, 20 g, 109.88 mmol) in DMA (250 mL) under a nitrogen atmosphere was added 4-methyl-1,3-thiazole (F, 21.88 g, 220.67 mmol), palladium (II) acetate (743 mg, 3.31 mmol) and potassium acetate (2166 g, 220.71 mmol) at room temperature. The resulting solution was heated to 150 C and stirred at this temperature for 5 hours, LC-MS indicated formation of the desired product. The reaction was cooled to room temperature, diluted with 1 L of water and extracted with ethyl acetate (300 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (200 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:5) to give the G (yield: 91%) as a white solid.
[0334] Step2: Synthesis of [4-(4-methyl-1,3-thiazol-5-yl)phenyli]methanamine (H)
[03351 To a stirred solution of 4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (G, 35.0 g, 174.8 mmol) in tetrahydrofuran (1000 mL)was added LiAlH 4 (20.0 g, 526.3 mmol) in portions at0C in 10 min under a nitrogen atmosphere. The resulting solution was then stirred at 60 C for 31. LC-MS indicated formation of the desired product. The reaction was then cooled to 0°C, quenched by the addition water (20 mL, added slowly), aq. solution of NaOH(15% 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v = 10:1)) to give H (yield: 56%) as a yellow oil.
[0336] Step 3: Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol 5-yl)phenyl]methyllcarbamoyl)pyrrolidine-1-carboxylate (J)
[03371 To a stirred solution of (2S,4R)--[(tert-buoxy)carbonyl]-4-hydroxypyrroiidine 2-carboxylic acid (I, 2.7 g, 11.7mmol) in N,N-dimethylformamide (20 mL) was added DIEA (2.52 g 19.50 mmol), HATU (4.47 g. 11.76 mmol) and [4-(4-methyl-1,3-thiazol-5 yl)phenylImethanamine (H, 2.0 g, 9.79 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight, LC-MS indicated formation of the desired product. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v = 20:1)) to give J (yield: 56%) as a yellow solid.
[03381 Step 4: Synthesis of(2S,4R)-4-hvdroxy-N-{[4-(4-methyl-1,3-thiazol-5 yl)phenyl]methylIpyrrolidine-2-carboxamide hydrochloride (K)
[03391 To a stirred solution of tert-butyl (2S,4R)-4-hydrox-2-({1[4-(4-methyl-1,3 thiazol-5-yl)pheny]ImethylIcarbamoyl)pyrrolidine-I-carboxyate (J, 45 g, 107.78 mmol), was added a solution of hydrogen chloride in dioxane (4N, 300 mL) . The resulting solution was stirred at 20 C for 2 hours. The solids were collected by filtration to give K (yield: 98%) as a yellow solid, which was used for the next step without any further purification.
[0340] Step 5: Synthesis of tert-butyl N-[(2S)--I(2S,4R)-4-hydroxy-2-({[4-(4-methyl 1.3-thiazol-5-yl)phenyl]methylcarbamoyl)pyrrolidin--yil]-3,3-dimethyl-1-oxobutan-2 yl]carbamate (M)
[03411 To a stirred solution of (2S)-2-{[(tert-btoxy)carbonyl]amino}-3,3 dimethylbutanoic acid (L, 15.7 g, 68.0mmol) in N,N-dimethylformamide (500 mL) was added DIlEA (29.2 g, 225.9 mmol), HATU (25.9 g, 68.1 mmol) and (2S,4R)-4-hydroxy-N{[4-(4 methyl-1,3-thiazol-5-yl)phenyl]methylI pyrrolidine-2-carboxamide hydrochloride (K, 20.0 g 56.5 mmol) at room temperature. The resulting solution was stirred at room temperature for 16 hours, LC-MS indicated formation of the desired product. The reaction mixture was diluted by
1II water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v 2:1)) to give M (yield: 51%) as a yellow solid.
[0342] Step 6: Synthesis of (2S,4R)--1[(2S)-2-amino-3.3-dimethylbutanoyl]-4-hydroxy N-{[4-(4-methyl-13-tlhiazol-5-yl)phenyl]methylpyrolidine-2-carboxamide hydrochloride (ULM-1) 103431 To a stirred solution of tert-butyl N-[(2S)--[(2S,4R)-4-hydroxy-2-({[4-(4 methyl-1,3-thiazol-5-yl)phenyl-methyllcarbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamate (M, 12 g, 22.61 mmol) in dioxane (20 ml) was added a solution of hydrogen chloride in dioxane (4N, 80 mL) at room temperature. The resulting solution was stirred at room temperature for 2 h, LC-MS indicated formation of the desired product. Precipitated solids were collected by filtration to give ULM-1 (yield: 48%) as a yellow solid. 'HNMR (400 MHz, CD 30D): 6 9.84-9.82 (s, 1H), 7.58-7.54 (i, 411), 4.71-4.41 (m, 411), 4.13-4.08 (m, IH), 3.86
3'.71 (,2H.), 3.36 (s, 1H), 2.60--2.58 (s, 3H), 2.35--2.07 (m, 2H), 1.19-1.12(m, 9H). LC--MS
(ES'): rz 431.11 [MH], tR = 0.73 min (2.0 minute run).
[03441 ULM-2: (2S,4R)-i-((S)-2-amino-3,3-dimethylbutaiiovl)-4-hydroxy-N-(4 (thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide: _N
HO S IN
HCI NH 2 ULM-2
[0345] ULM-2 was synthesized according to similar procedure described above for the synthesis of ULM-1, utilizing 4-bromobenzonitrile and 1,3-thiazole as starting natenals. LC-MS (ES): iz 417.10 [MH ]. tR = 0.51 min (2.0 minute run).
[0346] ULM-3: (2S,4R)-i-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1 (4-(4-nethylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide:
N-,
H 2N 11 (Boc)O BocHN F BocHN B Ste" Br S _JN N Step 2 p
FiI H 2N 'F H
Step3 N
[0347] HCi NH2 ULM-3
[0348] Step 1: Synthesis of tert-butyl N-[(IS)-i-(4-bromophenyl)ethvl]carbamate (0)
[03491 To a stirred mixture of (iS)-i-(4-bromophenyl)ethani-I-amine (N, 10.0 g, 49.98 mmol) in dichloromethane (100 mL) was added Et3N (10.0 g99.01 mmol) and (Boc) 2 0 (13.0 g, 59.63 mmol). The resulting mixture was stirred at room temperature for 2 hours. The bulk of solvent was then removed under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:10) to give 0 (yield: 99%) as a white solid.
[0350] Step 2: Synthesis of tert-butyl N-[(1S)-I-[4-(4-methyl-1,3-thiazol-5 yl)phenyl]ethylcarbamate (P)
[0351] To a stirred solution of tert-butyl N-[(1S)--(4-bromophenyl)ethyl]carbamate (0, 15.0 g, 49.97 mmol) in DMA (100 mL), under an atmosphere of nitrogen. was added4-methyl 1,3-thiazole (9.9 g. 99.84 mmol), potassium acetate (9.8 g, 99.86 mmol) and Pd(OAc)2 (112.5 mg, 0.50 mmol) at room temperature. The resulting mixture was then stirred at 120°C for 2 hours. The reaction mixture was then cooled to room temperature, diluted by water (I20mL). and extracted with ethyl acetate (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v 1:5) to give P (yield: 47%) as a white solid. LC-MS (ES+): iz 319.13 [MH], tR = 0.97 mi (2.0 minute run).
[03521 Step 3. Synthesis of (1S)--[4-(4-methyl-1,3-thiazol-5-yl)phenyi]ethan-1-amine hydrochloride (Q)
[0353] To a stirred solution of tert-butyl N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5 yliphenyllethylicarbamate (P, 7.5 g, 23.55 mrnol) in methanol (20 mL) was bubbled in hydrogen chloride (gas) at room temperature for 2 hours. Then the resulting mixture was concentrated under vacuum to give Q (yield: 86%) as a white solid, which was used in the next step without any further purifications.
[03541 Intermediate Q was converted to ULM-3 in a similar manner as described for the conversion of H to ULM-1. 'H NMR (300MHz, DMSO): 6 8.99 (s, 1H), 8.57-8.55 (d,,J= 7.8 Hz, I H), 8.01 (br. s, 3 H), 7.46-7.43 (d, J= 8.4 Hz, 2 H), 7.39-7.37 (d.J= 8.4 Hz, 2 H), 4.98 4.90 (m, 1 H), 4.57-4.51 (m, 1 H), 4.34 (br. s, I H), 3.94-3.92 (i, I H), 3.69-3.66(, 1 H), 3.53 3.49 (in. 1 H), 2.52 (s, 3 H), 2.10-2.07 (m,I H). 1.83-1.81 (m,I H). 1.40-1.30 (m, 3 H). 1.03 (s.
9H). LC-MS(ES*):z [MH p4 5.05 =], 0.53 min (2.0 minute run).
[03551 ULM-4:(2S,4R)-I-((S)-2-amino-3,3-dim ethylbutanoyl)-4-hydroxy-N-(4 (oxazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride: -C 'Ye (
CN - C \0-j 0 Raney-Ni Step 1 Step 2 0N::/ St R S
NHH T , N
NN T <0
ULM-4
[0356] Step 1: 1. Synthesis of 4-(1,3--oxazol-5-yl)benzonitrile (S) 10357] To a stirred solution of 4-formylbenzonitrile (R, 1.0 g,7.63 mmol) in methanol (40 mL) was added [[(4-methylbenzene)sulfony]methyl](methyliumylidyne)azanuide (1.6 g, 8.40 mmol) and potassium carbonate (1.4 g, 9.91 mmol), the resulting mixture was stirred at room temperature for 1.5 hours. The bulk of solvent was then removed under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate (20 mL) and was extracted with dichloromethane (30 mL x 3).The organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude product, which was purified by re-crystallization using dichloromethane and hexane to give S
(1.0 g) as a white solid. IH NMR (400 MHz, DMSO) 6 8.56 (s, 1H), 7.97-7.83 (in. 5H) LC-MS (ES'): in 170.95 [MH+], tR = 0.79 min (2.0 minute run).
[0358] Step2. Synthesis of [4-(1,3--oxazol-5-yl)phenyi]methanamine (T)
[03591 To a stirred solution of 4-(,3-oxazol-5-yl)benzonitrile (S, 900.0 mg, 5.29 m0ol) in methanol (15 mL) was added Raney-Ni (900 mg) and aq. ammonium hydroxide (3.0 mL). Hydrogen gas was then introduced into the reaction mixture via a balloon. The resulting mixture was stirred at room temperature for 16 hours. The solids were then removed by filtration and the solution was concentrated under vacuum to give T (yield: 81%) as brown oil, which was used in the next step without any further purifications. LC-MS (ES'): mz 175.90 [MH],R 0.26 min (2.0 minute run).
[03601 Intermediate T was converted to ULM-4 in a similar manner as described for the conversion of H to ULM-1. LC-MS (ES*): m/z 400.96 [MH], tR = 0.66 min (2.0 minute run).
[0361] ULM-5: (2S,4R)-1-((S)-2-amiiio-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4 methyloxazol-5-y1)benzyl)pyrrolidine-2-carboxamide: -c N' 0 CN N CN
o/N R U OH
NH 2 H2N N
________ H 0 N N V
ULM-5
[0362] [4-(4-methyl-1,3-oxazol-5-yl)phenyi]methanamine (V) was synthesized according to similar procedure described above for the synthesis of [4-(,3-oxazol-5 yl)phenylmethanamine (T).
[0363] Intermediate V was converted to ULM-5 in a similar manner as described for the conversion of H toULM . LC-MS(ES):mz415.10 [MH*], bR = 1.17 min (2.6 minute run).
[03641 ULM-6: (2S,4R)-I-((S)-2-amino-3,3-dinethylbutanoyl)-N-(4-chlorobenzyl)-4 hydroxypyrrolidine-2-carboxamide hydrochloride: CI N N 0
HCI NH 2 ULM-6
[0365] ULM-6 was synthesized according to similar procedure described above for the synthesis of ULM-1, utilizing 4-chlorobenzonitrile as the starting material.
[03661 ULM-7: (2S,4R)-1-((S)-2-amino-3,3-dinethylbutaiiovl)-N-(4-cyanobenzyl)-4 hydroxypyrrolidine-2-carboxamide hydrochloride:
HO; CN H
N 00 HCI NH 2 ULM-7
103671 ULM-7 was synthesized according to similar procedure described above for the synthesis of ULM-1, utilizing 4-cyanobenzonitrile as the starting material.
[0368] ULM-8: (2S,4R)-1-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4 nethylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride: N
HO 'S
0 HCI NH2 ULM-8
[03691 ULM-8 was synthesized according to similar procedure described above for the synthesis of ULM-1, utilizing (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid and 4 methyl-1,3-thiazole (F) as starting materials.
[03701 ULM-9:(2S,4R)-1-((S)-2-amino-3-nethiylbutanoyl)-4-hydroxy-N-(4-(thiazol 5-yl)beiizyl)pyrrolidine-2-carboxamide hydrochloride:
N HO S
HC NH 2 ULM-9
103711 ULM-9 was synthesized according to similar procedure described above for the
synthesis of ULM-1, utilizing (S)-2-(tert-butoxycarbonylamino)--3-metivbutanoic acid and 1,3
thiazole as starting materials.
[03721 ULM-10: (2S,4R)-1-((S)-2-aino-3-methylbutanoyl)-4-hydroxy-N-(4-(4 methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride: N
HO 0
N H
HCI NH 2 ULM-10
[0373] ULM-10 was synthesized according to similar procedure described above for the
synthesis of ULM-5, utilizing (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid as
starting material.
[0374] ULM-11: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(1 methyl-1H-pyrazol-5-y1)benzyl)pyrrolidine-2-carboxamide hydrochloride:
1-10, HOH
N 0 HC NH 2 ULM-11
[03751 ULM-11 was synthesized according to similar procedure described above for the
synthesis of ULM-1, utilizing 1-methylpyrazole as the starting material.
10376] ULM-12: (2S,4R)-4-tert-butoxy-N-(-hydroxy-4-(4-netlvthiazol-5 yl)beiizyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxanide:
HS HO,
,N S LAHIH N-' S NC Pd(OAc), KOAc Stp H Step N BG BH BI
OH OH N 0Fmoc O 0 OH piperidine
HATU DIEA DMF BJ Step 4 Step 3 S 5N
-rI H H N H
HAT U DIEA, DMF N Step 5 S<N "NN BK ULM-12
[0377] Step 1: Synthesis of2-hydroxy-4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (BH)
[0378] To a stirred solution of 4-bromo-2-hydroxybenzonitrile (BG, 28 g, 141.40 mmol) in DMA (300 mL) was added 4-methyl-i,3-thiazole (28.1 g, 283.40 mmol), potassium acetate
(28 g, 285.31 mmol) and palladium (II) acetate (940 mg, 4.19 mol) at room temperature under an
atmosphere of nitrogen. The resulting mixture was then heated to 150 C and stirred at this
temperature for 2.5 h. LC-MS indicated formation of the desired product. The reaction was then
cooled to room temperature, diluted by water (1000 mL) and then extracted with ethyl acetate
(500 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give a crude residue, which was purified by a flash silica
gel chromatography (eluent: ethyl acetate/petroleum ether (v : v = I: 1) to give BH (yield: 78%)
as a yellow solid. LC-MS (ES'): nz l16.95 [MH+], t= 1.25 min (2.6 minute run).
[03791 Step 1: 2-(aminomethyl)-5-(4-methyl-1,3-thiazol-5-yl)phenol (BI)
[0380] To a stirred solution of 2-hydroxy-4-(4-methyl-1,3-thiazol-5-yl)benzonitrile (BH. 15.6 g 72.14 mmol) in tetrahydrofuran (400 mL) under an atmosphere of nitrogen was added
LiAlH 4 (11 g, 289.86 mmol) in several portions at 10 TC. The resulting mixture was then heated
to reflux for 3 h, LC-MS indicated formation of the desired product. The reaction was then cooled to O0 C, quenched by the water (10 mL, added slowly and drop wise), 15% NaOH (aq.) (30 rnL) and water (10 mL). The solids precipitated were removed by filtration, the solution phase was concentrated under reduced pressure followed by high vacuum pump to give BI (yield: 65%). LC-MS (ES`): mnz 220.85 [MHI-],t 1=02mi(2.6 minuterun).
[03811 Step 3. Synthesis of 91-1-fluoren-9-ylmethyl (2S,4R)-4-(tert-butoxy)-2-({[2 hydroxy-4-(4-methvl-1,3-thiazol-5-yl)phenylImethyllcarbamovl)pyrrolidine-I-carboxylate (BJ)
[03821 To a stirred solution of (2S,4R)-4-(tert-butoxy)-1-(91-fluoren-9 ylmethoxy)carbonyl]pyrrolidine-2-carboxylic acid (BI, 18.6 g) in N,N-dimethylformamide (250 mL) was added DIEA (7.9 g, 61.24 mmol), HATU (17.3 g, 45.53 mmol) and 2-(aminomethyl)-5 (4-methyl-1,3-thiazol-5-y)phenoI (20 g. 90.79 mmo) at room temperature. The resulting mixture was stirred overnight at room temperature, and LC-MS indicated formation of the desired product. The reaction mixture was diluted by water (200 mL) and then extracted with ethyl acetate (300 mL x3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v: v = 25:1)) to give BJ (yield: 31%) as a yellow oil. LC-MS (ES+): m 611.20 [MHi], t = 1.12 nn (2.0 minute run).
[0383] Step 4: Synthesis of (2S,4R)-4-(tert-butoxy)-N- [2-hydroxy-4-(4-methyl-1.3 thiazol-5-yl)phenyl]methyllpyrrolidine-2-carboxamide (BK)
[03841 To a stirred solution of 9H-fluoren-9-ylmethyl (2S.4R)-4-(tert-butoxy)-2-({[2 hydroxy-4-(4-methyl-1.3-thiazol-5-yl)phenyl]methyllcarbamoyl)pyrrolidine-1-carboxylate (BJ, 17.2 g, 28.12 mmol) in dichloromethane (270 mL) was added piperidine (30 mL, 280.00 mmol) at room temperature. The resulting solution was stirred at room temperature for3 h, and LC MS indicated formation of the desired product. The reaction mixture was concentrated under vacuum to give a crude residue, which was then diluted by dichloromethane (300 mL), washed with water (300 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v: v = 20:1)) to give BK (yield: 71%) as a yellow oil. LC-MS (ES"): mz 389.95 [MH], lR = 0.88 min (2.0 minute run).
[03851 Step 5: Synthesis of (2S,4R)-4-(tert-butoxy)-N-{[2-hvdroxy-4-(4-methyl-1,3 thiazol-5-yl)phenyl]methyl}-1-[2S)-3-methyl-2-(1-oxo-2,3-dihydro1-1-isoindol-2 yl)butanoylipyrrolidine-2-carboxamide ULM-12)
[0386] To a stirred solution of (2S)-3-methyl-2-(1-oxo-2,3-dihydro-IH-isoindol-2 yl)butanoic acid (3.6 g, 15.43 mmol) in N,N-dinethylformamide (50 mL) was added DIEA (2.7 g0.93mmol), HATU (5.89g,15.49 mmol) and (2S,4R)-4-(tert-butoxy)-N-j[2-hydroxv-4-(4 methyl-1,3-thiazol-5-yl)phenyil]methyl}pyrrolidine-2-carboxamide (BK, 4.0 g, 10.27 mmol) at room temperature. The resulting solution was stirred overnight at room temperature, and LC MS indicated formation of the desired product. The reaction was diluted by the water (100 mL) and extracted with dichloromethane (100 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 2:1)) to give ULM-12 (yield: 43%) as a yellow solid.'H NMR (400 MHz. CDOD )6 8.88 (s 1H), 7.83-7.81 (d, J= 7.6 Hz, 11), 7.66-7.63 (m, 2 ), 7.61-7.59 (i, 1 H) 7.36-7.34 (d, J= 8.0 Hz, 1 H), 6.94-6.87 (d, J= 6.4 Hz, 1 H), 4.88 (s. 1 H), 4.564.39 (in. 6 H), 3.88-3.81 (in. 2 H), 2.51 (s, 3 H), 2.47-2.45 (in, 1 H), 2.15-2.13 (in, 2 H), 1.16-1.14 (d,J= 6.4 Hz, 3 H) 1.02 (s, 9H). 0.89-0.86 (d,!= 6.4 Hz, 3 H); LC-MS (ES'): nz 605.40 [MH*], tR-= 1.91 min (3.6 minute run).
[03871 Unless otherwise noted, the following intermediates and their analogs (for examples, but not limited to, analogs with substitutions such as halogens) were synthesized according to similar procedures described above for the synthesis of ULM-12, by utilizing corresponding starting materials and reagents.
[0388] ULM-13: (2S,4R)-4-tert-butoxy--((S)-2-(6-fluoro-1-oxoisoindolin-2-y)-3 nethylbutanoyl)-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxanide:
H
FULM-13
[0389] ULM-14: (2S,4R)-4-tert-butoxy-1-((S)-2-(7-cyano-1-oxoisoindolin-2-yl)-3 methylbutanoyl)-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl,)pyrrolidine-2-carboxamide:
0"
HH 0 N
NC /
ULM-14
[03901 ULM15: (2S,4R-((S)-2-Arniino-3,3-dimyetiylbutanoyl)-4-hydroxy-N-(R1) 2-hydroxy-1=(4=(4-rethylthiazol-5y)phenl)ethyl'pyrrolidine-2-carboxamide hydrochloride.
Intclaz:ie, OMAP =.yOTBS H 2 N' 1< N3H, THF, 85AE-t)H, TESCI, 0CM, (C)2T;O r4,T F - 78 IC Br Br retILuX'
(B ) (D)
C F/ HN I~ 2 N HC!, CH 3 0H.H------- ---- --- ~ 2.Bc20. TEA, DCM KI)Ac Pd'CA N2,_____ OTHS H E*\O it S
Br Br)(B N
(G)) (H)
Boci-IN
HAT UTEA,SCM OH
ULM-16
[0391] Step 1:Synthesis of (4-Bromophenvi)-2/-.hydroxviethanone (B).
[03921 To asuspension of 2-bro mo- I- (4-brorn ophenybeth anone (A) (60.0 g, 0217 mmoi) in EtOH (85%, 600 ml-)was added NaOCH()4.3g0.652mol) atroom teperature. The mixture was heated to I I00 Tuntil allsolid was dissolved and stirred for another 3hours. Then it was reduced to one-third of its volume in vacto. The residue was poured into ice water
12 1
(200)mL). After stirring for 30 minutes, the resulting off-white precipitate was filtered, washed with cold water (100 mL), and dried to afford the desired product (B) (39.0 g, 84%) as a white solid. IH NMR (400 MHz, CDCl3 ): 7.79 (d,J= 8.8 Hz, 2H), 7.66 (d.J= 8.8 Hz, 2H), 4.85(s, 211), 3.43(t, J= 4.4 Hz,1I).
[03931 Step 2: Synthesis of 1-(4-Bromophenyl)-2-(tert-butyldimethylsilyloxy)ethanone (C). 103941 To a solution of (B) (39.0 g, 0.181 mol) and imidazole (37.0 g 0.544 mol) in DCM (500 mL) was added TBSCI ( 32.75 g, 0.218 mmol) at0C. The reaction mixture was warmed to room temperature and stirred for another 3 hours. After it was quenched with1120 (200 mL), the organic phase was washed with brine (100 mL x 3), dried over Na 2S2O 4 and concentrated under vacuum to afford the desired product (C) (55.0 g,crude, 92%) as a white solid. IH NMR (400 MHz, CDC 3 ): 67.70 (d, J= 8.4 Hz, 2H), 7.49 (d,! = 8.8 Hz, 2H), 4.73 (s, 2H), 1.46 (d,,J= 6.4 Hz,1H), 0.81 (s, 9H), 0.00 (s, 6H).
[03951 Step 3: Synthesis of (S,Z)-N-(-(4-Bromophenvl)-2-(tert butyildimethylsilyloxy)ethyilidene)-2-methylpropane-2-sulfinamide (D).
[03961 To a solution of (C) (55.0 g, 0.167 mmol) and (S)-2-methyiprpane-2-sulfinamide (30.36 g, 0.25 mmol) in THF (600 mL) was added Ti(OiPr) 4 (142.4 g, 0.501 mol) at 25C. The mixture was heated to 80C overnight. After it was cooled to 0 C, the reaction was quenched by addition of H20 (100 mL). The mixture was filtered through Celite, and the solid was washed with EtOAc (1000 mL). The combined organic layers were washed with brine (200 mlx3), and concentrated under vacuum. The residue was purified by silica gel column chromatography with EtOAc/PE (1/100~10) to afford the desired product (D) (20.0 g 41%) as a brown syrup. H NMR (400 M Hz, CDCl 3 ): 6 7.66 (br, 21-), 7.47 (d, J= 8.4 1z, 2H), 4.92-4.96 ( i, 1), 3.63 3.69 (m, 1H), .24 (s, 9H), 0.76 (s, 9H), 0.03 (d, J= 5.2 Hz, 6H. 103971 Step 4: Synthesis of (S)-N-((R)--(4-Bromophenyi)-2-(tert butyldimethylsilyloxy)ethyl)--2--methylpropane--2--sulfinamide. (E).
[03981 To a suspension of (D) (18.0 g,,41.61 mmol ) in THF (100 mL)' was added BH3/THF(104 mL, 1.0 M, 104 mmol) at -78C. The resulting solution was stirred -78 C for4 hours. It was quenched by addition of acetone at -78 C (20 mL), and H20 (20 mL) subsequently. The organic phase was washed with brine, dried over Na 2 SO 4 , and concentrated under vacuum. The residue was purified by silica gel column chromatography with PE/EA (10-5 /1) to afford the desired product (E) (15.0 g, 83% ) as a light brown solid. 'H NMR (400 MHz, CDC 3 ): 6 7.52 (d,J= 8.4Hz, 2H), 7431 (d,J= 8.4 Hz, 2H), 4.44-448 (n, 1),,4.16 (in,11), 3.83-3.90 (m, 2H), 2.11 (t, J= 2.4 Hz,IH), 1.27 (s, 9H) 0.90 (s, 9H), 0.01 (d, J= 5.2 Hz, 6H).
[03991 Step 5: Synthesis of (R)-Tert-butyl 1-(4-bromophenyl)-2-hydroxyethylcarbamate (F).
[04001 A solution of (E) (10.0 g, 23.0 mmol) in HCl(g)/CH 3 0H (50 mL) was stirred at room temperature for 3 hours. The solvent was removed under vacuum to afford the desired product of (R)-2-amino-2-(4-bromophenyl)ethanol hydrochloride (6.0 g, crude). To a solution of
(R)-2-amino-2-(4-bromophenyl)ethanolhydrochlorideinCH 3 0H(50rmL)wereaddedTEA (11.6 g, 116 mmol) and Boc 2 0 (7.5 g, 45.0 mmol) subsequently at0°C.The resulting solution was stirred for 3 hours. The solvent was removed under vacuum. The residue was taken up with EtOAc (200 mL), and the mixture was washed with brine (100 mL x 2), dried over Na 2 SO4 . and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/4-1) to afford the desired product (F) (6.0 g, 82% yield) as a colorless oil. I H NMR (400 MHz, DMSO-d ): 6 o 7.50 (d, J= 8.4 Hz, 2H), 7.25 (d,J= 8.4 Hz, 2H), 4.81 (s, 1 H), 4.48-4.50 (m,1HI), 3.47-.349 (m, 21-), 1.40(s, 91).
[0401] Step 6: Synthesis of (R)--Tert-butyl 2-hydroxy--1-(4-(4-methylthiazol-5 yl)phenyI)ethylcarbamate (G).
[0402] To a solution of (F) (6.0 g, 18.9 7 mmol) in DMA (50 mL) were added 4 methylthiazole (3.79 g, 38.2 mnol) KOAc (3.72 g, 38.5 mnol) and Pd(OAc) 2 (426 mg, 1.90 mmol) subsequently. The solution was stirred at 130C for 5 h under N2 atmosphere. After cooling to room temperature. the mixture was filtered through Celite, and the solid was washed with EtOAc (200 mL). The resulting solution was washed with brine (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/4-1) to afford (G) (2.0 g, 32% yield) as a light brown solid.
[04031 Step 7: Synthesis of (R)-2-Amino-2-(4-(4-methylithiazol-5-yl)phenyl)ethano hydrochloride (H).
[04041 To a solution of (G) (2.0 g, 5.98 mmol) in DCM (20 mL) was added HCl (g) 4M dioxene (10 mL) at 25C. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under vacuum to afford the desired product (H) (1.1 g. 68%) as a light yellow solid. 1H NMR (400 MHz, CD 3 0D): 6 9.20 (s, 1H), 7.58-7.63 (m 4H), 4.42-4.45(m, 1H), 3.93-3.97 (m, 1H), 3.82-3.87 (m, 11), 2.53 (s 311).
[0405] Step 8: Synthesis of tert-butyl (S)-1-((2S,4R)-2-(((R)-2-Hydroxy-1-(4-(4 methylthiazol-5-yl) phenyl)ethyi)carbamoyl)-4-hydroxypyrrolidin- I-vl)-3,3-di methyl-I oxobutan-2-ylcarbamate (I).
[0406] To a solution of (H) (1.1 g, 4.06 mmol), (2S,4R)-1-((S)-2-(tert-butoxycarbonvl) 3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxvic acid 10 g, 6.09 mimol) and DIEA (1.60 g,13.0 mmol) in DCM (20 mL) was added HATU (2.30 g. 6.08 mmol) at 25C. The reactionmixture was stirred at 25C for 2 hours. Then it was quenched by addition of1-120 (20 mL). The mixture was washed with brine, dried over Na 2S0 4 , and concentrated under vacuum. The residue was purified by column chromatography with DCM/CH 30H (30-20:1) as eluent to afford (1) (1.7 g, 75%) as a light yellow solid. H NMR (400 MHz, CDCIj): 5 8.68 (s, 1H). 7.28 7.42 (in. 5H). 5.14-5.30 (m, 2H), 4.65 (t, J= 8.4 Hz. IH), 4.52 (s. IH), 4.21 (d, J= 9.2 Hz, 1H), 4.10-4.13 (in, IH), 3.94 (m, 1-1), 3.84 (m, 1-), 3.68-3.75 (m, 1H-), 2.96(s, 1H-), 2.53(s, 3 1-1), 2.35 (in, 1H), 2.16-2.19 (,in. 1H), 1.42 (s, 9H), 1.26 (s, 9H). 104071 Step 9: Synthesis of(2S,4R)-1-((S)-2-Aminio-3,3-dimethylbutanoyl)-4-hydroxy N-((R)-2-hydroxy-I-(4-(4-methylthiazol-5-yl)phenyl)ethyil)pyrrolidine-2-carboxamide hydrochloride (ULM-15).
[0408] To a solution of (1) (1.7 g, 3.03 mmol) in CH 30H (20 mL) was added AcC/CH 3 OH (v:v1:10, 10 mL, AcCiwas added dropwise to the methanol solution at 0°C and the solution was stirred for 1 hour). The resulting solution was stirred at 25°C for I hour. Then the solvent was removed under vacuum to afford the desired product (ULM-15) (1.5 g, 94%) as a yellow solid. 1 NMR (400 MHz, CD 3 tD): 69.77 (s, I1), 7.52-7.56 (m, 4H), 5.02 (t, J= 6.0 Hz, 1H), 4.73 (t, J= 8.0 Hz. IH), 4.49 (s. 1H), 4.06 (s, 1H), 3.82 (d,J = 4.8 Hz, 3H), 3.65-3.69 (in, 1H), 2.58 (s, 3H), 2.28-2.34 (m, 11), 1.94-2.01 (m, 1-1), 1.14 (s, 9H). Chemical Formula:
C231H32N 4 0 4 S / C 23 H3 N 2 4 4 S HCl; Molecular Weight: 460.59/497.05.
[04091 Synthesis of Linker Chemistry, L
[0410] L-1: 2-(3-(5-(tosyloxy)pentylox)propoxy)acetic acid
Step i Step 2 W X
Br 1YJ
ctStep:3
C H O OO TsC -|EA, DMAP
Step 4AA Step 5
Ts/ - ---------- ----------- TOOO LA
[0411] AStep
10412] Step 1: Synthesis of ({[5-(prop-2-en-1-yloxy)pentyil]oxylmethyl)benzene
104131 To a stirred solution of 5-(benzyloxy)pentan-I-ol (W, 4.0 g, 20.59 mmol) in N,N dimethylformamide (50 mL) was added sodium hydride (1.24 g, 51.67 mmol) in portions at 0 °C under an atmosphere of nitrogen. The resulting mixture was then stirred at room temperature for 1 hour.To this mixture was added 3-bromoprop-1-ene (3.71 g, 30.67 mmol), the reaction mixture was stirred overnight at 60 °C in an oil bath. LC-MS indicated formation ofthe desired product. The reaction mixture was cooled to 0 °C and then quenched by water (100 mL), the resulting mixture was extracted with ethyl acetate (200 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (60 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue. The residue was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:40)) to give 4.57 g of X. 'H NMR (300MHz. CDCl3): 6 7.36(s, 4 H), 7.32 (m, 1 HT), 5.98 (in, 1H), 5.33 (in, 1-1), 5.21 (in, 1H), 4.53 (s, 2H), 3.99 (in,211), 3.53 (n 411), 1.72 (in, 4H), 1.52 (m, 2H). LC-MS (ES): m/z 235.00 [MH], t 1. 18 min (2.0 minute run). 104141 Step 2: Synthesis of3-{[5-(benzyioxy)pentyi]oxylpropan-1-ol (Y) 104151 To a 250-mL round-bottom flask with 9-B3N (0.5 M in TIF, 77 iL) was added a solution of({[5-(prop-2-en-1-yloxy)pentyl]oxy}methyl)benzene (X, 3.0 g. L2.80 mmol) in anhydrous tetrahydrofuran (20 mL) with stirring at 0 °C under an atmosphere of nitrogen.The resulting solution was stirred overnight at room temperature. LC-MS indicated formation of the desired product. Methanol (15 mL, with 30% sodium hydroxide and 30%1 1202) was added to the reaction and the resulting mixture was stirred at room temperature for 2 hours. This mixture was then extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue. The residue was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v: v = 1:1)) to provide 1.96 g of Y as light yellow oil. i1 NMR (300MHz, CDC1 3 ): 67.34 (n, 5H), 4.49 (s, 2H), 3.75 (m, 2H), 3.59 (Im, 211), 3.49 (m, 41), 2.65 (bs, 1), 1.84 (m, 2), 1.68 (m, 4), 1.50 (m,2H). LC-MS (ES+): m/z 253.17 [MW], tR 1.44 min (2.6 minute run). 104161 Step 3: Synthesis of tert-butyl 2-(3-{[5-(benzyloxy)pentyl]oxy)propoxy)acetate (Z)
[04171 To a stirred solution of3-{[5-(benzyloxy)pentyi]oxy}propan-1-oI (Y, 3.7 g, 14.66 mmol) in dichloromethane (30 mL) was added a solution of NaOH in water (37%, 30 mL) followed by tert-butyl 2-brornoacetate (11.39 g, 58.39 mimol) and TBACI (4.17 g). The resulting mixture was stirred at room temperature overnight. LC-MS indicated formation of the desired product. The reaction mixture was then extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (60 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue. The residue was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:2) to give 3.2g of Z as a yellow oil.1H ' NMR (400MHz, CDC): 67.34(s, 4H, 7.29 (n 1 H), 4.50 (s, 411), 4.3 (m, 2H), 3.51 (i,411), 3.42 (m, 211), 1.98 (m, 2iH), 1.67 (m, 4H), 1.48 (s, 9H), 1.46 (m, 2H). LC-MS (ES'): m/z 367.25 [MH] t = 1.28 min (2.0 minute run). 104181 Step 4: Synthesis of tert-butyl 2-[3-[(5-hydroxypentyl)oxy propoxy]acetate (AA)
[0419] To a stirred solution of tert-butyl 2-(3-{[5 (benzyloxy)pentyl]oxvpropoxy)acetate (Z, 3.2 g, 8.73 mmol) in methanol (30 mL) was added AcOH (1.5 mL), palladium on carbon (1. 5 g) under an atmosphere of nitrogen. Hydrogen was then introduced to the reaction mixture via a hydrogen balloon, and the reaction was stirred at room temperature for 3h. The solid material was removed by filtration, the solution was concentrated under vacuum to provide 2.3 g of AA as light yellow oil, which was used for the next step without any further purifications. LC-MS (ES): m/z 277.10 [M ], tR 0.86mi (2.0 minute run).
[0420] Step 5: Synthesis of tert-butyl 2-[3-{5-[(4 methylbenzenesulfonyl)oxyIpentyl}oxy)propoxyIacetate (AB)
[0421] To a stirred solution of tert-butyl 2-[3-[(5-hydroxpentyl)oxy]propoxyIacetate (AA, 2.3 g, 8.32 mmol) in dichloromethane (30 mL) was added4-methyilbezene-1-suilfonyl chloride (3.17 g, 16.63 mmol), triethylamine (2.52 g, 24.90 mmol) and 4-dimethylaminopyridine (203 mg, 1.66 mnol) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to give a crude residue, which was purified by a flash silica gel chromatography (eluent:ethyl acetate/petroleum ether(v:v = 1:2) to give2.6 gof AB as a yellow oil. IHNMR(300MH z,CDCsi):67.77 (d,.J= 8.1 Hz, 2 H), 7.36 (d, J= 8.1 Hz, 2 H), 4.51 (s, 2H), 4.31 (m, 2H), 4.13 (,in. H). 3.52 m, 4H), 2.05 (s, 311), 1.97 (in, 2H), 1.69 (m, 411), 1.48 (s, 911), 1.46 (m, 21-). LC-MS (ES'): m/z 431.20
[MH*], tR = 1.21 min (2.0 minute run).
[0422] Step 1: Synthesis of 2-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentylIoxy)propoxy]acetic acid (A) 104231 To a stirred solution of tert-butyl 2-[3-({5-[(4 methylbenzenesulfonyl)oxy]pentylIoxy)propoxy]acetate (AB, 1.3 g, 3.02 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under vacuum to give 1.5 g (crude) of L-1, which was used for next step without any further purification. LC-MS (ES'): mnz 375.34 [MH'], t - 1.39 min (2.6 minute run).
[0424] The following Linkers (L) were prepared in a similar manner as for the preparation of L 1.
[04251L-2:2-(3-(3,3-dimethyl-5-(tosyloxy)pentyloxy)propoxy)aceticacid
TsO O -__'-O_ OH L-2 0
[04261L-3:2-(3-(3-hydroxy-5-(tosyloxy)pentyloxy)propoxy)aceticacid OH 0 TsO O" D O r L-3 0
[0427]L-4:2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)aceticacid
Ts~~~f~~ NaOH s ~~ ~ O
AC EOHI/H20, rt 2 h L-4
[0428] To a stirred solution of ethyl 2-[2-(12-{2-[(4 methylbenzenesulfonyl)oxy]ethoxyethoxy)ethoxy]acetate (AC, 2 g, 5.12 mmol, 1.00 equiv) in methanol (20 mL) was added a solution of NaOH (500 mg, 12.50 mmol) in water (4 mL), and the resulting mixture was stirred at room temperature for 2 hours. Aqueous hydrogen chloride (1 M) was then added to the reaction mixture to adjust pH to ~5. Solids precipitated were collected by filtration to give L-4 (yield: 98%). Mass (ES+): m/z 363, [MH+].
[0429] The following Linkers (L) were prepared in a similar manner as for the preparation of L 4.
[0430]L-5:2-(2-((2R,3R)-3-(2-(tosyloxy)ethoxy)butan-2-yloxy)ethoxy)aceticacid 0 OH TsO"' O10-_O _~OH
L-5
[04311L-6:2-(2- ((2S,3S)-3-(2-(tosyloxy)ethoxy)bitan-2-yloxy)ethoxy)aceticacid
OH O O OH TsO
L-6
[0432] L-7: 2-(4-(4-(tosyloxy)butoxy)butoxy)acetic acid
HO----H - --- TsO -01O NOH AD Step 1 AE Step 2
TsO O-- --- - -- TsO AF O Step 3 L-7
[0433] Step 1: Synthesis of 4-{4-[(4-methylbenzenesulfonyl)oxy]butoxy}butan-1-ol (AE)
[0434] To a stirred solution of 4-(4-hydroxybutoxy)butan-1-ol (AD, 2 g, 12.33 mmol) in dichloromethane (20 ml) was added Ag 2 O (4.25 g, 18.49 mmol), KI (409 mg, 2.46 mmol) and TsCi (2.345 g, 12.30 mmol). The resulting mixture was stirred at room temperature for 12 hours. The inorganic salt formed was removed by filtration and the organic solution was concentrated under reduced pressure to give a crude residue. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:1)) to give AE (yield: 28%) as a colorless oil.
[0435] Step 2: Synthesis of ethyl 2-(4-{4-[(4-methylbenzenesulfonyl)oxy]butoxy}butoxy)acetate (AF) 104361 To a stirred solution of 4-{4-[(4-methylbenzenesulfonyl)oxy]butoxy}butan-I-ol (AE, 1.1 g, 3.48 mmol) in dichloromethane (10 mL) was slowly added BF3 .Et2O (49.4 mg, 0.35 mmol) followed by ethyl 2--diazoacetate (794 mg,6.96 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was then quenched by water (2.0 mL). The resulting mixture was extracted with dichloromethane (50mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v: v = 1:4) to give AF (yield: 93 as light yellow oil. Mass (ES'): mIz 403.10 [MH*]+.
[0437] Step 3: Synthesis of 2-(4-{4-[(4-methylbenzenesulfonyl)oxy]butoxyvbutoxy)acetic acid (L-7) 104381 To a stirred solution of ethyl 2-(4-{4-[(4 methylbenzenesulfonyl)oxy butoxy }butoxy)acetate (AF, 1.3 g, 3.23 mmol) in methanol (25mL) was added a solution of NaOH (388 mg, 9.70 mmoi) in water (6 mL) at room temperature. The resulting solution was stirred at room temperature for 4 hours. The bulk of organic solvent was removed under reduced pressure, to the resulting mixture was added aqueous hydrogen chloride (1.0 M) to adjust the pH = -5. The solution was then extracted with ethyl acetate (250 mL x 3), the organic layers were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 1-7 (yield: 93%) as light yellow oil. Mass (ES,):- iz375.05 [MH+].
[0439] L-8: tert-butyl 2-(3-(4-(tosyloxy)butoxy)propoxy)acetate
HO''OH B AG PdICAH Al
Sp 3 0\ Stp AJ L-8
[04401 Step 1. Synthesis of 3-[4-(benzyloxy)butoxy]propan-1-ol (A)
[0441] To a stirred solution of propane-i, 3--diol (1.52 g, 19.98 mmol) in N, N dimethylformamide (20 mL) was added sodium hydride (840 mg. 35.00 mmol) at room temperature, the resulting mixture was stirred at room temperature for 30min. Then to the mixture was added 4-(benzvloxy) butyl 4-methylbenzene-1-sulfonate (AG, 6.68 g, 19.97 mmol) and the reaction was stirred overnight at 50 C. TLC indicated formation of the desired product, at this time the reaction was allowed to cool down to room temperature. Water (10 mL) was added slowly to quench the reaction; the resulting mixture was then extracted with ethyl acetate (80 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL). dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:2)) to give AH (yield: 67%) as a light yellow oil. 1HNMR (300 MHz, CDCI) 6 7.38-729 (m, 5H),4.52 (in, 21-1), 3.80 (i, 2H), 3.61 (m, 2H), 3.49-3.46 (m, 4H), 2.04 (in,2H), 1.82 (m, 2H), 1.68 (in.2H); Mass (ES'): nz 239.05 [MHI].
[0442] Step 2. Synthesis of tert-butyl 2- [3-[4-(benzyloxy)butoxy]propoxy]acetate (AI).
[04431 To a stirred solutionof 3-[4-(benzyloxy)butoxypropan-1-o (AH, 2.38 g, 9.99 mmol) in dichloromethane (15 mL) was added tert-butyl 2-bromoacetate (7.76 g 39.78 nmmol), TBAC (2.78 g. 10.00 mmol) followed by aqueous sodium hydroxide (37 %, 15 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was then extracted with dichloromethane (100 mL x 3), the organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1: 5)) to give Al (yield 57%) as a yellow oil. Mass (ES'): mz 353.10 [MH*].
[0444] Step 3. Synthesis of tert-butyl 2-[3-(4-hydroxybutoxy)propoxy acetate (Aj)
[0445] To a stirred mixture of tert-butyl 2-[3-[4-(benzyloxy)butoxy]propoxy]acetate (Al, 1 g 2.84 mmol), palladium on carbon (10%, 200 mg) in methanol (20 nL) was added acetic acid (0.05 mL) under a nitrogen atmosphere. Hydrogen was then introduced to the reaction mixture via a balloon, the reaction was then stirred overnight at room temperature. The insoluble solids were removed by filtration and the solution phase was concentrated under reduced pressure to give the desired product (yield: 94%) as a yellow oil. Mass (ES'): iz 263.05 [MH*].
104461 Step 4. Synthesis of ter-butyl 2-(3-{4-[(4 methylbenzenesulfonyl)oxybutoxy propoxy)acetate (L-8)
[0447] To a stirred solution of tert-butyl 2-[3-(4-hydroxybutoxy)propoxy]acetate (AJ, 700 mg, 2.6'7mmol) in dichloromethane (10 mL) was added 4-methylbenzene-1-sulfonyl chloride (558.4 mg, 2.93 mmol),TEA (539.5 mg, 5.33 mmol) and 4-dimethylaminopyridine 32.6mg. 0.27 mmol). The resulting mixture was stirred overnight at room temperature. The bulk of solvent was removed under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v= 1: 2)) to give titled product (yield: 52%) as a yellow oil. 11 NMR (300 MHz, CDCli) 67.79 (d,J= 8.4 Hz, 211), 7.35 (d, J= 8.0 Hz, 2H), 4.05 (,in. 211), 3.95 (s. 2H), 3.59 (m.2H), 3.48 (m, 2H), 3.38 (in, 2H), 2.46 (s, 3H), 1.82 (,in. 211), 1.70 (m, 2H), 1.57 (in, 211), 1.50 (s, 911); Mass (ES'): iz 417.05 [MH].
[0448]
[0449] L-9: tert-butyl 2-(4-(3-(tosyloxy)propoxy)butoxy)acetate
BnO'" OTs BnOs/s.-Os,-_s-'^OH 0 AK AL
H 2, Pd/C
AM O AN o
TsC_ TsO.O- O L-9 U
104501 L-9 was prepared in a similar manner as that used to prepareL-8, except that AK was used in place of AG. Mass (ES*): mz 439.15 [MNa].
[0451] L-10: tert-butyl 2-(6-(tosyloxy)hexa-2,4-diynyloxy)acetate O \ HO OH B HO\ Hte, Step11 = =/ AO AP
TsCl, K TsO 0 Step 2 L-10
[0452] Step1: Synthesis of tert-butyl 2[(6-hydroxyhexa-2,4-diyn-I-yl)oxy]acetate (AP)
[04531 To a stirred solution of hexa-2, 4-divne-1, 6-diol (AO, 100 mg, 0.91 niol) in N, N dimethylformamide (5 mL) was added sodium hydride (32 mg, 1.33 mimol) at 0 C. The resulting mixture was then warmed up to room temperature and stirred at room temperature for 30 min.
The reaction mixture was cooled to 0 C followed by addition of tert-butyl 2-bromoacetate (176 mg, 0.90 mmoil), and the resulting mixture was stirred at 0 C for 2h. LC-MS indicated formation of the desired product. The reaction was then quenched by water (10 mL, added slowly) at 0 C, and was extracted with ethyl acetate (20 x 2 mL). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:2)) to give AP (yield: 49%) as a yellow oiL
[0454] Step 2. Synthesis of tert-buty2-(6-[(4-methlvbenzenesulfonyl)oxy]hexa-2,4-divn-1 yl}oxy)acetate (L-10)
[04551 To a stirred solution of tert-butyl 2-[(6-hydroxyhexa-2, 4-diyn-1-yl) oxyl acetate (AP, 50 mg, 0.22 mmol) in ether (2 mL) was added 4-toluenesulfonyl chloride (51 mg, 0.27 mmol) at 0 C, followed by potassium hydroxide (125 mg, 2.23 mmol) in several batches at 0 C. The resulting mixture was stirred at 0 C for 4 hours. LC-MS indicated formation of the desired product. Water (10 mL) was added to the reaction, and the resulting mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:2)) to give L 10 (yield: 71%) as a yellow oil. 'H NMR (300 MHz, CDC): 67.83 (d,,J= 6.0 Hz, 2H), 7.39 (d, J= 6.0 Hz, 21), 4.79 (s, 21), 4.37 (s, 21-1), 4.05 (s, 21), 2.48 (s, 311), 1.51 (s, 911); LC-MS (ES'): i 401.05 [MNa*], tR = 1.71 min (2.6 minute run).
[0456] The following Linkers (L) were prepared in a similar manner as for the preparation of L 10.
[0457] L-11: tert-butyl 3-(6-(tosyloxy)hexa-2,4-diynyloxy)propanoate o- TsO 0 0
L-11
[04581 L-12: tert-butyl 4-(6-(tosyloxy)hexa-2,4-diynyloxy)butanoate
TsO 0- -C0
L-I2
[0459] L-13: ethyl 2-(2-(2-aminoethoxy)ethoxy)acetate hydrochloride
H2N ''''^'OH (Boc) 2() BcHN'O-''OH
' AQ Step 1 AR Step 2
^' ^ HC HC I 0 'A 0, * H 2N H Step 3 AS 0 L-13
10460] Step 1: Synthesis of tert-butyl N-[2-(2-hydroxyethoxy)ethyiicarbamate (AR)
[0461] To a stirred solution of2-(2-aminoethoxy)ethanol(AQ, 5.25 g. 49.94 mmol) in tetrahydrofuran (100 rL) was added aqueous solution of sodium bicarbonate (20% (w/w), 40
ml) and (Boc)20 (11.4 g, 52.23 mmol, added in several batches) at 0 °C. The resulting mixture
was then warmed up slowly to room temperature and stirred at room temperature for 5h. The
bulk of organic solvent was removed under reduced pressure and the resulting residue was
diluted with water (300 mL), extracted with of ethyl acetate (100 mL x 3). The organic layers
were combined, washed with saturated aqueous solution of sodium chloride (20 mL x 2), dried
over anhydrous sodium sulfate and then concentrated under reduced pressure to give AR (yield:
98%) as colorless oil.
[0462] Step 2: Synthesis of ethyl 2-[2-(2-{[(tert-butoxy)carbonyl]aminoIethoxy)ethoxy]acetate
(AS)
[04631 To a stirred solution of tert-btyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (AR, 4.0 g, 19.49 mmol) in dichloromethane (30 mL) was added -diazo-3-methoxypropan-2--one (3.34 g,
29.27 mmol) and BF 3-Et2 O (0.2 mL) at room temperature. The resulting solution was stirred at
room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, organic layer
was separated and washed with brine (20 mL), dried over anhydrous sodium sulfate and
concentrated under reduced pressure to give a crude residue. The residue was purified by flash
silica gel chromatography (eluent: ethyl acetate/petroleum ether (v: v = 1:2)) to give AS (yield:
18%) as yellow solid. H NMR (400MHz, CDC3): 6 4.25-4.22 (q,J= 7.2 H z, 2 H), 4.14 (s, 2 H), 3.74 (b, 2 H), 3.72 (b, I H), 3.67-3.32 (m. 4 H), 1.414 (s, 9 H), 1.31 (t,J= 7.2 Hz, 3 H).
[04641 Step 3: Synthesis of ethyl 2-[2-(2-aminoethoxy)ethoxy]acetate hydrochloride (L-13)
[04651 To a stirred solution of ethyl 2-[2-(2-{[(tert butoxy)carbonyl]amino}ethoxy)ethoxy]acetate (AS, 500 mg, 1.72 mmol) in 1.4-dioxane (10 mL)
was introduced hydrogen chloride (gas) via bubbling at room temperature for 2h. The solvent was then removed under vacuum to give L-13 (yield: 99%). LC-MS (ES`): m 192.00 [MH*], l = 0.41 min (2.0 minute run).
10466]1L-14: ethyl 2-(5-aminiopentyloxy)acetate
0
Boc20 BF 3 Et 2 0 H 2 NA OH Step I H AU Step 2 AT A
Boc. - TFA >Step H2 N O-~ B'N' O H AV O L-14 0
10467] Step 1: Synthesis of tert-butyl 5-hydroxypentylcarbamate (AU)
[04681 To a stirred solution of 5-aminopentan-I-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0 °C. The resulting mixture was then stirred at room temperature for 4h. The solvent was removed under reduced pressure to give a crude residue which was purified by flash silica gel chromatography (eluent:ethyl acetate/petroleum ether (v:v= 1: 2)) to give AU (yield: 98%) as a colorless oil. LC-MS (ES+): inz 204.00 [MH], tR =1.29 min (2.6 minute run).
[0469] Step 2: Synthesis of ethyl 2-[(5-{[(tert-butoxy)carbonyl]aminoIpentyl)oxy]acetate (AV)
[04701 To a stirred solution of tert-butyl N-(5-hydroxypentyl)carbamate (AU, 1.5 g,7.38 mmol) in dichloromethane (10 mL) was added BF 3 Et 2 O (0.1mL) at 0 °C. To this mixture was then
added a solution of ethyl 2-diazoacetate (850 mg, 7.45 mmol) in dichloromethane (2 mL) at 0 °C. The resulting mixture was allowed to warm up to room temperature and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (30 mL) was added to the reaction, the resulting mixture was extracted with ethyl acetate (150 ml x 3). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced
pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v= 1: 7)) to give AV (yield: 15%) as a colorless oil. LC-MS
(ES+): imz 290.05 [M1], I. =1.55 min (2.6 minute run).
[0471] Step 3: Synthesis of ethyl 2-(5-aminopentyloxy)acetate (L-14)
[0472] To a stirred solution of ethyl ethyl 2-[(5-{[(tert butoxy)carbonyl]amino}pentyl)oxy]acetate (AV, 400 mg, 1.38 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) at room temperature. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under vacuum to give L-14 (yield: 84%) as ayellow oil. LC-MS (ES'): wz 190.00 [MHJ, tIR 1.01 min (2.6 minute run).
[0473] L-15: methyl 2-(2-(2-(methylamino)ethoxy)ethoxy)acetate
CHO
H 2N OH nN -O HCHO AW Step 1 AX Step 2
Bn'N - O OH Step 3 BnN O AY AZ 0
Pd/C, H 2 HN O 0 Step 4 L-15 0
[04741 Step 1: Synthesis of 2 [2-(benzylamino)ethoxy]ethan-1-ol (AX)
[0475] To a stirred solution of 2-(2-aminoethoxy)ethan-1-ol (AW, 5.0 g) and benzaldehyde (5.0 g) in THF (50 rL)'was added sodium triacetoxyborohydride (15.8 g, 74.5 mmol) at 0 °C. The resulting solution was then stirred at room temperature for 4 hours. Water (50 mL) was added to the reaction and the resulting mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v = 3:1) to give AX (yield: 85%) as a white solid. LC-MS(ES*): wz195.95[MH t ], /R = 0.2.2m (2.0 minute run). 104761 Step 2: Synthesis of2-2-[benzyl(methyl)amino]ethoxyIethan-I-ol (AY) 104771 To a stirred solution of of 2-[2-(benzylamino)ethox]ethan-1-ol (AX, 10.0 g) in methanol (200 mL) was added formaldehyde (38% in water) (4.9 mL) and triacetoxyborohydride (17.0 g) at room temperature. The resulting solution was stirred at room temperature for 2 hours. Saturated aq. sodium bicarbonate (100 mL) was added to the reaction, and bulk of organic solvent was then removed under reduced pressure. The resulting mixture was extracted with ethyl acetate (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure followed by high vacuum pump to give AY (yield: 33%) as a yellow oil. LC-MS (ES+): mz 210.00 [MHii],tR = oA3 min (2.0 minute run).
[0478] Step 3: Synthesis of methyl 2-(2{2-[benzyl(methyl)amino]ethoxyIethoxy)acetate (AZ)
[0479] To a stirred solution of 2-{2-[benzyi(methyl)amino]ethoxy}ethan-1-ol (AY, 2 g) in dichloromethane (20 mL) was added a solution of sodium hydroxide (37%) in water (20 mL) followed by tert-butyl 2-bromoacetate (7.76 g)and TBAC (2.78 g) at room temperature. The resulting mixture was stirred at room temperature for 15 hours. The aqueous layer was separated, and to which aq. hydrogen chloride (4N) was added to adjust the p-I to -3 before it was concentrated under reduced pressure to give a crude residue. Methanol (20 mL) was then added to this residue and insoluble salts were filtered out. The solution was concentrated under vacuum to give 2-(22-[benzyl(methyl)aminoIethoxyIethoxy)acetic acid (yield: 78%) as a yellow oil. To a stirred solution of 2-(2-{2- [benzyl(methyl)amino]ethoxyIethoxy)acetic acid (2 g, 7.48 mmiol, 1.00 equiv) prepare above in methanol (50 mL) was slowly added sulfuric acid (2 mL) at room temperature. The resuming solution was stirred at 70 Cin an oil bath for 3h. The bulk of solvent was removed under reduced pressure to give a residue, which was diluted with H 20 (30 mL). Sodium carbonate was then added to the mixture to adjust the pH to -8. The mixture was then extracted with ethyl acetate (50 mL x 2), the organic layers were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure followed by high vacuum pump to give AZ (yield: 29%) as a yellow oil. LC-MS (ES'): inz 281.95 [MIHI, tR = 0.30 min (2.0 minute run).
[0480] Step 4: Synthesis of methyl 2-{2-[2-(methyliamino)ethoxy]ethoxyIacetate (L-15)
[0481] To a stirred mixture of methyl2-(2-{2-[benzyl(methyl)amino]ethoxy ethoxy)acetate (AZ, 600 mg, 2.13 mmol) and palladium on carbon (300 mg) in methanol (30 mL) under a nitrogen atmosphere was charged with hydrogen gas via a balloon. The resulting mixture was stirred at room temperature for 15 hours. The solid material was removed by filtration and the solution was concentrated under vacuum to give L-15 (400 mg) as yellow oil, which was used for next step without any further purifications. LC-MS (ES'):inz 191.95 [MH*], t- = 0.31 min (2.0 minute run).
[0482] L-16: ethyl 2-(5-(methylamino)pentyloxy)acetate
Boc'N O CHl, NaH Boc NH( Stepi H BA 0 BB 0
TFA NO Step 2 H 0 L-16
[04831 Step 1: Synthesis of ethyl 2-[(5-{[(ter butoxy)carbonyl](methyli)aminoipentyl)oxy]acetate (BB)
[04841 To a stirred solution of ethyl 2-[(5-{[(tert-butoxy)carbonyl]amino)pentyl)oxy]acetate (BA, 1.1 g .3.8mmol) in NN-dimethylforma aid(10 e mL) was added CH3I (0.71 mL, 11.4 mmol) at 0°C, followed by sodium hydride (304 mg, 7.60 mmol, 60% in mineral oil) in several portions at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. Water (1.0 mL) was added and the resulting mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v: v = 1: 10)) to give B:B (yield: 21%) as a yellow oil. LC-MS (ES+): m/z 326.20 [MNa+]. ti = 1.55 min (2.6 minute run).
[0485] Step 2: Synthesis of ethyl 2-1[5-(methylamino)pentyl]oxyIacetate (L-16)
[0486] To a stirred solution of ethyl 2-(5-{[(tert butoxy)carbonyl](methyl)amino}pentyl)oxy]acetate (BB,240 mg. 0.79 mmol) in dichloromethane (5 nL) was added trifluoroacetic acid (0.5 mL). The resulting solution was stirred at room temperature for 16 hours. The solvents were removed under recued pressure followed by high vacuum pump to give L-16 (yield: 99%) as a yellow oil. LC-MS (ES'): m/z 204.20 [MH*], tR = 0.56 min (2.0 minute run).
[0487] L-17: 2-(3-(2-(tosyloxy)ethox)propoxy)acetic acid
BC BD
0 Pd/C-HO O O -: TsCI Step 2 BE Step 3
9! TFA TsO 0 TStep4 BF L-17
[0488] Step 1: Synthesis of tert-butyl 2-{3-[2-(benzyloxy)ethoxy]propoxy}acetate (BD)
[0489] To a stirred solution of 3-[2-(benzyloxy)ethoxylpropan-I-ol (BC, 1.8 g, 8.56 mmol) and tert-butyl 2-bromoacetate (6.6 g, 33.84 mmol, 4.00 equiv) in dichloromethane (40 mL) was added
TBAC (2.4 g) and aq. Solution of sodium hydroxide (37%, 40 mL). The resulting mixture was stirred at room temperature overnight. LC-MS indicated formation of the desired product. The
reaction mixture was then extracted with ethyl acetate (150 x 3 mL), the organic layers combined,
dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude
residue, which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum
ether (v : v = 1 : 2) to give BD (yield: 90%) as a colorless oil.1 H NMR (300MHz, CDC 3 ): 6 7.35-.7.27! (m, 5H), 4.57 (s, 2H), 3.94 (,2H), 3.63--3.57 (mn, 8H4), 1.96-1.87 (m, 2H), 1.47 (s, 9H); LC-MS (ES*): m z 347.10 [MNa], R 72 min (2.6 minute run).
[0490] Step 2: Synthesis of tert-butyl 2-[3-(2-hydroxyethoxy)propoxylacetate (BE)
[0491] To a stirred mixture of tert-butyl 2-13-[2-(benzyloxy)ethoxy]propoxy}acetate (BD, 2.5 g.
7.71 mmol) and palladium on carbon (2.0 g) in methanol (20 mL) under a nitrogen atmosphere
was introduced hydrogen gas via a balloon. The resulting mixture was stirred overnight at room
temperature under hydrogen gas atmosphere. LC-MS indicated completion of the reaction. The
solids were removed by filtration, the solution was concentrated under vacuum to give BE (yield:
99%) as a colorless oil. LC-MS (ES): m/z 257.10 [MNa'], tR = 1.21 min (2.6 minute run).
[0492] Step 3: Synthesis of tert-butyl 2-(3-2-[(4 methylbenzenesuifonyI)oxy]ethoxyIpropoxy)acetate (BF)
[0493] To a stirred solution of tert-buty2-[3-(2-hydroxyethoxy)propoxy]acetate (BE, 1.8 g,
7.68 mmol) in dichloromethane (50 mL) was added 4-toluenesulfonyl chloride (2.2 g,1.54 mmol), triethylamine (2.33 g, 23.03 mmol) and 4-dimethylaminopyridine (95 mg, 0.78 mmol).
The resulting mixture was stirred overnight at room temperature. LC-MS indicated formation of the desired product. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v : v = 1 : 2) to give BF (yield: 80%) as a yellow oil.H NMR (400 MIHz,
CDC 3 ): 67.80 (d,,I= 8.0 iz, 2H), 7.34 (d, J= 8.4 liz, 2H), 4.15 (t, J= 3.6 Hz,2H), 3.93 (s, 211), 3.61 (t. J= 3.6 Hz, 2H), 3.55-3.49 (m, 4H), 2.45 (s, 3H), 1.85-1.78( H),1.48 (s. 9H); LC-MS (ES+):inz 411.00 [MNa], t R = 1.12 min (2.0 minute run).
[0494] Step 4: Synthesis of 2-(3-{2-[(4 -methylbenzenesulfonyl)oxy]ethoxy}propoxy)acetic acid (L-17)
[0495] To a stirred solution of tert-butyl 2-(3-{2-[4 methylbenzenesulfonyl)oxy]ethoxy}propoxy)acetate (BF, 400 mg. 1.03 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to give L-17 (350 mg) as a yellow oil, which was used for next step without further purifications. LC-MS (ES'): inz 332.90 [MHJ],
IR = 0.81 min (2.0 minute run).
[04961 Unless otherwise noted, the following intermediates and their analogs (for examples, but not limited to, analogs with substitutions such as halogens) were synthesized according to similar procedures described above for the synthesis of L-17, by utilizing corresponding starting materials and reagents.
[0497] L-18: 2-(2-hydroxyethoxy)ethyl 4-methylbenzenestilfonate
HO'-O -''OTs
[04981 L-19: ethyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy.)acetate
TsO 0 - OsCOOEt
[0499] L-20:ethyl3-(2-(2-(tosyloxy)ethoxy)ethoxy)propanoate
TsO-_ O,__O - CO2Et
[0500] L-21: ethyl 54tosyloxy)pentanoate
Tso"' C0E.
[05011 L-22: ethyl 3-(2-(tosykixy)ethoxy)propanoate
TSO_z'- 0 ,-C 2 Et
[05021 L-23: ethyl 2-(5-(tosyloxy)peiitykoxy)acetate
TsO.- O,C 2 E
[0503] L-24: ethyl 35-(tosyloxy)pentyloxy)propanoate
TsOO~0Et
[05041 L-25: 5-hydroxypentyl 4-nethylbelzeesullfonate
TsO,-.~OH
[0505] L-26: ethyl 2-(5-(tosyloxy)pentyloxy'aeetate
TsO---'O ,,CO 2 Et
[0506] L-27: ethyl 2-(3-(tosyhoxy)propoxy)acetate
TsO,.-OC 2E
[05071 1,28: ethyl 2-(2-(tosyloxy)ethoxy)acetate
[0508] L-29: ethyl 2-(4-(2-(tosyloxy)etlhoxy)butoxy)aeetate
0 TsO -O'-OCO 2 Et
L-29
[0509] L-30: 2=(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulftrnate
Tso-'--''-'10'I H
10510] L-3-1: 2+21R,311)-3 -2-.hydroxyethoxy)bu tait-2-.yox .ethyl 4-inetiylbenzenesulfonate
I40
TsO OK; O OH
[05111 L-32: 2-(2-piperazin-1-yl)-ethoxy-acetic acid
0 N OH HN
[0512] L-33: methyl 6-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)piperazin.-1-yl)nicotinate
oc known compound 0 CIN.Boc NH ON N f NFA N To' 10 10 17~ O DIPEANMP DCM 2 K CODMF 1
[0513] Step 1: Synthesis of tert-butyl 4-(5-(methoxycarbonyl)pyridin-2-yl)piperazine-1 carboxylate:
NBoc N N 10
0
[0514] A mixture of methyl 6-fluoronicotinate (2.0 g, 13.2 mmol), tert-butyl piperazine-1 carboxylate (2.4 g, 13.2 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.3 g, 26.4 mmol) in anhydrous 1-methylpyrrolidin-2-one (10 ml) was stirred at 90°C for 12 hours. TLC showed the reaction was complete. The cooled reaction mixture was partitioned between water (10 ml) and ethyl acetate (50 ml). The organic layer was collected, washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by column (eluted with 20% ethyl acetate in hexane) to afford tert-butyl 4-(5 (methoxycarbony)pyridin-2-y)piperazine-1-carboxylate (4.0 g, yield 95%) as yellow solid. HNMR (400 MHz, CDCIl): 6 1.48 (s, 911), 3.53-356 (in,4) 3.67-3.69 (i, 411), 3.87 (s, 311), 6.58 (d, J= 8.8 H z, 2H), 8.02-8.05 (m, 11H), 8.79-8.80 (m, 1). Chemical Formula: C16H123N0 4 ,
Molecular Weight: 321.37.
[05151 Step 2: Synthesis of methyl 6-(piperazin-1-yl)nicotinate
NH N N
0
[05161 A mixture of tert-butyl 4-(5-(methoxycarbony)pyridin-2-yl)piperazine-I-carboxylate (4.0 g, 12.4 mol) and 2,2,2-trifluoroacetic acid (10 ml) in dichloromethane (10 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up with dichloromethane (50 ml) and washed with aqueous sodium bicarbonate solution (IN, 15 ml), dried over sodium sulfate to give methyl 6-(piperazin-1-yl)nicotinate (3.8 g, crude) as yellow oil which was used in next step withoutfurtherpurification. HNMR(400MI-Iz,DMSO-d):63.13-3.16(n411), 3.80(s,311), 3.82-3.85 (m 4H), 6.96 (d,,J= 9.2 Hz, 1H), 8.00-8.03 (m, 1H), 8.67-8.68 (m, 1H). Chemical Formula: CH 1 5N 30 2, Molecular Weight: 221.26.
[05171 Step3: Synthesisofmethyl 6-(4-(-(2-(tert-butoxy)-2-oxoethoxy)ethyl)piperazin-1 yl)nicotinate.
If)
0
A mixture of methyl 6-(piperazin-1-yl)nicotinate (500 mg, 2.3 nmol), tert-butyl 2-(2 (tosyloxy)ethoxy)acetate (745 mg, 2.3 mmol) and potassium carbonate (1.2 g. 9.0 mmol) in anhydrous N,N-dimethylformamide (10 ml) was stirred at 40°C for 12 hours. TLC showed the reaction was complete. The cooled reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer was collected, washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 20% ethyl acetate in hexane) to afford methyl 6-(4-(2-(2-(tert--butoxy)-2-oxoethoxy)ethyl)piperazin-1-yl)nicotinate (L-33) (400 mg, yield 46%) as yellow solid.
[0518] Synthesis of Examples
[05191 Example 1:(2S,4R)-1-(S)-2-2-3-(5-(4-(3-(4-cyano-3-(trifloromethy)phny)-5,5 dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxv)pentyloxy)propoxy)acetamido)-3,3 dimethylbutanoyl)-4-hydroxy-N-(4-(4-niethylthiazol-5-yl)benzyl)pyrrolidine-2 carboxamide:
F-F 0 . -N, N Step F \N NN K2cO3 ABM-3 oH AB O BG 0
StepF2 F
2NHC N NY s s s OH BH
Step 3 Arnide coupling H | ULM-1 NO' N' -OH 01. Example NH
[05201 Step 1:Synthesis oftert-butyl2-(3-{[5-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidii-1-ylIphenoxy)pentylIoxyIpropoxy)acetate (BG)
[0521] To a stirred solution of tert-btyl 2-[3-[(5-[[(4 methylbenzene)sulfonyl]oxy]pentyl)oxypropoxy]acetate (AB, 150 mg, 0.35 mmol) in acetonitrile (10 nL) was added 4-[3-(4-hydroxyphenyl)-4,4-dimethlv-5-oxo-2 sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (ABM-3, 141 mg, 0.35 mmol) and potassium carbonate (144 mg, 1.04 mmol). The resulting mixture was stirred overnight at 80 °C in an oil bath. LC-MS indicated formation of the desired product. The reaction mixture was then extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v: v = 1:1) to give 0.22 g of BG as a yellow oil. H NMR (400MHz, CDCl3): 6 7.96 (s, 2H), 7.86 (d = 8.6 Hz, IH), 7.19 (d,,J 8.8 Hz, 2H1), 7.02 (d, J= 8.6 Hz, 2H-), 4.50 (s, 2H), 4.30 (t, J= 6 Hz, 2H), 4.02 (t, J= 6.4 Hz,
2H), 3.53 (m, 2H), 3.44 (m, 2H), 1.96-1.80 (m, 4H), 1.69-1.53 (m, 2H), 1.49 (s, 6H), 1.48 (s, 911), 1.44- 1.22 (m, 2H) Mass (ES'): mnz 686.35 [MNa].
[05221 Step 2: Synthesis of 2-(3-[[5-(4-[3-[4-cyano-3-(trifluoromethyl)phenyll-5,5-dimethyl-4 oxo-2-sulfanylideneimidazolidin-1-yi]phenoxy.)pentyl]oxy]propoxy)acetic acid (BH)
[0523] To a stirred solution of tert-butyl 2-(3-{[5-(4-{3-[ 4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-ylIphenoxy)pentyl]oxyIpropoxy)acetate (BG, 220 mg, 0.33 mmol) in dioxane (4.0 mL) was added hydrogen chloride (2N in water, 1.0 mL). The resulting mixture was stirred at 80 °C for 2h. LC-MS indicated formation of the desired product. The resulting mixture was concentrated under reduced pressure to provide 200 mg of BH as light yellow oil. Mass (ES'): m/z 608.25 [M1H].
[05241 Step 3: Synthesis of Example 1:
[0525] To a stirred solution of 2-(3-[[5-(4-[3-[4-cyano-3-(trifluoromethy)phenyl]-55-diimethyil 4-oxo-2-sulfanylideneimidazolidin-1-yl]phenoxy)pentyl oxy]propoxy)acetic acid (BH, 160 mg, 0.26 mmol) in N,N-dimethvlformamide (5 mL) was added (2S,4R)-1-[(2S)-2-amino-3,3 dimethylbutanoyl]-4-hvdroxy-N-{[4-(4-methyl-1,3-thiazol-5-vl)phenyl]methyl)pyrrolidine-2 carboxamide hydrochloride (ULM-1, 182 mg, 0.39 mmol), DIPEA (151 mg, 1 17 mmol), EDCI (101 mg, 0.53 mmol) and HOBt (70 mg, 0.52 mnol). The resulting mixture was stirred at room temperature for 5 h and LC-MS indicated formation of the desired product. Water (20 mL) was added to the reaction, the resulting mixture was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue. The residue was purified by Prep-HPLC to give 60 mg of Example 1 as a white solid. IH NMR (400 MHz,CD 30D): 68.88 (s, IH), 8.16 (d, 8.0 Hz, 2H), 8.00 (s, H), 7.49 7.42 (i,411), 7.28 (d, J= 8.8 Hz, 211), 7.06 (n 2H), 4.87 (s. 1H),4.59 (in, 311), 4.37 (i, 11), 4.05(m, 4H), 3.88 (m, 2H), 3.65 (m, 2H), 3.58 (m, 2H), 3.50 (m .2H), 2.48 (s. 3H), 2.25 (m, IH), 2.10 (m, 1H), 1.90 (m, 2H), 1.80 (m, 2H), 1.66 (m, 2H), 1.56 (s, 8H), 1.04 (s, 9H); LC-MS (ES): wn 1020.20 [M-I], t = 2.28 min (3.6 minute run).
[05261 Example 2: (2S,4R)-1-((S)-2-(2-(3-(5-(4-(3-(6-eyano-5-(trifluoromethyl)pyridin-3-yl) 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxv)pentyloxy)propoxy)acetamido)-3,3 dimethylbutanoyl)-4-hydroxy-N-(4-(4-nethylthiazol-5-yl)benzyl)pyrrolidine-2 carboxamide:
Ts' ^O O 6 Step1 ''O OH AB 0 L-1 0
F F-- F 0
N /'N- N.- ~ !S Step 2 Oe'N 0 ABM-4 H H ULM-1 Step 3 N, NH
BI
F N N=:'I (N S 0
Example 2 /iS 0 N NH
[05271 Step 1: Synthesis of 2-[3-({5-[(4-rnethylbenzenesuilfonyi)oxy]pentylIoxy)propoxy]acetic acid (L-1)
[05281 To a stirred solution of tert-butyl 2-[3-(5-[(4 methylbenzenesulfonyl)oxypentyl}oxy)propoxyjacetate (AB, 1.3 g, 3.02 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under vacuum to give 1.5 g (crude) of L-1. which was used for next step without any further purification. LC-MS (ES*): miz 375.34 [MH],tR= 1.39 min (2.6 minute run).
[05291 Step 2: Synthesis of(2,4R)-1-(2)-3,3-dimethyl-2-{2-3-([5-(4 methylbenzenesulfonyl)oxypentylIoxv)propoxy]acetamido-butanoyl]-4-hydroxy-N-{[4-(4 methyl-1,3-tlhiazol-5-vl)phenvl]methylpyrrolidine-2-carboxamide (BI)
[05301 To a stirred solution 2-[3-({5-[(4 methylbenzenesulfonyl)oxypentyl oxy)propoxy]acetic acid (L-1, 1.5 g, 4.01 mmol) in N,N dimethyformamide (20 mL) was added HATU (1.36 g 3.58 mmol). DIEA (0.7 mL) and (2S,4R) 1-[(2S)-2-amino-3,3-dimethyilbutanoyl]-4-hydroxy-N- {[4-(4-methyl-1.3-thiazol-5 yl)phenyl]methyl}pyrrolidine-2-carboxamide (ULM-1, 1.3 g 3.02 mmol) at room temperature. The resulting mixture was stirred for 2h at room temperature. It was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (60 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v: v = 10:1)) to give 0.5 g of BI. LC-MS (ES'): inz 787.34 [MH], R = 1.87m (3.0 minute run).
[05311 Step 3: Synthesis of (24R)--[(2S)2-2-3-{[5-(4-{3-[6-cyano-5 (trifluoromethyl)pyridin-3-yl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1 yllphenoxy)pentyl oxy }propoxy)acetarmido]-3,3-dimethyibutanoyl]-4-hydroxy-N-{[4-( 1,3-thiazol-5-yl)phenyl]methylpyrrolidine 2-cirboxamide (Example 2)
[0532] To a stirred solution of5-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2 sulfanylideneimidazolidin-I-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile (A:BM-4,52 mg, 0.13 mmol),(2S,4R)-I-[(2S)-3,3-dimethyl-2-{2-[3-({5-[(4 methylbenzenesulfonyl)oxyjpentylloxy)propoxy]acetamidolbutanoyl]-4-hydroxy-N-{[4-(4 methyl-1.3-thiazol-5-yil)phenyl]methylpyrrolidine-2-carboxamide (BI,100 mg. 0.13 mmol) in N,N-dimethylformamide (10 mL)was added potassium carbonate (34 mg, 0.25 mmol) under an atmosphere of nitrogen. The resulting solution was stirred for 2 h at 80°C. The resulting mixture was concentrated under vacuum to give a crude residue, which was purified by Prep-HPLC to give 38.1 mg of Example 2 as a white solid. '- NMR (300 MHz, CD 30D): 6 9.12 (s, 1H), 8.83(s,IN), 8.63(s,1H),7.44-7.39(m,4H), 7.00(dJ=9.0Hz,2H).7.20(dJ=9.0Hz.,2H), 4.80-4.26 (i, 5H), 4.06-3.65 (in, 61), 3.62-3.35 (in, 6H), 2.43 (s, 3H), 2.21-2.01 (in, 2H), 1.85 1.65 (m, 4H), 1.60-1.42 (in, 1H), 1.00 (s, 9H): LC-MS (ES): nz 1021.12 [MH]. 2.36 min (3.6 minute run).
[05331 Unless otherwise noted, the following examples were synthesized according to analogous procedures described above for synthesis of examples I and2, utilizing corresponding reagents, intermediates, and staring materials.
[0534] When referring to the specific exemplary compounds presented herein, the specification uses the terms "example #." For example, compound I (Table 2) is also referred to as Example 1.
[05351 Table 2 Exemplary Compounds.
Ex Structure Compound name and Analytical data
(2S,4R)-1-((S)-2-(2 -(3-(5-(4-(3-(4-cvano-3-(trsfiuoromethy)pheny)-55-dimethyl-4-ox-2
thioxoimidazolidin-I-yi)phenoxy)pentyloxy)propoxy)aestamido)-3,3-diriethylbutanoV-4 F hydroxv-N-(4-(4-metltvlhiazol-5-yl)beiizvl)pyrrolidine-2-carboxaiide
,-Nn
rs I 1H NMR (400 MI-z, CDC13): 3 7.96 is, 211)7.86(d,J= 8.6 1 1), 7.19 (d, J 8.8 Hz,
2HI, 7,02 (d, J = 8,6 Hz, 2H), 4,50 (s, 2H), 430 (t, J = 6.4 Hz, 2H1, 4.02 (t, J= 6.4 H- 2H), 3.53 (n, 211) 3.44 (m 211) 1.96-1.80 (i, 411), 1.69-1.53 (m, 2), 1.49 (s, 61), 1.48 (s,
9H), 1.44-122 (m, 211); Mass (ES+): m/z 686.35 MNa+]
(2S,4R)-1-((S)-2-(2-(3-(5-(4-(3-(6-cyan.o-5-(trifluoromrethyl)pyfrid i-3-yl)-5,5-dimiethyl-4 oxo-2-thlioxoimnidazolidin-1-y)phenosxyr)pentyloxyr)propoxy)aceamxido-33 liriethyibutanol)-4-hvdroxy-N-(4-(4-imethylthiazol-5-vl)benszyl)pyrrolidine-2 - rboxamide
.2 111 NMR (300 MHz, CD30D): 6 9.12 (s, 111), 8.83(s, 1H), 8.63 (s, 111), 7.44-7.39 (m,
4H), 7.00 (d J = 9.0 Hiz, 21, 7.20Id, J = 9.0 Hz, 2H), 4.80-4.26 (i, 5H), 4,06-3.65 (m, 61), 3.62-3.35 (m, 611) 2.43 (s, 311) , 2.21-2.01 (m, 211) 1.85-1.65 (m 411), 1.60-142 (i;, 101), 1.00 (s, 91H): LC-MS (ES+): /l 1021 12 [MH+], tR:= 2.36 in (136minute run).
0 NC N Prepared from ABM-16, L-1, and ULM-1 Ny F 5 F.1 C s (2S,4R)-1-[(2S)-2-[2 -(3-{[5-(4-(3-[4-cyano-3-(trifluoromnethyl)phenyl]-5,5-dimnethyl-4 oxo--2-sufanyideneimidazolidin-1-yl-2-uorophenoxynpentylioxy~propoxy)acetaiid
3,3-diriethsvlbutanoy]-4-hvdroxv-N-{[4-14-(4metyl-1,3-thiazol-5
3 yilpheiyilmetyl}pyrrolidie-2-carboxaide
'H NMR (300 MHz, CDOD) :6 8.84 (s, 11), 8.13-8.09 (m, 2H) 8.01 -7.93 n, IH),7.51
7.31 (m, 4H), 7.21-7.01 (in, 3H), 4.70-4.41 (i,4H), 4.35-4.22 (i, 1H), 4.15-4.03 (r,2H),
N O 3.95-3.90 (m, 2 11), 3.90-3.73 (m, 211', 3.61-3.56 (m, 2 H), 3.56-3.51 (m, 2 1), 3.50-3.42 (m, 2 H), 2.45 (s, 3H), 2.21-2.10 (m H), 2.0-2.12 (m, 11), 1.92-1.70 (M, 411) 1.63-1.50
(m, 3 11), 3.50-1.45(m, 7H), 1.04(, 911); LC-MS (ES'): m/z 1038.31 [MH], fp= 2.35 min N N\ (3.6 minute run) H OH
Ex Structure Compound name and Analytical data
0 NC -N i ~~Prepared front ABM-3.L-i,and ULMI-3
o~xo--2-suICaivideeiridaoiin-yi'pheoxy)p.,entyloxvflpropo-xvacetarrnidoj-3.3
3 yi)ph.eniviethyllpynohIdime-2-earboa11ide
'ItNMR (300 MIz, CD30D):(_.8 8s 111),,8.58 (4J= 7.5Hlz,111), 8.16 (n, 2114b, 00 0"s O (ins III)7_53 (ds= 0.3lz, 111),7-42 (n, 411),7-26(n, 211),7T05(n, 211).5.01 (m, III) NN 4.72~~~ ,d Iz 1, 4.58 (il 111),1.14(s,111), 404 (in, 4114,383-3.49 (ry, 811) 2.48 0 N (s. 31-,2.2,(m, 11I',1.83 (il, 51-b, 154(,131b, 103 (s.911): LC-MS (ES`):nz z518.20 < -1 [M±2/.i, 3.67 1rYiln,(5.6 minute ru n
0 - -f.Prepared fronABM17,IA, and IT M4
i 3 (2S,4R)-1[l(2S)_2-[2-(3-{[( ,-inty--4utr--tifrmtv~-x i c~ufav ideniridazolidin-I Ivperoxy)ety] oxvpropox)acetail ]dol -3 3
N 11 ~NMR (300 M-zCD0OD 68.8-1(s, 11H),8.15-813 (in,2H1), 8.01-7.93 (i H1). 751.31 (m, 41b4)7.2 -72 3 211),7.22 -7.05 ni211),4.71(s,.60-4.3 (il (m, 3 NH III,. H4.11-a.24 fi IHi, 2120-39 (m, H.93-375, 1,6-352 6-fi2H1),3I . 0 N 3.41 (m, 2-H)3.40-3 ( ni 21),2.45(s 31) 2-21.0(in,'1H), 2.09-20 (lim H1). H --4 9-1.72(in, 414H 1.5-1I fun, 3 H, 1.51--I.34(i, 7H1), 1.00 fs,91H); CI\(MS'Y bH inz71040.32[H 2.52min(3,6minte run)
OH l SPrepared from ABM-6 L-Isand ULMI1 HN '
0 2,R~-'S 41-yn--ehihnl)5-ieti4oo2
( ufainv'ideiieir.nidazolidii-1-ylipllcicoxv, )e-.-1loxvioropoxy'Liceta-.nido)-33
6o N ~ ~ a-boxainid
'11NMR(400 IH1z, CD 3D:C6-88 (s.I1) 83_7(ddJ80z11,753 , 61.7 2 (d J-= 9. ,211"z . 706(d,_J---8.8 i, _1',471 (s, 11I), 4.59 in],31-), 4.39(illJ = 15.6 iIL 1H, 4.05 fin,411), 3.88 fin, 21),3.68 (m,411), 152H). 211,261 (,31),.50 s,3H), 25 (ip 111)210 (m,I11),1.93-'il /1-1), 1.68 (rn, 1011). 106 (s.911): LC-MS(ES": CN4-83.95 [M+!'1/2, i =1.28 min (3.60 minute run)
C14
Ex Structure Compound name and Analytical data
OH Prepared fromABM-2, L-1, and ULM-1 H N) (2S,4R)-I-[(2S)-2-(-(3-[5-{4-[3-4 cn-3-fuorophenyl-55dimerhi-4-oxo-2 sufnyieniidazolidin-1-yl]phenoxy}penty)oxyIpropoxy}acetmido)-33
7 ( S dimnethylbutanoyl4hydroxyN-[44methl-1,-thiazo-5-ylphnylmethnylprroidine 2-crboamide
\HNMR(300M I(, CD3OD): 68.87 (s, 1),791 (t, H,), 63 (d,1=:8.1 Hz, 1H), 7.54-7.41 (, 5H), 7,26 (d, = 8.7, 2H), 7.03 (d 9.0 Hz, 2H), 4.70 (s, 1H 4.61
N 4. (14.51(m,3H), 4.37-4.32 (m, 111), 4.04-3.98 (m, 411), 3.98-3.81 (m, 211), 3.67-3.63 (m, 2H), 3.57(tJ 6. Hz, 2,3.57 (, J= 6.6Hz, MH), 2.48 (s. 3H), 2.23-209 (m, 211), 192
1.79 (m, 411) 1.67-1.53 (i 101H), 1.03 (s, 911); LC-MS (ES*): mz 970.55 [MH]tR 1.55 CN min (3.6 irnute run)
OH Prepared from ABM-1, L-1, and ULM-1 HN-N
5 0 0 O NH sulfanylideneimidazolidin-1-yI phenoxy pentyl)oxy]propoxyIacetamido)-3,3
6' diiethylbutanoyil-4-hydroxy-N-{[/A-(I-ethy-1,3-thiazo-5-y)heylJmediylprroliie N 2-carboxanide
'H NMR (400 MHz, CDOD):9.00 (s,1 H), 7.98 (d, J= 84 Hz, 1I H), 787 (Is, 1 H),7.66 (d, J 10.4 Hz,1H), 0(4H) 7.29 (d, = 8.8 Hz, 2H), 7.06 (d, / = 8,8 Hz, 2H), 4.71(s, 0 N 1v), 4.62 (m, 311), 4.39 (d, i = 15.6 Hz, 11), 4.05 (m, 41), 3.89 (m, 2H), 3.68 (m. 4H1). 3 3.52 (i, 211)s250 (, 3)2.(, 1H), .210 (ms '1H), 1.9 m, 41H), L68 (m, 2H). i 59 (w,
CN 8H), 1.05 (s, 9H); LC-MS (ES*": m/z 986.25 [MH*] t=3.44 min. (5.00 minute run)
Prepared from ABM-5, L-1, and ULM-1 HN i N? 0NHI sulH&fanylideneimiazidin1ylphenoxypentyloxy]propoxyacetamido)-33 dimethylibutanoyl-4-hydroxy-N-{[l4-nethyl-1,3-iazo3-5-yl)phenylnmediylpyrrolidie
H NMR (400 MHz, CDOD) 8.88 (s, 1 H), 7.77 (d, J = 8.0iz, 11), 749-7.42 (m, 41), N S 7.37 (d,-i= 1.6 Hiz, 'i,7i7.16(im,3H), 7.06-7.04 (m,2H),4.71 (s, H),4.62-4.54(m,
3/H), 4.39 (d, i = 15.6 Hz, 1H), 4.05-4.00 (m, 71), 3.91-3.80(m, 2), 3.72-3.49 (m, 611). 2.50 is, 3H), 227-207 (m, 2H), 1.93-1 8 (m, 411) 1.66-1 56 (m, 10H), 1.06 s, 911) LC CN MS (ES*): nz 982.55 [M*], i=2.67 rin (5.0 iniute run)
Ex Structure Compound name and Analytical data
H ,OH PreparedfromABM-16, L-1, and ULM-3 ( NO N 2 0 oJ (2S,4R)-1-[(2S)-2-[2-(3-{[5-(4-{3-[4-cyno-3-(trifuoronmethyl)phenyl]-5,5-dimethyl-4 0NH oxo-2-sulfanylidencimidazoidin1-yl}-fluorophenoxy)pentyl~oxyripropoxy)acetamido] S 3,3-dimethvlutanoyl]-4-hydroxy-N-[j(IS)-1 -[4-(4-moetl-1yi..,3-thiazol-5 F N yli)pletvhiedsylipyrrolidine-2-carboxaiide
N 'H NMR (300 MHz, DMSO) 8.98 (s, IH, 8.44-8,40 (m, 2H), 8.27 (s, IH), 8.08 (d, J=
O N8.4 Hz,1H),7.45-7.28 (m, 711) 7.17 (d,j= 8.7 Hz , 5.12 (d, J 3.3 lz,111). 4.92 4.88 (., 1H), 4.52-4.45 (m, 2H), 4.28 (s, 1H)s 4.12 (-, J 6.6 Hz, 21), 3.92 (s,2H),3.58
3.38 (n, 8H), 45 (s, 3H), 2.08-2.02 (m 1H), 1.83-1.74 (,i 511), 1.61-1.46 (m, 1 1 H). 1.38 CN (d, J 6.9 Hz, 2H), 0.93 (s, 9H); LC-MS (ES'): ml 1052.40[M I =1.79 lin
OH HN Prepared from ABM-18, L-1, and ULM-3 FiN- N 0 NH (2S,4R)-1-[(2S)-2-[2-(3-{[5-(4-{3-i4-cyano-3-(rifluoromethyllphenyl]-5,5-dimethl-4 oxo-2-sufanlideneinmidazolidin-I-yi -2,6 -jj ~difluorophienoxypenitylloxy'fpro~poxy)acetam.ido ]-3,3-dimfethyb~lbuaoyI]-4I-hydroxy-N
N [(1S)-1-I-(4-methyl-13thiazol5-y)penljethylpyrroiidinearb / F N'J1,'H NMR (400 MHz, DMSO) ( 8.98 (s, 11), 8.45-8.39 211), 8.26 (s, 11), 8.07 (d, J= S-- 8.4 Hz, 1 H), 7.44-7.28, 7H), 5. 12 (d,,1= 3.6 Hz, 1H), 4.92-488 (m, iH), 4.55 (d, J= 9.6 H=z,1H,44( = 8.0 Hz, 1), 4.28 (s, 1 H), 4.20 (t, J= 6.8 Hz, 2H), 3.91 (s. 2H), 3.57 , CF 3 3.37 (m. 81H), 2.45 (s, 3H), 2.08-2.02 (m 111), 1.80-1.71 h, 5H) 1.61-1.46 (m, 1011). 1.38 CN (d,,= 6.8 Hz, 3H). 0.93 (s, 9H); Mass (ES: m 1070.50 MH
H Prepared from ABM-3, L-2, and ULM-1
0 N O>NH oxo-2-suifanylideneiiidazolidin-I-yijphenoxy)-3,3
12 ~dimethylpeny]oxypropoxy)acetamido]-3,3-imetylbutaoy]]-4--hydroxy-N-{[4-(4 N miethyvl-1,3-thiazoi-5-yl)pheniyliimehylpyrroidne2-caboxamide
'H NMR (400 MHz, CDOD): j 8.88 (s.I, H)8,15 (*m , 2H), 8.01 (in, 1H), 7.49 (m, 4H), NN >S 7.30 (d,11= 9.2 Hz, 211), 7.06 (d,-J=8.8 -z, 2H), 471 (s, IH),461 ( 311), 4.39 (mi H), 4.13 (, 211) 3.98 (in, 2H), 3.88 (ms I H), 3.84 (n, 11), 3.66 (m, 211), 3.59 (m, 411) 2.49 CF3 (s, 3H) 2.28 (iI H), 2.14 (m, 1H), 1.91 (, 2H), 1.8 (in 2H), 1.64 (m, 2H' 1 .56 s, 6H', ON 1.05 (m, 1511); LC-MS (ES'): /z 1048.55 [MIH], R= 1-86 min (3-0minute run)
Ex Structure Compound name and Analytical data
FiN NY Prepared from ABM-3 L-3and ULMI1
(2HO)- C NH 1-2-F24-f [5-(4-i3--4-cy,-no-3-(riflu( oreiyl'pheny]-5,5-dine~yl-z4 s>~. oy-2-suifan.viideneimfidazolidini-1-yljphenoxy)-3
methyl-i.3-thiazol-5-yi)phenuylimethyll-r.(,Idie2c roxme
~N 'HINMR(300Ml.'z,CD 3 D68.86s,III),,.16-8B'3dJ=7-Sliz,21)8079-. N =~~~~ 9.1IH..87 (n41.7.29-7.26 (d,J= 9.9 I-z, 211), 7.07-7.0(dJ= 87 z 21-) 4.70-4,33 (n. MRH,4.19-4.13 (ff, 211),.04-3.81 im,5H). 3.65-3.56 (i.614),2.47(s F ~ ~~314, 2.23-1.70 (fi, 81),154 k, 6),102 d J= 60lz, 91)- LC-MS(ES');: N 103635 [MIA'], tp:=1.51 minl(310mnuka-run).
Prepared fr0,13ABM-3.L1-, and ULM/-6 N, ,O
K> YiphenoxyvpentyloxylpropoCXYactmidoi-3,3 dlmethlbvtnyl-4hvr ironn
2-carboxarnide
i ~ ~~~~~NMR (400 Miz, CD 30D) 68.13-8.17 (n.2114) 7.9 (d = 7.8H Iz, 111),7.32 7.6 il
2i 11), 7.25-7.31 (iin.411),7.05 (d, -0iz_'21),4.514.57 (fin,21,447 (dJ =16.0liz. 211),4-27 (ds.= 14.9 -z, 211),4.04 (t,.J1= 6.5 li, IH), 390 i/d,j=- 1.5Hz, 211 164-168 (inf,214),3156-3.61 (inf, 21),3150 (,i= 6.3fiz2HI),217-.24(m, IH), 2.07 dd, J 3.9, 13.3 iI-i1),.1.89-1.92~m2-)18-8~ 11),1.64 1.70 (m, lIII..76 I I,
+F130 (br. s., 611), 0.99-1 07 141,911),0.91 ft,.J 6.8liz, 4JU-L.C--MS iES') m~ 957.35
[Mlil
Ex Structure Compound name and Analytical data
N ~~Propared fromnABM-3, L-1. and UJI-7
K oxo-2-sulfanyideneimidazi idin-i-yll-phenoxy)penr-vlloxylpro.poxy'a-eraiioiA3
i 'IINMR(400OMI-LzCDOD)88 -8 (rni211).7.98(d.J=8.6H1z,111).7.64(d.J=8.6
Hz,.211),7.53 -AJ =8.2 Hz,21), 126 (, 1 9.0 Hz.21), 7.0 (d -0Hz.21),4.,68 (S.
11I),.4.58 (d, j= 16.0I-Iz,211), 4.54 (d 9.4Hlz, 11I, 4.48 (r. s,i114, 4.03 it, J= 6.3 S~ N Hz,"H),3,97 (d, 1= 2_7Hz, I H) 1.4388 Ou,1]H),3.78 (dd,i= 3.5,141.0 Hz IH), 3.61, 3.66 (mn.211),3!.55-360 (in,2H11) 3.49 (t,7 6.3Hz,211',188-1.92 (. "1H) 1.80-185 (n', lb 2H),i.63-I68 (i,211),1-55-1.59 (J-f 21-), 125--.33(mn,61H), 1.00 (hr. s., 911).0.89(t
/6.8Hz,4H).IC-M4S IFS']: tnI 949.3S[MHWJ. N k-F F
Prepaed from ABM-3, L-4, adUIM -0
K H oxo-2-suif-iiydeni;di-"iidn1ylpf)ienrer)ethoxyehoxyjehoxv aerainido-3.3
"'6 ol i i yl)phen ylimethyii nolride-2 -carboxa mide Oo, 'NH NJ~ 'HiNMR (400MWz, CD30r316 8.89 (s,1II, 8.18-S.15I(d, J -8.4lz, H)l, 8.01-7.99 ,,S (n, 11), 7.49-7./2 (mn,41),731-728(d, J - 10.0 Hz, 2 1-7.07 (il 2 11) 1.72(s, 7 i N 1 11~~~~l-), d.61-4. 52(m,3IH),4.38-4.34(, I H 1, 4_ 0 4' (m, Ili44.104-0(m. 2 141, 3.9 1
3.80in,411)i,3.77-3.72 (m.8 H),2.49 (s, 3H).i2.24-2105 (m 2 H),I".4 (, 6H 1fi .06ifs 9 11):LC-MS (ES'): mlz1008.50 [MIII],;= 1.49 mini(3.0inuteirun).
Prepared from ABM-19,14 -and ULMI-I
N--4 i j 2,4-dioxoin.idazolidin-1-yltfphenioxv)ethoxverhioxylehloxvLiera-inido]-33
/ "5direrhibuanol]--hyrox-N-[4-H-methyl-I,3-fiiazo-5 vi)plhenvtimer-hsvipvrroi(iid~une2c ,irboxamride
H, HNMR (400 MHz, CD;OD)06884 8.89 in,IHi, 8.67 J =567 HI 1H), 8.25(s, I 11Hi 8.08 - 85 (8m,211j),7.67i(d J= 9.00(,111), 7.43 (qf =-1- 411), 730 (d,.J 8.22 iz. 2 11),7.00 - 7.08 (J-f 21H), /0IdJ = 0.781-Izs 1d4-45 -4 61 (m, 31H),4.35 )' dd,J15.8S5, 4 9HIrIHi, 4.2-4 17 (in,2 H),4.04 (dJ = 191Hrz, H), 3.77 -3.90 (,4II), 3.67 -- 3.75 (in,8 11) 2.7(d, J 0.78l11z, 311), 22(ddJ =12.91, 8.61I-Hz,1I NH H), 2.03 - 2.12 (i,I 1), 1.46 -1.55 (ms 6 11). 0.98 - 1.10 fri 9H); Maiss (1S'): mz N \j 992.38 [MW]1+
Lx Structure Compound name and Analytical data
Prepared inn;ABM-6 L-4and ULA/i
S oxo,-2--suifaniv'!denieiridazolidini-I -y])-2
JI 1 0 0 A NH f-nrYophenioxy)etdm.xyie-tho-xv'ettlmx-y~acetarnido1,-3,3-d~irnthivibnsanioy]-4A-hvdroxy-N
-f N\'NMR (400 MHzCDODr:689.89 (F~i,84).18-8-16 (d,J =7.21z,211)s8&01 -7.99 (dj C3 =8.4Hlz,1H1),.49-714 (in,4.1) 78-7.21' 211' 7.16-714 (i. 111), 4.71Is. 111). CN4.61-4.53n311), 4.35-4.31-ill 111)4.28-4.26 (in,211). 4.10-4.06(n, 211),3.94-3.81 (in, 3H), 3.81-3.80 6-n, 1H), 180-3.7. (, 8H), 2.49I(s, 3H),226-2.24 (it, Iff 21 1 2.09I(,H11, 1.57Is.6H1),1.03 (s 911);LC-MS (ES4y)nz10263 4[MW).t =2.73nsin (,5.6rnsnnute run).
PreparedfroABM-17,L-4andi ;NMI
C0 y1)phenyImm1ethyI~oyrr-oldine-2 -carboxa midee (400~zD.OD:6889isJH' 8-16 , 214, 8.05 -8.02 frn. '11 7 49-7.42(n 41),N AH731-7.29 (dJ=8.8H1z,211),7.09-.07 d -8.Hz2H)j7` U 1)A.61-4.52 (it; 0 '311, 4.38-4. (in,111). 4.23-4.17(n. 211).-4.06-4.01 (mn,21-4b,3.91-3.80In,41I),3.78
3.8O 0814) 2.49 (sai,3.27-2.22 (in, 1H),2.13-207 1-i MH),1.56I(s,6H),1.060(s. 911): LCMS'(ES':m- 1028.50 [MH 3 '],~s 2.62mryii(5.0 minnierun).
PrepardfromrARM-3, L-4,aiid ULM-3
oxo2sYfnidneniaoldn1il )ovethoxy-ethoxy'eth-)xv,,ac-etainidol-33 FC)dii'-iethylbusanryli-4-hydrnxv-N-[I8)1I[44-iethy-,-Itlazl-5 S vi)fj11nyi ethy1pyrolidine-2-casboxamn.do
'11NMRi(300)Mz,CD3OD: 68.90(s, 114, 8.16-8.13 (d.J=81H'_t,2H(.8.00-7.97(0d,j = 8.1Htz,IH-),7.4-7.35(iiH),7077',d_-90Hlz,2HI,71]-'7.08id_/-90OHz
NN / 1) I0-500(n, 111). 4.69(s. I-I)4.60-157(-.111 ), z.54-4.43(i, 1H1), /A.23-4.22 (in \~~2 ~4.D 2 2 4H-1(i,1)399-3.88 ri 3H), 3.83-3171 (in,911)s2.54(s, 314 2.24-2-04(mn,
1Hf), 2.00-1.94 (in. IH), 1.571(sH,1.03' fs H), LGSES). inz1022.56 [MH'],ip, =-2.0)7mmn (3.6 minute run).
Lx Structure Compound name and Analytical data
Prepared from ABM-4. L-4,anid ULM-1 N(N1 ~ 2S4R)--1-[i_2')---)2-12-{2-I4' 3V[a--yn -- ftr fioromethy]pyr d;n-3il,5
Vl1hno j ix'enovethoxy)iietvrfiido] -3, d'1O'beio -4-hydroxy-N-{i[4 ) (Arnethy1-1,3--izaoi-5-ylhpheny m,,ntt'y!I yrrohoinc2 carlpoxarnide
'HNN4R (300\4HzCIVOD' 69,12(s, '1H), S.S(s, 1-I) 8.63Is,1H70~S~
1H), Hi7-7.30(fn, 4Hj).7.22 (d/J 9H11 I '11) 0 (d, '7 9la. 2H1),4.,80-426Itol 5H). 4.25-4.06Omw,411)3.92-3.7 (mn, 311),3175 -3.60ifn, 811),2143(s, 314 , 2120-2. 10irunI o H),.2. 10-2.01i. 1H),i1.52 (, 6H).1.00 (;,9111, LC-MvS (ES'): ir 1009.12 [TMW ,5 .H16in (a.6mrionte run).
.~ ~ PreparedfrmABNT-3,L-5,andULM-1
F din~'r~z'-~x--aril>"yideiri~idaiiidnI-9i oxletoethoxylbutai-2
0' a
- 1,3tl,zi-v)phel'irithylipvrimldine-2-arLoxaiide
0 OH 'flNMR 400 MVI,CD30DioS 881 8.94 in I H)8917 d,1=7.43 Hz,2 H),8.01 (d,.,, 8.61 H, IH).773- 7.89 (in, 1i-1)73 -7.5 3-H), 7 1 3 ~ini -7. 6 (n'l2 Hi,.01
H 7.17 (n,HI,5.48--5.54 (m. 111) 3.6 -488(il 20 1), 3.20 -3.29 (m. 2 1I), 2 .43 2.52 (-.i HMs2..6 -230 0nI.H,2.03 2.16(in, I1H),l1-2 1.59i(n3i,11,.39 (d, J ==4.30
Hlz.911), 1. 11 - I11tfn 3H1).1.06 (s,3H1), Mass (ESI:rea103647 [MH]
i ~~PrepDared fronx ABM-3.1-6, and ULM-i dN-ty---x-2-nfniieeniAzojdinI--all.-enox)emoxvjhu-,a1-2
i ~~ v1:rixvlettho.xy~acetarn~d-ii-3,3-dtme-ivtbnitanoyl-tvdr xy-N-f[4-4-ne .l,3-thlia-zo
01
~~~~~~~'11MR(),4.00M(,=7. 3 1zD1), .88a,1H.81 >lfl 2- 81n11),1-.7.9 dI (i,2H,36 .82
s (i' Hi, 3.56 -3.61In, IHY-), 347 -3.52r, IH).,2.44 -2.50fin, 3H), 2.19Q- 2.25 (Ii, I N- 11~I-), 2.06 2.`11 (in, 1H),1.53I(s,6 11)1.35d1=6.65 Hz,3H1),1.11I(d, J 6.26Hz1, 6
11I,.1.01- 1.07 (in, 9Hfi;Mass (FS'):rnz 1036.47
Lx Structure Compound name and Analytical data
Prepared (Irnn'ABM-3L-7,and ULM-1 F:
i ~ ~~~oxo,-2--suliv'idencirnidazolidini-I -yi~phenoxvy.bitoxylbnt.oxyiact mido)-3,5 Nl~~~o dimedsylbnsa ,noyil--:i-hvdr-oxy-N-K[-4-44-methyl-i,3-tliaizol,-5
i ~ ~~~yl)pheniyijn.iethJyiioyrr-.ohdie,-2-earbioxamiida d 'fl 'NMR1(400Mfz, CDOD:68.0(s, IH),.817-8.15 (d,Jd=-8.4iz, 21H),801 -8.01I(dJ
1.611z, III,, 7.49-72(i 411), 7.30-7.27(d, J= 116Hz,~H-11)(7.6-704(d J = 88sHz. 'H1),4.7 (s, 111',4.61-4.4(m 11 4.38-4.34(n. 11-),.07 -40t In,'_Hi.3.40-3.95(n.
IN, 4~ yN 2H), 391-3.83 .n; H, 3.61-3,8I ( '-IH) 3.51-3.50-in, 4H0, 2,50Is. 3H), 2.05-214(m,
111), 2.20-23Oin, 11H) 1.9-1.86 (i 211), 1.7 9-1723(in,6H1,1.56 (s,6H4,106s,91'; IC-M iTS1) mz 1020.30[MI 4-06m (5.6nnute rnof
Pre-,paredfr-om.ABM-16,1,-7,anid JAL-3
- NC IV I oxo-2 -su fanvi id en'-in ids'zoid n -I-yi[,- -flnoroph enoxy)ba toxvibatoxvi aetarndo(-3,
25 yl)phenyileth-.yikwryroidine-.2-cs-boxarnide
'1IN.NR(300Mfz,CD 3 0D) 68-88 (s. 1H,8.178141'(d, =7.5Hz 111) 8(0(-797'(d J=H 8.41 Hz(IH),7T46-7.39(ms. 411),7.27-7.14(0, 31) 5.01-4-86 (m, HI.4.69I(s,1M1,
1' .60-.55f.f= 7-5Hz, 'iH),.44(On, 'M 4JO-414 0, i= 6.01-1 3.98-3,97(d,
NH -~21z,1)38-3.76m21'3.6'-3.49 (m,61). 24 8- (;,, 3H,217(In,i11I), 2.00 5 1.89 (i,3H1. 84-1L75 (ms.211).,i.74-1.71 (in--Hi) I.5 (Isnil ' 1. 2-1.40(in, 3HI, 1.04
Is, 911;Mass (ES"': 057105120[M-lI
Prepared fron ABM-l6 L-7,and ULA/13 22 4 IY - (2S,4R). [iS [41J3 .yn..Ir~oost~ipexi-55-dinithj.4
i ox-2-snifan-vliideneimidazoiidin-I -vA -2-fluorophennoxy)bnitoxy-'bntoxy'ael io)33
'I '1NMR(100 MHz, CDOD): 68.88 (s, 11).8.17-8.15 (r, 2Hi1, 8.00-799 Id,J - 64 N .i.11,-4-.42 (m,4 1,'' 7.3714'3(m , 1,4.71 (s, 1 1, 4.61-4.5 5 x, 311),4.38 o< H 4.34 O 1H), .00-3.83Insf, ` H), 3.1-3.49Inm, 6 H,2.49I , 3 H), 2.30-2.10 (.1 2H)."'
Q N 1I92-189(i, 2Hl). 1.79-1-73 (n 6 1), 172(s, 6HI1.05(s, 911); LC-MS (ES'): 05nz
N H i038-50[MH', qt,== 3.05 mm1(5.0jnntrn)
Ex Structure Compound name and Analytical data
V-N Prepared from ABM-16, L-8, and ULM-1 -45 For (2,4R-1-(2S-2-2-{-[4(4-3-[4cyao-3(trfluromdiy~phnyi-5,5-dim-ediyl-4 F oxco-2-sulfanyvideneimidazolidin-i-yl}-2-fluorophenoxybtoxypropoy}aetamnido)-3,3 dimethylbutanoyl]-4-hydroxv-N-{[4-(4-methyl-1,3-thiazo-5 27 l)phenylimethylrprroiidine-2-carboxamide '1 NMR (300 MHz, CD 3 OD): 68.87 (s, iH), 8.10 (d.=8.6 Hz, 21), 7.93 (n,iH), 737 (, 4), 7.11 (m, 3H), 4.83-4.48 (m. 5H), 4.12 (m, 2H, 3.94 (n,2H), 3,78 (n,2H), 3.50 N mil 611) 2.44 (s, 31), 2.05( 2.), 1.73 (m, 61), 1.52 (s, 61), 1.00 (s, 9H); LC-MS
IES): m z71024.10 [MH*]It. =279 min (5.6interun). OH
Prepared from ABM-3, L-8,and ULM-1 N' ___ CN(2S,4R)-1-[(2S)-2-(2-{-['-(4-{3-[4-yano-3-(triforomneilphenyi]-5,5-diinediyl-4 2 - oxe-2-ufanyiideneinidazolidin-1-ylIphenoxy)btoxyIpropoxylacetani do)-3 3
diiethylbutanoyl]-4-hydroxv-N-{[4-(4-methyi-1,3-thiazo-5
28 28/ vi)phenyi]mneth-yi}pyrrolidine-2-carboxamide 'HNMR (300 MHz, CD 30D) 8.88 (s,1H), 8.14 (m, 2H), 7.97 (, 1H),7.49-7.41 (m. -4), 7.26 (m, 7.02 4.70 (s, 1H), 4.61-4.52 (m, 3H), 4.38-4.33 (ms i),4.03 3.98 -(t, JN= 6.3 Hz, 2H), (s, 211, 3.86-3.82 (m, 21), 3.68-3.51 (m, 61H), 2.48 (s, 3H), 2.23 2.09 In, 211), 1.93-1.73 (m. 6H), 1.55(s, 61), 1.02 (s, 9H); LC-MS (ES*): 1006.50 r N NJOH [MH], R =2.81 inn(5.6innuterun).
\ Prepared from ABM-3, L-8,and ULM-8 NC 'N N N (28,41)-i-[(28)-2-(2(3-[4-(4-{3-[4-yano-3-trinoromethylbphenyi]-5,5-dimethyl-4 F3C S oxeo-2-nufanyideneimnidazoidin-lylpheoxybutoxyipropoxy~acetami do'-3 0--, methyibutanoyi]-4-hydroxy-N-([4-(4-mnethyl-1,3-thiazo-5-yl~phenylimethyi'prrodn 2-carboxamide 29 H-NMR(400MHzCDOD): 68.88 (s, 1H), 8.17 (d,]7=8.8Hz,2H),8.01 (m, 1H), 47 (ni, 41), 7.30 (d.J =8.8 Hz, 2H), 7.06 (d, .= 8.8 H-, 2H), 4.66 (, i'1), 4.61 (m, I H),
HN / 4.54 (,2H), 4.42 (m, H), 4.08(mn, 2H), 4.01 I(, 2H), 3.85 I(, 2H), 3.67 , 211, 3.61 N S alt (to, 211), 3.56 (m, 212),.50 (s, 31), 2.25 (m 11), 2.16 (l, 2H), 1.93 (m 411 1.78 (i, 2H), 1 56(s, 6) 03 (m, 311), 0.96 (m, 3H); LC-MS (ES'): mT z992.55 [MH1] t, 3.3 min (5.6 minute run).
Lx Structure Compound name and Analytical data
0, --- ~~Preparedftrom ABNT-4.L-8,arid ULN1M
FC4-oxo-2-suifinv'-devnnit'daz'idri-1yllpenioxv)butxvriroioxy acetan-idol-33
Kdirrie-thiyibntanovlJ-4lajydiow-N-{ [4-(4-ulethy1-I,3-ffiazoI-5 po vyh eny imethyhmvr-r,,ddn'--2-carboxarnide 'H NMR (300 MPzCD3)O j69.05-9.40(in,i)i,880 (, I).8.66-8.62 (. 1H,7.45 30 H 7.36 -- nt 411' 7.257.18(im -1H) 7.02-6.92(m, 1H), /j.70-42m11,.041(n a N, 31). 4.35-4.26 (n.1H4, 4.10-3190(n, 411),3-89-3.69 (in,21-),3.65--340(n, 611)2.44 (F. 411),2,20-2.01(in, 211),I188-1.60(inn, 611, .52 (s.6H),1J.00a, 9):L;C-MS(ES",,: liz 1007.30[MH ,p=1.71min (3.0 minuter-un-).
OjPreparedfrom ABT-1, L-8,anndULM-1
sI a sutfanylideiniidaroidi,-...*jefnex'tbn,,oxyvpnpo~cxyacetamfidoic~f3,3 'wi
31 10 '11NMR (300 M1z,301) 8987 is, ]-H), 7.97(d..J 8.4Hz, '1i) T7 7(a.111),7.6 HN I (in,i1H,7.49in6,4-1), 7.2 8(t 2-1),'17. (m, 21l, 4.71(as, I', 4.59 (u, 3H) .38 (o
r N, 0 111)4.07 n411, 3.987 (t, H1, 3.68 (to,611) 2.48 (, 3H)227 (m, 2".1J.93 (m. 611), 2 0'" O (.54(is. 61141.03(F,.91-). LC-MS iES8¼: ni486.40 Ri'21H+,r N 2.21min (3.6 mintute run).
i Pre-paredfrom ARM-5,L-8andUL
_0dinlietiyibuan-nyl-4-hydinxN{[ nev-i3tizi
'I-INMR (400MHz. CD30D)6 8.89 j) H775dJ *8. lIz, 11) 7.9--742(mo411(.
3HN7.37 is,111.),7-27 (ds.J==8.81Hz7211'), 7.18-7.15 (m, 14, 7.06-7-04 (m, 2,488 (a, 1H, NS 4.59-4A6(n,,31-b, /A.38-4.35i i(m, I,107-4.00 (o 1H), 3.99-3.87 (mo 511) .88-3.76
il] / -K (.21-I,3.68-3.60(m, 211( .593.95 (to 211), 3.54 -3.5.3 (i 214) 249 (s.311), 2.28-2.19 in, 411),2.14-2.0.5(m, IHI,0 1.3186 (;4itH),1'.80-1.78fin, 211, IJ (s,.61-) .04 (s. 5 911;LC-XIS -,S+): lz 968-3 [MH41 tj =L. 7 ,,n(5.6 ,nnt u
Ex Structure Compound name and Analytical data
Preparedfrom ABM-3, L-8,and ULM-2 SN--- -N (2S,4R)-I-[(2S)-2-(2-{3-[4-(4-{
Es- oxo-2-sulfanylideneimidazolidin-1-ylphenoxybutzoxylpropoxyacetamido)-3,3 dimnediylbutanoyl]-4-hydroxy-N-{[4-(1,3-diazol-5-y)phenylmethyl}pyrrolidine-2 o carboxam-ide
'H NMR (400 MHz, CDOD): 8.94 (s. 1H 8.16 (dJ= 8.8 Hz, 3H), 8.00 (dJ= 1.6 Hz, )1H, 7.61 (d,J= 8.0 z, 21), 7.44 (d, J= 8.0 lz, 211), 7.28 (d, J= 8.8Hz, 211). 7.04 (dJ 8.8 Hz, 2H), 4.71 (s, 1H), 4.61-4.51 (ms 3H), 4.37-4.33 (m, 1H), 4.07-4.03 (ms 2H), HN 4.01-3.96 (m 211) 3.88-3.82 (m, 111) 3.81-3.77 (i, 1H), 3.69-3.3.62 (m, 2H), 3.61-3.55 m, 211) 3.54-3.53 (m, 2H), 2.28-2.19 (m. 1H), 2.14-2.05 (m, 1H), 1.96-1.84 (m, 411), 1.80-1.74 (i. 2H). 1.56 (s, 6H), 1.06 (s, 9H); LC-MS (ES*): m/z 496.85 [MH12], t,, NH "H 1.60 min (3.0 minute run).
Prepared from ABM-3, L-8,and M4 Fac (2S,4R)-1-[(2S)-22-{3-[4-4-{3-[-yano-3-triforomediyl~phenyl]-5,5-dimediyl-4 x-2 - ulfanylideneiii dazolidin-1-yiIphenoxy)butoxypropoxy}acetamido)-3,3
\ diimetiylbutanoyl]-4-hydroxv-N-{[4-(1,3-oxazol-5-yl)phenyllmethyI}pyrrolidine-2 carboxamide '1 NMR (400 MHz, CD 3OD) o 8.24 (s, 1H), 8.17 (d, J= 8.0 Hz, 211), 8.01 (dd, J 80, 34 1.6 Hz, 111),'7.70 (d, J:= 8.0 Hz, 2H), 7.49-7.45 (n, 3H)s 729 (d., = 8.8 Hz, 2H), 7.06 (d, HN j= 8.8 Hz, 2H), 4.72 (s, iH), 4.61-4.51 (m, 3H), 4,37 (i, IH), 4.08-3,83 (i, 6H), 3.69 0--- 3.54 (m, 61), 2.15-2.05 (m H), 1.93-1.76 (m, 6H), 1.56 (s, 611) 1.03 (s, 91); LC-MS
(ES): m/976.45 [MH],r =.69 m 13.0 minute rn.
N Preoared fromi ABM-3, L-8, and ULM-5 ' -F N (2S,4R).-1 -[2S)-2-(2-3-[4(4-3-4-yano-3-trifloroethy)pheny-5,5--dimethyl-4 F oxo-2-sulfaiivideneimidazolidin-1-yliphenoxy)butoxy]propoxyacetaido-3,3
dimnethyibutanoyl]-4-hiydroxy-N-{[4-(4-msethyl-1,3-oxazol-5 5, yi~phenylimethyl pyrroli dine-2-carboxaide,, H'NMR (400 MHz, CD;OD) 6 816-8.14 (d,J= 8.8 -z, 3 H), 7.98-7.98 (d,J= 2.0 Hz, 1
H), 7.61-7.59 (d,J = 8.4 Hz, 2 H), 7.49-7.47 (d,J=8.4 1z, 2 1' 7.29-7.27 (d,J=8.8 Hz, 2 H),7.05-7.03 (d, J = 8,8 Hz, 2 H), 4.71-4.52 (m, 4 H), 4.37-4,34 (in, I H), 407 3.99 (m, 4 H), 3.87-3.82 (n, 21 H,.68-3.53 (m, 6 H), 2.41 (s, 3 11), 2.21-2.00 (m 2 H), 1.76 (, 6 H), 1 55(s. 6 H), 1.05 (s, 9 H); LC-MS (ES'): m/z 990.60 [M t,, 0 N-, 3.50min (56minniute run).
Ex Structure Compound name and Analytical data
N /
Prepared from ARM-1 L-8, and LM-9
0-., sulia ,nyiidene- tiid,, z'idi.-- -yl-phenoxy 'butoxy propyoxyacetarid- -3-tyettvlbutanoyi ~~~4-hiydroxv-N-{[4 -!'-iaz)-- hey iehlpr-~iii--a~o~i.d
'H.NMR(400Ml~I, -OD):6&99 (F, I), 8.12 (s, 11),7.90 (d,.-:&84H-, II)s7.82 ('s, i'-bj'762-7.56(iwi3Hi,.40(d,,J=8.4Hz,2H),7.2,3(d,J=8.4Hz,2H).,,7.00(s,2H). A.61-4.52(n, 111". 45-.0(m, 1, 4.39-A.36 (ty, 11), 4.03-3.95 (m, 411), 3.78-3.74 36 1N '11).3.63-327 (msn711I),2.23-1.98 (m,341,1.89-171(n, 61),150 (s,6H), 0.97 (d,1
0-~ 6.6Hlz, 311).089 (d, J 66Ilil31): LC-MS (ES ):ml` 914.25M11", tj, 1.51 miii i~ (1J, 3.0 minute run.
pa ~refrom ABM- L-8,ard -1~
I (2,4R-i-112)-2f2-3-(-{4[3-5-ehoro6-c~noyrlin--yi-5,-dlet, yl-4-oxo-
37'H NMP(400MT~rz, (DOD): 68.87-8.6(iri 2 H 844 (s-), _7.9744H),
HN. 3 (,H),4-39-4.35 OrfljH)408-3.9(l, 4 H),1905-3.83(n2 H),3-6-835 r, 6i1ii.
21.50 (s, 3l) .215-2.05 (m.2H)., 1.92-1.88 (mn.6-1).1.56 (s,6I-", 1.0-1-s 9H1) LCMS (ES'): mz 973.30 [MPI'] i. 1.58 mill(3.0rmnut~erun).
Prcpa redfrmX BM-1 L18, nd IA1M5
-/\N1 (2S,4R)-I -[(2S)-2f2L 3( {+ -[3-(3-chl(-.oo-cvai~xophenyi)-5.5-dirnethyi-4'-oxo--' i - sufnidui~oId . - I - Iyuoy~mox~cta~do Nwi
-0
7.66-7.59 (m, 314, 7.,19-747 (dJ =8A Hz, 2I '1,28-726-dJ- =92 Hz, -11) 7.05 7_O!'03 dJ- = 8.8-iz, 2 ll)4.71 (s, 1 11, .7-45 (i. 3I1),4.38-434 (m, 1111407-3.99 N ~ (r,4H),3.87-3.80 fin, 2H)i3-.35 (m 6H), 242 (;,IH11, 2.20-200 rj, 2H), 1,9 `OHQ 1.'77(n,614, 1.54 (s,6 14,I106(s, 9H);LC-MS(ES') ml1- 956.30 [MW` t, 1.56min -NH -310iunute run).
Lx Structure Compound name and Analytical data
Prep-ared from ABM-E.L-S, and ULM-iO
sijliaanylidenirnjwdazolidi-I -vilhnx~noypooyaeaio--ntybsoy]
39a- s 'H NMR (400 MHz, CDOD) 68.1.51s, Ii 1),797-7.0i1=j8.4 Hz,1IH,78'7(s.H, 7.66-7.60(i, 3 H),7.48-7.45,(d, J= 8.41iz, 2 1-',7.28-726 dJ =9.2Hfz_ Hi),7.06 e 7.03ifd-f ::9.2Hlz, 1 H466-441(i5,5H)4.07-3.99 fn.4H,385-3.83 (n, 2H) HN / .66-353 (in, 6H), 2.41 (s, 3-), 22-2.00 (m,3H), 1.93-1_77 (il 6H)1 .53 (s. 6H1) .1.0 2 0(d 6.8H11, 3ID.)0.95-0.93dJz6.8 Hz. 3-I) LC-MS (ES'):Inz 942.30 -U (j[MMI,rt,=1,50min (3.0 minuterun).
N~" N-= D Preoared from;AB-M-20.L-8, and ULA/4 F-(--F S I ~ ~~~~(2S,4R)-.I-[i2S)-2-2-3-4--(-3[-y1O3(rfOriehip~fy]5-inty F 'N i ~~~~ox-2-suifaniv'ideneimidazoiidin-I -vilpyridini-2-yi)oxvibutoxvhipropoxy)a .
cetaml idol -3 3
40 0 'HfNMR'(310MHz, CD 30D)68.81 (, 1) .16-8.03'i 31-1,800-7.90(n1 H), 7.70 7.60 (mn,111),7.51-7.30 in.41-), 6.91-6.80(i.1 14, 4.67 is,lI-b4.60-4.40 (mi, AI) HN 43-2irri,3H1),3,89-3.70 fin, 4H) .6-3.40 (iu.6 H),2.41 (s, 3H).i2.23-2.01 (i,2
11)O~ H).90-1.62 (ipn.6H).1 1.55 (s,6 1b,1.02 s9 H)LC-MS (ES):iz, 1007.35 [MM),fp
L NH \-- 1' 58 un ni3 notfuern.
aPrepairedfromABM-21, L-8, and ULMI
cI > ,[snlfa nyfidenieinida"zoi din -1-vi)-2 -finuruph enox ytb uoxyllpopox y A1ac eta i idoIf-3,3
t v llohenyvlfinethvi -. r i~e2cibxftd
41 1NMR (40 MHz, CDD): 68.8(IH),7.97 id,j/=84-1zJH'~ T89(F,111, 7.66 7.64 (m,111),7-48-7.39 (m, 4H) .22-7.19 (m, 211) .14I(s. III)z.s, 111',42,59-4.47 N 0 3111,*i ~ 4.36I(d, j= 15.6- Iz.l-I ),4.14 (t, j= 6.4-iz, 211)4 00.1 , .6 61iz, 211),13.87 S HN 378 (in, 21H),3.67-3.54 (m.6),2.45(s3H)),126-2,21t(mH 2.13-204(in, H1,93 / N. 1.89'rn, 114) 1.83-174(in.N-11) 1.55 (s,611), 104 (s,9113; C-MS(ES'):0',/Z990.35
[VM1t,= 1-59mmin(3.0muinuteron).
Ex Structure Compound name and Analytical data
'l,, N:N... PreparedfroABM-22,1-8, and tAiN ' 2S4 R- I-[(2S)-2- f2--3-(4- f4 [3- 4-p-no--metoxpenv)-5, 5-dimyettvI-4-oxo-2 -- o 0--- F dirtntylbnsaoi.hdroxn 'V4e~ii3.hao
'H1NMR (400 MHzCD3ODi6S98 sI fi,77-775 (d,j=84 H, 2 ), 749-7.42 (n, 42 4' 4), 7-36-7(s, IHl)7.21-7."/A(mn 4H), 4.71 (s,I1H),42,5 9-4.52 (in, 3 14),4-9-435(ip. HN *~ ~~)( 11H), 4.16-4.13(in. 2I1I), 4.00-3.98 (m i)3.99-3.83 iIb3.68-3.66(n. 2 11),2.50 \/ N (,3H). 2.30-2. 10 (i,2H,1.3-1.89(inf 4H1), 1.80-1.76 , ,H)m.5(s, 6H'1 03ifs, NH ~~911): LC-MS (ES): tn2986.A5 [MIJ/ p 165 niii(3.0m-fiuter-un).
0 9~ ,)PreparedfroABM-8 L-8,anud.L1I
i q rN(2S.4R)-1-[(2S)-2-(2-{3-[4-(4-i-4c,-n--til(,oeilpey 4oo2
3 33-di..-fe.',ylbutinylI-4-hydor-,y-.N'-4-T.etl.yi.,3-tHiazol-5
yl)phcnylmeflthyi),oyrrofidine2-arbo\.'mid" 8 43 1 I fl ~~~'NMR (400 M',,CDIOD) 68.8883'(s, 11H),S8. .16 (d, J8-4 H-,2 11,'8-0'
ON 7.99 (in,114), 749-7.42(ip.411)7.12-7141(d, J =8A1--z.2 H), 7.08-7.06 (d, J =8A1Hz, ,k 1-i-',T 2I)4.80 (s,1H14, 4.72(s1 -b, 4.59-4.34(mn, 3 -,.'0-4.08 (n, 6I,3.99-3.87(n, 4
N% H) 367-3.56'in,611), 2.49(Is,3"H),2.21-1.87 (n,121H), 1.05(s, 9H):.C-MS (E':
0 IPrecpaedfroAHM-21, L-8,adUIM c'(2S,4R)-1-[(2S-2-{2-[3-(,4-4[3'(3-rhf(o4-eyaiiopheny-55-diehy--xo-2- dilnmeybanyl-4-hydrovN{1[4-( ntettvI-1,3-oxaznl)-5 / vphenyilrnet-iyifvrldl e!:sb ri 44 11.NMR (400MIIz. CD3 0)6 81-5 (, 111, 7.96 (d, J8.4lz,)7.7iii76
/ 7.60(fin,31), 7.48 (d,.)=8.4 Hz2H)7T24-714 (311)4.71s, 111), 4.61-4.52 (m,3) 0 /--o 4.38-133 (n, 1ii),4-14(il21), IA00(d J 4.0IIz 311',3.8-3.82ti (m, -11,368-3.54 I (nl, 61-), 2.42is, 31), 2-27-2. 18 r1iI H), 213 -2.04 (ra,111).1. 93 -I. 89 (Ms 411', 1.88--1.80 0 0 '~~(n2110,1'.55 (Is,611),.I06 (s, 91'LC-MS (ES)rrl 91725 f' ,,.7mn(.
-' minute ri n). H
Lx Structure Compound name and Analytical data
0 PreparedfrmmABM-21. L-8, and ITLM-4
eI carboxamrde
4-5 7.7 64(e31-i),'7.49-7.40 (m,~ '1 T22(ds J 8.4H, 2),7.14 (d,J=:8-0Hlz, H),471
N (s, J-11),i4.60-1.51(Un 3i)A 41.8432 '111)II4.18-.11 n i 4,100-3.96(m, 211), 92HN 3.76 (m,21-1,3.68-3.55 (,611,2272.11(m.Il) 1 11).1.95-1.86 .128-2J06(m.
0 (~~rn, 411', 1,8.-1.72ir, 21, z 960.30[4MM,) .55(s.6H), `06(s, 9HfifL-MSI(FS'): .. =R 1.5/1ui-n l(3.0 minute run).
0
N~ Prepa redfrm-mABM-21. L-8, and TINT2 (2S,4R)-1-[(2S)-2-2-3-(-4-[3'(3-rhf(o4-eyaophenyI-5.5-dim.,ethy-4 -xe-2- i cl
earhoxamide ,imtycpreiie ( '1- INIR (400 Mlz, CD3 00) 6 S.941 sP-I1),8.15 (,111),7.96 (d, J8.4iz,1, 7.87
46!1 N--\- s,.11),7.66-7.61 (i,3H),.7A4Id,]j=-8.4z,21)719-7.12 la. 311,4.71 (s,1),4.60 . N .51(in, 3H .38-.34 (iu 11H),4.17-4.11(in,)3.99-3.94I rj, 2H), 3.SS-3.75(n, 211), 3.71-3.5(in,611). 2.37-220 (n, 111-i2.13-2.06(n, 111).1.94- 1.89 (in,411',1.80
H 'O 0.0
N +
__/\ yN, Prepared freerABM-23. L-8, and UL1-4
F py'cd)t C) 3-dimie'.hyibutanecvil-4-hvdroxy-N-{[.I--(1.3ecxazol'i- Ahe'iiimethylepytxelitne-2
If arboxanucde 47 10 'H N4R (300 v-l CI) i69.16 1 ,H8.6 (, ai).8.23I(s, IH), .76 ( d,'dJ S I z,211), 7'48'74 (m3 1, 7.22-7.1"5(mn 3'1) 4'(,i4.604A '-it 11), HN 4.36-4.3(ini m111,4 16-4. 11 O'Hr4,3.99 (m, Hr,3.96-18'or2 11", 3.67I3.S3(1,6 NN 995.10 FMI'i, tR 2.266min (3.6 minute-.runI. OH
Ex Structure Compound name and Analytical data
N Prepared from ABM-23, L-8, and ULM-I1 N (2S,4R)-1-1i(2S)-.2-(2f-{3-d[4-(4-i3-[ - fl F -- oxo- 2-sulfanylideneimidazolui-1-yl}-2-fluorophenoxy)butoxyipropoxytacetamido) 3,3-dimnethyibutanoyl]-4-hydroxy-N-{[4-(4-mnethyl-1,3-thriazo-5 yl)phenyilmethylipyrrolidine-2-carboxamide 48 ' NMR (300 MHz, CDOD) 69.16 (s, 1H), 8,87 (s, 1H), 8.67(s, I H),7.48-7.40 (i, 4 N g N H)7.24-7.12 (m, 3 H), 4.70 (s, 1PH, 4.62-4.46 (m. 3 ),4.38-4.32 (i, 1 1), 4.15-4.09 O(m, 2 , H).399 (s. 2 H) 3.90-378 (in, 2 H), 3.67-3.52 (m, 6 11), 2.47 (s, 3 H), 2.27-2.17 OQ (m,.11H),216-206(m,1H), 94-1.83 'i 41-1), 182-1.71 (i, 2 H), 1.57(s, 6 H) 1.04 (s, NH H 9 11): LC-MS (ES): mIz 1025.30 [M ],= 2.27 mn, (3.6 minute run)
0
N--.- I-N Prepared from ABM-221 L-8, and ULM-4 s 2S,4)-1[(2)-2(2-3-(-{.43-(4-cyvano-3-mtoyhnl-,-iehl4oo2 suilfanylideneiidazolidi 1y]-2-fluorophenoxybutoxypropoxyacetaido} -3,3
dimethylbutanoyll-4-hydroxy-N-{[4-(1,3-oxaz.-5-yl)phenvlnmethvlpyTolidine-2 carboxamide
49 H'NMR (400 M11, CD3OD) 68.25 (s, 1H), 7.77 id, '=8.01 lz 11), 7.70(d, J= 8.4 iHz, 211), 7.50 (m, 311'7.36 (i, 1), 7.24 (in, 4H, 4.71 (s, 1H), 4.60 (m, 31), 4.37(m, 11H), 0 HN 4.16 (, 2H), 4.01 (m, 51), 3.88(m, iH),3.83m, IH, 3,69 (in, 6H, 2.28 (inH), 2.14 0. (n, 1H), 1.94 (n, 111), 181 (in, 211), 156 (s, 61), 1.06 (m, 911):LC-MS (ES*): m/z 955NM*, tRf 2. 17 mn11I3-6 minute run). N 0 OH
NN -N Prepared from ABM-21, L-8, and UAM-11 (2S,4R)-1-[I(2S)-.2-{2-[3-(4-{4-3-3-cloro-4-yanophenyl-55-diethy-4-oxo-2 suiianylideneimidazolidin-I-y]-2-luorophenoxybuox)propoxyacetanido}-3,3 dimnethylbutanoy]--hydroxy-N-{[4-(-muethyl-1H-pyrazol-5 9yi)phlenyl]methyl} pyrrolidn-2-carboxamide 'H NMR (3004Hz,(DOD) 6 7.96-7.93 (d,.)= 8.1 Hz, 1H),7.86(s, I H),7.65-7.61(d,
J = 9.6 Iz, I l) 7.50-7.41 (in, 5 H), 7.23-7.10 (m, 3 H), 6.34 (s, 1 H,4.71 (s, 1H), N.614.46 (I, 3 ), 4.41-4.34 (i, i ), 4.18-4.09 (i,2 H), 3.98 (s, 2 H),3.90-3.79(m, 5 N HN H-), 3.66-351 (1, I H), 1.93-1,83 (m, 4 H), 1.81 6 H), 2.28-2,16(m, 1 H), 2.1-1,01 (m, \ O 1.72 (m, 2 H) 1.54 (s. 6I), 1.04 (s, 911); LC-MS (ES'): /lz 973.35 [MHI], tR = 1.55 N mi, (3 minute run) -1H3
LX Structure Compound name and Analytical data
Prepar-ed from ABM-9.I-S, and ULM-i (2,SAIR)I-[(2S)-2-(2-{3-[4-(4-,35-i 4-cyano-3-(uritlu orometiyl)phenyil-8-niethyi-4-oxo-2 I'I
'-P irneiylbnsa",-noyil-4'-hvdr-oxy-N-I[4-(4-metyl- 3-tO'oLz-t5
~'It NMR 030)Mz, CD0D):68.8iV11)i8.16-8.03, ii 2 1-I,8.00-7.9( (mn I)750 7.30 (m.4H1),723-7.15 (in,21), 7.05-6.90 (ii, 2Hl', 4.67(s,1H)i, 4.60-4,30 (it,4HI). 4,12-391ni, 4H1I) 3N0-370 (in, 2H).l3.65-3.410(in6H), 2.80-261lin, 4_4H,241 (s. 3
/N- H, 2211(in, 6 H),2110-1.60(n, 9 H), 1.02 is, 9HI:LC-MS (S):in 53135 1 H -NH o0H [M!2±1]., p =1.86 niijn(3.6 ininnte run,.
Prepa redfrom ABM-3. L-9, and ULM-1
. .N/5 (2S,4R)- j[S)-212- f43-(z-3[A4-eyan-3(ro~roI ethylfph envi- -5,5-dimethy -4 s ~, 0oxo-2-snliaiivideneimnidazoidin-1-yl;penxypr.opoxvbntoxvaetaniido-3,3
0\ fapheniimeshox NHM(0M-iC 3 D6.35 1C1P80n1)79I,7 N.1z--<)
HN)NMR 7.473 Mi 1)7.dI= 68.73-(s,21-),7.0(d, ) 6 d-= 8.1 64.9in, 511).
SN- 1 4.09-378I(m,611),3,60-3.47(fin, 6H), 2.44fs, 31-),2,19-1.97 (in, 4H)17-16(in. 4H), - OH 1.50 (s, 61), 1.00 (s, 9H1),LCMS (ES4):z 100(6.30 [MHW, y= 1.7 1mini(3-0mryite run).
P-repared fromnABM-16, L-9. anid LM-1
F7/ di-iiethiylbntanoAil-4-hydoxy-N-{I[,I-(4-iledvl-1,3-hiazo-5
yl)pheuyl:.-nethllyipyrroiidine- 2 -carbox ami do
N'1-INMR(zl00 MliCD 3 D) 68.98 s1H)8.7-815dJ =8.A l.2 H)8.0 -7.99i; ~~~~~ .=~ l-,.974(n41,.42-7.20 (m.,3H'[).4.80 (s, I-,4.71-.d. f-_.8'I lI-li,1 n) 0 N_ 4.594.51 (in.4H), 4.38-4.20Ont 4Hi,3.99-387Inm, fill H3.65-3.52i raj 6H).i 2.50I(s.3 7 NH 0H 1-), 2.10-2.05Im,I/A 1, 1.72 (m, 4H)1,1.56 (s, 6 11,1.03I(s, 9H1I;LC-MS (ES'yi nz 1025.50 UMH'I, p= 3.50m 1nni5.6iinnemm.
[0536]Example 54:(2S,4R)-1-((S)-2-(24&,6(4-(3-(4-cyano-3-(trifluioromethl)pheny)-55 dimethyl-4-oxo-2-thioxoirnidazolidin-1-vl)phenoxy)hexa-2,4-iynylox)aeetamido)-3,3 dimethylbutanoyl)-4-hydroxy-N-(4-(,4-inethylthiazol-5-yl)benlzyl)pyrrolidine-2 carboxarnide:
~ VtO N-- O O V 0-O K2CO,, ABM-3 N-- -- TSO - ----- Step 1 CS L-I ~ NC IB L-1 CF3 BJ HO
HN ON N -O42-/_0
Step N--ULM-1S\ --
NCCF 3 BK Step 3
Step~~~~ ~ - N- - Y\ _ HO
C -N ~H COO
NC Example54
[0537] Step 1: Synthesis of tert-butyl 2-{[6-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl~phenoxy)hexa-24-diyn-I-yloxy) acetate (BJ)
[0538] This material was synthesized according to a similar procedure described in reaction step
I for the synthesis of Example 1. LC-MS (ES): m z 634.05 [MNa*], tR - 1.26 min (2.0 minute run).
[0539] Step 2: Synthesis of 2-{[6-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4 oxo-2-sulfanylideneimidazolidin-1-yI phenoxy)hexa-2,4-diyn-1-yl]oxy) acetic acid (BK)
[05401 This material was synthesized according to a similar procedure described in reaction step 2 for the synthesis of example 1. LC-MS (ES;): mz 556.10 [MHI], t = 1.54 min (2.6 minute run).
[0541] Step 3:Synthesis of (2S,4R)-1-[(2S)-2-(2-{[6-(4-{3-[4-cyano-3
(trifluoromethyl)phenyI]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-I-ylfphenoxy)hexa 2,4-diyn-1-yl]oxylacetamido)-3,3-dimethylbutanovil-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5 yl)phenyl]methyl}pyrrolidine-2-carboxamide (Example 54)
[0542] This material was synthesized according to a similar procedure described in reaction step 3 for the synthesis of Example 1. H NMR (400 MHz, CD 30D): 68.88 (s.1H), 8.15 (d, J= 8.4 Hz, 2H), 8.00 (d, J= 1.6 Hz, IH), 7.49-7.43 (m, 4H), 7.34 (d,, = 8.8 Hz, 2H), 7.14 (d,,J= 8.8 Hz, 2H), 4.93 (s, 2H), 4.71 (s, 1H), 4.60-4.34 (m, 6F), 4.08 (s, 2 ), 3.90-3.80 (n 211), 2.49 (s, 311), 2.25-2.22 (m, 1H), 2.13-2.05 (m, H), 1.56 (s, 6 ), 1.03 (s, 9H); LC-MS (ES*):inz 968.45
[MH'], tR = 1.67 min (3.0 minute run).
[0543] Table 3. Exemplary Compounds.
Ex Structure Compound name and Analytical data
55 o Preparedfrom AHM-3,L-11, and ULM No (~2S,4R)-1[(2S)-2-(3-{[6-(4;-(34-cya--(rfluoomethy)phenyl]-5,5-dimethyl4-oxo F/C s 2-sulanylideimidazolidin-1-yphenxy)hexa-2,4-diyn-.1 -y]]oxypropanaido)-3,3 diethlylbu-anryl]-4-hydroxy-N-{[4(mehl-1,3-thiazol-5 1)phenyl~methsyi}pyrrolidine-2-csarboaide H NMR (400MIz, CD 3 OD):888(s, H, 8.16(d,J=88Hz,2H), 7.99 (di 1.Nz 1H), 7.4-7.42 (m, 4H), 7.33 (d, J= 8 Hz,2 , 7.14 d. 8.8 Hz, 2H 4.3 (, 2H), s 4.66 (s, 1H), 460-4.38 (m, 3H), .38-427 (,n 311),3.92-3.80 (m, 411) 2.63-2.59 (m, 11), 2.58-2.49 (m. 411). 2.26-2.18 (m, 1 )1.56 s, 6H). 1.03(s, 91H); LC MS S): mIz 982.40[MH*j, t= 13 mi (5.6minuterun).
56 o Prepared from ABM-3sL12, and ULM-1 iN 2S,4R)-i-[(2S)-2-(4-{[6-(4-3-:4-Cyano-3-(trifiuoroeyli)pheny iy I-y-5,5-dimetyl-4-oxo s / 2-sulfanylideneimidazolidin-v-ldphenxy'exa-2,4-diyn-1-yloxy~butanamido)-3,3 dirmethylbutianoyl]-4-hydroxy-N-[[4-(4-methyl-,3thiazol-5 yi)phenyl] methylipyrrolidine-2-Carboxamide "-N-k - 'H NMR (400MH z CDOD 8.88(, , 8.16 (d, = 8.8 Hz, 2H), 7.99 (d, = 1.6 Hz,
ANH M, 11) 7A9-72(m, 4H),7.35 (d, i = 8.8 Hz, 2H), 7.14 (d, J = 88 Hz 2H, 4.93 (, 2) j 4.63 (!, 1H), 4.59-4.51 (m. 311), 4.38-4.27 (d, i = 12.4 Hz, 1H), 4.25 (s, 211), 3.93-3.79 (m, 2H) 3.53 (t, J= 6.0 Hz, 2H), 2,50 (s, 3H), 249-2.33 (I,2H), 2.26-2.18 (m, 1H), 2.13-2.05 (mi),1.90-1.86 (m, 2H), 1.57 (s, 61), 1.02 (s, 911); LC-MS (ES):m 996.40 [MH'],re 3.4imin (5.6 minute run).
Lx Structure Compound name and Analytical data
57Pre-jared from ABM-16.L-10, and UNI-1 (2S,4R)-l-[(2S,--12-[[,(- 4y3(flcoen'peni-.,5-dinedivih-4--ox -. 2-suift*.iyhdeneiridzoidin - -y -2fluorophenoxv I ea-l24-di n-1-yijoxy'acetamido) 3,3-AiiethvlNbtanoyi 4-hydrox -N4-t w-etP'i
'H NMR( 400MN(Hz, CD30D,. 68.88 H-D ~8.16 (d, 8.0Hz,fi,8.00 (d,= J 12 i \ --o ~~~~~I-liz,-1), 7.49 -7.43 (, 41)7.67.2 n 11,~7.19 (d, 8.0Hlz, 11H,5.0(s,_-14) 4.7 (s, 11H,4A61-4.42 (y, 311), 4.41-4-33 (m, 31-),409 (s,2H), 3.90-180(in, 214,2.49 (F,
31)2:17-2.15(m,l111), 212-2.06 (m, 1l) .56(s. 61-1)1.03 (s,91-; LC-MS (ES') nz
r~ 986.30 [Mll-i, t, 1.58Tamn3.0 minute -run). CS
5~ /~~/Preparedfroin ABM-1-10, and ULN/I-1
suifanylidencirnjdazol dii--v -y iheuxyllhexa-2,4-diyni.I-y)oxvjacetar..do.) -
dirnediylbtay."noyil--:i-hvdr-oxy-N-K [4-(4-methyi-i,3-tlia!zol)-5
'H1NMR (400Mliz, CD-,OD:8.88 is.111)7.06 (d.I= 8.4 Hz, 11I', 7.87 s. 111), 7.66 ~.~7.64 (iu,11),7.40T43 (rni,4iX7.33(d,1= 8.8Hz 17 , 714 (d.1=9-2H-,iMH,4.94 Is,211), 4.71 (s I'461442 (in,_3H1)41-129 (m, 31) 4'.0s 211), 3.92-3.86 (in. 11, 3.8--3.77' (m,1)2.49 (s.31-1)2.27-2.18, iI 212-206~ in, ,1.52 (, 611). 1.01t f 911) LCMS (ES m,z934.20 [MHl tR 1.54 ni (3.0minute runI. 599 0 Pre-jared from ABM-10 taidULMI-5 ci ' ~(2S,4R)-I-k2S)-2f2-'i6- -[3-3-chioro,4-cyaopienx,--,d) tiurndlvi-4-t -- 2 suifainvideiieinu dazolidii-1 -vivotlenoxvll exa2A -di~ynI -.1)xvl ace tai ido 1-3,3
yl) hen vlirnethh-pvrroli dine-2 cmboxamide 0j '1-NMR (400 Mi-l,CD3OD) 68.1 (F, I),7. idU= S.4Hz, H)s T87 (Fi,7.66 NH N ~7.5 n, 31H), T19-7.47 (In,211) -71.31 (mi211, 711 (d,7= 8.8li 21D, 4941(s 211), i~ ~ , 4.71 (s 114, 4.3-4.57 (, 11).441.-28 (m 31),-.09 211. 2 3.90-3.86 (n.111), 3.82
3.77 (m, M-).4"2(,; MR,2117-20(m lffi.2,12-2.02 (m, i~15(s, 6H),i1.03(s, 911);LC-NIS -,S):mz 918-25 [MI4],tj, .51mm(3.0 minute run).
0 ~~ Prepar-ed fromnABM-21 1-10,and ULN/VI4
Z\7 ) ~~~~suI any d en e m;dazo idi - -!j-- Iurohnoxy Ihexa- 2 -d!iyn -I-y oxvIa ct.'indo) F3.3-diliethyibutano'A1t-4-hyd-ofvN{ 4(13-oxazol-5-yl'phey!methyl yToidine-2 uarboxainide \-.O II , 'NMR (300 Xlz, CD;OD):C .2 s 11), 7.94 (d1=8.1lz, 111,786 (s11), 7.70 - H 7.63 (m,3'11).7T49-7 43 (ins31111 7.36-7.2 iny..214,7.18-T12(in, H)s.5 12 (n,214, 4.71 NH (s, Il), 4.61-4,47(On,3Hl, 4.44-.29(i O- , ,4.09 (s, 2H) 3.9-3.79 (m,2H), 2.22-2. 18 (m,l11. 2.12-2.06 (m,lID. .55 (s. 611), 102 (s, 91-1';LC-MS (ES"': mz 922.15[-MIl N -,N:=: 253 mur.(5.0muinute run).
LX Structure Compound name and Analytical data
61 / ~~~~~.< ~Pre-jared from''ABM-16.L-i0, and ULMI-4 -Iuns-,-in~y-o
rN(2S,4R)..-S-2-2[6J-3.Zcan--iiloonr
2-suif*.aiylidene~fidzoilidin-i-yiI-2-f:ioroohefnoxvIhexa-2,4-di n-1-yi'oxy'acoaiido) 3,3-dimeshvliybturanoyi]-4-hvdrlioxv-N-f4-(i.3-oxazo-5 y1)phenv1)mehvp .,yT1,'dne-2ec, rboxarsdeL 'HNMR('3 00 M iCDOD' . 68.2 3 M ,-S..1.5 d.17.5H1z,2J ,'79 8d,1 9,0 Hz, 11), 7~ -74 m 1) .67- 11 111), 7.71 (d, J= 7.8I-Iz,.21).7.49-74(n 1 .3-.21(n,2-,7.1871i HI 5.02(is, 211), 4.71 (s, IH),459-4.47 (in,311)s 4.44-4.29 (in,31H), 4.09s:,'H 214).9--3.4 8,1(i, 211)222-2. 18 (Yi, 1) .2-2.01 i, 'H) I.57 Is.6H1.04A(s, 911);LCS (S): n956.20[M- .~2.60 inln 5.0Minutemrun).
[0544] Example 62: (2S,4R)4-((S)-2-tert-butyl-16(4-(3-(,4-cyano-3
6,9-dioxa-3,12-diazaliexadecane)-4-hydroxy-N(4-(4-methylthiazol-5-yl'benzyl,)pyrrolidie 2 carboxainide:
F0 HCi
F. F H2 N O\ O -N L-13 n ------- N S - OH Step I ABM-12
F O\ F~~1;j r-~NaOH N __iN 0 O- Step 2 NSN BL H
HO
)I 0 S
N S~-~ N 0 N)i-' -- IO -,OHA ULM-1
BM 00 Step 3
F_ F HO N
Example 62
[0545] Step 1: Synthesis of ethyl 2-(2-{2-[4-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5.5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-ylIphenyl)butanamido]ethoxyIethoxy)acetate (BL)
[05461 To a stirred solutionof 4-(4-{3-[4-cyano-3-(trifluoromethyil)phenyi]-5,5-dimethyl-4-oxo 2-sulfanylideneimidazolidin-1-yiphenyl)butanoic acid (ABM-12, 417 mg, 0.88 nmmol) in N,N dimethyformamide (10 mL) was added HATU (669 mg. 1.76 mmol), DIEA (454 mg,3.51 mmol) and ethyl 2-[-2--aminoethoxy)ethoxy]acetate hydrochloride (L-13, 400 mg. 1.76 mmoil) at 0 °C . The resulting solution was stirred at 0 °C for 30 minutes, and then it was warmed up to room temperature and stirred at room temperature for 15 hours. A mixture of water/ice (1: 1, 50 mL) was added to the reaction, the resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:1) to give BL (yield: 35%) as a yellow solid. LC-MS (ES*): mz 649.15[MHj 1. 05 min (2.0 minute run).
[0547] Step 2: Synthesis of 2-(2-{2-[4-(4-{3-[z4-cyano-3-(trifluoromethy)phenyl]-5,5-dimethyl 4-oxo-2-sulfanylideneimidazolidin-1-yl}phenyl)butanamido]ethoxylethoxy)acetic acid (BM)
[05481 To a stirred solution of ethyl 2-(2-{2-[4-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfaiylideneimidazolidin-1-yl)phenyl)butaiamido]ethoxyIethoxy)acetate (BL, 200 mg, 0.31 mmol) in methanol (10 mL) was added a solution of NaOH (123 mg. 3.08 mmol) in water (10 mL) at room temperature. The resulting solution was then heated to 50 °C and stirred at this temperature for 2 hours. The bulk of organic solvent was removed under reduced pressure. To the remaining residue was added aqueous hydrogen chloride (1 M) to adjust the p-I to -3. The resulting mixture was extracted with ethyl acetate (50 mL x 2), the organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate and then concentrated under reduced pressure followed by high vacuum pump to give BM (yield: 78%) as a yellow solid. LC-MS (ES*z): w 621.20 [MH*], tR 0.96 min (2.0 minute run).
[05491 Step 3: Synthesis of (2S,4R)--[(2S)-2-[2-(2-{2-[4-(4-{3-[4-cvano-3 (trifluorornethyl)phenyil]-5,5-dimethyl-4-oxo-2-suilfanylideneimidazolidin-1
ylrphenyl)butanamido]ethoxylethoxy)acetamido]-3,3-dimethylbutanoyl]-i.4-hydroxy-N-{[4-(4 methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxarnide (Example 62)
[05501 To a stirred solution of2-(2-{2-[4-(4-{3-[4-cyano-3-(trifluorometlhyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-I-ylIphenyl)butanamido]ethoxyIethoxy)acetic acid (BM, 200 mg, 0.32 mmol) in N,N-dimethylformamide (20 mL)was added HATU (245 mg, 0.64 mmol), DIEA (166 mg, 1.28 mmol) and (2S,4R)--[(2S)-2-amino-3,3-dimethylbutanovI]-4 hydroxy-N- [4-(4-methyl-1,3-thiazo1-5-yl)phenyl]methylpyrrolidine-2-carboxamide hydrochloride (ULM-1, 226 mg, 0.48 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 30 min, and then it was warmed up to room temperature and stirred at room temperature for 15 hours. A mixture of water/ice (1: 1, 50 mL) was added to the reaction, the resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined. washed with saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by Prep HPLC to give Example 62 (yield: 6%) as a yellow solid. 1I NMR (400MI-z, CD 30D): 6 8.89 (s. IH). 8.18-8.16 (d, J 8.4 Hz, 2H), 8.01-7.99 (d,,J= 8.0 Hz, H), 7.47-7.41(m, 4H), 7.38-7.36
(d,J= 8.4 Hz, 2H), 7.30-7.28 (d,J 8.4 Hz, 2H), 4.87 (s.1H) 4.78-4.60 (m 3H), 4.39-4.35 (d, J= 15.2 Hz, 1), 4.04-3.98 (m, 2H), 3.98-3.85 (in, 211), 3.72-3.60 (n, 71-), 3.50-3.49(i, IH), 2.71-2.69(m,2H),2.49(s,3H),2.45-2.28(m.3H), 2.25-2.10 (min,1H), 2.10-1.95(m.2H), 1.58 (s, 611), 1.09 (s, 91-); LC-MS (ES'): mz 1033.50 [MH], 1,,= 3.06 min (5.6 minute run).
[05511 Examples 63-65 were synthesized according to similar procedure described for synthesis of example 62, by using corresponding starting materials and intermediates.
[0552] Table 4. Exemplary Compomids.
Ex Structure Compound name and Analytical data
63 Prepared from ABM-12, L-14, and ULM-1
- (2S,4R)-1-[(2S)-2-[2-([5-[4-44- (-4-cao-3-(rifuormethy)phenyl-55-dimethy-4 SNC oxo-2-sulfanylideneimiidazolidi1-1ylphenyl~butanamiidoipentylioxyacetamid]-3,3 dimethylbutanoyl-4-hydroxy-N-{[4-(4-methy-,3-hazol-5
yl)phenylimethyli pyrrolidine-2 -carboxmide 'H NMR(400 M 1z, DMSO):38.98 (s, IH), 8.60 (m, 1H), 8.40 (d, j= 8.0 Hz, 1H), 8.30 (s, H (, J= 8.0Hz, I1), 7.79 (m, 1H), 7.40 (i 41), 7.36 (m, 311) 7.29 (d, J= 8.0
NH Hz, 2H), 5.16 (n, i H), 4 57 (d J= 9.2 Hz,1H), 4.45 (m, 4H), 3.92 (m, 21), 3.66 (m, 2H), 3.48 (m, 2H1) 3.07 (m, 2H), 264 (n,2H), 2.51 (in, 31, 2.14, n3H), 1.90 (m 3H), 1.57 (, 211), 1.50 (s, 6H), 1.44 (Im,21),1.36m 21-), 0.94 (s, 9H): LC-MS (ES*): m/516.65
[M+2] /2,1t- = 2.5.5 min. (5,0 minute run).
64 F 3C FsC NPrepared from ABM-12, L-15, and ULM-1 "
NC AN (2S,4R)-lI-[(2S)-2-[2-(2-{2-[4-(4-{3-[4-cyan-r.ifluromethyl)phenyi]-5,5-dimethyi-4 oxo-2-rulfanylideneimnidazolidin-1-yl~phenyl)-N methlblutanamfido ]ethoxylethoxy ace tai do] -3,3 -dimethylbu tanoyl-4-hydroxy-N-{4
'N1H NMR (300 MHz, CD3OD) 6 8.87 (s, 1H), 817-8.14 (d J= 8.4 liz, 211), 8.01-7.98(d, J N-\ - 8.7 Hz, 1), 7.47-7.31 (m6 ,7.28-7.13d, 8.1 Hz, 211), 4.71(, H), 4.61-4.51 o r 'OH NH m3) 4.38-4.33(d, J 15.2 Hz, H), 4.04-4.02 (im, 2H), 3.86-381(m, 2H), 3.69-3.60 (m,711), 3.59-3.52 (mi, 1), 3.10 (s, 211), 297 (s, 1H), 2.75-273(il 211), 2.46 (s, 311) 2.46-2.41 (im ), 2.38-2.23 (rm, 11),2.21-2.09 (m, IH), 1.99-1-91 (m,211), 155 (s,6H), .02 (s, 9H); LC-MS (ES): ml 1047.80 [MH], t = 2.09 min (3.6 minute run).
Ex Structure Compound name and Analytical data
1 F3C N Prepared from AM-12, L-16, and LAM NC Sa (2S,4R)-I-[(2S)-2-[2-({5-[4-(4-( -4-cao-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4 0 oxo.-2-sulanyldeneimidazoiin-1-ylphenyl)-N
methylbutanaiidoipentyiloxy)acetaido] -33-dimethyibutanoyl]-4-hydroxy-N-([4-(l
'o~0 methyl-1,3-thiazoi-5-yi)pheny]methyl~pyrrolidine-2-carboamide
H11-NMR (400 Mz. DMSO) 5 8.98 (s 111), 8.60 (s, 1H), 840 (d, J= 8.0 Iz, 1H) 8.30 (s, 1), 8.10 (d, J = 8.0 Hz, 1 H), 746-7.27 (m, 9H), 5.15 (s, 1H), 4.57-4.55 (ri , 4.47 N, 4.23 (m, 411) 3.92-3.85 (n, 21), 3.68-3.59 (m, 2H), 3.47 (s, 211), 3.29-3.20(m, 211), 2.91 NH 2.64(m, 51H)2.44(,3H1),2.33-2.30p(.2H11), 2.09-2.03 (m, I1H),.1.95-1.81 (m, 31), 1.59 1.46 (i, 10H), 1,30-1.24 (m, 2H), 0.94 (s, 9H); Mass (ES*): rr 1045.40 [MH*]
[05531Example 66: 2-(2-(4'-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2 tiioxoimidazolidin-1-yl)biphenyl-4-yloxy)ethoxy)ethyl (S)-1-((2S,4R)-4-hydroxy-2-(4-(4 methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobuItan-2 ylcarbamate:
F F-A-F o L-18 F-- NNO - HO O--OTs N-- --- N N Step 1 ABM-14 OH BN
HO H LJ_ N 'IN F O\\V I u0"
Step F XN N- O --- NH ULM-1 N S\ Example 66
[0554] Step 1: Synthesis of 4-[3-(4-4-[2-(2-hydroxyethoxy)ethoxy]phenyllphenyl)-4,4 dimethyl-5-oxo-2-sulfanylideneimidazolidin-l-yl]-2-(trifluoromethyl)benzonitrile (BN)
[0555] To a stirred solution of 4-13-[4-(4-hydroxyphenyl)phenyl]-4,4-dimethyl-5-oxo-2 sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (ABM-14, 610.5 mg, 1.27 mmol) in N,N-dimethylformamide (10 mL) was added K 2 CO3 (318.46 mg. 2.29 mmol) and 2-{2-[(4 methylbenzenesulfonyl)oxy]ethoxy}ethan-1-oI (L-18,300 mg, 1.15 mmol) at room temperature.
The resulting mixture was then stirred at 80 °C for 2 hours in an oil bath, LC-MS indicated formation of the desired product. The reaction mixture was cooled down to room temperature, water (20mL) was added and the resulting mixture was extracted with ethyl acetate (100 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 7:3) to give BN (yield: 66%) as a light yellow oil. LC-MS (ES,): m/z 570, [MH],R 1.60 min (2.0 minute run).
[0556] Step 2: synthesis of 2-{2-[4-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-55-dimethyl-4 oxo-2-sulfanylideneimidazolidin-1-yI}phenyl)phenoxy]ethoxyIethyl N-[(2S)-1(2S,4R)-4 hydroxy-2-({1[4-(4-metlhyl-1,3-thiazol-5-yl)phenyl]methyllcarbamoyl)pyrrolidin-1-yl]-3.3 dimethyl-1-oxobutan--yl]carbamate (Example 66)
[0557] To a stirred solution of 4-[3-(4-{4-[2-(2-hydroxyethoxy)ethoxyphenyilphenyl)-4,4 dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (200 mg, 0.35 mmol) in dichloromethane (10 mL) was added triethylamine (106.5 mg. 1.05 mmol), followed by triphosgene (36.5 mg, 0.12 mmol) which was added slowly in 30 minutes at0 C.To this mixture was then added (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3 thiazol-5-yl)phenyjlmethyl}pyrrolidine-2-carboxamide hydrochloride (ULM-1, 196.9 mg, 0.42 mmol) at 0 °C. The resulting mixture was then warmed up to room temperature and stirred at room temperature for 2 hours. Water (20mL) was added to the reaction and the resulting mixture was extracted with dichloromethane (50 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by Prep-HPLC to give Example 66 (yield: 6%) as a white solid. 'H-NMR (400MHz, CD 3 0D): 6 8.88 (s, 11-), 8.20-8.17 (in, 2 ), 8.04-8.02 (d, J= 8.0 Hz, 1 -), 7.77-7.72 (in, 2-), 7.65-7.59 (in, 2 H), 7.48-7.42 (m. 6 H), 7.08-7.06 (d, J= 8.4 Hz, 2 H), 4.61-4.53 (m, 1 H), 4.47-4.44 (s, I H). 4.38-4.34 (i, 2 1-1), 4.25-4.20 (i,4 H), 3.92-3.90 (m, 3 H), 3.82-3.79 (i, 3 H), 2.48 (s, 3 H), 2.26-2.21 (m, H),2.13-1.09 (in, I H), 1.61 (s, 6 H), 1.30 (s, I H), 1.04 (s. 9 H); LC-MS (ES'): nz 1026.40 [MH], (R = 2.23 min (3.0 minute run).
[05581 Example67:(2S,4R)--((S)--(2-(2-(2-(4'-(3-(4-cyano-3-(trifluoromethyl)pheiiyl) 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-vl)biphenyl-4-yloxy)ethoxy)ethoxy)acetamido) 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2 carboxamide:
F O L-19 F F :~~> ~ TsO- OCOOEt
N~ S *-'Stepi1
ABM-14
F F F FF N---= N NaOH -= N----- NN s Step2
BO OPCOOEt BP
HO H
Step 3 FOIN
Example 67 S
[0559] Step 1: Synthesis of ethyl 2-(2-{2-[4-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-I-ylIphenyl)phenoxy]ethoxyIethoxy)acetate (BO)
[0560] To a stirred solution of 4-{3-[4-(4-hydroxyphenyl)phenyl]-4,4-dimethyl-5-oxo-2 sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (ABM-14, 300 mg, 0.62 mmol) in N,N-dimethylformamide (10 mL) was added K2CO3 (172 mg, 1.24 mmol) and ethyl 2-(2-{2
[(4-methylbenzenesulfonyil)oxy]ethoxyethoxy)acetate (L-19, 237.4 mg. 0.69 mmol). The resulting mixture was stirred at 80"°C in an oil bath for 2 hours. The reaction was cooled down to room temperature, water (50mL) was added and the resulting mixture was extracted with ethyl acetate (100 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (30 mL x 3), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by a flash silica gel chromatography
(eluent: ethyl acetate/petroleum ether (v:v = 3:7)) to give BO (yield: 48%) as lightyellow oil. LC t MS (ES*): m/z 656, [MH4+], = 1.19 min (2.0 minute run).
[05611 Step 2: Synthesis of2-(2-{2-[4-(4-{3-[4-cyano--(trifluoromethyl)phenyil]-5,5-dimethyl 4-oxo-2-sulfanylideneimidazolidin-I-y]IphenyI)phenoxy]ethoxyIethoxy)acetic acid (BP)
[0562] To a stirred solution of ethyl 2-(2-{2-[4-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-I-yilphenyl)phenoxy]ethoxyIethoxy)acetate (BO, 198 mg, 0.30 mmol) in ethanol (5 mL) was added a solution of sodium hydroxide (36.3 mg, 0.91 mmol) in water (2 mL) at room temperature. The resulting solution was stirred overnight at room
temperature, the bulk of organic solvent was then removed under reduced pressure. To the
remaining aqueous residue was added hydrogen chloride in water (IN) to adjust the pH to-5.0,
and the resulting mixture was extracted with ethyl acetate (250 mL x 2). The organic layers were
combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure
followed by high vacuum pump to give BP (yield: 99%) as a light yellow oil. LC-MS (ES'):m/z 628, [MH1]], 1 .08 min (2.0 minute run).
[05631 Step3: Synthesisof (2S,4R)-1-[(2S)-2-[2-(2-{2-[-(4- {3-[4-cyano-3 (trifluoromethyi)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-I yliphenyl)phenoxylethoxylethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4 methyl-1,3-thiazol-5-yl)phenylmethyllpyrrolidine-2-carboxamide (Example 67)
[0564] Toastirredsolutionof2-(2-2-[4-(4-{3-[4-cyano-3-(triluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}phenyl)phenoxy]ethoxyIethoxy)acetic acid (BP, 190 mg, 0.30 miol) in N,N-dimethyiformamide (10 mL was added -ATU (149.7 mg, 0.39 mmol), DIEA (156.4 mg, 1.21 mmol) and(2,4R)--[(2S)-2-amino-3,3-dimethylbutanoyl]-4 hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyllpyrrolidine-2-carboxamide hydrochloride (ULM-1, 183.9 mg. 0.39 mmol).'The resulting solution was stirred at room
temperature for 2 hours. Water (50mL) was added and the resulting mixture was extracted with
ethyl acetate (100 mL x 2). The organic layers were combined, washed with saturated aqueous
solution of sodium chloride (25 mL x 3), dried over anhydrous sodium sulfate and then
concentrated under reduced pressure to give a crude residue, which was purified Prep-HPLC to
give Example 67 (yield: 17%) as a white solid. !H-NMR (400MHz, CD30D): 6 8.82 (s. 1 H), 8.19-8.16 (d,J= 9.0 Hz, 2 1-1), 8.02-8.00 (d, J= 8.1 Hz, 1 -), 7.72-7.69 (d, J= 8.1 H z, 2H), 7.61
7.55 (m, 2 H), 7.46-7.37 (m, 6 H),7.08- 7.01 (m, 2 H). 4.71(s, 1 H). 4.61-4.51 (m, I1H). 4.47 (s, 2 H), 4.38-4.31 (rn, 1 H), 423-4.20 (rn.2 H), 4.01(s, 2 H), 3.96-3.78 (n, 4 H), 3.63 (s. 4 H), 2.43 (s,3H), 2.27-2.20 ( ,1H), 2.13-2.04 (m, I1H). 1.61 (s, 6 H), 1.04 (s, 9 H); LC-MS (ES t): n 1040,10 [MHI], I. = 2.26 min (3.0 minute run).
[0565] Examples 74 and 76 were synthesized according to sirnilar procedure described for synthesis of Example 66, by using corresponding starting materials and intermediates. Examples 68-73, 75, 77-79 were synthesized according to similar procedure described for synthesis of Example 67, by using corresponding starting materials and intermediates.
[05661 Table 5. Exemplary Compounds.
Ex # Structure Compound name and Analytical data
Prepared from ABM-14, L-20, and ULM-1 (2S,4R)-1-[2S--[3-(2-{2-[4-4-{3- 4-cyano-3-(trifluoromethylbphenyi]-5,5 dimediyl-4-oxo-2-sulfinyideneimidazolidin-i yllphenyliphenoxyethoxylethox )propainaijdo]-3.3 dirmeiyibutanoyl-44.-hdxy-N-{4-4-methyll,3-thiazol-5 ' ,oH yI)pheny!lmethy!}pyrroliinearboxamide H NHNMR (400 MHz, CD3)jOD 8.87 (s, iH),8.21-8.17 (m, 2H), 8.04 (d, J= 8.0
NH IL1)7.76(d,J= 84z21) 7.63 (d, J = 8.8 Hz211), 7.49-7.41 (m. 611), 7.07(d..= 8.8Hz,21-),4.67 is, 111), 4.61-4.51 (, 3H), 4.37-4.33 (m, H), 4.20-418 (mn 211) 3.92-3.66 (in, 1H), 2.62-2.45 (m, 5H), 2.26-2.17 (, IH), 68F F a-/ 2.14-2.05 (m, 1H), 1.61 (s 611),1.05 (s, 9H); LC-MS(ES*):xmz1054.50[MH*, F t=- 2,20min (3.6minute run).
Prepared from ABM-14, L-21, and ULMA-1 (2 ,4R)-1-(S--{-4(-3-4-ao--tilormtypey]5 dimethyl-4-oxo-2-sulfanyliden-eimidazolidin-1 0H yllphenyl)phenoxy]pentanamidol -3,3-dimetibutanoy]]-4-hydroxy-N-{[4-(4 C. *~ N methyl-1,3-th'iazo-5-yl)pn.ylnmethylpyr-rol.dine-2-carboxamide
NH 11 NMR (400 MHz, CD0D): F 8.90 (s, 111), 820-8.18 (d, J = 8.4 Hz, 2H), 8.04-8.02 (d J= 7. 0Hz, 111, 777-7.74 (d, ' = 8. -z,- 21), 7.63-7.61 (d, J= 8.4 Hz, 2H), 7.50-7.48 (m, 2H), 7.50-7.41 (m, 41), 7.06-7.04 (d, J = 8.8Hz, 211), S N s 4.67(s, IH), 4.61-4.52 (i,3H), 4.39-4,35 (i, H, 4.08-4.07 (, 2H), 3.95-3.93 69 (mIH),385-3.81 11NN (m, iiH), 2.48 (s, 311), 2.1-237 (in,211), 2.23-2.21 m, 1H), F F 214-2.10 n, 11), 1.86-1.85 (i,411), 1.62 (s, 6H), 1.06 (s, 9H); LC-MS (ES): nz 994.40 [MH], tR =171nn (3.0 minute run).
Ex # Structure Compound name and Analytical data
Prepared from ABM-14, 1-22, and ULM-1
(2S4R)-1-[(2S)-2-(3-{2-[4-(4-'3-[4-yano-3-(trifluoromiethvl)phenyl-5,5 dimethyi-4-oxo-2-suifanylidencimidazoiidin-1
yl}phenyl)phenoxy]ethoxy}propanaildo)-3,3 HN ,3thaoi5 N O ~dimsethyibuanoyi]-4-hydroxy-N-{[4t-(4i-methyl-1,3tizl5 a NH yI)phenvimethylpyrolidine-2-carboxaCide I INMR (400 MHz, CDOD) 6 8.85 (s, 1H), 821-8.17 (m, 211), 8.04 (d, J= 8.0 - Hz, 11), 7.74 (d,J= 8.4 Hz, 2H), 7.61 (d, J= 8.4 Hz,21),7.49-7.39 (m, 6H), Is S~. 7.08 (d,-= 8.8 Hz,2AH), 4.68 (s, 1H) 4.59-4.51 ,3,4.37 (s, 1H) 4.23-4,20 N - N (m. 211), 3.93-3.80(, 6), 2.63-2.45 (m, 2H), 2.45 is, 311), 2.23-2.06 (m. 21), 0 F F 1.62 (s, 61), .05 (s, 9H); F LC-MS (ES*): m/1010.30 [M1] , tR 68 min (3.0 minute run).
Prepared from ARM-14, L-23, and ULIM-I (2S,4R)-l-[(2S)-2-[2-([5 -14- (34-yano-3-(trluoromsethyl)phenyi]-5,5 dimrethyl--oxo-2-sulfahnylideneimidazolidin-i
yi}pheuyi)pfenoxv]pentyl}oxy)acetanidoJ-33
dinmethyibutanoyl].-4-hydroxy..N-{[4-(4-mnethyi-J,3-thiazo-5
yl)phenylimethyl}pyrrolidine-2-carboxamide 'H NMR (400 MHz, CDOD): F 8.84 (s, I H), 8.19-8.17 (d, J 8.4 Hz, 2H), 8.04-8.02 (d, J 8.4 Hz, .H), 7.73-7.71 (Id, J .4 Hz, 2H), 7.59-7.57 (d, J S8.4 8 Hz,201' 2 .-. 38 (m, 61), 7.02-7.00 (Id, J -841. 7.9-7 8Hz, 211), 4.72 (Is, 111), 4.59-4.46 (ms 3H). 4.37-4.33 (d, J 1 , 117H 4.08-406 (m, 21, 4.05 S 4.00(m 2H), 3.98-3.83 (m, 2H), 3.64-3.61 (nl2), 249 (s, 3H), 2.29-2.21 (m, 711 ~ N =N N 1d/ 14), 2.11 -2.01 (m, 1H)', 1.90-1.86 (m, 2H),1 1.78-1.75 (m,.2H), 1.66-1.62 (m, F--F 2.H), 1.61(s, 6H), 1.06 (s, 9H) LC-MS (ES*): m/z 1038.38 [M t], . 68 in (3.0 minute run). Prepared fro ABM-14, L-24, aid ULM-1
(2S,4R)-1-[(2S)-2--[3-( {5-[4-(4-{3-[4-cyano-3-(tnfluoromethyl)phenyl-5,5
dimethyl-4-oxo-2-silfanylidenreimidazolidin yl phenyl)phenoxy]perntyl}oxy)ropanamido]-3,3
dimethylbutanoyi]-4-hydroxy-N-([4-4methyl-13 -thiazoi-5 yl)phenyljmethylopyrrolidine-2-carboxamide
o x OH 'H NMR (400 MHz, CJOD). 8.84 s, I H), 8.19-8.17 (d, J - 8.4 Hz, 2H), N 8.04-8.02 (d, . - 8.4 Hz, i H), 7.73-7.71 (d, J- 8. Hz, 21), 7.59-7.57 (d, J 08.4 Hz, 2H), 749-7.38 (m 611), 7.02-7.00 (d, J 8.4 Hz, 2H), 4.72 (l, IH) 4.594.46 (, 3H). 4,37-4.33(d, 10.6 Hz, 1H). 4,08-4.06 (m, 2H), 4.05 S4.00 (;, 211), 3.98-3.83 (m, 2H), 364-3.61 (m, 2 2.49 .) (s, 3H), 2.29-221 (n, N- - 1H), 2.11-2.01 (m, 1H), 190-1.86 (m, 211), 1.78-L75 (m, 211), 1.66-1.62 (m, 72 -( O2H IN-f 1.61(s, 611), 1.06 (s, 9H); LC-MS (ES):ma105239[MH], ia= 181 inn F (3.0 minute run).
Ex # Structure Compound name and Analytical data
F FF Prepared from ABM-24, L-29,and ULM-1 N_--/ N (2S,4R)-1-[(2S)-2-[2-(2-{2-[4-(4-3-[4-cyo3-(trfluoromeyl)pheny]-5,5
dimnethyl4-oxo-2-sulfanyideneimidazolidin--yi}-2 fluorophenyl)phenoxy]ethoxy}ethox)acetamido]-3,3-dimethylbutanoyl]-4 F hydroxv-N-([4-(4-methyl-i,3-thiazol-5-yphenylmethvIpyrroliUine-2 carboxaride 73 NMR (400 M-z,CD 30D): 6 8.89 (s, 1H), 8.20-8.18 (d, J= 8.4 Iz, 2), 8.04-8.02 (d, 8.4 z 1) 7.62 -7.59 (ms 1H1), 759-7.57 (m, 211), 7.49
7.40(n, 24), 7.10-7.30 (m, 214), 7.30-7.10 (m, 2H), 7.08-7.06 (d, J = 8.4 Hz, N j 2 11), 4.72 (,H) 4.62-4.60 (m, 3), 374.34 (d,= 15.2 Hz, 11), 4.25-4.23 0 (m, 2H), 4.13-4.09 (m, 2H), 3.97-3,92 (m, 4H), 3.89-3.79(m, 4H, 2.46(s, 3H), NH 2.21-2.22(m, IH), 2.14-2.12(m, 1H), 1.63 (s, 6H), 1.06 (s911); LC-MS (ES) m z 1058.35 [MWI, 6= 1.47 min (4.6 minute run).
F F F Prepared from ABM-14,L-25, and ULM-1 N \ \ 7 N 5-[4-(4-(3-[4-cyano-3-(trifluoromethyl)phenl]-55-dimethyl-4-oxo2 N sulfanlviideneimidazolidin I-yl}phenyl)phenoxy]pentv N-[(2S)-1 -[(2Ss4R)-4 S i" hydroxy-2-({[4(4-methyl-1,3-thiazol-5 '7dIi'¾yi)phenvl:mehyv}carbamoyl)yrrolidn-1y]33dimnethyl-1-oxobutan-2 O yl] carbamate 'H NMR (300 MH z, CD30D): 6 8.87 (s, 1H), 8.18-815 (d, J= 10.2 Hz, 2H), 8.02-800 (d J= 8.1 liz, 111), 7.75-773 (d, J 8.4 2).63-7.60 (d, J= 0 8.4 Hz, 2H), 7.47-7.40 (im, 611), 7.0 J 8.7 Hz,2H), 4.61-4.51 (m, N>N S HN 3H),4.43 (m, 2H),4.16-402 (m,4H, 392-378(m, 2H), 2.47 (s, 3H-), 2.26-2.:1 (m, 11), 2.10-2.07 (m, I), 1.86-1.80 (n, 211), 1.76-164 (in, 2H) 0 N 1.60 (im-, 8), 103 (s. 9H) LC-MS (ES'): m/z 1023.82 [MH], t== 2.36 mn (3.6 minute run) OH --------- --- --------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------- i Prepared from ABM-14, L-26, and ULM-1 F F F (2S,4R-1-[(2S)-2-(2-{4-[4-(4-{3-[4-cyno-3-(trifluoromnethlphenyl]-5,5 N dimethyl4-oxo-2-sulfanylideneimnidazolidin-i yl}phenyl)phenoxv]butoxvacetamido)-3,3
dimethyibutanoyl]-4-hydroxyrN-{[4-(4-methyi-1,3rhiazo-5 yl)phenyllmethyl}pyrrolidine-2-carboxamide 75 ' H NMR (400 MHz, CDD): 6 8.83 (s, IH) 8.19-8.17 (d,J= 8.4 Hz, 2H), 8.04-8.02 (d, J= 9.6 Hz, iH), 7.75-7.72 Id, J= 8.4 Hz, 21), 7.60-758 (d, J b8.41z, 211) 759-7.39 (n, 6H), 7.04-7.02 (d,J= 8.8H z, 211) ,488 (s, i H), 4.71 4.40 (m, 3H), 4.37-4.32 (dJ = 15,2Hz, HI), 4.11-4.09 (m, 2H), 4.08-4.01(r, 2H), 3.98-3.90 (in, 111), 3.90-3.83 (m. 1H), 3.69-3.66 (m,2H), 2A4s,3H, S1225-2.23 (i, 1H), 2.12-2.10 (m,1H), 1.98-1.90 (m, 21), 1.90-1 84 (m, 2H),
OH 1.60s 61), 1.03 (s, 91); LC-MS (ES*): n/iz 1024.10 [MH*] tR 2.33 min -NH (4.6 minute run)
Ex # Structure Compound name and Analytical data
Prepared from ABM-24, L-18, and TM-1 2-1-[4-(4-{3-[4-eyano-3-(triluromethyyphenyi]-5,5-dimethy-4-oxo-2 F suifanylideneimidazolidin-I-y} -2-fluorophenyl)phenoxyethoxy}ethyl N-[2S) F.--tF Q. 1-[(2S,4R)-4-hiydroxy-2 -({[4-(4A-miethyl-1,3-thiiazol-5 yl)phenylmethyl}carbamoyl)Ipyrrolidin-1-yl]-3,3-dimethyl-1-oxhbutan-2 yllearbamate 76 H'11NMR (400 MHz, CD3D): 8.88 (s.1H), 8.20-8.18 (d, J 9.6 z, 121), 8.04-8.02 (d, = 8.4 1z, 'itH, 7.69-7.63 (i, 1H),'7.58-7.56 (d,.J 8.0 Hz, 2H), HN / 7.48-7.42 (m, 411 7.34-7.30 (m, 2H) 7.10-7.08 (d, J - 8.8 Hz, 2H), 4.61-457 N O No(m, 31), 4.53-4.47(m 2H' 4.38-4.21 (m, 41), 3.93-3.90 (in, 311), 3.84-3.78 "OH Im, 3H), 2,48 (s, 3 H), 2,26-2.17m H), 2 " -2.07 (m, 1H), 163 (s, 6H), .02 (s, 911); LC-MS (ES*): ml' 1044.33 [MH*], I= 2.21 mm. (3.6 minute run,. 0 Prepared froin ABM-14, L-27, and ULM-1 NC(2S,4R)--[(2S)-2-(2-[3-[4-(4-{3-[4-cyano-3-(rifluromethy)phenyl-5,5 - N Fac S dimiethyi-4-oxo-2-sulfanylideneimnidazolidini-i yl}phenylyphenoxyjpropoxy}acetamido)-3,3 O0 dimethylbutanoyl]-4-hydroxy-N-[4-(4-methyl-I.3-thiazol-5
7yl)phenylmethyl}pyrrolidine-2-carboxamde H 'NMR (300 MHz, CD-OD): - 8.83 (s, 1H) 8.19-8.16 (d. =9.0 Hz, 2H),
N q !J1NH 8.03-8,01 (d,. = 8.1 Hz, IH), 7.75-7.72 (d, J = 8.7 Hz, 2H), 772-7.69 (d, J= 0 J= 8.7 z, 211), 8.7Hz, 211), 7.63-7.36 (m, 611), 7.08-7.05 (d, 4.72 (s, 111), 4.62 4.51 (m, 3H)s 4.36-4.31 (d, j= 15.3Hz, 1), 4.22-4.19 (m, 2Hl) 4.04-3.98 (m, NH OF 2H), 3.91-3.76 m, 4H), 2.43 (s, 3H), 2.21-2,10 (m, 4H), 1.60 (s, 6H), 1.02 (s, 911): Mass (ES'): m/z 1010.30 [Ml*]
Prepared front ABM-14, L-28, and ULM NC \ N (2S,4R)-1-[(2S)-2-(2-{2-[4-(4-'3-[4-yano-3-(trifluoromethvl)phenyl]-5,5 } jN FC 6dimoethyi-4-oxo-2-sulifanylidencimnidazoiidin-1 yi}phenyi)phenoxylethoxyjacetamnido)-3,3 F3C s dimiethyibutainyi]-4-hydroxy-N-{[4-(4-mnethl-1,3-thiazo-5 yl)phenllv.methylpyrrolidine-2-carhboxaide 78 '1NMR (300 MHz, CD30D): 58.79 (s,1H), 8.7'-8,69 (mi, 1), 8.19-8.16 (d,J H O= 9.0 Hz2H')s803-8.01 (d,J= 8.4 Hz,11), 7.77-7.75 (d, = 4.8 Hz .11), 7.77- N S NH 7.75 (d, = 4.8 Hz, *H),.7.72-7.64 i, 4H), 7.55-7.45 (m, 4H) 7.17-7.14 (d, J =8.7 liz, ), 4.784.75d,= 6.6 lIz 1H) 4.75462 (m, 2H), 4.5542 S m 1)4.28-426 n, 311), 4.14 (s, 2H), 39-3.95 (i, 211), 3.88-3.84 2H), 238 (s, 31, 2.29-2.11(n, I), 211-2.01(m 111), 1.60 (s, 6H), 1.04 (s, 911); LC-MS (ES*): m/z 996.33 [MH*], iR = 2.92 min (5.0 minute run).
Ex # Structure Compound name and Analytical data
Prepared from ABM-24, L-19, and ULM-3 (2S,4R).-[2S)-2-2-(2-[2-[4-(4-(3-[4-cyano-3-(rifluromehyl)phenl-55 dimethyl-4-oxo-2-suilfanylideneimidazolidin-i-vi-2
F /fluorophenyl~phenoxy]ehoxyethoxyaetaid]-3,3-dimethybutanyl]-4 hydroxy-N-[(IS)-1-[4-(4-methyi-i,3-hiazl-5-lphenyiethyl]prrlidine-2 79 carboxanide 'H NMR (400 MHz, CD 3 OD): 8.76 (s, 1H1), 8.08-8.06 (d,J- 9.6Hz, 211), 7.91-7.89 (d,1= 7.2 Hz,1H) 7.56-7.53 (m, IH) 7.45-7.42(d,.1 9.2 Hz, 211) 7.33-729 (i 4H), 7.22-7.20 (m 2H), 6.99-6.97 (d,= 8.8 Hz, 211) 4.95-4.93 NH (m, 1 H), 4.60 (s, 11H), 4.504.47 (m), 4.45-4.34 (m. 111), 4.16-4.14 (m, 2H, O x 3.98-3.97 (m, 2H), 3.83-3.81 (im 2H), 3.77-3.74 (, .3.6 ), 3 (m, 5H), 2.36 (s, 311), 2.12-210 (in, 1H,1.89-1.85 (m, 1H) 1.51 (s, 64), 1.37-1.36 (m, NH \-OH 31) 0.93 (s. 91); LC-MS (ES'):m/z 0724I[MH*], n, = 146mi (4.6 minute run).
[05671 Example 80: (2S,4R)-1-((S)-2-(2-(3-(2-(4-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl) 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)piperidin-1 yl)ethoxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hivdroxy-N-(4-(4-methylthiazo-5 yl)benzyl)pyrrolidine-2-carboxamide:
OH HO4 HO
jN O-1 O OH I 0N H
O ~Step 1NH . H2
ULM-1 N BQ
N OH O \
ABM-25 NC)- N \/ ExampleN80 N F2 )18 0
18NH
[0568] Step 1: synthesis of(2S4R)-1-[2S)-3,3-dimethl-2-[2-(3-{2-[(4-methylbenzenesulfony) oxy]ethoxypropoxy)acetamido]butanoyl]-4-hydroxy-N-{[4-(4-methyl-13-thiazol-5 yl)phenyl]methyl}pyrrolidine-2-carboxamide (BQ)
[05691 To a stirred solution of2-(3-{2-[(4-methvlbenzenesulfonyl)oxylethoxypropoxy)acetic acid (L-17, 300 mg, 0.90 mmol) in N,N-dimethylformamide (5 mL) was added EDCI (350 mg, 1.83 mmol). HOBt (240 mg, 1.78 mmol) and DIEA (350 mg, 2.71 mmol) at room temperature. The resulting solution was stirred at room temperature for 10 minutes. Then to the solution was added (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5 yl)phenyljmethyl}pyrrolidine-2-carloxamide (ULM-1, 390 mg, 0.91 mmol), and the resulting solution was stirred at room temperature for 1 hour. Water (30mL) was added and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by a flash silica gel chromatography (eluent: dichloromethane/methanol (v:v = 10:1) to give BQ (yield: 64%) as a yellow solid. LC-MS (ES):rn/z 745.35 [M1], tR = 0.96 min (2.0 minute run).
[05701 Step2: Synthesis of (2S,4R)-1-[(2S)-2-[2-(3-{2-[4-(4-{3-[4-cvano-3 (trifluoromethyli)phenyil]-5.5-dimethyl-4-oxo-2-suilfanylideneimidazolidin-1-yil}phenyl)piperidin 1-yi]ethoxyipropoxy)aceamido1-3,3-dimnethylibutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol 5-yi)phenyl]methylIpyrrolidine-2-carboxamide (Exampl 80)
[0571] To a stirred solution of 4-{4,4-dimethyl--oxo-3-[4-(piperidin-4-yl)phenyl]-2 sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (ABM-25, 150 mg, 0.32 mmol), (2S.4R)-1-[(2S)-3,3-dimethyl-2-[2-(3-{2-[(4-methylbenzenesulfonyl) oxy]ethoxylpropoxy)acetamido]butanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5 yl)phenyli]methyllpyrrolidine-2-carboxamide (BQ, 236 mg, 0.32 mmol) in N,N dimethylformamide (5 mL) was added potassium carbonate (131 mg, 0.95 mmol). The resulting mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature, water (2mL)was added and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by Prep-HPLC to give Example 80 (yield: 7%) as a white solid. H NMR (300 MHz, CD30D): 68.91 (s, 1H), 8.15 (d, J= 4.5 Hz, 2H), 8.02 (d, J 4.5 Hz, H),7.40(m,7H), 4.45 (d,,J= 12.0Hz, 1H),4.45 (m,41H).4.02 (d.J=3.9 Hz,.2H). 3.70 (mIOH), 3.38 (m,2H), 3.11 (m,3H). 2.48 (s, 3H). 2.26 (m, 8H), 1.54 (s, 6H), 1.03 (s, 9H); LC
MS (ES*):z 1045.35MHt= 2.74min (5.6 minute run).
[0572] Example 81 was synthesized according to similar procedure described for synthesis of Example 80, by using corresponding starting materials and intermediates.
[0573] Example 81: (2S,4R)-1-((S)-2-(2-(4-(2-(4-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl) 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)piperidin-1 yI)ethoxy)butoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5 yl)benzyl)pyrrolidine-2-carboxamide
NC-
[05741
[0575] 1 HNMvR(300MHz.DM):6)8.98(siH)8.63-8.61(in,IH).8.40-8.37(n.1H),
8.37-8.34 (m, IH). 8.11-8.01(m.1H). 7.44-7.40 (m, 3H), 7.37-7.32 (m, 6H), 4.57-4.54 (d.,J 9.6 H-z,l1H), 4.47-4.45 (mn,211), 4.45-4.44 (m, 21-), 4.39-4.37I',111).3.92 (s,211), 3.7 1-3.65 (in, 2H).3.58-3.47('m, 5H), 3.45-3.40('m, 4H), 2.99-2.95 (m. 2H)2.51(s. 3H), 2.12-2.02 (m, 311' 1,93- 1.90 (in,1[-1), 1.90-1.79 (in,3[-1), 1.77-1.71(in,5f]), 1.67-1.61 (mn,61-1), 0.94 (s,9f]),Mass (ES-"):inlZ 10594[MH].
[0576] Example 82:(2S,4R)N-(2-(2(2-(2-(4-(3-(4-cyano-3-(trifhioromethyl)phenyl)-5,5 dimethvl-4-.oxo-24tiixoimidazolidin..k-yl)phteiioxy)ethioxy)ethoxv)ethoxv )-4-44 methylthiazol5=yl)benzvl)-4-hydroxy1=((S)3-methyl-2(1=oxoisoindolin-2 yl)bLitanoyl)pyrrolidine-2-carboxamide:
182'
F L-30 F O H - OTs F Ag 2O, Ki. TsCI 2cG3 N=K // N Step 1I rN Step 2
ABM-3 OH BR
F F 0 FF N \ N: H N N O
Step3 N S ^'O OTs ULM-12 BS BT
F F F 0 TFA OH N- - N H Step 4 \-/ N N N
Example 82 N
[05771 Step 1: Synthesis of 4-[3-(4-{ 2-[-(2-hydroxyethoxy)ethoxylethoxyphenyl)-4,4 dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl] -2-(trifluoromethyl)benzonitrile (BR)
[05781 To a stirred solution of 4-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2 sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (ABM-3, 405 mg, 1.00 mmol) in
CH3 CN (20 mL) was added potassium carbonate (276 mg, 1.98 mmol) and2-(2-{2-[(4 methylbenzenesulfonyl)oxy]ethoxylethoxy)ethan--ol (L-30,456 mg, 1.50 mmol) at room temperature. The resulting mixture was then heated to 80 °C and stirred at this temperature overnight. LC--MS indicated formation of the desired product. The reaction mixture was cooled to room temperature, concentrated under vacuum to give a crude residue, which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:1)) to give BR (yield: 91%) of as a brown oil.
[05791 Step 2: Synthesis of 2-{2-[2-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyli-4 oxo-2-suIfanvlideneimidazolidin-1-yI Iphenoxy)ethoxy]ethoxyIethyl 4-methylbenzene-1 sulfonate (BS)
[05801 To a stirred solution of 4-[3-(4-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxylphenyl)-4,4 dimethyl-5-oxo-2-sulfanvlideneimidazolidin-I-yl]-2-(trifluoromethyl)benzonitrile (BR, 490 mg,
0.91 mmol) in dichloromethane (10 mL) was added tosyl chloride (190 mg, 1.00 mmol), potassium iodide (30.2 mg) and silver oxide (314 mg) at room temperature. The resulting mixture was then stirred at 300 C for 6h, LC-MS indicated formation of the desired product. The inorganic salts were removed from the reaction by filtration, the solution phase was concentrated under vacuum to give a crude residue, which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1:3)) to give BS (yield: 60%) of as a light yellow solid.
[05811 Step 3: Synthesis of (2S,4R)-4-(tert-butoxy)-N-{[2-(2-{2-[2-(4-{3-[-cyano-3 (trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1 yl}phenoxy)ethoxy]ethoxy ethoxy)-4-(4-methlv-1,3-thiazol-5-yl)phenyl-methyl)-1-I(2S)-3 methyl-2-(I-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl-pyrrolidine-2-carboxamide (BT)
[05821 Toastirredsolutionof 2-{2-[2-(4-{3-[4-cyano-3-(trifluoromethyil)phenyi]-5,5-dimethyl 4-oxo-2-sulfanylideneimidazolidin-I-y]Iphenoxy)ethoxy]ethoxy ethyl4-methylbenzene-1 sulfonate (BS, 207 mg, 0.30 mmol) and (2S,4R)-4-(tert-butoxy)-N-{[2-hydroxy-4-(4-methyl-1,3 thiazol-5-yl)phenyl]methl}v-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2 yl)butanoyl-pyrrolidine-2-carboxamide (ULM-12,181 mg, 0.30 mmol) in N,N dimethylformamide (2 mL) was added potassium carbonate (83 mg, 0.60 mmol) at room temperature. The resulting mixture was then heated to 80 °C and stirred at the same temperature overnight, and LC-MS indicated formation of the desired product. The reaction was then cooled to room temperature, diluted by water (10 mL) and then extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 1 : 1) to give BT (yield: 54%) as a white solid.
[05831 Step 4: Synthesis of (2S,4R)-N-{[2-(2-2-[2-(4-{3-[4-cyano-3-(trifluoromnethyi)phenyl] 5,5-dimethlv-4-oxo-2-sulfanylideneimidazolidin-i-yiphenoxy)ethoxy]ethoxyethoxy)-4-(4 methyl-1,3-thiazol-5-yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H isoindol-2-yl)butanoyl]pyrrolidine-2-carboxamide (Example 82)
[05841 To a stirred solution of (2S.4R)-4-(tert-butoxy)-N-{[2-(-{2-[2-(4-13-[4-cyano-3 (trifluoromethyl)phenyl]-5,5-dimetlhyl-4-oxo-2-sulfanylideneimidazolidin-1 yl}phenoxy)ethoxy]ethoxyethoxy)-4-(4-methyl-1.3-thiazol-5-yl)phenyl]methyl}-1-[(2S)-3 methyl-2-(I-oxo-2,3-dihydro-IH-isoindol-2-yl)butanoylipyrrolidine-2-carboxamide(BT. 180 mg. 0.16 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. The resulting solution was stirred room temperature for 6 hours, LC-MS indicated formation of the desired product. Saturated aq. solution of sodium bicarbonate was added to the reaction to neutralize the trifluoroacetic acid. Organic layer was separated, the aqueous layer was extracted with of dichloromethane (10 mL x 2). The organic layers combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by Pre-lPLC to giveExample 82 (yield: 31%) as a white solid. 'I NMR (400MHz, CD 30D): 68.90 (s, I H), 8.40-8.38 (d,1 = 8.0Hz, 2 H). 8.29 (s, I H), 8.09-8.07 (d, J = 8.4 liz, 1H), 7.72-7.70 (d J 7.61-z, 1 1-1), 7.62-7.61 (d, J 4.0Hz, 2 H), 7.50-7.40(m, 111), 7.35-7.33 (d,.J= 7.6Hz, 1H), 7.27-7.25 (d, J 8.8Hz, 2 H) 7.10-7.06 (m, 3H), 7.05-7.00 (m. 1H), 5.09 (s, 11-), 4.72-4.69 (d, J=10.8Liz, 1-1), 4.61 -4.41 (m, 21-1), 4.41 -4.31 (m, 2H), 4.31 4.21 (m, 2H), 4.21 -4.11 (m, 2H), 4.11 -4.01 (m, 2H), 3.82-3.71 (m, 5H), 3.69-3.61 (m, 5H), 2.51 (m, 3H), 2.47-2.25 (m, I H), 2.10-2.00 (m, 1H). 2.00-1.95 (m, 1H), 1.48 (s, 6 H). 0.97- 0.96 (d. -=6.4Hz, 31-), 0.74-0.72 (d, J 6.41-z, 311); LC-MS (ES'): inz 1068.20 IMIf1H , tR = 1.59 min (3.0 minute run).
[05851 Examples 83-85 were synthesized according to similar procedure described for synthesis of Example 82, by using corresponding starting materials and intermediates.
[05861 Table 6. Exemplary Compounds.
Ex Structure Compound name and Analytical data
Prepared fromABM-3,L-30,andUIM-13 (2S,4R)-N-{[2-(2-{2-[2-(4-{3-[4-cano-3-(trifluoromethy)phenyl]-5,5
N -':SN NJ~ dimnethyl-4-oxo-2-sulfanylideneimidazolidin-1 yljphenoaxy)ethoxyethoxyiethoxy)-4-(4-methyl-1,3 F 0 thiazol-5-ylbphenvimethvli-1-[(2S)-2-(6-fluoro-1-oxo-2,3-dihvdro-1H1
83 isoindol 2-y])-3 N nHmethylbutanoyl]-4-hydroxvpyrrolidine-2-carboxamide NH OH NMR (400MHz, CD3OD): 6 8.89 (s, 11), 8.17-815 (d, -= 8.0 Hz, 2H), N 8.00-7.98 (d, J-8.4 Hz, 1H), 7.60-7.56 (m, 11H), 7.49-7.37 (m, 3H), 7.28-7.26 (, -(d,J=8.8 Hz, 2H), 7.08-7.05 (, 41H), 4.90-7.83( H), 4.59-4.46 (m, 6H) O 4l.26-4.25 (m, 2H), 417-4.15 2H), 3.98-3.86 (m, 6H), 3.79-3.7 m 4H), 251 (s, 3H), 2.50-249 (m, H), 2.25-2.15 (im, 1H), 2.01 -2.00 (m, H), L54 (s. 6 H), 1.07-L06 (d, = 6.8Hz, 3H), 0.85-0.83 (d, j = 6.8Hz, 3H); LC-vS
Ex Structure Compound name and Analytical data
Preoared frorn ABM-3, L-30, and ULNI-14
- '~"N r nar-hv~bvuanoy]-N-t[2 (-2:-~{-4can3(rfurneh1penvl
A }I ghen oxy)ethox 3,1ethoxyl ethn x y) -4-44- ruedll- 1,3 diiazoi-5 -yl)phen y!iflethy})--4-hydrnx ypyrroliidine-2-cearboxan iide 84 / HNMvR.(400M`vI-z,CD 3 0): 68.89 (s,111), 8.17-8.15(d, 1=7.2Hz7-.211) N 8.01-7.98 (d, 11=8.4Hz, 111). 7.98-7.76 (rn, 311) .44-7.4A2 (n, 114).7.29-7.25 S '~Y \(i, 2H),7.08--7.04 frin41),.4.87-7X85(in, 1H, 4.694.41(, 61-1) 4-423 NH (in, ?H,4.22-4.16 (in, 211), 4.10-4.00(in, IH),394-3.87 rfn 511) 37937 \ ' ~N'h (n],414),.2.51 (s, 31-1', 1.50--2.49 ii111) 2132.13(. 111) .05-200(n],i NC o1\ H , 1.54 (s, 64), 1-'0-1.07(d,j == 6811z, 3H,0.88-0-86 (d,J -6-8117, 3H) LC-MS (ES': nz 1093.00FMI'1., =222run, -3. 6nuute run'
Preoared forn ABM-'3-31, asd I.,LM (2S,.4R)-N-f[2-(2-,i[(2R,3R)-3-[2--(4-i3-[4I-cyanlo-3 -(iflnorol nedry11phenll' 0. .,.,O-.. ,5-dimn.emhl-4-~x-2-sulif"'.ylidencinridicazoidin- -ylphseox)etoxybu-"l i 2 -N I xylethoxy)-4z'i-xettiv-1,3-thiazo-5,-y)p.,henyli1ey>-4-yd rov -,(S)-3- mneit~i l-2-(I )bnt, -H-sonoly! butanyli uen 2 y~ "1carooxandde F1- NN '0 H"'l00 Tv4z C,OD 6 02(dJ 6.65 Hz, 3H), 1. 05(d,.J 6.65 3 NI rp NH iz 11), 1.15 (,-7=5.48Hlz, 611),1.44 -1.56 (i,611),1.98 - 2.1(i
N 0~r\~ 1.4- 2.24 (i, 1 H), 2.37- 2.52 (u,4A11), 3-52 - 3.62n, 2 H), 189 tLd oS N/OH 10.76, 4.70 Hz. 3H).i3.93 -4.01(iny, 3 HI,4.09 (br.s..2H) 4.16 -424(inj 2 /11 I)4A44 4.67(in, 6H1i,4.84 (dJ= 10.96I-Iz, 1 1I), .95 -7.08n(]i .1 0' -7.30n H),7.43 (d,J1=7.43 Hz.I H),7.46 -7.51 (, IHI), 7J2 -7.6.,
2H14,'7.78'(dJ-7.413 Hz,1 1, 797 (, =7.83Hlz1I11) 808 -8.171 2i 1H),8.43 (i,J=5.87 11z, 111), 8.87 (s, 1H1); Mass iES'):ir 1096.37[M 1
[05871 Synthesis of example 86.
O B N OHi BrH 'B N(O2ON HOr -B------N O-Os-O Stop 1 Step2 N O.
2 N N
PdC. H2 TMSCN 12I 6 St Step 3te S3 N C Step
0
N OH \\ OH sNN NH
NC Ste -6FN 0 Extmpp80
-CF,
[0588]~~~~~~~~~~~~~~~~~~Se 0 Stp16ytei ftr-uy -2[5booyii--loyehx~rpnae 0
Br1N N Stp F EBF'.i
[0588] StepI1:Synthesis of ert-butyl'3{2-[(5-biomopyridin" yb loxylethoxylpropanoate: NO~~~ ~ .- x-e8
Br
~n~ O'- O
[0589] To a stirred solution of 5-bromopyridin-2-ol (3.0 g. 17.24 mmol), tert-butyl 3-(2 hydroxyethoxy)propanoate (3.3 g, 17.19 mmol) and triphenylphosphine (6.8 g, 25.81 rmol) in tetrahydrofuran (120.0 mL) was added diethyl diazene-1,2-dicarboxylate (4.49 g, 25.78 mmol) dropwise at 0 °Ctunder an atmosphere of nitrogen. The resulting solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v/v =1/3) to provide the titled product (yield: 50%) as colorless oil.
[0590] Step 2: Synthesis of tert-butyl 3-(2-{[5-(4-itrophenyl)pyridin-2 yl]oxy}ethoxy)propanoate:
0 2 N,
[0591] To a stirred mixture of tert-butyl 3-2-[(5-bromopyridin-2-yl)oxy]ethoxypropanoate (3.0 g, 8.67 mmol) and (4--nitropheny)boronic acid (1.5 g, 8.87 mmol) in a mixed solvent of dioxane (90.0 mL) and water (9.0 mL) was added potassium carbonate (2.4 g, 17.36mmol) and Pd(PPh 3)4 (450.0 mg. 0.39 mmol) under an atmosphere of nitrogen.The resulting mixture was stirred for 12 hours at 100C. The bulk of solvent was removed under reduced pressure, and the resting aqueous residue was extracted with ethyl acetate (00 tmL x 2). The organic layers were combined, washed with brine (70 mL x 2). dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v/v =1/5) to provide the titled product (yield: 83%) a yellow solid. Mass (ES'): m z 389.00 [MH].
[0592] Step3: Synthesisoftert-butyl 3-(2-{[5-(4-aminophenyl)pvridin-2
yl]oxy}ethoxy)propanoate: H 2N,
N" '0.ny .Of 0
[0593] Toastirredsolutionoftert-butyl3-(2-{[5-(4-nitrophenyl)pyridin2 yloxylethoxy)propanoate (2.8 g, 7.21 mrnol) in ethanol (200.0 mL) under an atmosphere of nitrogen was added palladium on carbon (1.5 g) at room temperature. The reaction mixture was then charge with hydrogen gas and stirred at room temperature for 12 hours. The solids were removed by filtration and the solution phase was concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v/v=1/3) to provide the titled product (yield: 89%) a yellow oi LC-MS (ES'): nz 358.97 [MH'].
[0594] Example 86 was synthesized from tert-butyl 3-(2-{[5-(4-aminophenyl)pyridin-2 yl]oxylethoxy)propanoate, according to chemistry highlighted above (steps 4-8), utilizing similar procedures described for the similar chemistry carried out for the synthesis of examples 67, 75, 103, by using corresponding starting materials and intermediates.
[0595] Example 90 was synthesized according to similar procedures described for the synthesis of examples 86, by using corresponding starting materials and intermediates.
[0596] Examples 88, 91-92 were synthesized according to similar procedures described for the synthesis of examples 80, 75, 103, by using corresponding starting materials and intermediaes.
[05971 Examples 87, 89, 93-102, 104-134, 136-142, 146-149 were synthesized according to similar procedures described for the synthesis of examples 75, by using corresponding starting materials and intermediates.
[05981 Table 7. Exemplary Compounds.
Ex # Structure Compound name and Analytical data
1q (2S,4R)--[(2S)-2-[3-(2-[5-(4-{3-[4-cvano-3-(tifluoromethy)phenyl-5,5
HN *yijoxy}ethoxy)propanamido]-3,3-dimethybutanovl]-4-hydroxy-N-[4-4
ro 9 C e~ methyl-I,3-thiazol-5-yl)pheny]mnethyi}pyrrolidine-2-carboxamnide
86 H NMR (300 MHz, CD3D):8.80 (s, 1H), 8.36-8.30 (m, 11H) 8.17-8.10Onm
IQ 2 11), 7.96-7.88 (i, 2 H') 7.717.65 i., 2H), 7.46-7.26 (m, 6 H), 6.88-6.80(m .164-4.35 (in, 6 H), 430-4.21 (i, H), 3.89-3.65 (m, 8 H), 3.60-3.35 (m, 5 H), 2.23-1.98 (m, 2H),1.55 (s, 6H),1.02 (s, 9H); LC-MS iES): mz CN 1011.20 [MH*]
(2S,4R)-1-[(2S)-2-[3-(2-{[6-(4-{3-[4-cyano-3-(Lrifl ehy)phenyl-5,5 dimethyl-4-oxo-2-sulfanylidenieimaidazoidin-1-yl}phenyi)pyridin-3 2>0Cy ioxylethoxy)propanamido]-3.3-dimethyibu tanovl--4-hydroxy-N-{[4-(4 lmethyl-1,3-thiazol-5-yl)phenyi]methyIpyrrolidine-2-carboxamide N NHNMR (300 MHz, CD30D):68.80 (s, 1 H), 8.36-8.30 (m, I H), 8.17-8.10 (im 87 2 H-), 8.07-7.92 (m, 3 H). 7.81-7.75 (m, 1H), 7.46-7.26 (m, 7 H), 4.61 (s, 11), 4.54-4.50 (n, 1 H), 4.49-4.40 (m, 2H), 4.33-4.28 (m, 1 H), 4.26-4.15 n, 2 H) 3.89-3.65 (in,6H), 2.64-2.40 (m, 2 H, 2.38 (s, 3 H), 2_20-.10 (m. 1H), a 1.19-1.95 (m, 1 H), 1.55 (s, 6 H), 1.01 (s, 9 H): LC-MS (ES*): mIz 1011.20
-CF2
(2S,4R)-1-[(2S)-2-{5-[z4-(4-{4-[3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4 HO
H uXo-2-Slfaniyli~d e~im~idaZoidiu-i-ypheniyi~phenyijpiperaziu-1 / N- '.N. 0 a --HN 3 ylpentanamido) -3,3-dimethyibutanoyl]-4-hydoxy-N-{[4.-(1,3-oxazol-5 v)phenyl]methyllpyrrolidine-2-carboxamide ,) CON, r-NN
8HNMR (400 MHz, DMSO): 6 8.51-8.58 (m, 'H), 8.42 (s, H), 8.20 (d J= 88 8.4 Hz, 111), 8.05 is, 111), 7.87 i(, T = 9.3 z, 111), 7.73-7.79 (m, 311), 7.60 7.65 (m, 5H),,7.38-7.44 (m, 4H1, 705 (d, _ = 9.0 Hz, 21H), 5.13 (I, 1H), 4.58 N (d, 1 = 9.3 Hz, 1H).436-4.45 (m, 3H4.23 (n, 1H), 3.68 ii 24), 3.31 (s, 2H),3.21 (mn,4H),2.53i(s,2H),2.27-2.34I (i,31 27-219 m 1H), 2.07 (i, iH), 1.89 (m, 1H), 1.52 (i,10H), 0.96 (s, 9H); LCMS (ES ): n 998.30 CN
Ex # Structure Compound name and Analytical data
(2S,4R)-I-[(2S)-2-(2-{4-[(6-{4-[3-(3-chioro-4-cyanopheny)-5,5-dimethl-4 oxo-2-sulfaniyiideneimnidazolidin-i-pvihenyi}pyidin-3 o H yi)oxyibutoxy}acetaiido)-3,3-dimethyibutanoyi-4-hydroxy-N-i[4-1,3 oxazol-5-yi)phenyl]miethyi}pyrTolidine-2-carboxaiide
89 H NMR (300 MHz, CD30D):8.38 (s, 1H), 8.21 (s, 1 H), 8.10-7.95 (in, 3 H), 7.90 (, 11), 7.89-7.80 n, 1 H),7.71-7.60 (m, 311), 7.55-7.40 (m, 6 H), 4.70
$( -N -yn, 1 H), 4.63-4.45 (m, 3 H), 4.40-4.30 (m, 1 H), 4.22-4.13 (im, 2 H), 4.10-392 9 N (n, 2 H), 3. 0-3.79 (m, 2 H), 3.70 -3.60 (m, 2 H), 2.30-2.21 (m, H11 2.14 2.00 (m, H), 2.00-1.90 (m, 2H)1.90-1.80 (m, 211), 1.58 (s, 6 1), 1.01(s, 9 e H)LC-MS (ES)- 961.20 [MH" (2S,4R)--[(2S)2( -{4-[(5-{4-[ 3 -(3-lor--ynopheny)-5,5-diethy-4 2 Ho.
oxo-2-sulfanvlidenimidazoidn- Iviohenyl}pyridin-2
y) n buto acetamndo)- 33-dimethynbutanov -4-hydroxy-N-{[4-(1,3 ( oxazol-5-yV)phenylrmethyl}pyroI'lne-2-carboxamide
90 H NMR (300 MHz, CD30D):68.42 (s, 1IH), 8.21 (s, 111), 8.00-7.95 (n, 21H), 7.90 (s, 1 H), 7.79-7.71 (im, 2 H), 7.70-7.61 (m, 3 H), 7.55-7.40 (m, 5 H), 6.90 6 d, J.J= 6.6 Hz, H),4.70 (in, 1 H), 4.63-4.45 (m, 3 H), 4.42-4.30 (m, 3 H), 4.10-3.96 (m, 2 H), 3.90-3.85 (m, 1 H) 3.84-3.76 (m, 1 11), 3.70 -3.60 (m, 2 s H)2.30-2.21 (I1, H), 2.14-200 (m,' H), 2.00-1.90 (in2 H), I90-180 (i, CN 211),1.58 (s, 6 H), 1.01 (s 9 11); LC-MS (ESi): me, 961.20 [MHM (2S,4R)-1-[(2S)-2-f4-[--(4-{4-[3-(3-chloro-4-cvanophenyl)-5,5-diimethyl-4 No uxo-2.-snlfanyiideneimidazoidin-.-yilphenyl}phenyi)piperidin-I
yl]butanamido}-3,3-dim ethylbutanvl-4-hydroxy-N-{[4-(1,3-oxazol-5 HN r
v)phenyl]nethyl}pyrl.idine-2-carboxamide 0
} -N 91 H NMR (400 MHz, CD3D) 6 8.23 (s, 1H), 7.99 (d,) 8.0 Hz, IH), 7.91(s, 111), 7.80 (d,J= 8.8 Hz, 211), 7.69-7.63 (m,51), 7.49-7.45(m,5H),7.39(d,J N =8.4 Hz, 2H),4.67 (s, 1H), 4.60-4.52 (m, 311),4.38 (d,.J= 15.6 Hz, 11), 3.95
3.91 (n, 111), 3.88-3.81 (n, 11), 317-3.15 (n 2H), 2.66-261 (m, iH), 2.54
NO c2.45 (m, 2,11 2.38-2.31(, 211), 2.29-2.15 (m, 311), .13-2.06 (m, 1H), 1.88 1.85 (m, 6H), 1.61 (s6H), 1.08 (s, 9H); LC-M4S (FS) m7 983.45 [MH
Hg ~(28,4R)-1-[(2S)-2-(2-{2-[4-(-4-(4-[3-(3-choro-4-cyanonl)-5,5-5dimethyl-4 N oXn-2-SulfanylideneimnidaZoiidin-i -y'onhenylipeny:.iperidin-1 HN o HN yiiethoxy}acetamnido)-3,3-dimiethylbntannyl]"-4-ydroxy-N -{[4. -(1,3-oxazo-5 v)phenyl]methyl}pyrroidine-2-carboxamide 73 92 C 92I NMR (400 MHzCD3OD)68.1 , 1H), 7.99 'd,=8.4lHz, 1H),7.91(s, H),777-7.73(, 21),7.69-7.52i5H), 7.45-7.43(m51), 7.36(d,J:=:8.4 Hz, 2H), 4.73 (s, IH), 4.61-4.49 (n, 31), 4.36-4.32 (m, 1H), 4.13-4.01 (m, 211),3.91-3.77 (n, 4H), 3.21-3.12 (m, 211), .78 (t, j= 5.2lIz, 211), 2.68-2.61 NC (m, 111),2.37-2.30 (im t2H),228-219 (im, 1H), 2.14-2.05 (m, H), L92-1.88
Ex # Structure Compound name and Analytical data
tin, JH), 1.60)(s, 6H), 1.08(s,91); LC-MS (ES'): rwz 999.65-l
(2S,4R)-i-(S--2{-4(-{-4eao3(rfuootvpeyi55 rniiethyi-z4-oxo-2 -suifawivlideneirnidazoiid!n-
-- ~ ~~~ ~ (4r 51tu 15y)hefiv ]rnethv~ptrvJw di e-2-carboxamide
NI HNMPZ 00 MHz, CD30D) 6ippm 8.83 (s,.1H,) 8.67 (t, 1 6.06 Hz,1IH), 818 (d- 1.96 1 z 1H1),8.1')(d,-=. 22 1 z I 1,8. 00 (d d, J =8.22, 1.96 93 Hz,(I ',69 -14(0],211),'7.64 id,=:9.00117, 111,'7.54--7.60(in2), 7.37 - 746y Hi,fl, 6,96 -7.02 (m, 2H), 4.63 -4.69 (in, iIM,4.5.5 -4.61 (m.
1I11),448-- 5 (mn, 2H1).4.34 -4.411(in*, 1I-I,40.-4.10 (m,2 11),20.8
F F ~ ~~~~4.03 (, 2H),.3.83 -3.88 (mn, i),3.77 - 3.82 (m, IH,'164 it,J:= 62611.7 N 1{) .2-1.1 4'-t 3I 13.30.7.83l= 1M .8 z, I).,2.14 (HcJ 13.30, 6.65Hfz, 111),.2.07 (d d.J =13.30, 9.00,4.30Hfz, 111),1.80 1.97'1 2H),14.81 - 189 (inf, , 21',.59 (;,6H)i.01 (d.J=665 iz3H-, .9)1 1 J 6.26lIz,311):LC-MS(ES') .,',z'±010.36i'i1'
2(2S,4R)-i,-[I2S-2-{2-[4-(4-4-3-(3-ehloro-4-evainopheuyil)-5,5-diiethi-4
0ox, 2-ulfonylieeliidzoidiln-1iiieny~phenoxvybu oxviacaty.iit }' 0 3,3-diinethylbulanoylli-4-hvdr-.oxy-N-f [411,3-oxazo-5 y!i,9hernyil mefhyltpyrofidine-2--arboxamfjde
94 IH NMR (300',iCD-OD):68.14 (sIH), 8.00-T.91 (,11), 7.90-7.80 (1, iH731 / (1 5j_5H),7.59-7.51 (mn,2H1), 7.45-7.30 (m,.5H), 7.05-6.94(in, 2 11), 467,s. . 11), 4.55 -4.50(m(i,I111),4.49-4.40(m, 21-4b,4.313.5i,1)
4.10-4.0it'in 2 H), 3.99-.96 (i,211,.3.90 -3.70 (i,2-H),3.65-3.55(ni2 11.,2.22-21 (in, 114),2.14-2.00 (in J H), 2.00-1.72 (m, 4H1).1.5(s, 6H1) 1.011Is9 11 LC-MS (ES*): ml2, 960.30 FMH'1
Ex # Structure Compound name and Analytical data
so (2S.4R)- -[(2S)-2-(2-{4-[4-(4-{3-[4-cyano-3-(trifluoromethyl)pienyl]-55 C H dimethyl-4-oxo-2-sulfanvideneimidazolidin-1 NN
o yl}phenyl)phenoxy]butoxy}acetarmido)-3,3-dimnethvlbutanoyl]-4-hvdroxy-N '~'" (lS)-I -[4-(4-methyl-,3-thiazeJ-5-yi)phenyijethyljpyrroidine-2-carboxamide
N HsINMR (300MHz, CD ;OD): 8.86 (s, 1H), 8.18-8.15 (dJ = 9.0 Hz, 211), 95 8.03-7.99 (in),H, 7.76-7.71 (d, = 14.4 Hz, 2H7.64-7.59 (d, J = 15.3 Hz, 21), 7.45-7.39 (m, 6H), 7.07-7.04 (d, = 8.7 -z, 21H , 5.01-4.99 (l, 1H), 4.70
ss, H), 4.61-4.55 (m, IH, 4.45 is, 1H), 4.13-4.08 n, 2H), 4.03-3.96 (m 211), 3.84-3.80 (m, lH), 3.78-376 (m, H), 3.68-3.64 (i, 2H), 2,47 (s, 3H), 2,22 2.15 (m, 1H) ,.99-1.85 511), 1.60 (s, 6H), 1.51-1.48 (d J= 6.9Hz, 311), 1.05 (s, 911) LC-MS (ES*): wz 1038.50 [MH4]
< H (2S,4R)-1(2S)-2-(2- 4-[4-(4-{3[1 ano ifrethlphenv]-5,5
~~ dimiethyl-4-oxo-2-sulfanylideneimsidazolidin -1 ylpenyl henoxybutoxy aetmio)-3,3-dimethylbutanoyl-4hdoyN
S{-(I.13-oxazol-5-v)phenyl methyl}pyrrolidine-2-carboxanide
96 H NMR (300 MHz, CD3D): 6 8.23-8.15 (n, 3H) , 8.03-7.99 (d, = 9.9 Hz, -), 7.73-7.65 (m , 4H). 7.60-7.57 (d, J = 8.7z, 211), 7.46-7.41 (n,5H),7.05 2H) 7.00(d J=12.6fHz, , 471 (s, 1H.)s4.61-4.50 (n,3H),4.36-4.31 (d,J o0N s=15.6 Hz, 1I), 4.10-4,08 -, 4H), 4.03-3.82(mn2H), 3.68-3.64 (t. J= 7.3Hz, 2H), 2.22-2.10 (, H-1), 2.10-2.02 (m. 111), 1.98-1.85 (m, 411) 1.60 (s, 6H), 1.05is,9H) ;LC-MS(ES'):nmz994.65(MH*] N
H' HID (2S.4R)-1-(2S)-2(2-{4-[4-(-{3-[4-cyano-3-(trifluromnethy)pheny]-5,5
diiethyl-4-xo-2-sulfanvideneimsidazolidin-1 o NH y}pheny)phen oxy~butoxy}:scetamiido)-3,3-dimiethyibutanoyi]-4-hydroxy-N {[4-(4-nmethyl-1,3-xazol-5-yl)phenyl methyl}pyrrolidine-2-carboxamiide
HNMR (300 MHz, CDOD): 818-8.15d=9.3Hz,2,808(s. 1), 97 8.03-7.99 (d, = 9.9 Hz,lH), 7.73-7.70 id, J8.4lIz, 211), 7.61-7.56 (m, 411), 7.49-7.41 (m, 4H), 7.02-7.00 (d, 1=8.7 Hz, 2H) , 4.71(s 1H), 4.61-4.52 (m, 2 3H),4.37-4.11 (d-, = 15.6 Hz, ), 4.11-4.07 (m4l),3.96-3.82 (m, 2H) 3.68-3.64 (t, =6.0Hz2 211), 2.36 (s,311), 2.23-2.14 (m, 11),.2.14-2.09 (im F FH), I:.9 81.84 (, 4H), I60 (s, 6H), L,05 (s, 91) ; 1 -MS (ES*): /z F 31008.20 N [MH]
Ex # Structure Compound name and Analytical data
(2S.4R)--[(2S)-2-(2-{4-[4-(4-{3-[4-cano-3-(trifuoromethyl)phenyl]-5.5
dimethyl-4-oxo-2-sulfanvlideneimidazolidin-1 y~}phenyl)phenoxy]butoxy}acetamido)-3,3-dimethvlbitanoyI -4-hvdroxy-N 4-(I,3-thiazo-5-i)phenyl]nethI}pyrrolidine-2-carbomide 0
/ i r N H NMR (300 MHz, CD 3OD): 68.89(s, Il), 8.18-8.15 (d J= 9.0 Iz, 21), 98 8.10 (sH) 8.03-7.99 (d_,=12.0 Hz, H), 7.73-7.70 (d, J=84 Hz, 2H), 7.62 4 N 7.56 (m.4H),7. -7.41(m, 411), 7.05-7.00 (d, 7=14.1 z, 211 , 4.71 (s, IH), o4A ~~ ~ 4306((,1),i 2.08(42]..8z -- o 4.61-4.51 (m, 3H), 4.35 4.12 (m, 2H), 4.08-4.03 (m, 2H) .3.95-3.82 (in, 2H), 3.68-3.64 ('J 6.0 Hz, 2H), 2,22-2.20 (i, 1H) 2.13 F. 2.08(m, ll) 1.98-1.84 1.60 (s, 6H), 1.04 (s, 911) LC-MS (ES): in/z 1010.30 [MH*]
diimethyl-4-oxo-2-sulfanvideneimidazolidin y}phenyl)phenoxy]butoxy}acetaiido)-3,3-dimethvlbuitanoyl]-4-hydroxy-N N 3 f4-e4-merJhy-i,3-thiazo1-5-yiiphenvl~nmethyl jpyvodine-2-carboxamnide
99 'H NMR (400 MHz, CDOD): 6 8.82 (s, 111), 8.20 (d, 5.4 Hz, 2H), 8.02 (d, J=8.0 Hz,1' ),7.77 (d, = 5.4Hz, 2.)7.52 (m, 4H), 7.44 (in,31), 7.24 (d, J= 8.4 Hz, 2H).6.96 (d, J= 8.4 iz, III". .71 (s, 111),4.56 (m 31'4341(m 1H), 4.12 (m, 21),4.00 (m, 211),3.84 ,H), 3.72 (ml, H), 167 (m, 2H),
2.45 (s. 311, 2.24 (m, iH), 2.10 (, 1H), 1.90 i 41H), 161 (s. 61H) 1_3 (s,
911); LC-MS (ES*): mz 1024.35 [MlH]
HQ H (2S,4R)-i-t(2S)-2-{2-[4-(4-{4-[3-(3-cloro-4-cy anophenyl-5,5-dimethyl-4 Ssxo2-sulfnylideneimidazoidin--y!]-3 NH fluorophenyl}phenoxy)butoxylacetamido -3,3-dimethybutanovl-4-hydroxy N-{[4-(4-methyl-1,3-oxazol-5-y)pheniiiethylpyrOiidie-2-carbxaide ,
100 'HNMR(400MHzDMSO)58.61( 1H), 8. (s,1H),8.21 (dJ= 8.4Hz, 1H), 8.08 (s, 111), 7.78-7.64 (m, 511), 7.53-7.42 (m, 6H1), 6 704 (, ' = 88 Hz,
211), 5.16(s, .11),4.58 (d,J=9.6Hz, 111), 4.57-4.27 (m,411),4.20 t, J=6.8 0 s z, 2H), 1.3.91 (s, 2H) 3.68-3.53 (in, 4H), 2.33 s, 3H), 2,07 (s, ]H), 1.90-1.72
(m, 511), 1.60 (s, 311), 1.48 (s, 3H), 0.95 (s, 9H) LC-MS (ES'): n/ 992.30
N
Ex # Structure Compound name and Analytical data
HN (2S,4R.)-i-[(2S)-2-(2-{4-[4-(4-{3-[4-cvano-3-(trifluoromethyl)phenyl]-5.5
Hdimethyl-4-nxo-2-sufaivlideneimidazolidin-1
yl}hienyi)phenoxy!butoxy}acetamido)-3,3-dimnetyibutanoy]-4-hydroxy-N NH 1) 1)henyliethyi~pyrrolidine-2-carboxaide
10 NMR (400MHz, CD;OD): 3 8.19-8.14 (i, 3H), 8.03-801 d,J=8.4 z H), 7.77-7.73 (d, J=16.0 Hz, 2H), 7.64-7.60 (i,4H).T45-7.42 ( 4H), 1, 7.07 7.05 (dJ=8.4 Hz, 2H) , 5.01-5.00 (m, 1H),i4.71(s, IiH), 4.61-4.56 (m, 1H), N 4.45 (,1), 4.13-4.10 (m, 21), 4.07-4.01 (m, 2H), 3.88-3.85 (m, 111), 3.78
3.75 (m, IlH), 3.69-3.66 (t,J=12.0Hz, 2H), 2.40 (s. 3H), 2.21-2.19 (m 111) 2.00-1.86 ( l 5H), 161 (s, 611), 1 1-1.49 (d, J= 7.2 Hiz, 31 1 .06 (s, FF 911); LC-MS (ES*): m/i 1022.45 [MH" N
(2S,4 R)-1-[(2S) -2-(2-{4-[4-(5-{3-[4-cyano-3-(tifluoromethyl)phenyl]-5,5
dimethyl-4-oxo-2 -sulfaiindeneimnidazolidin-1-yl}pyridin-2
v )pviIhenoxylbutoxyacetamido)-3,3-dimethxyibutanoy]-4-hydroxy-N-{[4-(4 NHS 0 _ methyl-1,3-thiazoi-5-yi)phenyviimethyi}pyrrolidine-2-carboxamide
00<
102 !H NMNR (400 M111z, CD-;OD): 6 8.96 (s, 1H1), 8.62 (mi, 2H1), 8.42 (d, J1 8.4 Hlz, ), 8.33 (s, ), 8.12 (m, 41), 7.89 mn, Il), 7.44 (i, 5H). 7.07 (d, J = 8.8 0
F Hz,2H),5.17 (m, H), 4.59 (d, I = 9.6 Hz, H), 4.4'1-4.48 (m, 41), 4.38 (, 211), 4.29 (m, I11), 4.07-4.10 (m, 211), 3.97 (m, 2), 3.55-3.67 (m, 4H', 2.45 (s,3H), 2.08 (nm, 1), 1.81-191 (m 3), 1.72-1L77 (i, 2H), 158 (s, 61), 0.95 (s, 911) LC-MS (ES*): mz 102555 [MH] (2S.4R)-l-[(2S)-2-[2-(4-{[4-(4-{34-cyan--trflornmehyny1]-, HO
}phenylphenyltaminobutoxy)acetamid]-3,3-diimethylbutanoyl]-4
NJ..KH hydroxy-N-{[4-(4-mediyl-1,3-thiazol-5-yi)phenyi]mediylpyrroiidine-2 0 1 carboxamide ."N
103 NH H-NMR (300 MHz, CD 3OD) I 8.71 (s, 11), 8.18-8.15 (dJ=8.4Hz, 211), 8.03-8.00 (d,J = 7.8 iz, i), 7.68-7.66 (d.j= 8.4 Hz, 2H), 7.47-7.35 (Im,
U/ 811), 6.74-6.71 (d J= 8.7 ,tH211), 4.72 (s, 11), 4.62-1.50 (m, 311), 437-4.32 (d,J= 15.2 liz, 111), 4.00-3.98 (, 211), 3.94-3.79 (m, 2), 3.64-3.61 (m, 211), 3.21-3.11 (m, 2H), 2.48 (s,3H), 2.28-2,21 (miH, 209 m .05(i, 1H,93 NC 189 (m, 4H) 1.59 (s, 611), 1.01 (s, 911); LC-MS (ES*): mmz 102330 [MH]
Ex # Structure Compound name and Analytical data
HO ~ ~ ~~2S,4R)--(Sl 2-2{-4(-3[-vn-3(nlnnnty~ley]55 d direthyi-z-ox-2-suifaniv'deneirnidazoiidi!n- I yilphefnvl,,phennxyjbntnxylaeetar.nidn)-3,3-dirniethvlbnitLinny -. l.-hvdrncxy-N II !'f4-ill-rneshvi-li-irn.idazi.5-yi) honylJntylyrl~~~ c'boxarnile
14oI-iNMR(300Mliz, CD-,OD: 881(d,.0 1z,2111, 802-7.99 (d.J =10.2?Hz,H1-, 7.73-7.70(d,,J=8.4 Hz,2H), 7.59-7,56(d 1-8. i, 2H), 7.50-7.39 (n,1H4, 7.03-7.00 (dJ=8.7Hz2H-) 6.0" 1-s 111)4.1-1)l 7, 4.62-4'.50.311),4.39-4.33(,J,[=15.2Hi,1111.4- 1 .8(i,2H,)4.08-4-00 fin, 2H), 3.87-3,80 (,51)..6-3.64 ( J=6.0 Hz2H, 2.2',5i, IHt)
2.10--2.00(in, 111).1.97-1.8. n,,411). 1.60 (s, 611).1.04*(s,911) _fMS N (ES'):rn/iz1007.50 [MH1
f2S,4R)i-N-f[-4cir-,-xii5v)linin-li1(5--2{-4
_ )~snlfanylidenleirniidaznhdin ',viIphonyl)phenntxvibutoxvlaesaln'dn)-3,3
115H HNR(00 MH,CD03O): 863- 8.66(n, IH).8.53 (s,I H).8.41(d.) ')J ~ ~~8.4 HzI H),8.3 (sIH),8.12(,=8. 8H, IH, 780(d, 3= S0-Pz,2M, 7.7(418/I~z21)77i =8.4 I-z,211A7.50(m,511, 7.04 (d..1=8.8 N- "S ~ ~~~117211 517 mn H), 4.59(d1 := 8.4Hi,1]H),4.48 (in.211),4.39 (m, 1111. FF ) 4.32(n, Hl)V.0 ni, 211), 3.97 -'il4, 3.5367 (ir.411),2.06-2.08(mn,
N 1111.8 119, 3HI 1.2177 (m.,211),1.55is611),0.95 is,911)2 LC-MS (ES'):Inz 102850 [TvH-1]
( '(2S,4R)--.'jF2Si-2-f 2-[.4-(4-'4 -'3-(3-e-hinrn-4-cvannp.,henyi)-5,5-d'mehyi-4 0 *~ ~ oxn- -suifanyliden.eiiidazniidin-1-v:-s
r)N- [-4-1,3-oxazol-5-y]bplen vlinethyvlpvrrn idin--carboxanlide
106 1~IR(400M-\HzCD30D)6820(s.q,11),.00-l=84lHzz111),7.905. '11",7370-7.44 (n,H), 7.5 J8.8-li, 211).4.72Is,(11),4.61-4.52(n,
N S. li',, 3H)4.37-4.33(m, IH), 4,14-4.02 (m, 4H),3.98-3,84(i, 211),3.67 (L.J =6.4 H'", 11).224-2_22 (mn111) 2.1-2.09 (m, l-)1.99-1.86(in, 411), 1.66 (s, 3H)1,54 (c,3H), 1,06 (s,9H);LC-MS(iES's:mz T97.25[MI1
Ex # Structure Compound name and Analytical data
(2S.4R 4-(2)2{2[-4-4) (2'4)--[2S--{-[-(-{-[-3-clioro-4-cyanophenyl)-5,5-dimethyi-4 oxo-2-sulfanylideneimidazolidin--yl-3 olufioroohenyltphentoxy)butoxyacetamido}-3,3-dimethylbutanoyl]-4-hydroxy N-{[4-(4-methyi-i,3-thiazol-5-yi)phenyi]methvl}pyrolidine-2 ~' carboxamtide
1070 107 HNMR (400 MHz, DMSO) j 8.96 (s, 1H), 8.61 (m, 1H, 8.20( 8.4 Hz, H1), 8.19 (s. I-H), 7.78-764 (m, 5), 7.70-7.37 (m, 611), 7.03 (, j= 8.8Hz,
S2).1(s- i ,4.57 1d,J= 9.6Hz iH),4.57-4.27 (m,41),4.08 (t,=6.8
Hz, 2H), .6 (s2H), 3.66-3.55 (m, 4H), 2.43 (s, 3H), 216 (m, H), 1.92-1.75 (m, 5), 1.60 s, 3H1), 1.48 (s, 3H), 0.93 (s, 9H); LC-MS (ES'): m/z 1008.50 N Ifi 7 H*
HO (2S,4R)-1(2S)-2-{2-[4-(4-{4-[3--chloro-4-cyanophenyl)-5,5-dimethyl-4 oxo--sulfanylideneimidazoidii.1-1-y-3
NH nluorophenyl phenoxy)butoxyaeamrdo}-3-dimethylbuanoy)]-4-hvdroxy
'-I ' N-{[4-(1,3-thiazoi-5-yi)phenyliamethl}pyrroidine-2-arboxamisde t.=N
108 1H0NMR (400 MHz, DMSO) 6 9.04 (s,1H), 8.61-8.56 (m, 1H),8.27 (s, 111), N 8.21 (dsJ= 8.4 Hz, 1H). 8.08 (s, IH) 7.78-7.36 (n, 1111), 7.06 (d, J= 8.4 Hz, ON- F Ns 12H), 5.16 (s, iH), 4.58-4.56 (m, IH), 447-4.22 (m, 4H), 4.09-4,06 ( , 2H), 3.96 (s, 211), 3.66-3.55 (m, 411), 2.07-2.04 (m, 1l), 1.89-1.72 , 511),1.60 (s, ih N ~ ~ ~ 3H),1.48 (s,3H),0.95 (s,9H; LC-MS (ES):amz 994.5(MH*]'
(2S,4R)-i-[(2S)-2-{2-[4-(4-{4-[3-(3-ehloro-4-cyanophenyl)-5,5-dimethy-4 HQ Hoxo-2-sulfanylidenteimtidazolidit-1-l]2 fluorophenbylphenoxy)btoxy]acetamido}-3,3-dimethybutanoyi]-4-hydroxy -NH -N-{[4-(1,3-oxazol-5-yl)pienyl]methylpyrrolidn--carboxamide 0' op
1 H NMR (300 MHz, CD30D): 6 8.23 (s, 11) 8.19-7.99 (d, J= 5.9 Hz,-i I), 1097.96 (s, 11H),7.78-7.61 (m, 41, 7.587.51 (m, 2HI), 7.47-7.46 (m, 2H', 7.46 7.41 (m,I3H),7.31-7.29 (m, 2H), 7,05-7.02 (J= 8HI.7Hz, H, 4.71(s, IH), 4.614.51 (m,31), 4.36-4.31 d,J= 15.2 Hz, 11-, 4.134.11 (, 2H), 4.09 4.01 (.2H), 3.96-379 (im, 211), 3.69-3.65 (t, J= 6.0 Hz, I2H),223-2.20 m, NCl H), 2.13-2.09I(m,iH),1.96-.87(m,4H), 1.60(s,6H),1.03s, 9H) ; C-MS
(ES*): m/z 978.25 [MH t )
Ex # Structure Compound name and Analytical data
HO (2S-4R)-1-[(2S)-2-{2-[4-(4-{4-[3-(3-chiorn-4-cyanophenyl)-5,5-dimethyi-4 Nnxo-2-sulfanylidenemisdazoidin-i-yljpheny}phenoxy)butoxyacetamido}
o §,NH S3,3 -dinehylbutanoyl-4-hvdroxy-N-{[4-(4-methyl-1,3-oxazol-5
a-' yi)phenyi]methy}pyrrlidine-2-carboxamnide
110 HINMR (300 MHz, CD;OD): o8.08 (s, 1), 7.77-7.72 (m. 311), 7.69-7.6 (m 4H), 7.48-7.39 (, 5H),7.19-7.17 (d,,J= 6.3Hz, 1), 7,02-6.99 (, J= 90 Hz 21), 4.71 (si 1), 4.61-4.52 (m, 3H),.36-4.31 (m, 1H), 4.11-4.08 (m 211), 4.03-4.01 n, 5H), 3.95-382 (m, 211, 3.68-3.64 (i,21) 2.36 (s, 3) 2.22 c: 2.09 (m, iH), 2.09-2.01(mn, H), 195-`.84 (m, 4H), 1.58 (s, 6H), 1.04 (s, 9H); NC LC-MS (ES): /z 974.30 [MH']
H HQ (2S.4R)--[(S)-2-{2-[4-(4-{i4--(3-ch-lro-4-cynonyl)-5,5-diethyldn N \NN nxn-2-sulfanylidencimidazolidin-i-vlphnylpheoybuoyaetmd} C KHN 3,3-ditinetsyibn-ann-yl-4-hydrn-xv-N{1[4(13-tiz-I'l-5
111 0 'HNMR (300 MHz, CD;D): 68,89 Is,H), 810 (s, 1H), 7,98-7.95 (d, J= 8.4Iz, 1), 7.89-7.88 (dJ= 1.8 Hz, 1H), 7.72-7.56 (m, 711), 7.44-7.39 (m, 4H), 7.03-7.00 (d,J:= 8.7 Hz, 2H), 4.70 (s, ), 4.61-4.50 (m, 31) 4.35-4.30 (,=15.2Hz, 1H),4.12-403(i, 2H), 4.01-3.95 (m, 2H), 3.86-3.82 (m, 2H) 3.68-3.64 (m, 21), 2.22-2.18 (m, 1H), 2.12-2.08 (m, i H) 1.98-1.85 (m,4H), C 58 (s, 611) 104 (s, 911) ; LC-MS (ES): m/-z 976.20 MH]
NC (2S,4R)-i1(2S)-2-{2-[4-(4-{4-[3-(3-chloro-4-cyanophenyl)-5,5dimethyi-4 NC..( 9 xn-2-sulfanylideneimidaznidin-1-ylrheny1phenoxy~butoxy'cetanmidn } -5h/~.NK 3,3-diiethylbutanyi]-4-hdrxy-N-{[4-4-methyl-",--5 1)phnyllmethylpy--rolidine-2-carboxamidte
11 0 CG 'N>MR (300MHzCDsOD:68.81 (s,11H),7.98-7.95(d, =8.4-H,1H-), 7.89-.884d =181-Hz.(i) 7.73-7.64(,31), 7.85(d,18.7z,21), a 7.48-7.38 in, 6H), 7.02-6.99(d, J= 8.7Hz, 2H), 4.71 (Is,1-H, 4.62-4.51 (
HN 3H), 4.36-4.31(m 1H), 4.11-4.07 (m, 211), 4.02-4.00 (dJ5.4 liz, 211), 3.87
3.82 (me2H), 3.6-3.64 (tJ=6.0Hz, 2H), 2.44 (s, 3H), 2.23-2.10 (m, 1H) 2.09-20( 1H,1.97-1.84 MH (im,4H1), 1.58(s, 6H), 1.041 (s, 9H) LC-MS
ES'): m/ 990.30 [MH*
Ex # Structure Compound name and Analytical data
2 NC.f' (2S,4R)-i-[(2S)-2-(2-{4-[4-(4-(3-[4-cyano-3-(rifiuoromethsyl)phenyl]-5,5 0 EsC g' ~~dimsethyl-4-oxo-2-suifanvlideneimsidziin-y}3 Ffluorophenyli)phenoxybutoxyacetamido).-3,3-dimethylbutanoyi]-4-hydroxy t N-f[4-(1,3-oxazol-5-yl)phenylumethyi prroidn-2-arboxamide
0 H1NMR1(300 MHz, DMSO)6o8.62-8,56n, 1),8.41 (, 1),8.39 (, 1), 8.35 (s,111) 8.15 (d,J= 8.4iz, 111) 7.76-7.63 (m, 71), 7.51-7.38 (m. 411), 7.06 (d, J= 8.7 Hz,2H,'515 (d, /= 3.3 Hz, HI), 4,58-4.26 (m, 5H),4.09-4,05 (n, 211), 3.96 (s, 211), 3.66-356 (m, 411, 2.12-.04(1-, 1), 1-93-1.73 (,n NH 5H), 1,60 (s, 3H), 1,50 (s, 3H), 0,95 (s, 9H); LC-MS (ES*): z1012.30 [MH]
(2S,4R)-'-[(S--2-{3-4-4-(3-[4-cano-3-(trfuoromehyl)phenl]-5,5 0 dimsethlsv-4-oxo-2-sulfanylideneimsidazolidin-1 NCNy'}phensyi'phenoxyphienoxyaeamnido)-3,3-dimsethylbuanoyl]-4-hydrox-N
F3 S{[4-(4-methyl-i3-tiazol.<-5-ylnhenyyi~methyi}pyr-roiidine-2-carboxanmide '114 HNMR (300 MHz, CD30D):68.81 (s, H), 8.14-8.05 (m, 21),8.00-7.95(m H[t iH),7.75-7.69 (,2H),? 765-7.59 (m, 2 H), 7.44-7,20 (m, 7 H), 710-7.00'(m rS ' 2H), 6.80-6.78 (m, 1H), 6.75-6.55 (m. 211), 4.68 is, 111), 4.60-4.40 (m, H.) 4.30-4.20(m, 1 1),390-3.65 in',2 H),2.40(s,3H), 2.25-2.21 (ms 1 H),214 2.00 H), 1.55 (s, 6 H), 0.99 (s, 9 H); LC-MS (ES*): n, 1044.30 [MH*] HO H (2S,4R)-'-[(2S)--2-[4-4-{4-[3-(4-cyano-3-mehoxypheny)-5,5-dimethv-4 oxo-2-sulfanylideneimidazoidin-1-vilphenyl}phenoxy)butoxy acearido}
O>..NH '~ 3,3-diinethylbutanoyl]-4-hydroxv-N-{[4-(4-medl- 3-xaz15 SphenylImethylIpyrrolidine-2-earboxanide
115 H1NMR (300 MHz, CD3OD): 68.08 (s, 11,7.76-7.69 (m, 3H),7.60-7.55 (d, J-15.9 Hz, 4H), 7.48-7.37 I, 5H),'7.19-7.16 (d, =9.9 Hz, HI), 7.02-6.99 (d 1=8.7Hz,2H1),4.71(s, 1), 4.61-4.51 (m,311),-4.36-4.31 (m, i)4.10-4.00 (m, 711), 3.98-3.82 (im,2H),3.67-3.63 (t,J= 6.0lz,2), 2.35 (s,3H), 2.22 2.12(, iH),2.12-2.09 (m, 111). 1.97-184 (, 411), 1.58 (s, 61), 1.04 (s, 6N 911) ; LC-MS (ES'): m/z 971.45 [MH')
(2S,4R)-'i((2S)--2-14-[4-4-(3-[4-cyano-3-(trifluoromethyi)phenol]-5,5 NC dimnethyl-4-oxo-2-sulfanylideneimsidaszlidin-l-y}-3 3C )-N s lu orophenyl)phenoxyibu toxy }acetamdo)-3,3-dimothylbutanoyl]-4-hydroxy F N-[[4-(4-methyi-1,3-oxazol-5-vl)phenyi]methyi) pyrolidine-2-carboxamide
0 116 'H NMR (400 Mz, DMSO) 6 8.66-8.61 (m, I H), 8.42 (d, J 8.0 lz, Il), 8.35 (s, 1H). 8.29 (s, 1H). 8.15 (d, == 8.4 Hz, JH) 7.76-7.64 f' 41), 7.53
HN 740 (m, 611),7.05 (d/,= 8.8 Hz, 2H) 5.16 (s, 111) 4.58-427 (n, 51), 4.09
0 N OH 4.06(m,211),3.96 (s,211),3.66-3.55 m'1,4),2.33 (s, 311) 2.07-2.02((m, 111), N .94-1.73 (n, 5H), 1.61 (s, 3H), 1.50 (s, 3H), 0.95 (s, 9H); LC-MS (ES):muz 1026.30 [MH']
Ex # Structure Compound name and Analytical data
(2S.4R)--[(2S)-2-(2-{4-[4-(4-{3-[4-cyano-3-(trifuoromnethyl)phenyl]-5.5 rimethyl-4-oxo-2-sulfanvideneimidazolidin-I-yl}-3 N3C N fluorophenyl)phenoxynbutoxy}acetamido)-3,3-dimehybutanoyl]-4-hvdroxy
l N-{[4-(1,3-thiazol-5-ylpnyl,'methylpyrrlidie-2-carboxamide FA
11 NMR (400 Mz, DMSO) S 9.04 (s, 1H), 8.60(s, 1H), 8.42-8.35 (m. 211), 11 7 -D 8.27 (;, iH), 8.14 (d,j= 8.0 Hz, 2H,.7.75-7.67 (i, 311), 7.66 (d,.j=80 liz, HN-K H1N, OH IH7.59 (m, J= 8.4 z, 2H), 7.4 8(t J= 8. lz, H), 7.41-7.36 (m, 311), 7.05 (d, J:=: 8.8 Hz, 21', 5.19 s il ,A.57 (d, J= 9.2 z-li H, 4.58-4.44 (1, S, NH S{ NHH),4.42-4.34(n, 2H), 4.35-4.33(m ')i , 4.08 (s, 2H), 3.96 (s, 2H), 3.66-3.55 (m, 4H), 2.10-2.02 (m ll), 1.89-1.72 m 5 1.61 (s, 31), 1.50 (s, 311), 0.95 (s, 9H);1C-MS (ES*): m/7 1028.30 [MH*I, (2S,4R)-i-[(2S)-2-(2-{4-[4-(4-{3-[4-cyan-3-(ruromethyi)phenyi]-5,5 o dimethyl-4-oxo-2-sulfanvideneimidazolidin-1[-yl-3 NC- FN fluorophenyl)phenoxy]butoxy}acetamido)-3,3-diiethvlbutanoyl]-4-hvdroxy
N-{[4-(4-methyl-i,3-thiazol-5-y)phenylmethyl}pyrrolidine-2-carboxamide
118 H NMR (400 MHz, DMSO) 5 8.96 (s, 11), 8.61 (s, 11), 8.42-8.35 (m 21), 8.15 (dj= 1.6Hz, 2H),7.76-7.64 (i,411), 7.51-7.39(m, 61), 7.04 (d, J= 8.8 N j z, 211), 5.17 (s.1H), 4.57 (d, J= 9.6 Hz, 1', 4.56-4.38 (m, 31H), 4.36
NH 4-27(m '1i), 4.08 (s, 2), 13.96 s, 2H), 3.66-3.55 (m, 411), 2.45(s, 311), 2.10 2.02 (m, Hl), 1.93-1.84(,i 1H-),184-1.82(m, 2H),175-173(m, 211), 1.61 (s, 311) 1.50 (s, 311) 0.94 (s, 911); LC-MS (ES*): m z 1042.25 [M] (2S 4R- -[(2S)-.2-(2-{4-[4-(4-{7-[4-cy.ano-3-(trifioromnethyi)phenyl]-8-oxo 6-sulfanylidene-5.7-diazaspiro3.4]nctan-5 0 NC yl i}pheny)phenoxy]butoxy}acetairdo)-3,3-dimethybutanoiyj-4-hydroxy-N Fa ,vN ([4-(4-methyl-1,3oxazo-5-ylpheny~mehyiyroidine-2-carboxamnide
\9 HNMR(300Mlz,CD;OD): 68.17-8.15 (d J= 8.1 z, 211), 8.09 (s, 111), 8.02-8.00(d, J= 8.7iz, ffH),7.7-75 (d.j='84 Hz,2H), 7.62-7.57 (,411)s H OH 7.49-7.43 (m, 4HI),7.04-7.01 (d,J= 8.7Hz,2), 1.71 (s, 1H), -. 62-4.53In, S- 311), 4.37-4.32(d,J= 15.3 Hz, 1H), 4.12-4.1 (m, 21I), 4.09-4.01(m, 211),3.96 H-S ~N 8 (m, 2H 369-.65 (m, 2H), 280-2.55 (m, 4H),2.41 (s, 3H) 2
(i, 1i) 210n,211). 1.98-1.88 (m, 4H), 170-.66 (m,1H), 1.03 (s, 9H); 1C-MS (ES'): m/z 1020.35 IMH*]
Ex # Structure Compound name and Analytical data
(2S.4Ri-[-:(2S)-2-(2-{4-[4-(4-{7-[4-cyano-3-(trifluloroethy)phenyl]-8-oxo N 6-suilfanylidene-5;7-diazaspiro[3.4]octan-5 N F F N yi}phenyl)phenoxy]butoxy}acetamido)-3,3-dietiybutnoyl]-4-hvdroxy-N Q (4-4-methyl-,3thizl5yi)phenlethylprdie-2-caboxamnide
H11 NMR (300 Mliz, CD-,0D): 6 8.821 (s, 1H1), 8. 17- 8.15 (d J = 7.8 Hlz, 2H), 120 0 K 0 8.02-800 (d, J=8.iHziH),7.78-775'(d S=4814 Hz,2) 7.61-7.59 (d,.7=
8.4 Hz, 2H), 7.8-7.42 (m, 611) 7.04-7.0 (d,7 = 8.7 Hz, 2H), 4.71 (s,11H), HN O' NOH f-\ OH 4.62-4.51(m,.3H), 447-432(d, /= 15.9Hz, 1H)44.2-410I(m, 2H), 4.08 S4.01(m, 2H), 3.96-3.82 (m, 2H), 3,69-3.65 (m, 2H), 80-2 ,55 ,4H),2.48(, \NH 311), 2.23-2.21n, 1H1), 2.14-2.10 (m, 111), 1.98-1.89 (m, 4H) 70-1.66(, 1MH), 1.03 (s, 9H); LC-MS (ES): m/1036.25 [MH*] (2S,4R)-i-t(2S)-2-{2-[4-(4-{4-[3-(3-chloro-4-cvnopheyl)-5,5-diiethiyl-4 NC-/ N x-2-sulanylideneimidaz-lidin-,-yl]phenyl}-3 C N fluorophenoxv)butoxv]acetanido}-3,3-diii;ethlvbutanoyl]-4-hydroxv-N-[[4
(13-oxazol-5-yi)phenyi]methyl}pyrroisdine-2-carboxarmde
121 H NMR (300 MHz, CD3 OD):68.14 (s, 1 H), 8.00-7.91 (m, 1 H), 7.90-7.80 (m, I H), 7.71-7.58 (ry 5 H), 7.50-7.41 (m, 6 H), 6.90-6.71 (m, 2 H), 4.67 (s, 1 H) 4.58-4.41 (m,3 H), 4.30-4.22 (m. 1 H),4.12-4.01 (n ,2H),3.99-3.94 (m, 211) OH 3.90 -3.70 (im, 2 H), 3.65-3.55 (, 2 H), 222-2.13 (m, 1 H), 2.14-2.00 (im, I fi-C 0 NH 11), 2.00-1.72 (in, 4 ), 1.56 (s, 6 1), 101 (s, 9 H); LC-MS (ES*): mz, 978.30
(2S,4R)-i-[(2S)-2-(2-{4-[4-(4-{3-[4-cyano-3-(trifluoromethy)phenyl]-55 dimethyl-4-nxo-2-sulfaivideneimidazolidii-1 C ylN-}phenyi)phenOxyninny}:cetaiido)-3,3-dimnethylbutanviyl-4-hydroxy-N j4-(1H-pyrazoi-5-ylphenlmethy} prrolidine-2-arbxamide
H2NMR (400 MHz, CD-OD): 8.25-8.15 (m, 211), 8.05 -8.00 (s, I H), 7.78-7.70 122 (m, 411), 7.70-7.58 (i.,3 1), 7.48-7.39 (ms 4 ),7.08-7.00( 2 IH) .669 6.60, (s, i H), 4.95-4.85 (s, 1 H), 4.65-4.58 (s,11H), 4.55-4.49 (m, 2 ),4.40 0 'OH 4.30 (s, I 1),4.15-4.08(, H ),4.05-4.00(m,2 11,3.90-3.85 (s, i H), 3.82--3.75 (s, I H), 3.70-3.60 (m,2 H), 2.28-2.20 (s, I H), 215-2.05 (s, I H), 1.98-1.89 (n, 4 H), 1.63-159 (m, 6 1.10-1.00(m.9 H); LC-MS (ES*): mz 993.35
Ex # Structure Compound name and Analytical data
(254R)-i-[(2S)-2-{2-[4-(4-{4-[3-(3-chorn-4-cyano-2-uoropheny)5,5 NC dimethyl-4-oxo-2-sulfanvlideneimidazolidin-I N Ci p N ylpheiiylfphenoxy)butoxyacetamidn}a-3,3-diiethlutanioyl-4-hvdroxy-N F
13H NMR (400 MHz, CDOD) 8.21 (s, lH), 7.88-7.87 (d, J= 1.6lZ, 1H), 123 7.86-7.73(i,31-1), 7,69-7.67(d,.J= 8.48Hz,2H,'7.61-7.59(d, J=8.4Hz, 21), 7.48-7.43 (m, 511) 7.05-7.02 (d, -= 8.8 Hz, 21), 4.88 (s. 11), 4.73-4.59 H N. )Nm, 31), 4.52-4.37 (d, = 15.2Hz, 1H) 4.08-4.02 en, 2H), 3.98-3.82 ( 211), 8 rO o ' 3.89-3.88(, in1H), 3.84-3 13(m, 1H),3.69-3.66 (t,. = 6.0 Hz, 2H), 22-2,20 (m, 1H), 2.13-2.04 (ml,1), 1.97-1.88 (im 4H), 1.62 (s, 611), 1.04 (s, 911); LC MS (ES'): mz 978.26[MHl
(2S,4R)-i-[(2S)-2-{2-[4-(4-{4-[7-(3-ehloro-4-cyanophenyl)-8-x-6 CI ~- sulfanylidene-5,7-diazazpiro[3.4]octan-s NC -/N~i N yl]pheiiyl[phenoxy)butoxy]acetamido}-3,3-diietvhlbutanoyl-4-hydroxy-N
([4-(l.3-oxazol-5-yI)phenyl methyl}pyrrolidine-2-carboxamide
124 'H NMR (400 MHz, CD 3OD) 6 8.18 (s, 1H), 7.99-7.96 (d,.J= 8.4Hz, 1H), 7.89
0(s, 1H), 7.79-7.77 (d,J= 8.41Hz, 2H), 7.67-7.61 (m, 5H), 7.48-7.43 (m, 5H), H N- '7.06-7.04 (d, J= 8.8 liz, 2), 4.88 (s, 'I'), 4.73-4.59 (m,311') 4.52-4.37 (d,J 0 OH = 15.2 Hz, 11), 4.14-4.1 1 (ms 2H), 4.05-4.02 (m, 2 3),.99-3.83 i-, 2H), N1-l> J NH 3.70-3.67(t,F= 6.0 liz, 2), 2.66-2.62 'i, 4 213-2.00 (n 3H), 1.98-1.88 (m, 411), 1.80-1.70 (m, 1), 1.04 (s, 9H11) LC-MS (ES*): mlz 972.25[mlMH]
(2S.4R)-i -[(2S)-2-{2-[4-(4-{4-[3-(-ano-3-methyihenyl)-5,dimethl-4
N oxo-2-suifaiylideneimidazolidin- -y!heinylphenoxy)butoxy'acetamido}
N 3,3-dimethylbutanoyl]-4-hydroxy-N-{[4(1,3-oxazol-5 yl)pheny]nethy}pyrroiidine-2 -carboxamide
0 125 H NMR (400 MHz, DMSO) 6 8.60 (t, J= 6.0 Hz, 11H), 8.40 (s, I1H, 7.97 (d V0 ,
O= 8.0 lz, 1H), 7.79 (d, j= 8.4 Hz, 211', 7.67-7.63 (m, 6H), 7-54 (d,J= 8.4 Hz,
lHH7.44-7.39 (m, 5H), 7.05 (d, 8.8 Hz, 21), 5.16( 11), 4.58-4.56 (, S447-4.26 (m, 411), 4.08-4.05 (m, ), 3.97 (s, H 3.66-3.57 (m, 411), - NH 2.56 (s, 31), 2.06-2.02 (n, 1H), 1.93-172 (m, 5H), 1.52 (s, 6H, 0.93 (s, 9H); LC-MS (ES*)1: mz 940.30 [MIH*]
Ex # Structure Compound name and Analytical data
0~~~~(2S,4R)-i.-'2S)-2-f2-[4-(4-'4 -3-(z--yaio-3-[L:iuorohenuy"-5,5-drnrettivi-4
fi-i)ioherylirnethylltpyvsrT'ldiue-2-c-arboxamfide
126 0 l,I R1400M-\Hz,DM80)68.60(1,1=6.0Hz1113,8.40(s.111),8.15 (d,J -0H, - 8.( 1z,i114, 7.85-7.78 (m,.311,7.67-7.63(n, 611), 7.43-7.39 (mn,511.7.05
(dJ= 8.8 Hz, 2H).55.16ifs 'H)' 158-4.56(On, H, 4,47-4.26 (us,4H),4.08 0 4 05 (m, H) 3.97(s 21H).3663u.5-,'206-2.02 (n,1),1.3-17-1 (ms,5H), 1.5 (s,6H),095(s9)LC-MS (E'): tm1794450M']1
(2S,4R)~~~~~~ ~ ~~~ 12)1 ~4~4eao3(iioosdlheiv]l-5,5
NC-
127 HNMR (300 MHz, CD H D):68.8s,IH), 8.1,4-805(m,2 11) H).00-7.95 (u. 1 1I), 7.7.5-7.69 (m,'21' 7_55-7_32 il 8Hi)720-7.15(..11), 7.10-7.00(s, 0 X O.H 4 11,.6.99-68 5 (m,1HI).4658Is,1H I)465-4.60 frn.2 H), 4.63-455(us1).
~j-)NH 4.50-4.40 (nn, 2H),4.30-4.20 (m, 1Hl)3.90-3.80 (us.111), 375-3.65 (us, IH), 2.40(ss,3I-I), 2.25-2.21(u, 1H),214-2.00 (m, 1H), 1.55 (s, 6H1i,0.99 (s, 9 Hill;LC-MS (ES')- ilz, 104141.30 [MH 10 411--12S-2[2-13-14-(4-13-[4cyano-3(uslooetvxhuyj55 di,vsi-A-oxo-2.-suIfauvideneirnidazolidin1 yllphenyllphen yiimetsoxy Ipropoxyace-aruso.,i3,3 -dill edsybutan oyl]-4 ihvdroxy-N-{[-(-rsehy-0iiazoioivpfnyiretytpyiroiii-2 cabar).dde 128 'Hf NMR(400MNHz, CD30D) 6 8.85 (s,1)8.20 (s,211),8.02(d, -84 H1z, 111,7.80d,.J7.6H1z, 21-I',7.66 (d,.J8.0H11z, 211-b,7.48(s, 611), 73 fin, 2H), 4.71 (s, IH), 4.6'1(m, 5H,4.`4usf, fi),4.01 (m.2H)3.84us,2)., 3.72(us, 411),2.45~ (s1).225(n,11), 2.12(usil111), 1.97 (m, 21 62(~ 61),1.02 (,91H);CMS (FS') mz 024.20 [MH1
(2S,41)-i'2S-I2 [442[-yo3-tiirostvhel)5 1 HO du'ei~y-4-oo-2su~auv~deniusdaioid~i-~s' 1t~e1Y1 pheyl-5
Ho-< ~ hdoyuovaeaudl5.~stvbtuy14hdovN(4(
0- ill~~ethyl-I,3-thiazol-5-yl)pheviylmsllesyI ys-roidine-2-c-aiboxasde
129 CO H NA/R400 MHz, DD) 6882 (, 111, 8.20 (us,211),8.03 (m, 1113,7.74 (ms, 2H),i760(m2), 7.4 8 (61),7.07 (, 211)4.74(s, 111,4.60-4.53(ms, 'U',,4.37/(m, IH), .11(sin, I)4.08, 4H), 3.92-3.88 (i,H1),3.83-3.75
(nn,3.1), 11 (s 3H1),2.26 (nil111), 2.14 (m, 211,1 .87 (s,11),1.62 s611), 1.03(s,5l 91() L.MS (ES')us1041025 IMH'I
Ex # Structure Compound name and Analytical data
(2S,4R)-i-[(2S)-2-{2-[(2R)-4-[4-(4-{3-[4-cyan-3-(trfluoromethyi)pheny] 5,5-dimethyl-4-oxno-2-sulfanylideneiiidazolidin-I-yllphenyl)phenoxy]-2 hydroxybutoxv]acetanido -3,3 -dimehylbutanoyl -4-hydroxy-N-{[4-(4
methyl-1,3-thiazo-5-yJ)pheny::mnthy}pyrridn-2-aroamde
130 IH NMR (400 MHz, CD-OD): 6 8.81 (s, IH), 8.18 (d, -8.4 Hz, 21), 8.04 (d, J=8.4 Hz, 1),771 (s, J= 8.4 Hz,2H), 7.57 (d,,J= 8.8 Hz, 2H), 7,44 (m, - 61),7.021 (d,J= 8.8 Hz,211, 4.71 (s, 1H), 4.56 (m,3H)4.33 (n, 1H),4.17
FrF(, 2H), 4.05 (, 311), 3.75 (m 21), 3.65 i,2'_H), 2.44 (s,3H, 2.22 (m, 1 H), F 2.08 (m, 2H), 1.90 in, 1H), 1.60 (s, 6H), 1.05 (s, 9H); LC-S (ES*): m/z N 1040.20 [MI (2S,4R)--(S--2[2)4[-4(-4cao3 (trifluoromethyi)phenyi]-5.5-dimethyi-4-nxo-2 sulfanyiideneimidaiudin-i-y Iphiinl)phenoxv-2
H, hydroxybutoxyacetamnidol-3,3-dimethlvbutanoyl-4-hydroxv-N-{[4-(4 methyl-1,3-thiazol-5-yl)phenyl.methy}pyrrolidine-2-carboxamide
1 31N H INMR (400MHz, CDOD): 6 8.84 (s,1i), 8.18 (d,j= 8.4 Hz, 2H), S04 (d, =84 Hz, i H), 7.71 (s, J= 84 Hz, 211), 7.57 (d,J = 8.8 Hz, 211), 744 (m, F 6)117.02 (d, J=: 8.8 z 211), 4.71 (s, 111), 4.56 (m, 3H), 4.33 (m, 11H), 4.17 in, 2H), 4.05 (n, 3H), 3,90 (m, 1H), 3.83 (m, iH), 3.60 On, 2H), 2.44 (s, 3H), 2.22 (m, 1)1,2.08 (m, 211), 1.90 I ., 160s6H),105(s,9LCMS (ES): miz 1040.20 [MH'i (2S,4R)-i-(2S)-2-{2-[4-(4-{4-[3-(3-chloro-4-cvanophenyl)-5,5-dimethyl-4
5 y N\ 3,3-diiethylbutnanoyl]-4-hvdroxy-N-[(1S)-I-[4-(1,3-oxazol- cH yi)phe-nyi]ethylwpyrroidine-2-carboxamnide 9
r N 1H NMR (300 MHz, CDOD): 6 8.22 (s, IH),7.97-7.95(d - 8.4 Hz, 111), 1 32 '7.89-7.88 (d, J=1.8HzI 1H), 7.75-7.58 (m,74), 7.47(s, 1H), 7.43-7,38(m, 4H) 7.06-7.01 (d, J14.1 lIz, 211) ,5.00 (m, 114), 4.69 (s, 1H), 4.61-4.55(m. 11), - N s 0 4.44 (s, 1H) 4.13-4.09It, =6.0 lIz, 211), 4.02-4.00 (d,,J=6.0 iz,2H), 3.8'7
3.76 (m, 2H), 3.68-3.64 (n 2H), 2.19-2.16(m, 1H),2.03-184 (, 511), 1.58 (s,
611), 1.9147id, J-6.9 lIz, 311) 1.04 (s, 911); LC-MS (ES'): m/z 974.20, 976.20 MH*]
Ex # Structure Compound name and Analytical data
(2S,4R)-i-[(2S)-2-{2-[4-(4-{4-[3-(5-chloro-4-cvano-2-iluorophenyl)-5,5 F C ~dim'ethy-4-ox-2-sufanyideeimidamoiidin-I NC,/ )ic N4- yliphenyl}phenoxy)hutoxyacetamde}3,dimehyibutanoyi]-4-hydrxy-N {[t-(1,3-oxazol-5-yl)phenyli]mehy'lpyrrolidine-2-carboxamide
133 H NMR(300 MHzCD3OD)68.23"(, 1H),..18-7.94 (m,2H), 774-7.65 (m, H OH 611), 7.50-7.40(m,511),7.04-7.01 (d,j= 8.7lz,211),4.71 (s. ll),4.60-4.56 m H), 4.53-4,34 (d,J= 15.2Hz, 1H), 41 2-4.0 (in, 2H), 4.08-4,01 (n,2H),
3.96-3.82 m, 211), 3.69-3.65 (m, 21), 2.23-2.20 (n, 111, 213-2.04 (n, 1H), 1.98-1.85(m, 41), 1.59 (s, 6H), LO(s,9H):IL-MS (ES): mz978.26[MH]
(2S,4R)-!-[(2S)-2-(2-{4-[4-(4-{3-[4-cyano-3-(trifluoromethylphenl]-5,5 HO dimethyi-4-oxo-2-suifanylideneimnidamoiidin-J-yl}phenvi)-2 methylphenxy]butoxy}acetaniido)-3,3-dimethyibutannoi]-4-hvdroxy-N-{[4 0 .,..NH ~ (4-methyl-1,3-thiazo-5-y)phenyi]mnethyijpyrrnuidine-2-carboxamide NHC
H NM.R (400 MHz, DMSO): 6 8.96 (s, IH), 8.61 (m, IH, 842 (d, J= 76 iz, 134 1 1),8.33 (s, H), 813 (d, J =8.4 Hz, 1H), 7.50 (d, J = 8.0 z, 2H), 7.43(d, J = 10.4 Hz, 71), 7.19 (d,I= 8.0 liz, 1), 6.83-6.89 (n, 2H), 5.17 (m, 1), 4.59
s (d,)= 9.6 Hz, 1H), .40-4.48 (m, 1H), 4.37-1.38 (m 211), 4.25-4.29 (n, IH), F 4.02-4.05 (m, 2H), 3.97 (s, 2H), 3.55-3.69 (m, 411) 2.45 (s, 311). 2.25 (s, 311), F1 .
F 2.05-2.10 (in, HI), 1.91-1.93 (m, 'H), 1.81-1.84 (m, 2H), J.72-1.75 (n,2H), N 1.55 (s, 611), 0.95 (s, 911) LC-MS (ES*): m/z 1038. 3 5 [MH*]
(2S,4R)--[(2S)-2-[2-(3- -(4-{3-[4-cy ano-3-(tifromethy)phenyl-5,5 diimethyl-4-nx,-2-sulfanyimdeneimidazlidn-1
yi}phenyl~phenyiicarbamoyi~propoxyace.tamid']-3,3-dimethybutanoyl]-4
Shydiroxy-N-{[4-(4-meCyl-1,3-oxazol-5-y')phenylmethyl}pyirIlidine-2
carboxai'de
135 I NMR (1400 Mz, CD 3 0D) 9-808.16 (d, 12.41Hz, 2, 8.13 (s, 111), N 8.04-8.01(d,.J= 1081z,H 7.78-7.75 (d,, = ''.2Hz, 2H), 7.75-7.60 (m,
N OH 611), 7.57-7.14 (i 411), 4.87 (s, 111), 473-4.57 (m, 3H), 4.52-437 (d,,J= 15. 0- H1 lz, 1H)s 4.10-4.05 (n, 2H), 3.96-383 (m 2Hl, /.70-3.66 (m, 21)s 2.59-2.54 (t, J = 9.6 Hz, 2H), 2.36 (s, 3H), 2 24-2.22 (m, It) 21'7 2.04 (n, 3H), 1.05 (s,
611), 1.03 (s, 911); LC-MS (ES*): iz 1021.25[MII
Ex # Structure Compound name and Analytical data
N diimcthyl-4-ojxo-2-suifaniideeivniridazolid'ini- I -IIphenvbl-3 inethyiphen.oxvibutoxylacetarido)3,3dir'-li(butarioyl.-i]-4 roxy-N-f[4
S- (4-mnethyl-i.3-dd~azil-5-vib hefnvlm.ethv ,)y.- iedine-2-c-arboxarntide
136 HINMPZ(400 MHz, CDOD):6 8,80(s, IHi, 81-8.IS fin 2H, 7.99-8Oi,0 fl 1 H). 7.72 (d. J=8.4 Hz, 2H),7.38-747 (m, SH) 6.98 (d. J=8.8 Hz, 11),41.70
N(Fi, 14,4.50-4'(m, 311), 4.31-4.34(m, ilIH), 3.96-4.11i(m-,4HX.181 -3.87
(On,"H),3.65-3.68(i.2H), .43(s. 3H),2.26 (m,4H1), 2.09 Ji, IH), 1.87 F 411), 1.59 (s. 611),1.0Y4(s. 91-);LC-MS (ES ): inc/ 1038.40 [MHv1 N~1.98(in.
S -- qfuno-phenyl)phenoxy'butoxylaceaLipdn)-3,3-dinehylbianoyi...i-hvd:oxy
caiboxafiide
137 o 11>A"l(40MHz,DM8)68.99(s.111),8.416-8-40(fi 211).8.36(s, 111), 8.15 (d.J= 8.0iz,I11). 7.78-7.67 (m, All, 7.45-7.35 (in.611)7.0(d4j=8.8
Nf n, 11) 4_0~ 4,11)111-4.08 m, 2H),3.96 js,211'.360-3._56(in, 41,2.46 (F, 1 4H, 2.07-2.03 (in 111), 1.8- 1.74 (in,5H1).1.62 (s, 311), 1.50(s, 3H), 1.3
(d,.J68 Hz 3H) 0.95 (s,9H); 1C-MS ffES ):mln1056.30 [MH]
i1ieffii--omo-2-su1fai ~deneimdazol idin -J1-yi3-3 0 NG fluormihenylhpheioxy iutoxyjacetaiido-3,3-dii.-edwbnanoyl4'lroxy FC N[(1S--[4-(4-riet flx-3-oxa.zo-5-v)fjjll IyI tvipyrroliie-2
caioxailde
138 1NIIR400 MHz, DM0) 6 8.416-84(m 211' 8.36 (s,1 81)A 1(1, S5 (ds..J==8.4Hz,1I111.7-78-7.67 in 4,7.57-748(n.1-1) .- 07.3s(, Hh-lry-- 1-1C7.09 (d,1=8.4Htz, 2H),S.15 (,; fiH'4.93-4.89(On,Hi,4.57'(d , 9.
H'11III'. 4.46-40 (m, 1lI-,4.28 s,114, 4.1-.07(in. 21-I),3.96Is211', 3.9 N. QW~H 1(n.11.235s.11,20-2.03Jim, 111), 1.84.,.73 (in,511),.1 6 S 311) .51 (s, 3H1)1.39 (J=6.4 liz, 311095 (s9H);:LC-MS (ES'): iz 100.252
Ex # Structure Compound name and Analytical data
(2S,4R--[(2S)-2-(2-f4-[4-(4-{3-[4-cyano-3-(trifluromnethyl)phenyl]-5.5 F,, P 0 dirmethyl-4-oxo-2-sulfanvlideneimidazolidin-i-yljpheny)-2 Na methioxvpheinoxybutoxy }acetamiido-3,3dimethylbutanoyl]-4-hydroxy-N-f[4 4-methyl-13-thiazo-5-y)pheuyImethylipyrrolidine-2-earboxami
0, 139 "I H0NMR (400 MHz, DMSO) 8.96 (s, 1H), 8.61 (s, 1H), 8.41 (d, J= 8.4 Hz Hi),8.33(s., H),8.11 (d, =8.0 Hz, 1H),7.83 (dJ=u8.4 z 2
HN (, i), 7.30-7.23 (im 21), 7.06 (d, -= -tI zI1 , 5.17 (s, 11), 4.57 (d, -= 9.2 Hz, I H), 4.46-4.36 (m, 3H), 4.30-428 (im, 1H), 4.06-4.03 (m, 2H), 3.96 (s, N H2H), 3.86 (s;, 3), 3.67-3.56 (m, 4H), 2,44 (s, 3H), 2,08 (s, I1), L85-1.75(m 5H), 1_55 (s, 611).095 (s, 911) LC-MS (ES): z1054.25 [MHW] (2S,4R)-i- (2S)-2-(2-{4-[4-(4-{3-[4yan-3-(trifluoromethyl)pheny]-5.5 dimethyl-4-oxo-2-sulfanylideneinidazolidin -1-ylIpheny)-3
Nmethoxvpeiioxy]bJtoxyaceamiiid)-3,3-dimethylbiuranovl-4-hydroxy-N-{[4 ONH ( (4-methyl-1,3-tnizo-5-yl)phenylmethylpyrrolidine--crboxamide
140 H1 NMR (400 M1z, DMSO) 6 8.96 s 111), 8.61 (s, 1l), 8.41 (d, J= 84 iz, H), 8 33 (s, H), 8P12 (d J = 1.6 H z, 1 ') (d 7.64 J = 8.4H z, 2) 7.43-7.37
(i, 7D, 7.28 . 8 Hz, 1H), 6.68-6.61 (m, 517IsD),4.57(d F F 9.6Hz, 1-(11), 4(m )4.30-4.28 (m, 1H),4.06-4.03 (m,211),3.96(s,
2H), 3.86 (s 3H), 3.67-3.56 (m, 4H), 2.44 (s, 3), 2.08 (s, I1), 1-85-1.75 (m, 51) 1.56 (s, 6H), 0.95 (s, 911); LC-MS (ES): nz 1054.25 [MH] (2S.4R)--(S)2(2-[(4)-4-4-(4-3-[4-can-3-ifluromiehyl)phenyl] Fly 5,5-dim'ethyl-4-x-2-sulfanylideneimidamolidin-1 yl phenyl)phn aoxypentyloxyacetamido)-3,3-dimethylbItanoyl]-4-hydroxy -NH ci ' -- N-f[4-(4-methyl-±,3-thiazl-5-y)phenylimethylfpyrrlidine-2-carboxamiide aN
(2S,4R)-1-[(2S)-2-(2-f[(4R)-4-[.4-(4-{3-[4-cvano-3-(triluoromethyl)phenyl]
5,5-dimethyi-4-oxo-2-sulfanylideneimidazolidin-1 ylfphenyl)phenoxyipentyloxy}aetamido)-3,3-dimiethylbutanoylI--hydnoxy N-f[4-(4-methyl-1,3-thiazol-5-v)phenyl]methylipyrrolidine-2-carboxamide
141, 14 2H NMR (400 MHz, CD3OD) 6 8.84 (s, 1H), 8.19-8,17 (d,J= 8.0Hz, 2R), 142 8.04-8.02 (d, J= 8.4Hz, 11H), 7.75-7.73 (d,J = 8.4Hz, 2), 7.607.58 (d, = H C4Hz, 2H), 7.49-7.41 (in, 611), 7.03-7.01 (d,J:= 8.81Hz, 21H,4.87 1sH 4.734.58 (m, 4H), 4.50-4.39 (d, J= 15.2 ilz 1), 4.0-24.00 (n, 2H), 3.91 3.88 (m, 1), 3.84-3.83 (im, 1),3.64-3.62 (m, 211),.46i(s,311), 2.25-2.23 (i, ID), 2.13-2.11 (m i H) 1.78, 4H), 1.62(s, 6H), 1.37-1.34 (m, 3), 1.12 (s, 91) LC-MS (ES*): m/z 1038.15[ID]
H NMR (400 MHz, CD3OD) 6 .884 i s, I), 8.19-8.17 (d, J= 8.OHz, 2H), F 8.04-8.02 (d,,.= 8.4Hz, 1H), 7.75-7.73 (d, J= 8.4Hz, 211), 7.60-7.58 (d,J= 8.4Hiz, 211,7.49-7.41 (ms 6H),'7.03-7.01 (d,J = 8.8Hiz,2H), 4.87 (s, i H),
Ex # Structure Compound name and Analytical data
4A.73-4.58 (mi,41-b, 4.50-4.39(illJ=- 15.214-'114'".4.02-4.00(11,1,3.91 31.88(im, M1) 3.4-3.83(1,114i),3,64-3.62(in2H146 s3) -2,23 6 (i, 111).2.13-2 11 (mi, 1 1).1.86-178 --in,411),1- 2(s,61', 137-1.34 (in.311),
1.12 (s.91-i):ILC--MS (ES*): mz1038.5M14
(2S,4R)-1-(S--2(-[)-4{-4cain3(riuriehipiiyi55
N r c arbox arnido
143 IIINMR (400Mliz, CD 30D) 68.20-8.17(in, 3148, 8.380- , I.i-z. 114).773-7.7 ( d, J= 84fi2-)14 7.70-7.67(d,Jj:- 41z, 21).63 -7.61 (d,J i =8.-I-li.21-),7.57.40(i, 414.678-676 (d,'-=8AHz1211, 501-500 (i, 111 4.487(-.t) 4.62-4.60,iim Ib) 4.58-A.56(n. 111), 4.07-4.00 (m, 211).
F3.88-3.85i 1-1), 3.8-.7 i(m, -3.63 'rfi, 214)31.23-3.22(,14)
NFF2.41 (s 314' 22422 2(inI1), 1.97-1.96 (n H 1.80-1.7(it,414).1.61 (s, 61) -. 48i (d' 4.4fiz,3 I.-(FC9H41 1C-ivfSFS'):r 102 1. 5SI'MH 42SAR('('12[(' a )i [-.eyao-i(tr~lnrorehI)phenyli-5,5
'~-~" ,.-N v:re.n-Yt'ofvaceamnd1-3,3-dimnethytbi'tanoyi1-4-tlvclroxy-N-f-.4-(,4-mnethy
144 II4NMPZ(400 MHzCD-01)6 9,01(s114), 8,89Is,114)t, 8.72-8.70 fIn, t 0, ~~11'. 8.21-8.18(in, '1)04-7.96(in,.11H), 7.65-74' (mi 11)i46-7.38 (ini,4 ~N- II') 14 734TI IHs4 63 50 fn--i 3 H, 4.41-437(mIH) 14.05 -399 (m, 2 I)
@-( 3.89-.8(isII), 3.85-8n'r-i, 11H), 3.63-3.60(In, 2l 1),314-3.i0(in.2 I-I, 2((s3I11),20228 (m, '[-I).2.15-2.0)3 (n 1 149(mn.2-1),
N- ~178-1.76 fn,2 H), 1.31 59 (m, 8 tl).1.01 fs, 91) C-M'18'):12 10234141N1
207~
Ex # Structure Compound name and Analytical data
(2S.4R)i-i-(2)-2-[2-4-([-4-3-4-yan-3-(ifluromethyi)phenyl]-5,5 HO iimethyl-4-oxo-2-sulfanvideneimidazolidin-I
yl}phenyl)phenyl'amino}butoxv)acetamido]-3,3-dimethylbutanoyl]-4 a o~ obhdroxyvN-[()--[4-4-metyl-3-thiaoi-5-y)phenlehylpyrroiidine-2
145 ¶CS~ ~~~carboxamnide 145 e'irN H NMR (300 MHz, CDOD) 8.95 (s, H), 8.19-8,16 d,= 8.7Hz, 2H, 4 8.03-8.00(d,J= 8.11zi Hm4),7.87-7.82(m,411), 7.53-7.37 (m, 8H1),5.01-4.99 N s n, IH),4.87 (ss,4H),4.70-4.68n1H),4.56-4.54 (mi (m, 1H)4.08-4.05 nm, F 2H), 3.83-3.80 (m, 2H), 3,70-3.59 (m, 2H), 3.52-3,47 (i,2), 2.48 (s, 3H), S2.2-2.22 (m, 1H), 1.98-1.89 (m, 5H), 1.61 (s, 6H), 1.61-1.60 (m, 11), 1.56 1.54 (m,2H), 1.03 (s, 9H); LC-MSES*): m/7 1037.10[MHI HO (2S,4R)--(2S)-2-(2-{4-[4-(4-{3-[4-cyann-3-(riromethyiphenyl]-5,5 H diimethyl-4-oxo-2-sulfaiivideneimidazolidin-1-yll-3 - NN oD NH lnuorophenyl)phenoxy]butanamido}acetamido)-3,3-dimnedlvibutanioyl-4 HI hvdroxy-N-{[4-(4-miethyi-i.3-thiazol-5-yl)phenyli]rethyl}pyrrolidine-2 N. carboxaide 146 H NMR (400 MHz, CD30D) 8.87 (s. H), 8.19 (m, 2H), 8.05(in, IH), 7.64 F (d,J= 8.8 liz, 211), 7.59 (m, ), 7.49 (m, 311), 7.41 (m, 211), 7.04 (d, J= 8.8 Hz, , 2 4.88 (s, I H), 4.66 (m, 3H), 4.3 (m, I H), 4.1 i (im, 2H), 3.92 (m, 3) 3.80(m H) 2.54(im 2H), 2.47(S,3H), 2.23-2.09(ni,411), .68(s,311),1.57 N (s, 3H4),1.05 (s, 9H); LC-MS (ES'): m/z 1055.10 [MI 1
(2S,4R)-1-(2S)-22--[(2S)-5-[4-(4-{3-[4-cyano-3-(tifluoroiethyl)phenyl] 5,%5-imethyl-4oo2slayiecmdzldini-1-yl Ifphenyl)phen1oxyl pen tanl 2--:oxy acetamid)-3,3-diethlvbutanoy]-4 -hydroXy-N-{[4-4-methyl- 1 ,3
NN~~h 5,5-hinzol-5yl4he nlfethlidpyrro znl-2-boxamienihnxvPi
(2SR -[(S)-2-(-{[(2R--[4-(4-{3-[4-cyan-3-(rifluromethl)henyl] 5,5-diimethyl-4-oxn-2-sufanlideimidamolidin-I-y'i}phei)phenoxy~pentan s 2-yi]oxy}acetaiido)-3,3-dimethylbutanVo'-4-hydroxy-N-i[4-(4-nethyl-1,3 F- J, thiazol-5-yl)phenyl]iehylpyrrolidine-2-caroxamide 147, F HO0 148 H NMR(400 MHz, CDOD): 6 88 (s, HI , 818-8.15 (m, 2H), 8.02-8,00 (d 1=8.4Eli,11H),7.7270 -N (d, J= 8.8 Hz, 2H), 7.58-7.55 (d, j= 8.8 Hz, 211), 'H 7.47-7.38 (m , 611), 70'-6.09 (d, 4.8lz, 21), 4.86 (s, 1), 4.58-4.50 (m, 311), 4.35-4.31 (m, 1H), 4.09-4.05 (m, 3), 3.86-3.81 (m 311), 3.71-3.61 (n, - N I), 2.47 (s 311), 2.37-2.23 (m, 1H), 2.11-2.09 (m, 11H), 2.02-1.87 (m. 211), .84-1.68 (, 2H), 1.59 (s, 6H), 1.26 (s, 3H), 1.02 (s, 9H); LC-MS (ES'): r/z 1038.10 [MHl]
FH NMR (400 MHz, CD-0D): 6 8.88 (s, IH) 8.18-8.15 (in,2H), 8.02-8.00 (d, F J=8.4 Hz, 1 H), 7.72-7.70 d = 8.8 lz 211), 7.58-7.55 (d,,J= 8.8 HI,2H, N
Ex # Structure Compound name and Analytical data
7.47-7.38 (in 61i, 7.01-6.99 (dJ=4.8 Hz, 21H,,4.87 (s, 111),14.70-4.50 (i, 3H), 4.36-4.32 (m, IH), 4,09-4.00 (m, 4H), 3.86-3,81 (m,3H),2.47(s,3H), 2.37-2.23 (rn, 1H)2i1-2.09 (m, I111) 2.00-1.85 (i 211), 1.84-1.68 (n, 21), 1.58 (s, 6H)1.23 (s, 311,.01 (s, 9); LC-MS (ES*):Wz 1038.10 [MH4"
(2S,4R)--[(2S)-2-(2-{4-[4(-{3-[4-cyaio-3-(trifiuromethl)phenvl]-5,5 dimethy-4-oxo-2-sufanyidJeneimisdazoiidin -1-yl}pheny)-3 -Y' H fluor-ophenoxyibutoxyaetaido)-3,3-dimethylbutanovi]4-hydroxy-N-{[4-4 -methyl-1,3-thiazoi)phenylmethyijpyrroiidne-2-carboxaide
149 H NMR (400 MHz, CDtOD): 8.80 (s, IH).8.18-8.12 (m,2 H), 8.00-7.95 (s, I H), 7.65-7.60 (m, 2 11), 7.45-7.35 (m, 7 H), 6.88-6.72 (m, 2 11), 4.65 (s, 111) 4.61-4.52 (s, 1 H), 4.50-4.35 (m, 2 H)s 4.32-4.22 (s, I H), 4.18-4.02(, H),
F- 4.00-3.94 (n, 2 H),3.95-3.75 (m, 2 H), 3.74-3.55 (m, 211),2.40 (m, 3 HI 2.28 2.15 (s, 1 ), 2.14-2.01 (s,1iH),2.00-1.72 (m, 411),1.68--.48 (m, 611), 1.00 9 H); 1LC-MS (ES*):im 1042.05 [MH]
[05991 Examples 135, 143-145 were synthesized according to similar procedures described for
the synthesis of examples 103, by using corresponding starting materials and intermediates.
[0600] Synthesis of example 103:
H2N NH(oc) 2CK 2C H2N N TMSCN 2 NC'\I N -N - N c -------- -------- ------- H2 \. \ N 2 Stepl /Sep 2 NCS
Nuc2 '~ \-- HN NNHBoc HC --NH2 O DMAP r 4 HOAc NaBH(OAc 2 Step 3 S S Step 5 NC NC CF 3 3
0 - 0,O OTFA N N--//H INC CNN- -,N- H N Step 63 \S
S NC
HN 0H
N NHN - H o
-IAT-', DIPEA DMF Step 7- Ct 3 Example 103 <S- I1 N
[0601] Step 1: Synthesis oftert-butyl N-44-aminophenylphenyillcarbamate:
H 2,N / / NHBoc
[0602] To a stirred solution of 4-(4-aminophenyl)aniline (15.0 g, 81.42 mmol) in a mixed solvent of N,N-dimethyiformamide / tetrahydrofuran /water (v/v/v = 100/300/50 mL) was added
potassium carbonate (9.5 g, 68.74 mmol) and di-tert-butyl dicarbonate (13.67 g, 62.63 mmol) at
room temperature. The resulting mixtire was stirred for 5h at room temperature. The reaction was
then diluted by water (500 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers
were combined, washed with brine (50 nL x 2), dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to give a crude residue which was purified by silica gel flash
chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:2) to provide the titled product
(yield: 97%) as a yellow solid.
[0603] Step 2: Synthesis of tert-butyl N-(4-{4-(1-cyano-1 methylethyl)amino]phenylphenyl)carbamate:
NCHN- NHBoc
[0604] To a stirred solution of tert-butyl N-[4-(4-aminophenyl)phenyl]carbamate (7.0 g, 24.62 mmol) in acetone (100 mL) under an atmosphere of nitrogen was added trimethylsilanecarbonitrile (4.9 g, 49.49 mmol) drop wise at 0 °C, followed by addition of iodine (630.0 mg. 2.48 mmol) in several batches at 0 °C. The resulting mixture was stirred for 15h at room temperature. The reaction was then quenched by the addition of water (100 mL), and the resulting solution was extracted with ethyl acetate (100 mL x 2). The organic layers were combined, washed with brine (70 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:3) to provide the titled product (yield: 87%) as a yellow solid. Mass (ES'): mlz 352.20 [MH+].
[0605] Step 3: Synthesis of tert-butyN-[4-(4-3-[4-yano-3-(trifluoromethyl)phenyl]-4-imino 5.5-dimethyl-2-suIfanylideneimidazolidin-I-yl}phenyl)phenyl]carbamate:
HNI N -- NHBoc
NC CF3
[06061 To a stirred solution of tert-butyl N-(4-{4-(1I-cyano-I methylethyl)aminolphenyl)phenyl)carbamate (3.1 g, 8.82 mmol) in toluene (40.0 mL) was added 4-dimethvlaminopyridine (1.6g 13.10 mmol) and 4-isothiocyanato-2 (trifluoromethyl)benzonitrile (2.0 g8.76 mmol) at room temperature under an atmosphere of nitrogen. The resulting solution was stirred for 12h at 100°C in an oil bath. The reaction mixture was then concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:1) to provide the titled product (yield: 36%) as a yellow solid. Mass (ES*): m/z580.30 [MH].
[0607] Step 4: Synthesis of 4-{3-[4-(4-aminophenyl)phenyl]-4,4-dimethyl-5-oxo-2 sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile:
C -2
NC: CF3
[0608] To a stirred solution of tert-butyl N-[4-(4-{3-i[4-cyano-3-(trifluoromethyl)phenyl]-4 imino-5,5-dimethyl-2-sulfanylideneimidazolidin-1-yllphenyil)phenyl]carbamate (2.0 g) in methanol (20 mL) was added hydrogen chloride (3 N solution in water, 5 mL) at room temperature. The resulting solution was stirred for 2 h at 70°C in an oil bath. The reaction mixture was then concentrated under reduced pressure to remove the bulk of methanol. To the resulting aqueous mixture was added sodium bicarbonate (sat. aqueous solution) to adjust the p-I to -- 8, and the resulting mixture was extracted with ethyl acetate (80 mL x 3). The organic layers were combined, washed with brine (30 mL x 2). dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v:v =1:2) to provide the titled product (yield: 45%) as a yellow solid. Mass (ES'): i/z 481.15 [MHI].
[06091 Step5: Synthesis of tert-butyl 2-(4-{[4-(4-{3-[4-cano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-sulfanyilideneimidazolidin-1-yllphenyl)phenyl]aminoibutoxy)acetate:
NC
NC'y CF 3
[0610] To a stirred solution of 4-{3-[4-(4-aminophenyl)phenyl]-44-dimethyl-5-oxo-2 sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (200.0 mg. 0.42 nnol) in dichloromethane (10 mL) was added acetic acid (0.01 mL) and tert-butyl 2-(4-oxobutoxy)acetate (93.0 img, 0.46 mmol) at room temperature. The resulting mixture was stirred for 10 min at room temperature, then to the mixture was added sodium triacetoxyborohydride (124.0 mg, 0.59 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted by water (30 mL), extracted with dichloromethane (20 mLx 3). The organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v:v = 1:2) to provide the titled product (yield: 36%). Mass (ES'): i/z 667.20[MH].
[06111 Step 6: Synthesis of2-(4-{[4-(4-{3-[4-cyano-3-(trifluoromethyli)pheny]-5,5-dimethyl-4 oxo-2-sulfanylideneimidazolidin-I-yiIphenyl)phenyl amino}butoxy)acetic acid:
2 12
HOH
NC CF 3
[0612] To a stirred solution of tert-butyl 2-(4-{[4-(4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5 dimethyl-4-oxo-2-suIfanylideneimidazolidin-1-yI)phenyl)phenyl]aminoIbutoxy)acetate (100.0 mg, 0.15 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2.0 mL) at room temperature. The resulting solution was stirred for 2h at room temperature. The reaction mixture was then concentrated under reduced pressure to give a crude material (yield: 99% based on crude) which was used for next step reaction without any further purification. Mass (ES'): wZ 611. 10[MH*"]
[0613] Step 7: Synthesis of example 103.
[0614] This compound was synthesized from-(4-{[4-(4-{3-[4-cyano-3 (trifluoromethyl)phenyl]-5,5-dimethiyl-4-oxo--sulfanylideneimidazolidin-1 yl}phenyl)phenyl]aminolbutoxy)acetic acid and(2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl] 4-hydroxy-N-{[4-(4-metlhyl-1,3-thiazol-5-yl)phenyl]methyllpyrrolidine-2-carboxamide hydrochloride, according to similar procedures in the last step (amide coupling) described for the synthesis of example 75.
[0615] Synthesis of tert-butyl 2-(4-oxobutoxy) acetate:
HO 0 ~ DMP
[0616] To a stirred solution of tert-butyl 2-(4-hydroxybutoxy)acetate (1.0 g, 4.90 mmol) in dichloromethane (10 mL) was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.7 g, 6.37 mmol) at room temperature. The resulting mixture was stirred for 12h at room temperature. The reaction mixture was then diluted with water (20 mL), extracted with ethyl acetate (20 nl x3). The organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v/v 1:2) to provide the titled product (yield: 50%) as colorless oil. 1H NMR (300 MHz, CD 3 0D) 6 9.68 (s, 1H). 3.95 (s, 2H), 3.48-3.45 (m, 2H), 2.51-2.50 (m,2H). 1.81-1.63 (m, 2H), 1.42 (s, 9H).
[0617] Table 8. Exemplary Compounds.
Ex # Structure Compound name and Analytical data
HO (2S,4R)-1-[(2S)-3,3-dimethy-2-(2-{[5-(4-{[trans-3-(3-chloro-4t-cyanopheinoxy) 22,4,4-tetramethvicyclobutvlcarbamovilphenoxy)pentyl]oxyiacetamnid)butanoy NH 4-hydroxy-N-{[4-(1,3-tinazo-5-yl)penylrmethyl}pyrrolidine--crboxamide
N 1 0H NMR (400 MHz, CDC 3): 610.95 (s, 9H), 1.22 (s, 6H), 1.27 (s, 6H), 1.56-158 (m 150 2H), 1.68-1.70 (m, 2H), 183-1.86( 2.11-212 (ms 11-),2.54 (br, 1H), 3.52
3N63 (, 3H), 3.91-4.16 (i, 7H), 4.28-4.54 (m, 5H), 4.70-4,71 (,iH), 6.19 (d,,,= 6.8 Hz, 1H), 6.80-6.97 (m 411', 7.17 (d, = 8.4 Hz, 1H)', 7.32 (d,J= 6.8 Hz, 2H), 7.48-7.58 (m, 3H), 7.72-7.4 (m,2H), 03-810(, 2H), 8.8 (br,1H); LC-MS:
N (ES): nz 941.20 [M+H*]
(2S,4R)-1-(2S)-3-imetl-2-(2-[5-4{[tlans-3-(3-chloro-4-cyanophenox HO S2,2,,4-tetramethyleyelobutvll carbamoilphenoxy)pentyloxyiacetamido)butaov
4l-hydroxy-N-{[-4-(4-m.,ethyl-1,3-thliazoli-5-yl)phenyl rmethyltpyrrolidine-2 NH CarboXamide
H NR (400 MHz, CDC) 5 8.67 (s, 1H), 7.72 (d, 1= 9.0 Hz,2H, 757 (d, J= 8,6 151 H 1H), 7.3 1-7.8 (m, 4H), 7.20 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.92 (d J = 8.6 Hz, 1H), 6.81(dd, J= 25,8.8 Hz, H), 6.19 (d, J =8.2 Hz, H), 4.72 (t, = 78 Hz, 1H), 4.47-4.58(i 311, 4.31-4.41 (m, 1H), 3.87-4.18 (m, 7H), 3.73 (s, 1H) 0 3.58 (br.s., 21,354 (t J=6.5 Hz,2H), 3.48 (s, 1H), 246-2.55 (m, 3H), 2-08217 ci (1H), 1.80-1.88 m,.2H), 1.65-1.74 (in, 2H), 1.53-1.61 (m, 2H), 1.46 (s, IH), 1.26 (br. s., 61),1.22 (s, 61), 0.95 (s, 91). LC-MS (ES*): m z 955.42 [MHF]
(2S,4R)-I-[(2S)-3,3-dimethvi-2-(2-{[5-(4--{trans-3-(I -chloro-4-cyanophenoxy) 2,4,4-tetramethylicyciobutyljcarbamoyl}phenox)penty]oxvy}acetamido)butanoy] HO 4-lvdroxy-N-f{-4-(4-methyl-1,3-oxazol-5-yl)phenyl-methyllpyrrolidine-2 carboxaimde ONIH
H NMR (400 MHz, CDC 3) 8 7.85 (s 111), 7.72 (d, 8.6 Hz,21), 757 (d, J 86 152 Hz,1H),7.52 (d, J = 8.2 Hz, 2H), 7.35 (d, I = 8.2 Hz,31H), 7,20 (d, J = 8.6 Hz, i ), 6.97 (d, J = 2.7 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2I), 6.81 (dd, J = 2.3, 8.6Hz,1 6.20
(d= 7.8Hz, II), 4.70 (t, J=: 7.8 H i H1), 4.8-4.56 (m, 311), 434 (dd, J= 53, 15.1 o Hz, 1H), 4,12-4.16 (in, 1H), 4.04-4,09 (m, 2H), 4.01 (t, J = 6.3 Hz, 2H), 3.85-3.97 (m
N : 211), 3.63 (dd, J = 3.3,11.2 Hz, 1H1), 353 (t, J 6.5 Hz, 211), 2.49 (ddd, J = 4.7, 8.0 131 Hz, 21), 2.4 (s, 31), 212 (dd, J:= 82, 13.3 H z,IH) 1-80-1.86 (n, 2H),1.65 1 172 (m 2H), 1.53-1.60 (n _ H), 1.26-1.28 (m 6H), 1.22 (s, 6H), 0.96 (s, 91). LC MS (ES'): m/z 940.44[MH-,
Ex # Structure Compound name and Analytical data
(S,4R)-l-[(2S)-3,3-dimnethy-2-(2-{[5-(4-{[trans-3-(3-chioro-4-ceyanophenoxy) HQ ,2,4,4-wetamethyicyciobutylcarbamoylijphenosy)pentyl]oxy jaCesamido)burtainy O N 4-hydroxy-N-{[t-(1,3-oxazol-5-vl)phenyl]methyli}pyrroldine-2-caboxamide
H1NMR (400 MHz, CDCI3) 67.91 (,0H)7.72 ( .0 Hz, 211),7.54-T57 (m, o W111)7.34 (s, 311) 7.21 (d, J = 8.6 Iz, 111), 6.96 (d, '=.3 1z, IH), 6.92 (d, J = 9.0 153 Hz, 2,11 6.81 (dd J:= 2.5, 8.8 Hz,i H) 6.21 (d1 J=78 Hz, 1 H), 4.69 (t, J=: 80 Hiz HN 1H1), 4.484.55 (m, 3H), 4.32 dd, J = 5.3, 15.1 Hz, 1111, .15 (d, J = 7.8 lz,1H), 3.98-4.08 (m,4 ,3.84-3.97 (m. 211),3.63 (dd,J=3.5 11.3 Iz, 1H), 3.53 it, J = 6.3 Hz, 2H), 2.40-2.57 (n, 4H), 2.11 (dd, =8.0, 13.5 Hz, 1H, L79-1.88 (m, 2H), 1.64 S1'73 (m, 211) 1.51-1.60 (in 21), 1.27 (s, 6H), 1.22Is, 6H), 0.96Is, 9H). LC-MS (ES ): m/z 926.42 [MH*] (2S,4R)-i-[(2S)-3.3-dimethyl-2-(2-([5-(4-{[trans--3-[4-cyan-3 (trifluoromethyl)phenoxy]-2.2,4,4 tetramehyleyiclobutyiarbamnoyl}phenoxypenyi]oxy}acetamido)butany]-4 hydroxy-N -{[4-(4-mnethyi-1,3-oxazol-5-y)pheny]]methyi}pyrrlidine-2-cearboxamiide
154 1 HNMR(300 MHzCD 3 OD):8.10(s,111),7.90-7.83 (in, 1 H), 7.80-7.71( 2 H), 7.60-7.52(m,2 H),7.49-7.541 (r,2iH), 7.32(s, I H), 723-7.19 (m, i H),T7.0-6.89 (m, 2 H), 4.67(, 1 H), 4.60-440 (m, 3H), 4.35-4.25 o, 2 1), 4.154.10 (, 1 H), 1.09-3.98 (m, 2 1), 3.97-3.90 (m, 2 H), 3.85-3.70 2 11, 3.63-3.49 (m, 2 11), 2.40 N i(s 3 H), 125-210 (m, I H), 2.09-2.00 (in, I H), 1.89-1.79 (m, 2 H),.80-1.45m, 4H), 1.33-1.14 (in, 12 1), 101 Is, 9 H); LC-MS (ES*): mz, 973.35 [MH*] (2S,4R)-i-[(2S)-3,3-direthyi-2-(2-{[5-(4-{[trans-3-[4-cyano-3 (rifluoromethyl)phenoxyi-2,2,4,4 tetrarnethycyclobuylcarbamylpenxypentyloxv)aetamido~butannyl] O>NH a iroxy-N-{[4-4-methyl-1 3-tiazol-5-vli)henylrmethyl}pyrrolidine-2-carboxamide
155 o H1NMR (300 MHz, CD3OD): 8.84 (s, I ).7.90-7.84 (n, H),7.80-7.70 (, 2 H), 7.45-7.32 (m, 4 H), 7.26-7.2 ,1),7.28-7.20 (im, 1 ), 7.00-6.89 (m, 2 H), 4.67 NH (s, Hi,4.60-4.50 (, I H) 4.46-4.40 (m, 1H), 4.27-4.20 (, 2 H), 4.13 (s, H), 4.15-4,00 (m, 1H), 3.99-3.95 (im, 2 ), 3.90-3.80 (m, 2 1), 3.59-3.51 (i, 211), 240 (s,311, 225-2.10(m,I IH2 1-2.00(m, 11H), 1.85-).75 (m,2H), 1.70-1.50 (in4 H), 1.33-1.14 (m, 12 H), 1.01 (s, 9 H); LC-MS (ES*): mz, 989.30 [MH]
Ex # Structure Compound name and Analytical data
(2S,4R)-i-[(2S)-3.3-dimethy-2-(2-([5-(4-{[trans--3-(3-chloro-4-cyanophenoxy) 2,2,4-tetramethyleyeinbutylcarbamoyl}phenoxy)pentylloxyaceamildo)butaiinov HO 4-hydroxy-N-[(S)--[-(-mety-1,3-xaz-5-yl)pheniyl]ethyl]pyrrolidiie-2 0H - carboxamide 01NH
N 1H NMR (300 MHz, CDOD): 8 8.14 (s, I H),7.85-7.80 (n, 2 H), 7.78-7.72 ( iH 156 2 H7.47740 (m. 211), 7.15-7.10 (m, .7.5-7.55(m, I 11, 7.15-6.95 (m, 3 H), 5.03 NH 4,94 (i, U), 14.67 is, ' H)4.60-4.50 (m, I H), 4, 46- 4.4 0 (m, I H), 4.27-4,25 (m, ),415-4.00(in, ), 3.99-3.95 (, 2 H),3.90-3.80 (m, 1 11) 3 79-3.80 1 3.63-3.49 (m, 21H,2.40(s,311), 2.25-2.10(m., 1H), 2.09-1-80 (m,311), 1.79-1.50 (m, 4 H), 1.48-1.46 (m, 3 H), 1.33-1.14 im, 12 H), 1.01is, 9 H) L-MS (ES*): m z 953.35 [MH*] (2S,4R)- -[(2S)-3,3-dimretln-2-(2-{[5-(4-{[trans-3-(3-chlr-o-4-cvanophenoxy)
HO 2,2,4,4-tetramchylcvcbutyljearbamoyllphennxv)pentyl]oxyjacetamido)butanoyl N >- HA 4-hydrnxy-N-j(IS)--[4-4-methyl-,3-hiazni-5-y)phenyliethylipyrronidine-2 %NH carboxamide N
157 iH NMR (400 MHz,, CD3OD): 8 8.90 (s, I Hl)sT785-7.00 (mn, 3 H), 7.50-7.39 (m, 4H), .15-7.10(s,H,7.05-6.95 (m. 3 H), 5.05-4.98 (m, 1 1)4.70(, IiH) 4n54.5 S(m, 1 H), 4.48-4.40 (m,i H), 430 (s, 1H), 4.15-4.10(ms 3 1), 4.00 (2 H), 4.02 3.70(m 2 11),3.70-3.58 (m, 2 H), 2.50(i, 311), 2.45-2.35 (m, 1 H), 2.28-2.15 (m, Hm,2.08-i.82km.411),1.80-1.45 (m,7 11),1.39-1.20 (im, 1211),1.10-1L00 (m, 9H) LC-MS (ES): mz969.50 [MH*] HQ
N 0 QNH
(2S,4R)-1-[(2S)-3,3-dimethyl-2-(2-[(2R)-6-(4-{[trans-3-(3-chinrn-4-cyanophennxy) 2,24,4-tetamethyleyclobutvliecarbamvl}phenoxy)h1exan-2 Syloxy }acetaiidobutanoyl-4-hydroxy-N-{[444-methyl- 1,3-diiazol-5
158, 1' yhenyi]methyl}pyrroiidine-2-arboxarnide IN Ho 159 H N (2S,4R1)-I-[(2S)-3,3-dimsethyi-2-(2-[2)--4{[dtras--3-hor--caopeox) S 22,4,4-tetramethvicvcibutyl'carbamoyilphenoxv)hexan-2 s l-oxy}acetamido)butanoyl]-4-hydroxv-N-{[4-(l-metl'-1,3-thiaznl-5 0 iy)phenyl]merhyl pyrroldine-2-carboxainide
N
Ex # Structure Comnpound namneand Analytical data
I (2S4R)-i-IS-33 Omtv-2i-[(5S)-5 -(4-{[tIratts-3-( .Ino--ynohnx 1 ,,~'-tetr-arethyicyciobutvlie-a-bamni(vllphenoxy)hlexvy'oxvlae-etrnidnL.)butanosll1]4
O'NH
N (1S,4R)- -[2S)-33-d~rie1;vi-2-(2-{[I5R)-5-(4 -{[trans -3 -(3 -chlno4cnn~nxt -1 2,4,,4,-tctrarnethy!yccbtyI carbany phenoxv1.hexv] oxyl aceearidlobutancxiI 4
HIINMR(300 MH,CDODI): 6 88(s, 111), 775-7.67 (r.3H), 7.4,1736 (n, 4H).1 1N. 700(s,11-i), 6.06-6.91(i, 31), 4-84 (:,]IH), 4-66-4.47fn, 4 H), 4.36-4-31(MS 161 H H, 426Is,1H)t, 4,24I(s,1Ht,4140 s,1H)l393-391 fin, 2H), 3.83-.5.78I(ni2 H), 3.5-3.51 (in,2-1-,1,2-43 (s, 3 1,2.12-2.10(in. 1-1), 2.09-1.95 (in, I11).1.67-1.62
i.6 H),1.30-1298(m, 9H),1.18(s6H'', .00(s9OH) LC-MS (E ):~7m/z96U
[MI]
NH I fi~~NMR(300Mliz.CD 3OD):68.88(sIH),'.75-7.67(i,3Hi),7.44 7.6( in 4H, 7.10(s,IH1). 6.96-6.91(nH,6IH,5-.8riI ~(sr cl ~ ~ ~ ,4.24 (s, 11',,4.10I(s, 11I', 3.921-3.86(in, 2Hv)3.83-".5I ( , ,3533.5.
( N ~ ~~~2H1). 2.43 (, "3H).2.20-2.10 (m il,,209-2.01in,1H),1.67162 (n,6H f 130 (s, 9H1). 1.19 (s, 614),1100(s,9 14);LC-MS -ES+):wnz 9691 5[MII"
[0618] Synthesis of example 150:
HO~-O H 0.I O
H: H2 HATU,D:PEA,r)MF s1 o ) HF,H20 Step Step 2
PH OH
HOt P`:-K 4-N
HATU, DIPEALIMP OFc / Step 3 NC ExamPle 150
N
[0619] Step 1:Synthesis of m thl 4{[5( [2S)- 1--2S,4R)-4--hydrox..2.( [4-.(i,3-.thiazoi-5 yi)phienyiltmethyllca.rbanx.y)pyrroidin-i -yi]-3,3-dimethyl-1I-oxobutan-2 yl]carb~amoyllmethoxy)pentyl]oxyilbenzoate:
21 7 o0y0 JH
[0620] To a stirred solution of 2-({5-[4-(methoxycarbonvl)phenoxy]pentyl}oxy)acetic acid (200 mg), (2S,4R)-I-[(2S)-2-anino-3,3-dimethylbutanovli--4-hydroxy-N-{[4-(1,3-thiazol-5 yl)phenyl]methyllpyrrolidine-2-carboxamide hydrogen chloride salt (149 mg. 0.32 mmol), N ethyl-N-isopropylpropan-2-amine (185 mg, 1.44 mrnol) in anhydrous N,N-dimethylformamide (5 mL) was added HATU (2-(7-aza-iH--benzotriazole-l-y)-l.,1,3,3-tetramethyluronium hexafluorophosphate )(203 mg, 0.54 mmol) at 0 °C. The resulting mixture was allowed to warm up to room temperature and stirred at room temperature for20 min.TLC and LC-MS showed formation of the desired product. The mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was collected, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent 2% methanol in methylene dichloride) to afford the titled product (yield 25%, 2 steps) as a white solid. Mass: (ES'): m/z 695.30 [M+HJ].
[0621] Step2: Synthesis of 4-{[5-{t[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(1,3-thiazol-5 yl)phenyl]methyl}carbamoyl)pyrrolidin-i-yl]-3,3-dimethyI-1-oxobutan-2 yl]carbamoyllmetlhoxy)pentyl]oxy}benzoic acid:
OH HO N N
[0622] To a stirred solution of methyl4-{[5-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(1,3-thiazol-5 yl)phenyli]methyllcarbamoyl)pyrrolidin-i-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamoyl}methoxy)pentyl]oxy}benzoate (150 mg.0.22 mmol) in a mixed solvents of tetrahydrofuran (4 mL)-water (2 mL)-methanol (1 ml) was added lithium hydroxide monohydrate (36 mg, 0.86 mmol) at room temperature. The resulting mixture was stirred at 35°C overnight. TLC and LC-MS showed formation of the desired product. The reaction mixture was acidified with aqueous ICI (3N) to pI =3-4 and extracted with methylene dichloride (50 mL x 2). The organic layers were combined, washed with brine, dried over Na2S04 and concentrated to afford the titled product (110 mg, crude) as a white solid which was used for next step without further purification. Mass: (ES): m/z 681.20 [M+H4].
[06231 Step 3: Synthesis of exmaple 150:
C N~
NC N'.
[06241 To a stirred mixture of 4-{15-(1[(2S)-1-[(2S,4R)-4-hvdroxy-2-({[4-(1,3-thiazol-5 yl)phenyl]methyllcarbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2
yl]carbamoyl}methoxy)pentyl]oxy}benzoic acid (110mg, 0.16 mrnol), 2-chloro-4-[trans-3 amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile hydrogen chloride salt (50 mg, 0.16 mmol), N-ethyl-N-isopropylpropan-2-amine (77 mg, 0.64 rnmol) in anhydrous N,N-dimethylfonamide (4mL) was added HATU ((2-(7-Aza-iH-benzotriazole-1-yl)-1,1,3,3-tetramethlvuronium hexafluorophosphate ))(68 mg, 0.18 mmol) at 0 °C. The resulting mixture was allowed to war up to room temperature and stirred at room temperature for 20 min. TLC and LC-MS showed formation of the desired product. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (40 mL). The organic phase was separated, washed with brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluent: 5% methanol in methylene dichloride) to afford the titled product (yield 25%, 2 steps) as a white solid.
[0625] Synthesis of 2-({5- [4- (methoxycarbonyl)plienoxylpentyl}oxy)acetic acid
H rCH 2CO2,', B n Ct 2O3 Step1 Step 2
Ts\ ".C Ot-Bu -1FA-C
Step 4 Step 5
[06261 Step 1: Synthesis of tert-butyl 2-{15-(benzyloxy)pentyloxy acetate:
Bn O 0 0
[0627] To a stirred mixture of5-(benzvloxy)pentan-1-ol (10 g, 51.5 mmol), tert-butyi 2 brornoacetate (40.2 g, 206 mmol) and tetrabutyl ammonium chloride (14.2 g, 51.5 mmol) in methylene dichloride (60 mL) was added sodium hydroxide (40 ml, 35% in water) at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between methylene dichloride (200 mL) and water (100 mL). The organic layer was collected and washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: 5% ethyl acetate in hexane) to afford tert-butyl 2-{[5 (benzyloxy)pentyl oxyacetate (yield 31.6%) as light yellow oil. LC-MS: (ES): m/z 331.10
[M+Na'], H NMR (400 MHz, CDC): 6 1.48 (s, 9H), 1.63-1.67 (m, 6H), 3.46-3.53 (m, 4H), 4.10 (s, 2H), 4.50 (s, 211), 7.28-7.34 (in, 51).
[06281 Step 2: Synthesis of tert-butyl 2-[(5-hydroxypentyl)oxy]acetate:
[0629] To a stirred solution of tert-butyl 2-{[5-(benzyloxy)pentyl]oxy}acetate (5 g, 16.2 mmol) in ethanol (100 ml) under a nitrogen atmosphere was added palladium on carbon (10%, 600 mg) at room temperature. The resulting mixture was stirred at 50°C overnight under hydrogen atmosphere (hydrogen balloon). TLC showed formation of desired product. Palladium on carbon was removed through filtration and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 2-[(5-hydroxypentyl)oxy]acetate (2.5 g crude) as colorless oil which was used in next step without further purification.
[06301 Step 3: Synthesis of tert-btyl2-({5-[(4-methylbenzenesulfony)oxy]pentylIoxy)acetate:
TsO OY 0 ~
[0631] To a stirred solution of tert-butyl 2-[(5-hydroxypentyl)oxyjacetate (2.5 g, crude) and triethylamine (3.5 g,34.5 mmol) in anhydrous methylene dichloride (50 mL) was added a solution of 4-toluenesulfonyl chloride (2.7 g, 13.8 mmol) in anhydrous methylene dichloride(8 mL) drop wise at 0 °C. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. TLC showed formation of desired product. The mixture was quenched with aqueous solution of potassium carbonate (IN, 50 mL) at room temperature and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 rnL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent: 1% methanol in methylene dichloride) to afford tert-butyl 2-({5-[4 methylbenzenesulfonyl)oxylpentyl}oxy)acetate (yield 35.1%) as colorless oil. Mass: (ES'): m/z 395.10 [MNa+].
[06321 Step 4: Synthesis ofmethyl 4-({5-[-(tert-butoxy)-2-oxothoxy]pentyloxy)benzoate:
0 -1 0
0
[0633] To a stirred mixture of tert-butyl 2-({5-4 methylbenzenesulfonyl)oxylpentyl}oxy)acetate (1.0g, 2.7 mmol) and potassium carbonate (266 mg, 1.6 mmol) in acetonitrile (15 mL) was added methyl 4-hydroxybenzoate (500 mg, 3.29 mmol) at room temperature. The resulting mixture was refluxed overnight. TLC showed formation of desired product. The reaction mixture was cooled to room temperature, and partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was washed with washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluent 10% ethyl acetate in hexane) to afford methyl 4-({5-[2-(tert-butoxy)-2 oxoethoxy]pentyl}oxy)benzoate (yield 33%) as colorless oil. Mass (ES*): m/z 353.10 [M+Na*]; HINMR (400 MIz, CDCI 3 ): 6 1.48 (s, 9H), 1.55-1.61 (n, 2H), 1.68-1.72 (m, 211), 1.80-1.87 (m, 2H), 3.55 (t.J= 6.4 Hz, 2H). 3.88 (s. 3H). 3.96 (s, 2H). 4.02 (t,,J= 6.4 Hz, 2H), 6.89 (d, J= 9.2 Hz, 2H), 7.97 (d, J= 9.2 Hz, 2H).
[06341 Step 5: Synthesis of 2-({5-[4-(methoxycarbonyl)phenoxypentyl-oxv)acetic acid:
-O OH
[06351 To a stirred soluionof methyl 4-({5-[2-(tert-butoxy)-2-oxoethoxy]pentyl}oxy)benzoate (300img, 0.85 mmol) in DCM (4 mL) was added andTFA (2ml) at room temperature, the resulting solution was stirred at room temperature for 1 hour. TLC showed formation of the desired product. The solvent was evaporated to afford 2-({5-[4 (methoxycarbonyl)phenoxy]pentyloxy)acetic acid (200 mg, crude) as yellow oil which was used in next step without further purification.
[0636] Examples 151-157 were synthesized according to similar procedure described for synthesis of example 150, by using corresponding starting materials and intermediates.
[06371 Table 9. Exemplary Compounds.
Ex # Structure Compound name and Analytical data
(2S,4R)-i-[(2S)-3,3-dimethiyi-2-(2-{2-[4-(4-{[tranis-3-(3-choro-4-canophenoxy) 2,2,4,4 tetramedylcyclobutyl carbamoyllphenfoxy)butxv]ethoxylacetamido)butanoyl]-4
b1o2.0hydrxyN-{[4-(1,3-thiazl-5-yl.penyl~methylUpyrroidine2-arboxamhide
162
(d, J 8.0H1z, 1 H), 6.79-6.97 (n, 4H), 7.26-7.33 (m, 3H), 7.49 (d, J:= 8.0 Hz, 2H), 7.57 S(d,1 88 Hz, 1), 7.72 (d, J 8.4 Hz, 2H), 8.03 (s, 1H), 8.78 (s, 1H). LC-MS: (ES"): cN n/z 971.20 [M+H*]
(2S,4R)-[(S)33-dimethiy-2-{2-[4-(4-([trans-(3-(-hlorO-4-canopcnoxy)-2,2,4,4 tetramethycycobty!carbamoy!p~enoxy)btoxyacetaido71nutanoyl]-4-hdroxy-N-. S{[4-(4-mnethyl-1,3-thiazol-5-yl)phenyl]miethylDyrrolidine-2-carboxamide
'H NMR (400 MHz, CD 3OD) 6 ppm 8.85 (s, 1 11, 7.75 - 7.81 (rn, 2 H), 7.72 (d,J= 9.00Hz, 1 H), 7.44 - 7.50 (m, 2 1), 7.38 - 7.43 (m, 2 H), 7.13 (d, J= 2.35Hz, I ), 163 6.94 - 7,02 (m, I3H), 4.70 (s, I H, 4.54 - 4.61 (im 2 H), 4.48 - 4,54 (m,2H), 4.36 (dL J = 15.65 Hz, I1H) 4.28 (s, H), 4.14 (s, 1 H), 4.10 (t, J= 6.06 Hz, 2 H), 4.01 (d, J= 7.43, Hz 2 H1, 3.85 3.90 (m, I H)s 377 - 384 (im, H), 3.64 (,, J= 6.26 Hz, 2 H), 2.45(s, 3H) 224 dd,J= .30 7.43 Hz, I H), 2.09 (ddd, = 13.21, 9.10, 4.30 Hz, 1 11), 1.89 - 1.98 (m, 211) 1.80 - 1.88 (, 2 11), 1.28 (s 6H 1.22 (s. 6 1), 0.99 - 1.06 (m9 H); LC-MS (ES*): m/z 941.41 [MH*]
Ex # Structure Compound name and Analytical data
(2S,4R)-1-[2S)-3,3-dimethy-2-(2-[4-4-[trans-3-3-horo-4-canpenoxy)-2,2,4,4
N tetramethylcyclobutvicarbamov}phenoxy)butoxy acetamidkobutanoyl]-4-hydroxy-N {[4-('4-methy-1,3-oxazol-5-yl)phenyliimethylpyrrolidine-2-carboxamnide NH
'H NMR (400 MHz, CDOD) 6ppm 8,12 (s, I H),775 -7.81(im, 2 H),'7.72 (d,,'= 9.00 Hz, 1 H). 7.56 -7.64 (m. 2 11, 7.47 (d, J= 8.61 lz. 21), 7.13 (d, -= 2.35 ,li.I 164 H), 6.95 -7.03 (m, 3 H), 4.70 (s,1iH), 4.56 - 4.61 (m 11), 4.55 (s, 1 ), 4.46 - 4.53 m, 2 iH), 4.35 (d, J= 15.65 Hz i H), 4.28 (s, 1 H), 4.12 - 4.15 mi1 H), 4.06 - 412 m, 2 ),3.98 - 4.03 2 11), 3.85 - 3.92 (m, 1H), 3.78 - 3.84 (i, 1i1), 3.65 (t,J= 6.06 Hz'2 H), 2.38 (s, 3 H), 2.19 2.28 (m, 1 ).2 08 (ddd, = 13.30, 9.19,4.50 H z, I
H), 1.91 - 1-98 (m, 2 H), 1.82 - 1.89 ,(m 2 11), I28 (s, 6 H), 1.22 (s, 6 H), 1.04 (s, 9 H); LC-MS (ES*): miz 925.43 [MH]
H (2SAR)-1-[(2S)-3,3-dimei2{2-[4-4-{[ns-3-[4-cano-3
trifiuoromethyi)phienoxy]-2,2,4,4 Ni tetramvetyleclobutylarbamoyllphenoxv)butoxyvacetainidolbutanovl-4-hydroxy-N
[4-(4-methvl-1.3-thiazol-5-yl)phenylimethlipyvrolidine-2-calboxamide
165 0 'H NMR (300 MHz, CDOD): F 8.88 (s,. H),7.75-7.67 (m, 3 H)'7.44-7.36 (m, 4 H),
NH 7.09 (s, 1 H), 6.96-6.91 (m, 31), 4.84 (s, i H), 4.66-1.47 (,-4 H), 436-4.31 (n, 1 Hi), 4.26 (s, 1H), 4.24 (s, 1 H), 4.10 (s, 1DH), 3.93-391 (m 211), 3.83-5.78 (m, 2 ), 3.55-3.51 (m,2 H), 2.43 (s.3 H), 2.12-2.10 (m, 1 H), 2.09-1.95 (n, 1H), 1.67-1.62 (m
6 1), 1.30-1.28 (m, 9 H). 1.18 (s 6 H) 1.00 (s, 9 I); LC-MS (ES*): m/z 969.10 [MHW]
(2S,4R)-1-[(2S)-3,3-dimetlyl-2-{2-[4-(4-{[trans-3-[4-cvano-5 N (rifluoromethylhphenoxy]-2,2,4,4 t etramethylceloburtylicarbamnoyi}phenoxy)butoxyjacetamidlo~butsanoyl]-4-hydroxy-N
1[4-A4-methyl1,3-oxazo-5-yltphenyiimethyi~pyrrolidine-2-carboxamide 16 NM' R (400 MHz, CD3D):8.09 (s, H),7.89 (d, 1I ), 7.80-7.70 (in, 2 H), 769-7.50
(m, 2 H), 7.49-740 m2H),7.3(s 1 -7.08 (m, 1 1), 7.00-6.82 (m, 2 H), 4.72 (s, I H), 4.60-4.40 (m, 3 H), 4.39-4.20 r, 2 H), 4.19-4.00 (m, 3 H), 3.99-3.95
(m, 21H392-3.70 (, 2 H),3.69-3.53 (m, 2 H), 2.40-2.32 (m 3 11), 2.30-2.18 (m, I F3 H),.2.5-.01 (i, I , 200-1.60 F, 4 H),1L35-1-28 (m, 6 H1)1.25-15 (m, 6 H1)103
1.00(m, 9 H); LC-MS (ES*): m/z 959.60 [MH*].
(2S,4R)-1.-[(2S)-3,3-dimethyl-2-{2-[4-(4-{[trans-3-(3-chloro-4-cyanophenox)-2,2,4,4 H
tetramnethlvcvclobutylJarbamoyllpheinxv)butoxvacetaiidolbutanovl-4-hydroxv-N
[(, S)-1-[4-(4-miethyl-1,-hao--lpey~ty~yrldn--abxmd 00C> NH
'HNMR(400MHz,CD3OD): 8.82 (s, HI),781-7.75 (m,2H),7.74-762 (s, 11 ),7.61 167 7.53 (mn, 2 H 749-7.35 (m 2 H), 7.19-7.10 (s, 111), 7.08-6.80 (km 3 H), 5.08-4.91 (m, I H),4.65 (s, I H), 4.60-4.59 (m, 1 H, 4.45-4.36 (m, I H),4.22 (s, 1 ), 4.11-4.05
m,3H401-3.96 (nm,2 H), 3.95-3.70 (m, 2 ),D 3.69-3.45 (m,2 H), 2.40-2.35 (im, 3 1), 2.21-204 (s, 1H21 ( ),1.60-1.40 (m, 3 1), 1.21-1.12 ( 12 H), I, ei 1.00-0.95(m, 9 ); LC-MS (ES): m/ 478.45 [(M/2)l]
Ex # Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-3,3-diimethyl-2-{2-[4-(4-{[trans-3-(3-chloro-4-cyanopheox)2,44 1V/tetramethyicyclobutyiicarbamoyliphenoxyibutxylacetamido butanoy]-4-hydroxy-N
[(S)-1-[4-(4-iethyl-1,3-oxazol-5-ylnhenylethyl]pyrroldine-2-arboxamide
168NM1 R (1400 MHz, CD30D): 8.82 (si),7.81-7.75 (m,2 H), 7.74-7.62 (s, 1 H), 7.61 1681 7.53 .497.35 (m. 2 11), 7.19-7.10 (s, 11), 7.08-6.80 (m, 3 1), 5.08-4.91 ( I H, 4.65 (s., 1 H), 4.60-4.59(m, 1H), 4.45-4.36 (i, 1 H),4.22 (s, 1 H), 4.11-4.05 (H, 3 )401-3.96 (n, 2H), 3.95-3.70 (m, 2 H), 3.69-3.45(m, 2IH),2.40-2.35 (n, 3 H, 2.21-2.04 (s, 1 H),2.00-1.70 (m, 4 H),1.60-1.40 (in, 3 ) 1.2-1.12 (n, 12 H), 1.00-0.95(m, 9 H)1C-MS (ES*): .mz 478.45 MHi
(2SR)--[(-choropeny~mehyl-i -(2S-3,-diethy2-{-[4(4-[tran s-3-(3
chloro-4-cyanophenoxy)-2,2,4,4 t HO;, ' j tetramedylcyclobutyl]carbamoyl}phenoxv)butoxv]iacetamido}butanolv-4 -N CI Lydroxypyrroiddine-2caboxamide -I-0
1HNMR (400 MHz, CD0OD) 6 ppm 7.80 (d,J= 8.61 Hz, 21), 7.72 (d, J=9.001Hz, 1 169 H), 7.24 -7.37 (m, 4 H), 7.13 (d, J=2.35 Hz, H), 6.94 - 7,04 (m, 3 H), 4.69(s, 1H), 4.54 (dd, J= 8.80, 7.63 Hz, 11H), 4.43 - 4.51 (m 2 11), 4.24 - 4.32 (m, 2 H), 4.08 - 4.16 i ~(3m, H')395 -'4.06(m, 211),3.84- 3.90 (m, 1H),3.76 -3.83 (n, 1H), 3.65(,4= 6.26 Hz, 2 H), 2.21 (dd, J= 13.11,7.63 IHz,I H), .06 (ddd, =13.30, 9.19,4.50 Hz, 1 H), 1.90 - 1.98 (m, 211) 1.80 - 1.89 (m, 2 H), 1.28 (s, 6 11), 1.22 (s. 611), 0.95- 1.15 (Im, 9 H; LC-MS (ES*): m/z 87S.28tMHi
(2S,4R)-N-(i4-cyanophenyl'methy4]-l-[(2S)-3,3-dimethyl-2-{-4-4-{[tns-3-(3 H chleboro-4-cyaniophenoxy)-2,2,4,4 N. N tetramethylyclobutylvcarbamov}phenoxy)butoxyacetamido}butanoy]-4
NH iydroXynyrroiidine-2-carbo~amide r4\
170 0 'H NMR (400 MHz, CDOD) 6 ppm 7.80 (d,J=8.61 Hz, 2 H) 7.72 (d,J= 8.61 Hz, 1 H), 7.64 (d, J = 8.22 Hz, 2 H), 7.54 (d, J = 8.22 Hz, 2 H), 7.13 (d,J= 2.35 Hz, I H), 6.94 -7.05 (m, 3 11), 4.69 (s, H), 4.49- 4.62 (m, 4 IH),4.34 (d,J= 16.04 Hz,I 1), 4.29 (st, 1H), 4.08 - 417 (m, 3 11, 3.95 -4.06 (m, 2' H), 3.8 - 3.91 (m, 1 H), 3.80 (dd, N' -= 11.15, 3.72 Iz, 11), 3.65(t, J=6.06 Hz, 21, 2.23 (dd, =13.11, 7.63z,), 2.06 (ddd, J=13.11, 9.19,4.30 lIz, 1 11), 1.90 - 1.99 (m, 2 1), 1.81 - 1.90 (m, 2 11),
Ex # Structure Comnpounidnamneand Analytical data
1.28 (s. 611),1.22 ls, 611),0.92 1.18(in9H1i;112-MS lES'i: rw_ 869.31[M'
H hlR--(5-,3drelv--2[4(l-[rn--3-hnn4eaolenoxy -2,2,4,
[~i)-)[4~4-mthy-i,-thazo-5-i~penivipnyroidne-2-caboxa de
r 'H NtR'(400 MHzCD-30D)6 8.85(s, IH).7.79 (mn.3), 7.58 (d,.!= 8.4Hz,21i' 171 17.42(d.J=8.0Hlz, 21)7.15 (, 111). 7.01 (mn.311), 5.00 (in,111),4-69 (m, 211).4.53 (S, - (11).4.30(s, ff1).4.16'(s, ff).4.13 (un.21H),4.01 (s,21),3.91-3.85(n, 'ii).3.85- 0<--d 3.78 (i, J1H1),65(lm, 2H),2.46 (s,3H),2.30-2.19 (m, 11), 2.18-2.05 (i. IHCI,99
1.92 (m, 21-4b,1.89-1.82 (m. 211),.3 (m,31),1.30 (s61i4) .4(s, 614, 0.92 (s, 911)
N ~~Mass (ES'): inz95545jMH+IA
106381 Synthesis of example 163:
H 0
0, O\' NaOH
---- 0 NHH
HO~~~Se -) -c 2~O Stp Examle16
[039 Sep:sntessomehy4{4([251- ~4R4-ydox--(!4(4mehy-1-4iaoi5 ylpenimehl~abaolpyrlii-.-ll33NieH2 l.1-AxbuanH2 yi~crbaoyi}ethxy~btoxlbeaoat
22*5t
HO
__0 f Nc
0 *NH
s
[06401 To a stirred solution of 2-{4-[4-(methoxycarbonyl)phenoxv]butoxy }acetic acid (22.0 mg,77.9 pynol) and (2S,4R)-I-[(S)-2-airino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-I-[4-(4-inethvl-1,3-thiazol 5-yl)phenyl]ethylpyrrolidine-2-carboxamide hydrochloride (36.3 mg, 77.9 pmol) in methylene chloride (2.0 mL) was added O-(benzotriazol-1-v)-NN,N',N'-tetramethyluronium tetrafluoroborate (25.0
mg, 77.9 pmol) and diisopropylethylamnine (40.5 pL,233 pmol) at room temperature.The reaction mixture
was stirred at room temperature for 30 minutes, LC-MS indicated formation of the desired product. The
reaction mixture was concentrated under reduced pressure. The crude material was purified by flash silica
gel chromatography on a Teledyne Combiflash ISCO (gradient fluent: Heptane/Acetone (v:v = 100:0 to
0:100)) to give the titled product (yield: 78%) as a white solid. LC-MS (ES*): mz 695.3138 [MH].
[0641] Step 2: Synthesis of44-4({[(2S)--[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenvlimethvl}carbamnoyi)pvrrolidin-1-yil]- 3,3-dimnethvl-I-oxobutan-2 yl]carbamoyl}methoxv)butoxy]benzoic acid:
HO
HoH
0 0
S - LN.
[0642] To a stirred solution of methyl 4-[4-([(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol 5-yi)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamoyl}methoxy)butoxy]benzoate (42.4 rg, 61.0 pmol) in methanol (2.0 mL) was added 1 M
NaOH in water (0.5 nL, 12.5 mnol) at room temperature. The reaction mixture was stirred at room
temperature for 16 hours. LC-MS indicated formation of the desired product. The reaction mixture was quenched with 1.0 M aqueous ICI and then concentrated under reduced pressure to remove the methanol.
The aqueous residue was extracted with EtOAc (15 mL x 2). The organic layer was washed with brine (5
mL),dried over Na2 SO 4 , filtered and concentrated under reduced pressure to give the titled product (yield:
82%) as a white solid.The material was used in next step without any further purification. Mass (ES*): m/z
681.2986 [MIH].
[0643] Step 3: Synthesis of example 163:
[0644] To a stirred solution of 2-chloro-4-[trans-3-amio-2,2,4,4 tetramethylcyclobutoxy]benzonitrile (13.9mg, 50.2 pmol) and 4-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4 (4-methyl-1,3-thiazol-5-vl)phenyli]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-i-oxobutan-2 yl]carbamovllmethoxy)butoxy]benzoic acid (34.2 mg, 50.2 imol) in methylene chloride (2.0 mL) was added O-(benzotriazol-I-yl)-NN,NN'-tetramethyluronium tetrafluoroborate (16.1 mg, 50.2 pnol) and diisopropylethylamine (26.0 pL, 150 pmol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. LC-MS indicated formation of the desired product. The reaction mixture was quenched with water (5 mL) and extracted with DCM (15 rL x 3). The organic layers were combined, washed withaqueous NaHCO 3 (5 mL), brine (5 mL), dried over NaS 4. filtered and concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO (eluent: DCM/MeOH (v:v = 90:10)) to give the titled product (yield: 39%) as an off white solid.
[06451 Synthesis of 2-{4-[4-(methoxycarbonyil)phenoxy]butoxy}acetic acid:
0
OC -OH
Step 1 Step 2
0 O
Step 3
[06461 Step 1: synthesis of tert-butyl 2-{4-[(4-methylbenzenesulfonyl)oxybutoxy}acetate:
[06471 This material was synthesized from tert-butyl 2-(4-hydroxybutoxy)acetate and 4-toluenesulfonyl chloride according to similar procedures described above for the synthesis of tert-butyl 2-({5-[(4 inethylbenzenesuilfonyl)oxy]pentyl}oxy)acetate.
[0648] Step2: synthesis of methyl 4-{4-[2-(tert-butoxy)-2-oxoethoxy]butoxylbenzoate.
[0649] Toastirred mixtureof methyl4-hydroxybenzoate (27.99mg, 184.0pmol) and tert-butyl 2-{4
[(4-methylbenzenesuilfonyl)oxybutoxy }acetate in acetonitrile (2.0 mL) was added potassium carbonate (34.67 mg, 250.9 pmol) at room temperature. The reaction mixture was then stirred at 80 °C for 16 hours. LC-MS indicated formation of the desired product. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography on a
Teledyne Combiflash ISCO (gradient eluent: heptane/acetone (v:v = 100:0 to 50:50)) to give the titled
product (yield: 94%) as a clear oil. Mass (ES'): m/z 361.16 [M+Na].
[06501 Step 3: Synthesis of Synthesis of 2-{4-[4-(m thoxycarbonyl)pher.oxy]butoxy}acetic acid:
[0651] To a stirred solution of methyl 4-{4-[2-(tert-butoxy)-2-oxoethoxylbutoxylbenzoate (53.1r g, 156
imol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 ml, 12.9 mmol) at room
temperature.'The reaction mixture was then stirred at room temperature for 30 minutes. LC-MS indicated
formation of the desired product. The reaction mixture was concentrated under reduced pressure to give
the titled product (yield: 99% based on crude material) as an off white solid. The crude material was then
used in next step without any further purification. Mass (ES*): mz 305.10.
[0652] Examples 162, 164-171 were synthesized according to similar procedure described for
synthesis of example 163, by using corresponding starting materials and intermediates.
[06531 Table 10. Exemplary Compounds.
Ex Structure Compound name and Analytical data
(2S,4R)-1-[(2S)-3,3-dimethsliyi-2-[2-({5-[(4-([trans-3-(3-chloro-4-cyanophenoxy) 12,2,4,4 N i tetrametlcyclobuty]a]cabanioylphenyl)ainolpenty}oxyacetamidbutanl]-4 eii hydroxy-N-{[4(4-ethyl-1,3thiazol-5-y'lpenlethlpyrolidine-2-caboxamide H NMR(400MHzCDC) .68(s,1 H), 7.63(d,. J=8.6Hz,2H),7.5'7 (d,1= 8.6 Hz, ]`), 7.35 (q, J =8. H1z 411, 6.97 (d, J =2.3 Hz, 1H), 6.81 (dd, J = 2.S 8.8 Hz, 1]H), 660 (d, J= 9.0 Hiz, 2H), 6.07-6.12 (m, H), 4474 (s,IH), 450-4.59 (ml, 3H) 4.37 OH.
(d, J = 5.1i Hz, 11), 4.11-4.17 (m 211), 3.64 ddJ = 3.5 11.3 lz, 1H), 3.53 (d, J = 70 o-I Hz, 2H), 3.19 (t, J = 7.0 Hz,2H), 2.55-2.61 , 2.52 (s, 3H), 2.10-2J9 (W, 2H), L65-1.71 (m,4H), L50-153 (m, 211), 1.24-1.33 (in, 9H1), 22 (s, 6H), 0.96 (s, 9H) 172 0.86-0.91 (m. 311). LC-MS (ES*): m955.43 [MH*] (2S,4R)-1-[2S)-3,3-dimethyl-2-[2-({5-[i4-f(trans-3-(3-chloro-4-cvanophenoxy) 22,4,4 N
ci tetr'imethyliyclobutvliearbatovlphenyl)aiinoipentyloxyacetamido'butanoyv]-4 Shydroxy-N-[-4-(4-methyl-1,3-oxazol-5-yl)phenylimethyl}pyrrolidine-2-carboxamid
N'H H1 NIMR (400 MHz, CDC )7.82(s 3 7.63 (d, J = 8.6 z, 2), 7.53 (d, J = 8.6 Hz, 2H), 7.35 (s, 2H), 7.18-7.21 (i,1), 6.97 (d, J = 2.3 Hz, 111), 6.81 (dd J = 2.3, 8.6 Hz, 1),6.59 (d. J= 8.6 z 211, 6.08-6.12 (i, iH), 4.73 (t, J = 8.0 Hz, iH), 4.49-4.60 HN
e H (m,> 3H-)4.32-4.39 (m, 1H),411-4.17 (m,.2H), 3.63(dd, J1 3.5, 11 3Hz,1H), 349
HN liz, H), 2.53-2.61 (m, 11 ), 2.4-2 (Is 3), 2.08-2.18 (m, .57 (m,21), 3.18 (tJ= 6.8 2H), 1.68(td,J=7.2, 14.5Hz,41), 1.50-153(i,2H1), .26(d,.1J=:0.8 Hz,91),1.22(s, 173 6H), 0.96 (s, 9H), 0.86-0.91 (inm, 3). LC-MS (ES*): n/z 939.46[MH-]
Ex Structure Compound name and Analytical data
!(2S,4R)-lI--[(2S8)-3,3-diminshx-2-12-({,5+4- [(4-ans-3-I3-chin.ro-4'-cyanophen.oxy)
fi Yrh_-oxy-N-[(1S)-1-[+I-(rnri-,thal--irevehlprrdi-2 ca'lnx aijde H NNW (300,/Mz.CD 3 D:88 (SIH),780-765(rr, 3H)C.750-733(O'riA
6
, 7.16 is, 111) .03-6.93 (m, 1H1). 6.54-643 (m,.2 1-,5.02 --4.95 (m.-I),4.67(s. J.'1 4A;-4.50 (i. III),4.46440(in, 1 1) 4.20-. (in, IH)14 20-4.15 H) H4.04 390((i,2H)1 .89-385' 1HI3.80-3.73 (r111)3.66-35 In';211.3.20-1.10 (m. 2 1-l), 240 (s.311), 2.25 -1.95,(mn, I1117.2.02 -- 1.90 (m, 11H),].SO- 1.68On.m,4H11 I.65-.50 (m,2H1), 1..9-1.43(in,211I,13-..(m, 6H),1.2-1(m,O).Iil.0( 174 9)11"; LC-MVS (ES')mz 968.40 [mH' 1(2IS,4R)-l-[(2S')-3,3-dineshi-x-2-(2-{4-[i4-{[rrians-3-(3-e-hinro-4-cvacnp.,henoxy)-'l244 tet-aitcrhylcvc'inbutyijcarbacsoyilpheciiviN ariiicibutoxvlaeraiid)buricli]-4
H\l MR(3100Mlz, CD 3 0D):68.88 (s,I111, 7.7507.65 (i 3Hi),7.50-7.33In, 411). 7flI7..05 (m. 1-I), 6.99-6.90 (m, I11'176.54-6.43 m,2 '),4.67 (slI-,), 4.60-4.50 (m.'
3 i, 4,48-4.5 IH),4.21(s, IH), 4.13-4.05I (mIH1), 3.9-3.90 (in, 2H)If 88 370 (il211", 3.66-3.48 (i, 211), 3.20-3.03 On, HI11,2.4(s, HI, 2.25-2.12(o In 14),I2.09 -- 1.99 Or,lI-i1),I180--L69 (rn, 411).1.30-1.10 (i,12HI4, 1.01 (,9HI) LIC S 175 (ESiiisOT,940.15 I'f (23R-1[(8)2-2-{5[(-fcon--[trans -3 -(3 -hlo o-4-cvaz opheinoxyl-2.,2 ,
dsiethyibutacc-vii--4-hydrnxy-N-i[4-(4-cxlethly-,3-ihiazo-5 1yi,1pheiiyiiriietdi1}prniiieverbxii 'IIINMvR (300Mhz, CD30D):68.86 (s111), 7.80-7.70(0-1, 1114, 760755 (I "ic' A 7.5/0-7.37 (i.,4H), 7.14 (s,.,H.), 7.00-693 (n, IHl)6.80-6.65 On, I HI,4711, 1'H),
4.65-450 (rn,311),44-0-4.311(mIIf,.1'4-29-4-1 (i,1H)4.20-1.5 (rn 11) 4.11 30)(n,11.38-3.85 (im,1IH), 3.80-3.73 (n, I1H),3170-3.65 Iin. IH R6-3'~
_-0 nf 211, 3.30-3.15(mn IH',2401s, 3Hf,225-1.95(inf, I1H),2.02 -1.90 (in IH'
1.80-1.68 (m,-4li),1.65-1.50 (mi,2 1),1.30--I.23O, 6 11), 1.22-.1 (111n 6 11)1 I4l s 176 9H 1(7 LC-MS (ES": l-, 972.10i rll
t- raniethycychntv c arnovipht-eviamiihntoL,,xlaeaniisibutanoslI-4
0,N L 1h _-oxy-N-1[(1S)-1-[I oz ieyf-,3tiao-5y~ leieiyl p Tr, idiz'.2 0-- cs .arbox .m jde
Nil r ~ ~~HMR1(400AMz D3068,86 s,IH, 772-7.64 (in 3H), 7.44 (s,4H), 71 l-),698 (dJ = 2Hz 1),664 (d_-- 8.8Hlz_'4),5.00 (d6J= 6.8Hlz, 1HX+ 469 (, NH H~~~~1),4.624598(rI In,1-4.4i (s,1IIn,4.28 (s ,11.4.12 s,I1).00-3.93 (m, 211,
3.87-3.75 (rn,211),'165-3.59'i, 211,3.21 (s,211), 2.7 (s, 311,227-2.15 (m, 11), 1.9 m. 1 11), 1. 76 (s41), 1.58--I49(m, 311), 1.26 (d,]= 9_6-Hz, 1211),l102 (s, 911): Mss 177 (ES"). iinlci955.20 [MUJ'
Ex Structure Compound name and Analytical data #
(2S,4R)-1-[(2S)-3,3-dimethyl-2-(2-{4-[(4-{[trans-3-(3-chloro-4-cvanophenoxy)-2,2,4,4 tetramethylcyclobutyl carbamoylpheiyiaiinolbutoxylacetariido)butanoyfl-4
hydoxyN-((JR)-.I[4(4methy1,3-tiazo-5-y)phenyviethylpyrrolidine-2 car-boxamide H NMR (400 MHz, DMSO) 6 8.96( H) 8.49 (d, J= 7.6 Hz, 11), 7.90 (d, J= 88 "- Hz, JH), 7. 63 (d. j= 8,4 Hz, 2H), 7.51 (d j= 8.0 Hz, 2H), 7.42-7.21 (m, 411) 720 (n, 11), 700 (d,J= 8.8 Hz, 11), 6.55 (d,,J= 8.8 Hz, 2H), 6.19 (s, 1H), 5.16 (s, 1H) 4.89 H (s, 1H), 4.56-4.47 (m, 211), 4.36 -4.40 (m, 211) 4.03 (d J= 9.2 Iz, I ) 3.94(, 211' 3.67-3.57 (m, 2H), 3.56-3.50 rn, 2H)3.07 (s, 2H), 2.44 (s, 3H), 2.08-2.01 (m, IH) 1.98-1.92 (m, H), 1.6 (i,4H), 1.38 (dCH= 68 Hz, 311) 1.20 (s 611). 1.11 (s, 611 178 1091 (s, 9H) Mass (ES): m 954.15 [MH'].
[06541 Synthesis of example 172:
O0 -- ---------- O S Step2 Step3 6 OH
Step 4 C)Step 5 HN O Se 0 0~ N<
OH
0 H
0 I H ~.fHN Step 7 / /
0- N -HN / i/cExample 172J N
10655] Step7:Synthesisofexampe 172:
[06561 TBTU (21.5 mg, 0.067 mmol) was added to a solution of 4-{[5-({[(2S)--[(2S,4R)-4-hydroxy-2 ({[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylIcarbamovyl)pyrrolidin-I-y]-3,3-dimethyl-1-oxobutan-2 yl]carbarnoyl}inethoxy)pentyl]amino}benzoic acid (31 mg, 0.044mrnol), 2-chloro-4-[rans-3-arnino
2,2.4,4-tetramethylcyclobutoxyibenzonitrile (12.4 rg, 0.044 nnnol) in DMF (3.0 nL) and DIPEA (15.4 piL, 0.089 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for
1hr. LC-MS indicated formation of the desired product. The reaction mixture was diluted with EtOAc (30 mL), washed with water (15 mL x 2), brine (15 ml x 1), filtered through a Biotage universal phase separator and then concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatographyon aTeledyne Combiflash 1SCO system eluting with MeOH/DCM (v/v= 0:100 to 10:90) to yield the desired title product (yield: 41%).
[0657] Step 6: Synthesisof 4-1[5-({[(2S)--[(2S,4R)-4-hydroxy-2-{[4-(4-methyl-1,3-thiazol-5 yl)phenyli]methylIcarbamoyi)pyrrolidin-1-yl]-3,3-dimethyil-I-oxobutan-2 yl]carbamoylimethoxy)pentyl]aminoijbenzoic acid:
NN 7
HO H O OH.
[0658] Lithium hydroxide (9.0 mg, 0.38 mnol) was added to a solution of methyl 4-{[5-({[(2S)-1
[(2S,4R)-4-hydroxy-2-({[4--(4-methyl-1,3-thiazol-5-yl)phenyljmethylicarbamoyi)pyrrolidin-1-yl]-3,3 dimethyl-1-oxobutan-2-yicarbamoyllmethoxy)pentylaaminolbenzoate(96 mg, 0.14 mmol)ina mixed
solvent of THF/water/methanol (v/v/v = 1/I/1 2.00ml) at room temperature. The resulting mixture was
stirred at room temperature overnight. Aqueous HCi (1 N) was added to the reaction mixture to adjust pH
to -3. The resulting mixture was diluted with EtOAc (30 mL), washed with brine (15 mL x 2), dried over
sodium sulfate, filtered through a Biotage Universal Phase Separator and then concentrated under reduced
pressure to give a crude product, which was used for next step withoutany further purification. LC-MS
(ES'): mz694.33[MH*].
[0659] Step 5: Synthesis ofmethyl 4-{[5-({[(2S)--[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenyl]methylicarbamoyi)pyrrolidin-I-yl]-3,3-dimethyl-I-oxobutan-2 yl]carbamoyljmethoxy)pentyllaminolbenzoate.
N N 'H OH
[0660] TBTU (81.5 rig, 0.25 mmol) was added to a solution of 2-[(5-{[4 (methoxycarbonyl)phenyl]amino pentyl)oxy]acetic acid (50.0 mg, 0.17 mmol), (2S,4R)-1-[(2S)-2-amino
3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl~pyrrolidine-2 carboxamide (72.8 mg, 0.17 mmol) in DMF (3.0 mL) and DIPEA (59 pL, 0.34mmol) at room temperature. The resulting mixture was stirred at room temperature for lh.The reaction mixture was diluted with
EtOAc (30 mL), washed with water (15 ml x 2), brine (15 ml x 1), dried over sodium sulfate, filtered
through a Biotage universal phase separator and then concentrated under reduced pressure to give a crude
residue, which was purified by silica gel chromatography on a Teledyne Combiflash ISCO system eluting
with MeOH/DCM (v/v = 0:100 to 10:90) to yield the titled product (yield: 51%, 2 steps). LC-MS (ES*): m 708.35 [MH].
[06611 Step 4: Synthesis of 2-[(5-{[4-(methoxycarbony)pheny iaminoIpentyl)oxy]acetic acid:
H O OOH
o
[06621 Trifluoroacetic acid (2.63 mL, 34.5 mmol) was added to a solution ofmethyl 4-{1[5-(2-methoxy 2-oxoethoxy)pentyl]aino}benzoate (270 mg, 0.7682 mmol) in DCM (3.00 ml) at room temperature. The
resulting mixture was stirred at 45 C for 2h. The reaction mixture was then concentrated under reduced
pressure to give a crude product, which was used for next step without any further purification. LC-MS
(ES*): mz 296,15 [MH].
106631 Step 3: Synthesis of methyl 4-({5-[2-(tert-butoxy)-2-oxothoxyipentylamino'ienzoate:
00
[06641 Toasolution oftert-butyl 2-[(5-oxopentyl)oxy]acetate(2h69 mg1.24 mmol)and methyl4
aminobenzoate (187 mg, 1.24 mmol) in dichloroethane (5.00 mL) was added acetic acid (199 pL, 2.48 mmol) and sodium triacetoxyborohydride (394 mg, 1.86 mnol) at room temperature. The reaction mixture
was stirred at room temperature for 18h. NaOH (IN solution in water) was then added to neutralize the
acetic acid, the resulting reaction mixture was extracted with DCM (100 mL x 3). The organic layers were
combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude
residue, which was purified by silica gel chromatography on a Teledyne Combiflash ISCO system eluting
with MeOH/DCM (v/v = 0:100 to 15:85) to yield the desired title product (yield: 62 %).LC-MS (ES4): m/z 352.21 [MH]
[0665] Step 2: Synthesis of tert-butyl2-[(5-oxopentyl)oxy]acetate:
23 2
H O 0
[0666] To a solution of tert-butyl 2-(hex-5-en-1-yloxy)acetate (300.0 mg, 1.40 nunol) in acetone (15.00 ml) were added potassium osmate(VI) dihydrate (15.5 mg, 0.042 mmol), follow by NMO (491.9 mg, 4.20 mmol) in water (4.5 nl) at room temperature. The resulting reaction mixture was stirred for 18h at room temperature. The reaction was monitored by TLC (EtOAc/Heptane, v/v =25/75). Sodium periodate (898.2 mg. 4.20 mmol) was then added to the reaction mixture, the reaction was stirred at room temperature for another 3h. The reaction mixture was diluted with water (10 mL) and DCM (100 mL). The organic layer was separated and the aqueous layer was extracted with DCM (100 nil x 3). The combined organic layers were washed with brine (10 mL x 2) and then passed through a Universal Biotage Phase Separator and concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography on a Teledyne Combiflash ISCO system eluting with EtOAc/Heptare (v/v = 0:100 to 50:50) to yield the titled product (yield 90%) 1H NMR (400 MHz, CDC 3 ) 8 9.75 (t, J = 1.8 Hz, IH), 3.89 3.93 (m, 2H), 3.51 (t, J = 6.1 Hz, 2H), 2.47 (dt, J = 1.6, 7.2 Hz, 2H), 1.69-1.78 (i.2H), 1.64 (d. J = 8.2 Hz, 2H), 1.46 (s, 9H).
[06671 Step 1: Synthesisoftert-butyli2-(hex-5-en-1-yloxy)acetate:
0
[0668] Tetrabutylammonium hydrogen sulfate (677.7 mg, 2.0 mmol) was added to a mixture of sodium hydroxide (23.9 g, 599 nunol) in water (20.0 mL) and toluene (20.00 ml) at 20 °C. To thismixture was added hex-5-cn-l-ol (2.00 g,20.0 nmol), the resulting mixture was stirred at 20 °C for lh. The reaction was then cooled to 5 °C and tert-butyl 2-bromoacetate (20.0 mmol, 3.89 g) was added slowly while maintaining the internal temperature below 15 °C The reaction mixture was then stirred at room temperature for additional 16h. The mixture was diluted with heptane (30 mL) and washed with water (20 nl).The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography on a Teledyne Combiflash ISCO system (gradient eluent: EtOAc/Heptane, v/v = 0/100 to 25/75) to afford the desired product (33%). H NMR (400 MHz, CDCI) 6 5.75-5.87 (im, IH), 4.82-5.10 (m, 2[), 3.95 (s, 21-), 3.52 (t, J = 6.7 Hz, 21-), 2.08 (d, .1 = 7.0 I-Iz, 21-), 1.57-1.69 (in, 2), 1.45-1.53 (m, I1H). LC-MS (ES'): mz 237.14 [MNa']
[0669] Examples 173-178 were synthesized according to similar procedure described for synthesis of example 172, by using corresponding starting materials and inermediates.
[06701 Alternatively, steps 5-7 of example 174 is synthesized as following:
[0671] Step 7: synthesis of (2S,4R)--((S)-2--(2-((.-(-((trans-3-(3-chloro-4-cyanophenoxy) 2,2,4,4-tetramethyicyclobutyl)carbamovl)phenvl)amino)pentyl)oxy)acetamido)-3,3 dimethylbutanoyl)-4-hydroxy-N-((S)--(4-(4-methylthiazol-5-yl)phenyl)ethvl)pyrrolidine-2 carboxamide:
0 N/H N0 0 / 0 N 1
ci /--, HO
[06721 A solution of 4-((5-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-I-(4-(4-methylthiazol-5 yl)phenyl) ethyl)carbamoyl)pyrrolidin-1-y)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 oxoethoxy)penty) amino)benzoic acid (L 17 g,1.65 mmol) in methylene chloride (10 mL) was charged with HATU (688 mg, 1.81 mmol) and diisopropylethylamine (859 PL, 4.94 mmol).The reaction mixture was allowed to stir at room temperature for 10 minutes, then 4-(trans-3-amino 2,2,4,4-tetramethvlcyclobutoxy)-2-chlorobenzonitrile hydrochloride (545 mg, 1.73 mnol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (30 mL), then washed with water (10 mL), brine (10 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The crude material was purified by silica eil chromatography on a Teledyne Combiflash ISCO eluting with DCM/MeOH (100:0 to 90:10 to yield the desired product as a white solid (0.86 g, 54%). LC-MS (ES+): m/z 968.42
[MH+].
106731 Step 6: synthesis of 4-((5-(2-(((S)--((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylithiazol-5 yl)phenyl) ethyl)carbamoyl)pyrrolidin-1-y)-3,3-dimethyl-1-oxobutan-2--y)amino)-2 oxoethoxy)pentyl) amnino)benzoic acid
H 0 S,
N0 .ONH~
/ OH N N HH HO
[0674] A solution of methyl 4-((5-(2-(((S)-i-((S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol 5-yl)phenyl)ethyli)carbarnoyl)pyrroiidin-1-yl)-3,3-dirnethyl-I-oxobutan- 2 -yl)amino)-2
oxoethoxy)penty)amino)benzoate (1.2 g, 1.66 mmol) in methanol (5 mL) was charged with 3 M NaOH (2.0 mL, 50.0 mmol). The reaction mixture was allowed to stir at room temperature for 72 hours. The reaction mixture was quenched with 1.0 M HCI and then concentrated under reduced pressure to remove the methanol. The aqueous was extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with DCM/MeOI (100:0 to 90:10) to yield the desired product as a white solid (1.17 g, 100 %). LC-MS (ES+): m/z 708.32 [MH+].
[0675] Step 5: Synthesis of methyl 4-((5-2-(((S)--((2S,4R)-4-hydroxy-2-(((S)-I-(4-(4 methylthiazol-5-yl)phenyi)ethyl)carbamovl)pvrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 yl)amino)-2-oxoethoxy)pentyl)amino)benzoate.
/N 0S
NH HO
[06761 A solution of 2-((5-((4-(methoxycarbonyl)phenyI)amino)pentyl)oxy)acetic acid (1.68 g, 5.68 mmol) and (2S,4R)-1-((S)2-amino-3,3-dimethybutanoyl)-4-hydroxy-N-((S)-1-(4-(4 methylthiazol-5-yl)phenyl)ethyli)pyrrolidine-2-carboxamide hydrochloride (2.73 g, 5.68 mmol)
in methylene chloride (15 mL) was charged withO-(benzotriazol-1-yl)-N,NN',N'
tetramethyluronium tetrafluoroborate (1.82 g, 5.68 mmol) and diisopropylethylamine (2.95 mL, 17.0 mmol). The reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was quenched with water (15 mL) and then extracted with DCM (15 mL). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with DCM/MeOH (100:0 to 90:10) to yield the desired product as a white solid (1.2 g, 29%). LC-MS (ES+): m/z 722.34 [MH+].
[0677] Table 11. Exemplary Compounds.
Ex# Structure Compound name and Analytical data
(2S,4R)-1-4(2S)-3,3-dlimethyl-2-{4-[4-(4-{[trans-3-(3-chiloro-4.-cyanophenoxv)-2,2,4,4 ietraimethyicyclobutyi]carbamnoy}pssheny)phenoxybuitanaiido}butanoyl]i-4-hydroxy-N-{[4 (4.-methy-l,3-thiazol-5-yl)phenymethy}pyrrolidine-2-carboxamide
'H NMR (400 MHz, CD-OD) 6 ppm 8.87 (s, I H), 7,84 -7.90 (I,2 H), 7.73 (d, J= 8.61 Hz,
179 1H), 7.66 - 7.71 (m, 2 H), 7.58 - 7.63 (m 2 H), 7.45 - 7.49 (m, 2 H), 7.38 -7.3 (21, 7.14(d,J= 235Hzli, 1Hi.01 -7.06(m2H), 6.99(dd,/:=8.80,2.54 Hz, i H),4.65(s, I
S OH H),4.56-4.60(i, H),4.52-4-55)(m, I H),.4.51 (br.s.1 H),4.35(d,.=15.65Hz, 1H), 0 N 4.31 (s,11H),4.18(sI 1-1),4.06(dd, J=9.39,6.36,3.28,3.28H-z,211),3.93(d,J= 10.96 Hz, H), 3.81 (dd,= 10.96s3.91 Hz, I H), 2.48 -2.57m ), 2.42 - 2.47 (m, 3 H, 2.22 (dd, J= 13.11, 7.63 Hz, 1 11), 206 - 2.15 (, 3 H), 1.31 (s, 6 H), 1.25 (s, 6 H), 1.04 (S, 9 H) LC-MS (ES'): lz 973.41 [M I
(2S,4R)-1-(2S)-3,diethyl-2-4-4-({1tras3-(3-choro-4-cyvaohenxy),2,4,4-. tetramnetlvicvloibutylcarbamoyIlphenyl)phenoxybutanamsidobitanoyl]-4-hydroxy-N-{[4 (4-methyl-1,3-oxazol--y)phenymetylpyrrolidine-2-carboxami1de
'H NMR (400i Mz,zCD3 OD)6ppmrn8.14(s,1H),787(d,J= 8.22Hz.2H),7.73Id,.1-8.61 . 180 Hz, I H), 7.67 -771 (i, 2), 7T57 - 7.63 (ms4 H), 7.45-7 51 (m,2fI),7.14(d, J=2.74 Hz, SIH), 7.031 00Hz,H),6.99(dd,./=8.80,2.54Hz.1H,,4.65(s, 1H),4.55-4.59 (m, 11, 4.47 - 4.55 (i2H), 4.34 (d, .=15.65 H-z, 1 H), 4.31 (s, 1 ), 4.19 (s, 11H), 4.06 N- H ] I J--\ 1 (ttH. = 6.16, 323 Hz, 2HI) 3.93 (d,J= 10.96 Hz, I H), 3.81 (dd, J= 10.96, 3.9'i Hz, H), 2.48 - 2.55 (m 2 11), 2.39 (s. 3 11) 2.22 (dd, J= 13.30,7.43 Hz, 1 H), 2.06 - 2.14 (m, 3 H), 1.31 (s, 6 H),1.25 (s, 6 H),1.04 (s, 9 H); LC-MS iES*): rdz 957.44 [MH]'1
N,
o (2S,4R)-1-[(2S)-3,3-dmethyl-2-(2-{2-[4.-(4-{[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 6tetramiethylcyclobuty!]carbamoy}phenyl)phenoxy ethoxy acetamido)butaol]-4-hydroxy HN N N-{[4-(4-msethyl-1,3-oxazol-5-yl)ph'eniylmethyl}pyrroidine-2-carboxamide
181 ' I-NMR (400 MHz, CDCis) 6ppm 8.05 (s, H), 7.8 ' -7.87 (m, 2 H), 7.73 (d, J= 9.00 Hz, 1 1), 7.58 - 7.64 (m, 2 H), 7.51 - 7.58 'i4 11, 7.43 - 7.51 (m, 2 H),7.10 - 7.19 (in,3H), 6.99
iddlJ= 9.00, 2.35 Hz, 1 1), 4.76 (s, 1 1), 4.55 - 4.64 (m, 3 H), 4.51 (d,J= 1.96 iz,1I ), 4.31 (,, J ='7.83 Hz, 2 H), 4.25 (q, = 4.17 Hz, 2 H), 4.19 (s, 1 H), 4.14 (S, 2 H), 3.96 (t,J= o-- 4.30 1z, 2 H, 3.86 - 3.91 (m, I1H, 3.78 - 3.86 n 1 H),2.26 - 2.32 (n, 3 H), 2.18 - 2.26 (i, HAN -- N IH, 2.05-2.13(m,)H), 1.31 (s,611, 1.25 (s,61),0.99 - 1.11 ,1i,9H);.C-MS(ES'):
Ex# Structure Compound name and Analytical data
m z973.43 1(MH
(2S,4R)-1-[(2S)-3,3-diiethyl-2-(2-{2-[4-(4-f[trans-3-(-choro-4-canophenoxy),44 -ci tetramethyicvclobutylcarhamoyi}phenyl)phenoxvethoxy aceumido)butanoyi]-4-hydroxv N-([4-(4-nerhyl-1,3-thazo-5-ylpheyl]etyl}pyrrolidine-2caboxamide NH
'H NMR (400 MH, CDCLs) 6 ppm 8.66 (s.1I H), 7.82 (d, J 8.22 Hz, 2 H), 7.60 (dd,J= -211.5, 8.41 Hz, 3 11), 7.53 (d, J=8.61 Hz, 211), 7.27 - .4 6 1H, 7.04 (d, J=8.61I H. 2 182 H), 6.99 (d, J= 2.35 Hz, 1 H), 6.83 (dd, J= 8.80. 2.15 Iz 111), 6.31 (d, J=8.22 Iz, 11), 4.75 t, i= 7,83 Hz, 1 H), 4.52 - 4.64 (m, 2 H), 4.50 (d, J 8.61 Hz, 1 H), 4.34 (dd,= ° O. oH 14.87, 5A8 Hz, 11, 417 - 4,24 (m, 3 H)4.04 - 4.17 (m, 4 ), 3.88 - 3.97 (m, 2 H),3.63 (dd, J= 11.35, 3.52 Hz, 1 H), 2.61 (ddd, J:=: 13.30, 7.83,4.70 Hz, 11), 2.49 (s, 311), 2.12 NH s (dd,J= 13.69.8.22 Hz, 1H)1.31(, 6H)1.26 (,H09%(,9 H);LC-MS(ES*):m z 989.27 [MI-It
[0678] Examples 179-181 were synthesized according to similar procedure described for synthesis of example 182, by using corresponding starting materials and intermediates.
[06791 Synthesis of example 182:
, OH 1 Step 2 - H O . OK Step3
Step Step 7 HO 6tp H.O0 IO O
s
HO \ --- --- --- - N
0 0 OH
Example0182HsC NN
[0680] Ste 8:e Sytei f xml8
2K~ 0 -NIl
Example 182 S
[0680] Step8:Synlthesisofexamptle18S2
[0681] To a stirred solution of 4-{4-[2-(I[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-I,3-thiazol-5 yl)phenyl]methylcarbamoyi)pyrrolidin-1-y]-3,3-dimethyl-1-oxobutan-2 yl]carbamoyl methoxy)ethoxy]phenylibenzoic acid (89.0 mg, 122 pimol) in methylene chloride (2.0 mL) was added HATU (55.5 mg, 146 pmol) and diisopropylethylainine (63.7 pL, 366 pmol).The reaction mixture was stirred at room tem perature for 10minutes. The reaction mixture was then charged with 2
chloro-4-[trans-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile (34.0 mg, 122 pmol). The reaction
was stirred at room temperature for 30 minutes.The reaction was monitored by LC-MS, which indicated
completion of reaction.The reaction mixture was quenched with water (5 mL) and then extracted with
DCM (25 inL). The organic layer was washed with brine (5 mL), dried over Na 2 SO4 , filtered and
concentrated under reduced pressure to give a crude material, which was purified by flash silica gel
chromatography on aTeledyne Combiflash ISCO fluentt: DCMIMeOH (v:v = 90:10)) to give titled product (yield: 37%) as a white solid.
[06821 Step 7: Synthesis of {44-[2-({[()-1-[(2S,4R)-4-hydroxy-2-({[4-(4-inethyl-1,3-thiazol-5 yl)phenyIlmethylIcarbamoyi)pyrrolidin-1-yl]-3,3-dimethyl-I-oxobutan-2
yl]carbamoyllmethoxy)ethoxy]phenyllbenzoic acid:
HQ HO ( N
I, 0) 0
[0683] To a stirred solution of ethyl 4-{4-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({i[4-(4-methyl-1,3-thiazol 5-yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-I-oxobutan-2 yl]carbamnoyl}methoxy)ethoxy]phenylIbenzoate (188.4 mg, 248 pmnol) in methanol (2.0 mL) was added I M NaOH in water (0.5 mL, 12.5 mmol). The reaction mixture was stirred at room temperature for 16
hours. The reaction was monitored by LC-MS. which indicated completion of reaction. The reaction
mixture was quenched with 1.0 M ICI in water and then concentrated under reduced pressure to remove
the methanol. The aqueous was extracted with EtOAc (25 mL)The organic layer was washed with brine
(5 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a crude material,
which was purified by flash silica gel chromatography on aTeledyne Combiflash ISCO (eluent:
DCM/MeOH (v:v = 90:10)) to give titled product (yield: 50%) as a white solid. LC-MS (ES*): mz 729.18
[MH]
[0684] Step 6: Synthesis of ethyl 4-{4-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenylimethyl}carbanoyl)pyrrolidin-1-yl]-3,3-dimnethyl-1-oxobutan'-2 yl]carbamoyl}methoxy)ethoxy]phenylIbenzoate:
/ on /
NN
[0685] To a stirred solution of 2-(2-4.]4-(ethoxycarbonyl)phenyl]phenoxylethoxy)acetic acid (100 mg, 290.3 pinol) and (2S,4R)-1-[(2S)-2-amrino-3,3-dimethyIbutanoyl]-4-hydroxy-N-[(1S)--[4-(4-methyl 1,3-thiazol-5-vl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (135.5 mg,290.3 pimol) in Dichloromethane (2.0 nl.) was added O-(benzotriazol-1-yl)-N,NN',N'-tetramethyuronium
tetrafluoroborate (93.20 mg, 290.3 pmol) and diisopropylethylamine (151.6 pL,870.9 pumol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS, which
indicated completion of reaction. The reaction mixture was concentrated under reduced pressure to give a
crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO
(gradient eluent: Heptane/Acetone (v:v = 100:0 to 0:100)) to give titled product (yield: 86%) as a white solid. LC-MS (ES*): m/z 757.3283 [MH*].
[06861 Step 5: Synthesis of 2--{4-[4-(ethoxycarbonyl)phenyI]phenoxy}ethoxy)acetic acid:
0 / .H
[06871 To a stirred solution of ethyl 4-(4-2-[2.-(tert-butoxy)-2-oxoethoxy]ethoxy}phenyl)benzoate (245
mg, 611 inol) in methylene chloride (1.0 mL) was added trifluoroacetic acid (1.0 mL, 12.9nmol). The reaction mixture was stirred at room temperature for 30 minutes.The reaction was monitored by LC-MS,
which indicated completion of reaction. The reaction mixture was concentrated under reduced pressure to
give titled product (yield: 100% based on crude) as an off white solid. The material was used in next step
without any further purification. LC-MS (ES*): m1z345.1330 [MH*].
[06881 Step 4: Synthesis of ethyl 4-(4-{2-[2-(tert-butoxy)2-oxoethoxyethoxylphenyl)benzoate:
o0.
[06891 To a stirred mixture of ethyl 4 -hydroxy-[i,1i-bipheny]-4-carboxylate (146.6 mg, 605.3 pmol) and tert-butyl -{2-[(4-methylbenzenesuifonyl)oxy]ethoxyIacetate (200.0 mg, 605.3 pmol) in
acetonitrile (2.0 mL) was added potassium carbonate (125.4 Ing. 907.9 pmol) at room temperature. The
reaction mixture was then stirred at 80 °C for 16 hours. The reaction was monitored by LC-MS, which
indicated completion of reaction. The reaction mixture was concentrated under reduced pressure to give a
crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO
(gradient eluent: Heptane/EtOAc (v:v = 100:0 to 50:50)) to give titled product (yield: 99%) as a clear oil.
LC-lMS (ES*): m/z 423.18 [MNa'].
[06901 Step 3: synthesis of tert-butyl 2-{2-[(4-.methylbenzenesulfonyl)oxy]ethoxyIacetate:
0 .0
[06911 To a stirred solution of tert-butyl 2-(2-hydroxyethoxy)acetate (1.44 g, 0.19 mmoil) i methylene
chloride (10.0 nL) was added 4-methylbenzene-1-sulfonyl chloride (1.713 g, 0.21 mmol) and triethylaine (1.707 nL, 12.25 mmol) at room temperature. The reaction mixture was stirred at room temperaturefor 16 hours. The reaction was monitored by LC-MS, which indicated completion of reaction.
The reaction mixture was concentrated under reduced pressure give a crude material, which was purified
by flash silica gel chromatography on aTeledyne Combiflash ISCO (gradient eluent:
Heptane/Acetone (v:v = 100:0 to 0:100)) to give titled product (yield: 69%) as a clear oil. 'H NMR (400 MHz, CD 3 OD) 6 ppm 7.77 - 7.83 (m, 2 H), 7.44 (d, J= 7.83 Hz,21 H), 4.14 - 4.19 (m, 2H), 3.93 (s, 211), 3.68 - 3.74 (m, 2 H), 2.46 (s, 3 H), 1.46 (s, 9H) LC-MS (ES): m z 353.1053 [MNa*], tj = 2.56 min.
[06921 Step 2: Synthesis of tert-butyl 2-(2-hydroxythoxy)acetate:
[0693] To a stirred solution of tert-butyl 2-[2-(benzvloxy)ethoxyIacetate in Ethanol (10.0 mL) was
added palladium on carbon (10% wt.) (1.99 g, 1.87 mmol).The reaction mixture was evacuated and
purged with H2 gas (3 x). The reaction mixture was stirred at room temperature under an atmosphere of
H2 for 16 hours. The reaction was monitored by TLC analysis, which indicated completion of reaction. The
reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced
pressure to give titled product (yield: 87% based on crude) as a clear oil. The crude material was used in
next step reaction without any further purification.
[0694] Step 1: Synthesis of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate:
'I/
[0695] To a stirred solution of 2-(benzyloxy)ethanol (5.0 g, 32.8 imol) and tert-butyl 2
bromoacetate (7.02 g, 36.0 rmol) in acetonitrile (10.0 mL) was added potassium carbonate (6.78 g, 49.1
mmol) at room temperature. The reaction mixture then stirred at 80 °C for 16 hours. The reaction was
monitored byTLC analysis, which indicated completion of reaction. The reaction mixture was diluted with
water (10.0 mL) and extracted with EtOAc (20.0 mL).The organic layer was washed with water (5.0 mL),
brine (5.0 mL), dried over Na 2SO 4 , filtered, and concentrated under reduced pressure to give titled product
(yield: 100% based on crude) as a yellow oil. This crude material was used in next step reaction without
any further purification.
[0696] Table 12. Exemplary Compounds.
Ex# Structure Compound name and Analytical data
Ex# Structure Compound name and Analytical data
(2S,4R)-1-[(2S)--3,3-dimethyl-2-(2-{[-4---trans-3-(3-chloro-4-cyanophenoxy)-22,4,4 tetramlIethycyclobutyljcarbamoyli}phenoxy)phenyliimethoxylacetaiido)butanoyli]-4-hydroxv-N N, {[4-(4-methyl-1,3--hiazol-5-yl)phenyl-methy}pyrrolidine-2-carboxamide
IH NMR (400 MHz, CD 3 0D) 6 ppm 8.83 - 8.90 (m, 1 H). 7.79 - 7.86 (m, 2 HI,7.72 (d,= 8.61 SHz, 1,H),7.43-7.50(m,4 H),7.37 7.42(i,2 H),7.13(d=-2.35 Hz,I H),7.00- 7.09(.,4 H),6.98(dd,= 9.00,2.35 Hz, 1 H), 4.71 (s, 1 H), 4.63 (s, 2 H), 4.55 - 4.61 (i, 2 H), 4.47 - 4.54 (m, 2 H) 4.35 (d, J= 15.65 Hiz, IH), 4.28 (s, 1 1), 4.15 (s,I 1H), 4.00 - 4.08 (m, 211), 3.86 - 3.92 HNO(, H), 3.77 - 3.84 (ms 1 H),2.44-2.48 (m,3HI), 2.24 (dd1J== 13.30, 7.43 Hzs 1 H),2.09 (ddd,
N- , 1=13.21.9.10,430Hz, 1H,1.28 (s, 6H), 1.22 (s,6H), 1.00 - 1.09 (m, 9 H): LC-MS (ES*) NH m z 975.39[Mi* 183 q (2S,4R)-1-[(2S)-3,3 -dimethyl-2-/2-{[4-(4-1 1 r3r)- 3-(3-chioro-4-cyanophenoxy)-2,2,4,4 tetramethyleyelobutvliearbaimoyllphenoxy)phenylimethoxyfacetanido)butanoyl]-4-hydroxy-N
< {[4--(4- methyl-1,.3 -oxazol-5-yl)phenyllmethyl 1pyrrolidine -2-calrboxamde
H- NMR (400 M z,CD 30D) o ppm 8.10 - 8.15 (m, 1 H), 7.79 - 7.85 (' 2 H), 7.72 (d, 9.00 Hiz, I H), 7.55 - 7.61 (m, 2 H), 7.44 - 7.51 (m,4H), 7. 12 (d,, 1=2.5 Hiz, 11H), 7.00 - 7T09 (m, 4
Y I ~H), 6.9 8 (dd,, J= 9.00, 2, 35 Hz, I YH), 4.71 (s, I YH), 4,63 (s, 2 H-), 4J55 - 4.61 (m, 2 H), 4.46 - 4.54 (mi .21H), 4.34 (d,j= 15.261Hz,J R ), 4.28 (s, I H) .1s - H) 4. (S, H),14.02 -4.06 (m,1 1 H), 3.85 - 3.92 (my., 11H), 3.'7'7 - 3184 (ms 11H, 2.35 - 2.42 (m, 3 H), 2123 (d, J 13.30, 7.43 Hiz
N1 1 H), 2.04 - 2.12 (mn, 1 Hf), 1.28 (s, 6 H1), 1.22 (s, 6 H),. 0.97 - 1.12 (m-., 9 H1); LC-MS (ES*): m /z
184 NH 959.41
FIN ~~~(2S,4R)-1--[(2S)--3,3-dimrethyl-2-(2 -{2-[4-(4-{['trans-3-(3-chilor--c--yanopheno)xy)-2,2,4,4'
H1 NMR (400 M11z, CD3OD) 5 p-pm 8.83 (s, I Hj), 7.74 - 7.82 m,2 H)', 7.721 (d, J= 8.61 H1z, I
H), 7.42 - 7.49 (m, 2 H1), 7.33 - 7.40 (m, 2 H), 7.12 (d, J = 2.35 Hz, I H), 7.06 - 7,11 (m, 2 H)",
S6.87 - 7.01 (m, 5 H), 4.741 (s, I H), 4.55 - 4.61 (m, 2 H) 4.49 - 41.55 (m, 2 H1), 4.32 (d, J = 15.26 ,OH N ~ Hz, I H), 4.28 (s, I HI)s 4.17 - 4.22 (mn, 2 H), 4.14 (s, 1 H1), 4.13 (s, 2 H), 3.91 - 3.96 (m, 2 H),
0A3.85 - 3.90 (mn, 1 H1), 3.79 - 3.85 (m, iH), 2.40 - 2.49 (m, " H)', 2.23 (dd, -j=1330, 7.83 Hz,
j1H), 2.05 - 2.14 (m, 1 H1), 1.28 (d, J= 1.17 H1z, 6 H1), 1.22 (s, 6 H1), 1.01 - 1.09 (m, 9 H); L-MS
185 N- (ES*): m z i 005.40' fMH
Ex# Structure Compound name and Analytical data
(2S,4R)--[(2S)-3,3 -dimethyl-2-(12-{2-[4f(4-([trans-3 -(3 -chloro-4-cvanophenoxy)-2.24,4 tetramethylcyclobutvilcarbamoviIphenoxy)phenoxy ethoxy acetamido)butanovll-4-hydroxy-N
{[4-(4-nethyl-1,3-oxazol-5-yliphenylmethyl pyroidine2-carboxamide 'HNMR (400 MHz, CD.OD) 6ppm 8.10 (s, 1 H),7.74 --7.83 (m, 21H) 7.72 (dJ=8.61 Hz, I 1 H), 7.52- 7.59 (m, 2 H), 7.43 - 7.50 (mY, 2 H),7.07 - 7.15 (m, 3 H), 6.86 - 7.02 m,S5 H), 4.75 (s, N 1 1), 455 - 4.61 (rn, 2 H),4.52 (d, =8.61 Hz, 2 H,4.33 (s, 1 H),4.26 - 4.31 (in, 11), 421 (q, NH =3.78Rz, 2 H). 4.10 - 4.17 Or% 3 1 1) 3.94 (dd1J=4.03.191Hz,2H.385 - 3.91(in1 H), 3.78 - 3.85 (in, H), .33 (s, 3 H), 223 (dd, = 3.11, 7.63 Hz, 1H), 2,09 (ddd, J=13.30, 9.19
186 N 4.50 Hz, 1 H), 1.28 (s, 6H),1.22 (s, 6 H) 1.00 - 1.10 (m, 9 11):LC-MS(ES 989.44[M
0,NH
HN
(2S4R)1-[2S)3,3dimthy-2-(2-{[4-(4-{ trans-3-(3-chloro-4-cyanophienoxy)-2,2,4,4 tetramethylcvclobutyl-carbamnoyllphenoxy)phenyllformamidolacetamido'butanoyl]-4-hydrox
N-{[4-(4--mnethyl-1,3-thiazol-5-yl)phenvl]mtethyioyrroiidine-2-carboxamide NH Mass (ES*): nz 988.10 [MH-F]
187
[0697] Examples 184-187 were synthesized according to similar procedure described for synthesis of
example 183, by using corresponding starting materials and intermediates.
[0698] Synthesis of Example 183:
'o~' "" -- ~c" 6c'O -N - o~ r-,0 i :------------- -0 OH Step 1 Step 2 OH Ste3 Step 4 HO HO
0 OH
OO \=N
Stp7 0:-/' Ste
Example 183
[0699] Step 7: Synthesis of Example183
[0700] To a stirred solution of 2-chloro-4-[trans-3-amino-2,2,4,4
tetramethylcyclobutoxy]benzonitrile (25.3 mg, 90.9 pmol) and 4-{4-([(2S)-1-[(2S,4R)-4-hydroxy-2
({[4-(4-methyl-1,3-thiazol-5-yi)pheny]methyIcarbamoyl)pyrrolidin-I1-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamovlimethoxy)methyliphenoxylbenzoic acid (65 mg, 90.9 pmol) in methylene chloride (2.0 nL) was added O-(benzotriazol-I-yl)-N,N.,N',N'-tetramethyiluronium tetrafluoroborate (29.1 mg, 90.9
p mol) and diisopropylethylamine (47.3 pL, 272 pmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LC-MS, which indicated
completion of reaction. The reaction mixture was diluted with water (5 mL) and extracted with DCM (25
mL). The organic layer was separated and washed with brine (5 mL), dried over Na 2 SO4 , filtered and
concentrated under reduced pressure to give a crude material, which was purified by flash silica gel
chromatography on a Teledyne Conbiflash ISCO (eluent: DCM/MeOH (v:v = 90:10)) to give titled product (yield: 22%) as a white solid.
[0701] Step 6: Synthesis of 4-{4-[({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenvl]rethyl}carbamoyl)pyrroilidin-1-yi]-3.3-dimethyl-1-oxobutan-2 yl]carbamoylImethoxy)methyl]phenoxy benzoic acid:
HQ
AII I HO 00 N~I
N.
[0702] To a stirred solution ofmethyl 4-{4-[({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol 5-yl)phenyl]methyllcarbamoyl)pyrrolidin-I-yl]-3,3-diniethyl-1-oxobutan-2 yl]carbamoylimethoxy)methyl]phenoxybenzoate (68 mg, 93.2 pmol) in methanol (2.0 ml) was added 1
M NaOH solution in water (0.5 mL, 12.5 inmol) at room temperature.The reaction mixture wasallowed to
stir at room temperature for 16 hours. The reaction was monitored by LC-MS., which indicated completion
of reaction. The reaction mixture was quenched with 1.0 M IHCI solution in water (0.5 nL) and then
concentrated under reduced pressure to remove the methanol. The aqueous was extracted with EtOAc (25
mL). The organic layer was separated, washed with brine (5mL.), dried over Na 2 SO4 , filtered and
concentrated under reduced pressure to give titled product (yield: 98% based on crude) as a white solid.
This material was used in next step reaction without any further purification. LC-MS (ES'): mlz
715.28[MH]2
[0703] Step5:Synthesisofmethyl4-{4-[({2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]--3.3--dimethyl-1-.oxobutan.-2- yl]carbanoyl}methoxy)methvl]phenoxyibenzoate:
HO. N
. 0 11-11 - , z- NHI
[07041 To a stirred solution of 2-({4-[4-(methoxycarbonyl)phenoxyjphenyi}methoxy)acetic acid (30.0 mg, 94.8 pmol) and (2S,4R)--[(2S)-2-amino3,3-dimethylbutanoyl-4-hydroxy-N-[(1S)--[4-(4-methyl 1,3-thiazol-5-yl)phenyi]ethyl]pyrrolidine-2-carboxamide hydrochloride (44.2 mg, 94.8 pmol) in methylene chloride (2.0 mL) was added0-(benzotriazol--yl)-N,NN',N'-tetramethyluronium tetrafluoroborate (30.4
mg, 94.8 pmol) and diisopropylethylamine (49.4pL, 284 pmol) at room temperature. The reaction mixture
was allowed to stir at room temperature for 30 minutes. The reaction was monitored by LC-MS, which
indicated completion of reaction.The reaction mixture was concentrated under reduced pressure to give a
crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO
(gradient fluent: Heptane/Acetone (v:v = 100:0 to 0:100)) to give titled product (yield: 99%) as a white
solid. LC-MS (ES*): mz 729.30 [MH*].
[0705] Step 4: 2-({4-[4-(methoxycarbonyl)phenoxy]phenyi}methoxy)acetic acid:
0~ 0 o' 0 OH 0
[0706] A solution ofmethyl 4-(4-f[2-(tert-butoxy)-2-oxoethoxy]methyl}phenoxy)benzoate (200.0 mg, 537 p mol) in hydrogen chloride solution (4 M in dioxane, 2.0 mL) was stirred at room temperature for
2 hours. The reaction was monitored by LC-MS, which indicated completion of reaction. The reaction
mixture was concentrated under reduced pressure to give titled product (yield: 95% based on crude) as an
off white solid.This material used in next step reaction without any further purification. LC-MS (ES*): nZ
339.0858 [MNa'].
[0707] Step 3: Synthesisof methyl 4-(4-{[2-(tert-butoxy)-2-oxoethoxy]methyljphenoxy)benzoate:
o'~
[0708] To a stirred mixture of sodium hydroxide (1.16 g, 29 mmol) in water (2.0 mL) and toluene (2.0 mL) at 20°C was charged with tetrabutylammonium hydrogen sulfate (32.86 mg, 96.79 pmol), followed by methyl 4-[4-(hydroxymethyl)phenoxybenzoate (250.0 mg, 967.9 pmol), the resulting mixture was stirred at 20 °C for lb. The mixture was then cooled to 5 °C, tert-butyl 2-bromoacetate (207.5 mg, 1.064 mmol) was added slowly and the internal temperature wasmaintained below 15 °C. Upon the completion of this addition, the reaction mixture was allowed to warm up to room temperature and stirred for 16h at room temperature. The reaction wasmonitored by LC-MS, which indicated completion of reaction.The mixture was diluted with water (5 miL) and extracted with EtOAc (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a give a crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO (eluent (gradient): Heptane/EtOAc (v:v = 100:0 to 70:30)) to give titled product (yield: 56%) as a white solid. LC-MS (ES*): iz 395.15 [MNa*].
[07091 Step 2: Synthesis of methyl 4-[4-(hydroxynethl)phenoxybenzoate:
O -OH
[07101 To a stirred solution of methyl 4-(4-formylphenoxy)benzoate (750.0 mg, 2.92 mmol) in methanol (2.0 mL) wasadded sodium borohydride (121 mg, 3.21 mmoil) at room temperature. The reaction mixture was allowed to stir at room temperature for 30 min. The reaction was monitored by LC-MS, which indicated completion of reaction. The reaction mixture was slowly quenched with 1N HCl (solution in water), concentrated under reduced pressure to remove the bulk of methanol, and then extracted with DCM (30 miL).The organic layer was separated, washed with brine (5 mL), dried over Na 2S04, filtered and concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO (eluent(gradient): Heptane/EtOAc (v:v= 100:0 to 50:50)) to give titled product (yield: 94%) as a white solid. LC-MS (ES): mz 259.10 [MH].
[0711] Step 1: Synthesis ofmethyl 4-(4-formylphenoxy)benzoate:
01
o 0.
[0712] Toastirred mixtureof methyl4-hvdroxybenzoate(.Og,6.57i rnmol) andpotassium carbonate (1.36 g, 9.85 mmol) in dimethylformamide (2.0 mL) was added 4-fluorobenzaldehyde (815 mg, 6.57 mmol) at room temperature. The reaction mixture was then stirred at 80 °C for 16h. The reaction was monitored by LC-MS, which indicated completion of reaction. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (50 nL x 2). The organic layer was separated, washed with brine (10 niL x 2), dried over Na2SO 4 , filtered and concentrated under reduced pressure to give a crudematerial, which was purified by flash silica gel chromatography on a Teledyne
Combiflash ISCO (eluent (gradient): Heptane/EtOAc (v:v = 100:0 to 50:50)) to give titled product (yield: 90%) as a white solid. LC-MS (ES'): m.257.08 [MH-1].
[0713] Table 13. Exemplary Compounds.
Ex# Structure Compound name and Analytical data
(2 (2,R)1[(S-3,3-dime ,R -[2S -e thyl-2-(2-{[5-(4'-{[tran-s-3-(3-chlor.)Io-4-cyanophenioxy)-2,2,4,4 tetramethylyclobutylcarbamoyiphenoxy)pentylainno acetamido)btanoyl]-4-hydroxv-N-(4 (4-methyl-1,3-oxazol-5-yl)phenylimethylipyrrolidine-2-carboxamide 'HNMR 00MHz,CDCi)8.68(s, 1H,763(d,J-8.6H2).57 (d, J 8.6 Hz, IH), 7.35 188 8H 4,697(d,J=23HiH),6.81(ddJ=2.588Hz H 6.60 (d, I = 9.0 Hz, 2H), 6.07-6.12 (m, 1-),4.71 (s, 1I)450-49 (m, 3H), 4.37 (d, 5.1 iz, 1H), 4 11-4.1 7(m, S211,3.64 (cd,-=3.5, 11-31Hz, 11H), 3.53 (dj= 7.011z, 2H),3.19 (,J== 7.0fHz, 2H 2.55-2.61 (m, iH),2.52(s,3H),2.10-2,19 (m, 2H),1.65-1.71 (m, 4H), I50-1.53 (in, 2H), 1.24-1.33 (m, 911),1.22 (s, 611) 0.96 (s, 9H), 0.86-0.91 (m, 3H). LC-MS (ES*): rz954.43 [M11
(2S,4R)-1-[(2S-3,3-dimethy-2-(2-{[4-{[rans- -co-4-cyanophenoxy-22,4
NH' tetramethylcyclobutylIcarbamoyhplkenoxy)pentylamo'aetaido)butano-4hdrxyN-{[4 HN -4-methyl-l.3--oXazol-5-yl)phenylimethylpyrrolidine-2-c.rboxamide *HNMR(40OMHz, CDClI)7.79 (s, 1H),7.72 (d,J = 8.6Hz, 2)7_54-7.60(, IH),7.51 (d,J 189 8.2 Iz, H) 7.34(dJ= 8.2lHz,2H).6.96(d,J= 2.3IHzH),688(d,= 90Hz,2H, 6.81 d,=2.3s 90 Hz,1IH), 4.534.67 (i,2H),4.40 (br. s, 1H), 4.14 (d, J= 8.2 Hz, 1H),4.05 (s, HN), 3.92 (br. s. 2H),3.74 (br. s, 1H), 3.60 (d, = 8.6 Hz, 111, 2.39 (s, 311),2.23 (br. s., 21), 7 .;1)(rm ., 4H), 1.43 (r. s., 211), 1.27 (s. 1211),1.22 (is, 611),0.99 (br. s., 8H), 0.86-0.93 (m. 61 ). LC-MS (ES'): miz 938.45 [MH*]
[0714] Example 189 was synthesized according to similar procedure described for synthesis of
example 188, by using corresponding starting materials and intermediates.
[0715] Synthesis of example 188:
O H
Se 6 S A2 o Step )HO
N OHH Ste 4N1 N HOH Se N H |O N N
0 0
plyExample N'H 18 N
~0 '1 N > N 'O- StepSCSep 7
S Example188 K
107161 Step 7: Synthesis of example 188
[07171 Trifluoroacetic acid (1.12 rL, 14.7 ninol) was added to a stirred solution of tert-butyl N-({[(2S)
1-[('2S,4R)-4-hydroxy-2-({[4-(4-nethvl-1,3-oxazoi-5-yl)phenylimethyl}carbamoyl)pvrrolidin-1-yl]-3,3 dimethyl-I-oxobutan-2-yi]carbarnoyI}methyl)-N-[5-(4-{[trans-3-(3-chlioro-4-cyanophenoxv)-2,24,4 tetramethylcyclobutyl]carbamoyl}phenoxy)pentyl]carbamate (34 mg, 0.0327 mmol) in DCM (3.00 ml) at room temperature. The resulting mixture was stirred at 45OC for 48h. The reaction mixture was then
concentrated under reduced pressure to give a crude material, which was purified by flash silica gel
chromatography on a Teledyne Coinbiflash ISCO system, eluting with MeOH/DCM (gradient: v:v = 0:100
to 10:90) to yield the desired title product (yield: 62%).
[0718] Step 6: Synthesis of tert-butyl N-({[(2S)--[(2S,4R)-4-hydroxyv-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenyli]methyl}carbamoyl)pyrrolidin-1-yi]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}methyl)-N-[5-(4 {[trans-3-(3-chlioro-4-cyanophenoxy)-2,2,4,4
tetramethylcyclobutyl]carbainoyljphenoxy)pentyl]carbamate:
OH N N W)N HN
[0719] TBTU (23.0 mg, 0.072 mrnol) was added to a stirred solution of 4-[(5{(tert butoxy)carbonyl]({[(2S)-i-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenyiimethylIcarbamoyi)pyrrolidin-1-yl]-3,3-dimethyl-I-oxobutan-2 yl]carbamoyl}methyl)amino}pentyli)oxybenzoic acid (38 mg, 0.04786 mmol) and 2-chloro-4-[trans-3 anino-2,2,4,4-tetramethylyclobutoxy]benzonitrie (13.3 mg,0.04786 mmol) in DMF (3.0 mL) and DIPEA (16.5 p L, 0.095 nnol) at room temperature. The resulting mixture was stirred at room temperature for Ih. The reaction was then diluted with EtOAc (30 rL), washed with brine (5 mL x 2), filtered through a Biotage Universal Phase Separator and then concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO system, eluting with MeOH/DCM (gradient: v:v = 0:100 to 10:90) to yield the desired title product (yield: 60 %).
[07201 Step 5: Synthesis of 4-[(5-{[(tert-butoxy)carbonyl]({[('S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4 methyl-1,3-thiazol-5-yl)phenyl]methyllcarbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamoyl}methyl)amino}pentyl)oxy]benzoic acid:
H
H~/
0 N,
[0721] Lithium hydroxide (3.0 mg, 0.128 mrnol) was added to a stirred solution ofmethyl 4-[(5-{[(tert butoxy)carbonyl]({[(2S)-i-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5 yl)phenvlimethvl}carbanoyi)pyrrolidin-1-yi]-3,3-dinethyl-1-oxobutan-2 yl]carbamoyl}methyl)aminoIpentyl)oxylbenzoate (37 mg, 0.046 rmmol) in a mixed solvent of THF/water
(v:v = 1:1, 2.00 mL) at room temperature. The resulting reaction mixture was stirred at room temperature
overnight. To the reaction mixture was added IN HC (aqueous solution) to adjust pH =-3. The resulting
mixture was extracted with EtOAc (20 miL x 2), washed with brine (5 ml. x 2), filtered througha Biotage
Universal Phase Separator and then concentrated under reduced pressure to give a crude material (yield:
100 % based on crude). This crude product was used for the next step reaction without any further
purification.
[07221 Step 4: Synthesis of methyl 4-[(5-{[(tert-butoxycarbonyl]({[(2S)--[(2S,4R)-4-hydroxy-2-({[4 (4-methyl-1,3-thiazol-5-yl)phenyl]methyllcarbamoyl)pyrrolidin-I-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamoyllmethyl)aminolpentyl)oxybenzoate:
0, N N. H [IN'
C
[0723] TBTU (36.6 rg, 0.1142mmol) was added to a stirred solution of 2-{[(tert-butoxy)carbonyl]({5
[4-(methoxycarbonyl)phenoxy]pentyi})amino}acetic acid (37 mg, 0.076 mmol) and (2S,4R)-1-[(2S)-2- amino-3,3-dimethylbutanovi]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)pheny]methyl}pyrrolidine-2 carboxamide (32.8 mg, 0.076 mmol) in DMF (3.0 mL) and DIPEA (26.4 p L, 0.15 mmo) at room temperature. The resulting reaction mixture was stirred at room temperature for hr. The reaction was then diluted with EtOAc (30 mL). washed with brine (10 mL), filtered through a Biotage Universal Phase Separator and then concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography on aTeledyne Combiflash ISCO system, eluting with MeOH/DCM (gradient: v/v = 0/100 to 10/90) to yield the desired title product (yield: 64%).
[0724] Step 3: Synthesis of2-([(tert-butoxy)carbonyl]({5-[4 (methoxycarbonyl)phenoxy]pentvl})aminoacetic acid:
[0725] Palladium on carbon (96.8 mg, 0.91 mmol) was added to a stirred solution of methyl 4-[(5-{[2 (benzyloxy)-2-oxoethyl][(tert-butoxy)carbonyli]aminoIpentyl)oxy]benzoate (83.0 mg, 0.171 mmol) in ethanol (20 ml) at room temperature. The reaction mixture was degassed and charged with H( and then stirred at room temperature for 16h under a hydrogen atmosphere. Solids were then removed by filtration and the solvent was concentrated under reduced pressure to give a crude material (yield: 98% based on crude). This crude product was used for the next step reaction without any further purification.
[0726] Step2: Synthesisofmethyl 4-[(5-{[2-(benzyloxy)-2-oxoethyl][(tert butoxy)carbonyl]aminopentyl)oxv]benzoate:
[0727] Di-tert-butyl bicarbonate (47.7 pL, 0.21 mmol) was added to a stirred solution ofmethyl 4-[(5 {[2-(benzyloxy)-2-oxoethyl]aminopentyl)oxy]benzoate (73.0 mg, 0.19 mmol) inTHF (5.0 ml) at room temperature. The reaction mixture was heated to reflux at 80 C and stirred at 80 C for 14 hours. The reaction was then cooled to room temperature, diluted with ethyl acetate (20 mL), washed with saturated aq. NaHCO3 (10 rL). The organic layer was separated and filtered using a Biotage Universal Phase Separator and then concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography on aTeledyne Combiflash ISCO system, eluting withEtOAc/Heptane (gradient v:v = 0:100 to 40:60) to yield the desired title product (yield: 95%).
[0728] Step 1: Synthesis of methyl 4-[(5-([2-(benzyloxy)-2-oxoethyl]amino}pentyil)oxy]benzoate: 0
[0729] To a stirred mixture of methyl 4-[(5-oxopentyl)oxylbenzoate (269 rg, 1.13 mmol) and benzyl 2 aminoacetate hydrochloride (186 mg, 1.13 mmol) in DCE (5.00 rL) was added acetic acid (181 pL, 2.26 mmol) and sodium triacetoxyborohydride (358 mg. 1.69 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18h. To the reaction mixture was added IN NaOI- aqueous solution to adjust pH = ~10, the resulting mixture was then extracted with DCM (30 mL x 3).The organic layer was separated, washed with brine (10 ml x 2), dried over Na 2SO4 , filtered and concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography on a Teledyne Combiflash ISCO, eluting with MeOI-1/DCM (gradient v:v = 0:100 to 15:85) to yield the titled product (17 %).
[0730] Table 14. Exemplary Compounds.
Ex# Structure Compound name and Analytical data
Ex# Structure Compound name and Analytical data
F' N (2S,4R)-1I[(2S)-2-2-{4-4-(4-3-[6-yano-5-trifluoroetlv)yridin-3-y]-5,5 diN-methy -4-oxo-2-sufanylideneimidazolidin- -yI}pheny)phenoxy]butoxy}acetamido)
3,3-3imethylbutanoyl-4-hydroxyN-{[4-(1,3-oxamoi-5-ylhenylmethylprroldine-2 a I carboxamide 190 HNMR (300 Mlz, CDOD):9.14 (s, 11H), 8.65 (d,,J= 21 liz, 1H), 8.21-8.10(m, 1 0 S1H), 7.74-7.50 (-, 6 ), 7.47-7.29 (ms 5 ),7.10-6.97 (m, 2 ) 4.70-4.22 (m, 5H),4.15 HN 3.96 (m. 4 H), 1395-3.70 tem, 2 H).70-3.50 (mn,2 H), 2.24-2.00 (m, 2 H),2.00-1.80
-. 4
CI-) NN-.
(1S,4R)-I-[(2S)-2-{2-[4-(4-{4-[3-(5-chloro-6-cvanopyridin-3-)-5,5-dimethyl-4-oxo-2 sulfanylideniidazolidin-1-yl]phenuyl}phsenoxv)butoxv]acetanidO1-3,3
191 drimetlwbutanoyl]-4-vdroxy-N-{[4-1,3-oxazol-5-yl)phenyl]methyl}pyrrolidine-2 -O carboxamide Mass (ES mz 961.20 [MH*] OH -
N X< /)
F F a (2S,4R)- 1-[(2S)-2-(2-{4-[4-(4-{3-[6-cyano-5-(trifluoromethyl)pyridin-3-yl-5,5 dimetylv-4-oxo-2-sulfanyidencimnidazoldin-I-yI}phenyl)phenoxybutoxy}acetamido)
192 3,3 -dimnethlibutanoyl]-4-hydroxy-N-{[4-(4-methsyi-1,3-oxazo-5 yn)phenylmethyl}pyrrolidine-2-carboxamide Ho IMass- (ES*): 1009.20 [MH'] OH ro N NH
-N
(2S,4R)-[(S2-(2-{4-[4-(-{3-[6-can-5-(riluormehy)pyridi-3-l-5,5 dimethy-4-o-2-sulfanylideneimidazolidin-1.ylpheyl)phenoxyhbutox) acetamido)
193 3,3-dimettlbutanoyl-4-hydroxv-N-{[4-(4-methyl-1.3-hiazi-5 T yl'phe'nlmethlpyolihdine2-carboxamitde N Mass (ES'):'0z 1025.45 [MHW]
NH
Ex# Structure Compound name and Analytical data
Nsk NA (2S,4R--[(2S)--12-2-{4-4-(4-5 F F -N diethlv-4-oxo-2-sulfanylideneimidazolidin-1-ylphenyl phenoxy]butoxylacetamido)
3,3-dimethylbutanoyl-4-hydroxy-N-[IS)-1-[4-(4-nethyl-1,3-thiazol-5 'yl)phenylethyl]pyrroidine-2-carboxamide
194 H NMR (400 M z, CD 7 D): 69.19 (s, 111), 8.86 (s, 1H), 8.70 (s, 1H), 7.75 (d, J 8.8
HzI, 2H) 762(d,J= 8.8-H, 2H)f,7.40(in, 611)7.05(d, = 8.8 Hz, 211),5.00 (d,J= 7.2 HN Hz, iH), 4.56 (s, H), 4.64 (m1H),4,44(, )4.0(m, 2H),4.06 (, 2H), 3.86 n,
s 1H)CH 3.76 (m 1H),-3.66 (in, H),2.47 (s, 311). 2.22 (m, 111) 1.92(, 5), l 62 (s,61), H 1.49 (d, 1= 6.8 Hz, 3H), 1.02 (s. 9H); LC-MS (ES+): m/ 1039.50 [MH'I
F/N (2S,4R)-1[(2S)-2-2-{4-4-(4-3-[6-yano-5-trifluoromethy)pyridin-3-y]-5,5 F Ndimethyl -4-oxo-2-suIfanylideneimidazolidin-1-yI}pheny)phenoxybutoxy}Iacetamido) 4 3,3-dmetybutano7yl:- -hydroxy-N-[(lS)-1-[4-(4-methyl-13-oxao-5
\ v)phenyljethyl]pyrrolidme-2-carboxamide H NMR (400MI, CD3 OD): 59.19 (s, 1H), 8.70 (s, 1H), 8.12 (s, 11), 7.75-7.71 (dJ 195 8.4 Hz, 2H1,),7.61-7.55 (i, 4H), 7.42-7.38 (m, 4H), 7.05-7.01 '(J= 8.8Hz,2H5), 5.00-4.96 (d, J= 7.2 Hz, 1-), 4.56 (s. 11), 4.4-4.62 (m, 11), 4.4-4.41 (in, 1H), 4.12 4.01 (m 2H), 4.00-3.98 (m, 211), 3.86-3.81 (m, H), 3.74-37' 0(m, InH), 3.67-3.65 (m, 2H), 2.38S (s, 3H). 2.22-2.18 (m, 11), 1.98-1.88(m 31), 1.88-1.82m, 2H),1.62 (s, 6H), N NH1.48-1..46 (d, J=6.8 Hz, 3H)', 1'.03 (;, 9H); LC-MS (ES+): =..z 1023.-50 [MH*
(2S,4R)-1[(2S)-2-(2-{4-[4-((4-{3-[6-cyano-5-trfluoromethyl)pyridin-3-yl]-5,5 dimethl-4-oxo-2-sufanyideneimidazolidin-I-yl}-3
196 1fluoropheny'l)phenoxybtoxy Iacetamnido)-3,3-dimenthlbutanoyl1-4-hydroxy-N-[(1IS- 4
[ -(4-methv-J,3-thiazol-5-yl)phenllethylpyrroidine-2-carboxamide
H Mass (ES'): n/z 1057.15 [MW]
N OH N
00
NF N v
F F
2 4 4 4 (2S,4R)-l-[(2S)-- - -[ -( -13-[6-cyano-5-(trifluoromethylpyridin-3-yl-I,
'7-3 4dehy-4-xo-2-slfanylideneimidazolidin -1-yi}-3 4 197 fluorophenl)phenoxvbutoxvacetmamido)-3,3-dimetfhylbutanovlI-4-hydroxy-N-{[ -(4 rethyl-I,3thiazo-5-yl)phenyi]methypyrrodine-2-arboxamide Mass (ES*)': az 1043.20 [MH*'] ..OH
Ex# Structure Compound name and Analytical data
N> N '2S,4R)-1-[(2S)-2-(2-(444-4-{7-[6-cyao-5-(trifluoromethyl)pyridin-3-y-8-oxo-6 F N I sulfanvlidene-5,7-diazaspiro[3.4]octan-5-ylphenyl)phenoxy]butoxyjacetamido)-3,3
Fdimethybutanyl]-4-hydroxy-N-{[4-(4-methyi-1.3-oxazol-5
yl-phen-y]methyl}pyrrolidine-2-cearboxamide HNMR(400 MHz,CDOD):69.20i(s,),868(s,iH,810(s, H,7.78-7.75 (d, 198 8.4 z, 211H), 7.69-7.60 (m, 411), 7.48-7.45 (m, 4H), 7.08-7.01 (d,j= 8.8Hz, 211), 4.73 '0
HN H(s, H), 4 56-4.51 (m3H), 4.33-430 (ms 'H), 4.17-4.09 (m, 2H), 4.06-4.01 (m, 21 N OH 3 3 3.78 (m 211), 2.80-2.61 (m, 4H), 2.38 (s, 3H), 2.3-202(m, 311), 11),(9238, 1 N, 1.99 -1.85 (41), 1.72-1.61 (m 111), 1.48--1.39 (m, 211), 1.05 (s, 911): LC-MS (ES ): <NH mz 1021,40 [MH*]I'
o ('2S,4R)-1-[(2S)-2-(2- 4-[4-(4 -7-[6-cyano-5-tifor-omethyopyridin-y8oxo-6 F N' suhlnlidene-5,7-diazaspiro[3.4]octan-5-yipnhenyl)phenoxy]butoxy acetamido)-3,3
\ dimedylbutanoyl]-4-hvdroxy-N-{[4-(4-mehl-13-thiazo-5 yl.pheny ]methyl}pynrlidine-2arboxamide IHNMR (400 Miz, CDOD): 6 9.20 (s, 1H), 8.90 8 ( )86s, 1), 7.78 (d,= 8.4 199 ,2H1), 7.61 (di, = 8.8Hz, 2H), 7.52-7.1(,6H7.04 (d, = 8.4121), 4.73 (s, K0 H), 4,60-4.51 (n, 3H), 4.374`35(m, 'MH), 4.17-4.11 (m, 2H, 4,05-4.01 (m, 2H), 3.90 3.88 (m, 1H), 3.84-3.78 (, 111), 3.68-365 (i,211) 2.76-2.60 (i,4H, 2.42 (s, 31), -S NO OH 2.30-2.05(m, 3H), 2.01-1.85 'm, 4H), 1.68-1.64 (m, 1H), 1.41-1.29 (m, 3H),05 (s, 9H); N KLC-MS ('ES+): nz 1037,10 [MH-]
[07311 Examples 191-199 was synthesized according to similar procedure described for
synthesis of example 190, by using corresponding starting materials and intermediates.
[07321 Synthesis of example 190:
Ft3C~ 5NY HNN-'/_ s IN-~N NCS NN-- IN-- 1CI N NNK<~ - -------------- ----- ---FC S N----------N---------- - 3 H F F3 S Step 3
OHOH
/'NK~rC~ - o --1OrNAO,>O HATU. DIA,OHS'. -t---------------- Step 4 Step 5 NON N S NC NC CF, F3
OH
NC Example 190
[0733] Step 1: Synthesis of 5-{3-[4-(4-hydroxphenyl)phenyil]-5-imino-4,4-dimethyl-2 sulfanylideneimidazolidin-1-yl}-3-(trifluoromethyl)pyridine-2-carbonitrile:
HN N NF OH
[07341 To a stirred solution of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (440.0 mg, 1.92 mmol) in N,N-dimethylpyridin-4-amine (322.0 mg, 2.64 mmol) and toluene (10.0 mL) was added 2-[[4-(4-hydroxyphenyl)phenyl]amino]-2-methylpropanenitrile (400.0 mg, 1.59 nimol) under a nitrogen atmosphere at room temperature. The resulting solution was stirred at 100 C for 12h. The reaction mixture was then concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v/v 1/1) to give thetitiled product (yield: 17%). Mass (ES"): mz 482.20[MHI*].
[07351 Step 2: Synthesis of 5-{3-[4-(4-hydroxyphenyl)phenyl]-4,4-dimethyli-5-oxo-2 sulfanylideneimidazolidin-1-vl-3-(trifluoromethyl)pyridine-2-carbonitrile:
N
FaC N OH
[0736] To a stirred solution of 5-13-[4-(4-hydroxyphenyl)phenyl]-5-imino-4.4-dimethyl-2 sulfanylideneimidazolidin-1-vl-3-(trifluoromethyl)pyridine-2-carbonitrile (160.0 mg. 0.33 mmol) in methanol (5.0 mL) was added hydrogen chloride aqueous solution (2N, 2.0 mL) at room temperature. The resulting solution was then refluxed for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v/v I/1) to give the titled product (yield: 69%) as a yellow solid. LC-MS (ES*): i 481.15[MH*].
[0737] Step 3. Synthesis of tert-butyl 2-4-[4-(4-13-[6-cyano-5-(trifluoromethyil)pyridin-3-yl] 5,5-dimethyil-4-oxo-2-sulfanylideneimidazolidin-1-ylphenyl)phenoxy]butoxylacetate:
01V/ J / / N N..
NC
[07381 To a stirred solution of 5-{3-[4-(4-hydroxyphenyil)phenyl]-4,4-dimethyl-5-oxo-2 sulfanylideneimidazolidin-1-y--)(trifluoromethyl)pyridine-2-carbonitrile (110.0 mg, 0.23 mmol) and tert-butyl 2-14-[(4-methylbenzenesulfonyl)oxylbutoxyIacetate (163.0 mg, 0.45 mmol) in N,N-dimethylfornamide (3.0 mL) was added potassium carbonate (62.9 mg, 0.46 mmol) at room temperature. The resulting mixture was stirred at 60°C for 3 hours. The reaction was then cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude material, which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether, v/v =1/1) to give the titled product (yield: 98%) as a yellow solid.
[07391 Step 4. Synthesis of 2-4-[4-(4-13-[6-cyano-5-(trifluoromethyl)pyridin-3-yi]-5,5 dimethyl-4-oxo-2-suilfanylideneimidazolidin-1-ylphenyl)phenoxy]butoxyacetic acid:
N0
-S
NC CF3
[0740] To a stirred solution of tert-butyl 2-4-[4-(4-13-[6-cyano-5-(trifluoromethyl)pyridin-3 yl]-5.5-dimethyi-4-oxo-2-sulfanylideneimidazolidin-I-yl}phenyl)phenoxy]butoxy acetate (150.0 mg, 0.22 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (2.0 mL) at room temperature. The resulting solution was stirred for 2h at room temperature. The resulting mixture was concentrated under reduced pressure to give a crude material, which was used for next step reaction without any further purifications. Mass (ES,): m z 613.00 [MI-I].
[0741] Step"5. Synthesis of example 190: 0H
NN / 1 OQXNHA
N>' CF 3 K N
[0742] To a stirred solution of2-{-14-[4-(4-{3-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-5,5 dimethyl-4-oxo-2-suIfanylideneimidazoidin-1-yIpheny)phenoxy]butoxy) acetic acid (80.0 mg, 0.13 mmol) and(2S,4R)-1-[(2S)-2-amino-3,3-dimethyilbutanoyl]-4-hydroxy-N- {[4-(1,3-oxazol-5 yl)phenyl]methyl}pyrrolidine-2-carboxamide (53.8 mg, 0.13 mmol) in N,N-dimethyformamide (2.0 mL) was added 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (51.0 mg, 0.13 mmol) and N-ethyl-N-isopropylpropan-2-amine (43.0 mg, 0.33 mmol) at room temperature. The resulting solution was stirred for 2h at room temperature. LC-MS indicated formation of the desired product. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude material, which was purified by a silica gel flash chromatography (eluent: ethyl acetate/petroleum ether, v/v = 1/1) to give the titled product as a white solid (yield: 45%).
[0743] Table 15. Exemplary Compounds.
Ex# Structure Compound name and Analytical data
N
(2S R)-[(2S)--2-({[6-({4-[13-(cloro-4-cyanoohenyl)-5,5-dimethl-4-oxo-2 sulfanylidencimiidazolidin-1-ylphenoxymethylspiro(3.3]heptan-2
200 1 m'ehoxyiacetamido)-3,3-dimsethylbutanoyl]-4-hydroxv-N-{[4-(1,3-oxazo-5 yi~lpenymethilpyrrolidine-2-carboxamide Mss (ES)':mz 950-50 [MH*]
0 (2S,4R)-1-[(2S) 2-[2-((6-[4-{3-[4-yano-3-(tifluoromsethlhenyl-5,5-dimethl-4 N N oxo-2-sulfanylideneimiidazolidin-1-yl~phenoxynmethylspiro[3.3]heptan-2
thiazo-5-yl)phenylimethlyllpyrrolidine-2-carboxamide
H NMR (400 MHz, CD 3 D) 68.86 (s, IH), 8.16 (d, J= 8 Hz, 21), 8.01 (d,J= 8.4 Hz, 1l), 7.51-7.42 (m,41), 7.27 (d, J= 8.8 Hz,2H), 7.07-7.00 (n, 2H)4.71 (s, IH). HN 63-4.53 (m, 3H), 4.38-4,33 (mi, Hi 4.04-3.95 (in, 2H, 3.93-3.85 (m, 3H), 3.84-3.80 N/"OH n H 3.53 (s, H), 2.63-2.59 (m. 1H-), 2.57-2.49 (m, 41), 2.29-2.19 (m, 3H),2.18 2.06 (n, 3H)2.01 -1.87 (n,4H), 1.55 (s, 6H), 1.05 (s, 9H); LC-MS (ES*): m/z 1014.20
[MH*]
Ex# Structure Compound nameand Analytical data
(2S,4R--[(2S)-2-[2-((6-[(4-{3-[4-cyano-3-(trifluoromethioyl)phini-5,5-dimehyl-4
F N oxo-2-sulfanylideneinidazoidin-1-v}phenoxy)methvlIspiro[3.3]epan-2 F F a l vimehoxy)acetamidoi-3,-dimicthylbutanoyl]-4-hydroxy-N-[(iS)-l-[4-(4-nethyil-3
thiazo-5-yl)henyllethyi~pyrroidinearboxamide HNMR(400MIHz,DMSO) 68.99 (s, 1H),8.45 (d,]7= 7.6iHz, 1H, 8.39 (d,7= 8.0 202 Hz, 1H), 8.29 (s, iH), 8.08 (d,.J= 9.6 Hz, IH), 7.44 (d,,]= 8.4 Hz, 2H), 7.38-7.25 (M
*5H) 7.07 (d, =8.8 Hz, 2H), 5.17 (s, 1H), 4.91 (s, iH),4.54 (d, J= 9.6 Hz, IH), 4.45 OH 4.38 (m, 1H),4.29, ), 3.96-3.94 (m, 21), 3.93-3.90 (m, 211),3.60-3.57 (m, 2H), NH 3.43 (s, 2H), 2.5-241 (m, 5H), 2.23-2.04 (i, 5H) 1-93-1.77 (r,5H), 1.49 (s, 61), 1.37 (d, 7.2 Hz, 3H). 0.95 's, 9H); LC-MS (ES*:m: 1028.20 [MH*]
F F3 F F S(2S,4R)-l[(S---{6-[(-{7-[4-cano-3-(trifluoromnethylphenyl]-8-oxo-6 203 sulfanylidene-5,7-diazaspio[34otn5-lpeoymehlsio3.]etn2 203 y;s}ethoy'cetmio]-,3diethylutaoyl]4-hdrox-N{[-(4mehy-13 thiazol-5-yl)phenyl]metiylpyrolidine-2-carboxaimide H Mass (ES': m1026.25 [MH'] .> ~OH NH
[07441 Example 201was synthesized according chemistry shown below utilizing similar
procedures used for the synthesis of example 75.
HO pH TsCI H O TO- C N'
< 2CO NC CF,
OH.
_sm,N/ 'HKHIU, DIPEA NC'
CFC>
[0745] Examples 200,.202-203x-as synthesized according similariprocedure described for synthesisofexample201,byusingcorrespondingstarting materials and intm dis
[07461 Table 16. Exemplary Compounds.
Ex# Structure Compoundnamecand Analytical data
te tramethyl Cyel obu tYlearbat IYI ~phenyl' ph e-. iifariioe thoxyla etarid'
204 HN- -3,3-dirnetlijyibutanoy t -4,vdrxy-N f-4 -(4 -metby1 -h iazo -5 0 /yiph e nvll-medhyvl Ipy'-ol din e2 carlboxat ide 'IN N as ES):in,1988,20 [TvI-1]1
[07471 Table17. Additional Exemnplary(opuns
Ex#Measuired Mass lon Structure Data
'105
1082.37
2206
. N 1024.33
207
N~ 1152.45
Measured Mass Ion Ex#Structure Data MH+ I MH½
209
0 10
z......N"..... ..
¾~~'-~ 111.33
2101
11113
---- -- - --- - --- -- --- -- - -- - -- - -- - -- - -- - -- -- - -- - -- - -- - -- - -- - -- -- - -- - -- - -- - -- - -- - -- - -- -- - -- - -- - -- - -- - -- - -- -- - -- - -- - -- - -- - -- - -- -- - - - -- - -- - -- - -- - --
.NN ."½. ~ ... 1.1.56.
loN
S\:½'. "'' .<A. N"11404
Measured Mass Ion Ex#Structure Data MH+ I MH½ 2'13
K 1200.4
214
N 'J,~"~-< " ~ 'yN~.' ''1170.42
215
11844
216
CAV
Measured Mass Ion Ex#Structure Data MH 1 MH½ 218
N N N"1198.46
219
'N ' "1256.50
'I' N<"~1284.53
221
N "''N" ¾1096.39
1138.46
262'
Measured Mass Ion Ex#Structure Data MH 1 MH½
1152.47
224
1180.50
'4 -.. 4-N"1050.40
-- - - -----------------------------------------------------------------------,---N- "----- - -------------------------------------
226
z"% t4"
"I 1090.47
227
1076A46
Measured Mass Ion Ex#Structure Data MH+ I MH½
V 1020.40
229
N ~ N 1068.36
230
QNY
1009.36
231
1033
----- -- ------ ------ ----- ------ ------ ----- N-- -- ------ ----- ------ ---- 0------ ------ -------- N- ----95----- ------ ------ ------3 6----- ---- ---
'N N'< 264-
Measured Mass Ion Ex#Structure Data MH 1 MH½ 2133 401
\~ ""' -'\~'3934.32
234
1108.44
-135
N ' 1052.37
"I,
236
. ,'.920.29
237
904.30 4 NH
Measured Mass Ion Ex#Structure Data MH 1 MH½
'"-'7-992.35
----------------- --------------------------------------------N----
239
'N 1008.34
-- ------ ---------------------------------------------------- -------
140O
10223
N.. t§
'N ~A1032.33 N'
.241
(7 N 10233
----- --- ---- ------ ----- ------ ---------- ----- ---------- ------ ----- ----- ------ ----- ----- ------ ----- ------ ----"- ---- ---- N- --- .........................
Measured Mass Ion Ex#Structure Data MH 1 MH½
978.35
244
'N 948.34
145
1037.37
-- - - -- - - -- - - -- -----------------------------------------------------------------------------------------------------------N'----- '--:- ---
246
INM 1004.40
247:
kN~V~<'> 0 N -~1006.38
Measured Mass Ion Ex#Structure Data MH 1 MH½
"484
1022.35
1040.40
'1503
<A'N"1052.35
251
NC " . N1006.35
2
50~' 1036.36
Measured Mass Ion Ex#Structure Data MH 1 MH½ 153
1022.36
254
6 NC-
N. 994.31
'155
t-SC~Y* -wN-1034.40
256 p
N
2~5 5'-2
'7'.01.0.3
Measured Mass Ion Ex#Structure Data MH 1 MH½
1024.35
2-9
N 1052.38
260.
'C 1024.34
261 0%. N NN
00 4''V '.~.980.28
1036.37
N
Measured Mass Ion Ex#Structure Data MH 1 MH½
1054.35
264
,, ~' N'1026.32
265
INN
£7?\
Measured Mass Ion Ex#Structure Data MH 1 MH½
k> N.1006.37
269
K 1036.36
1050.38
271
3.'
V i'.'.952.27
272
Measured Mass Ion Ex#Structure Data MH 1 MH½ )-73
N-> 1050.36
27-4
.... 1040.34
15
-. ~. ¾'.996.31
276
277 NO
101.33.
Measured Mass Ion Ex#Structure Data MH 1 MH½
4 N 1010.33
279
- c'~1066.36
'<'c K980.30
281
994.32
282 N
§ N",-1048.30
274.
Measured Mass Ion Ex#Structure Data MH 1 MH½
284
7'~N',.1072.34
'185 O4z
<N~' \""- 71086.36 N~N>..<..NS
286
1058.33
287
:1077.41
Measured Mass Ion Ex#Structure Data MH 1 MH½ ''88
1054.37
289
jr\N" 1063.41
,)go'
190 0
~\ N~ I1043.38
292j
~ N.~"".024.44
---------------- --------- ---------- ------ ------ ------ ---------- --------- ------- ----- ------ ------ ----- -------- ------ ---
N v276
Measured Mass Ion Ex#Structure Data M I ME-;t
1059.48
294
C) ~ 4.1073.49
295
1020.46
296 N
'N'" 1054.46
297 N
Ny N 1122.49
Measured Mass Ion Ex#Structure Data MH 1 MH½ "'98
1054.46
299
"N> N > N>'1022.41
'.... .... N?
1006.44
301 N
1020.45
302
1024.42
Measured Mass Ion Ex#Structure Data MH 1 MH½ 303 O
N~C: '7 S
1010.41 S
3044
1108.44
1032.4
so 1012.41
307
100.41
(27
Measured Mass Ion Ex#Structure Data MH 1 MH½ 308 ~.N ~ ~ ~ O
1020.47
1015.49
1062.51
311
1031.48
i N
312
.7 ' <'*N~:1006.45
Measured Mass Ion Ex#Structure Data MH 1 MH½ 313
3]4
N 974.40
315 '
o~w' '¾1006.46
316
N.'N'NA'1005.48
317~
-- --- --- ------ --- --- ---- --- ---------- -- ------------------------------ -- -------- -- 01- 9--------- 0---
Measured Mass Ion Ex#Structure Data MH 1 MH½ 318
1031.40
988.32
321
100.37
321
Measured Mass Ion Ex#Structure Data MH 1 MH½
3243
1017.39
32~
315
1017.40
326
"'N N N1018.20
327
K; K>1032.55
Measured Mass Ion Ex#Structure Data MH 1 MH½ 32 8
1047.34
329
0
1002.10
S NN '331.05
331
1089.39
332
.4,,
284.
Measured Mass Ion Ex#Structure Data MH 1 MH½ 333
1005.40
334 f
K; 1004.40
e, ZI 942.40
336 N,_
960.50
N
33'7
.7 ' .- ~,-942.40
Measured Mass Ion Ex#Structure Data MH 1 MH½ 338
957.4.0
339
7340
1023.40
3414
342.
341.3
----------- -- -- ----- -------- -------- -------- --------- -------- -------- --------- ---------------- -------- -------------- ----- N'. 286
Measured Mass Ion Ex#Structure Data MH 1 MH½ 34-3 N
-<-7 "920.30
344 W
' / \:.N "N8
S 956.30
A' 956.35
346
34'7
N>-- s ~'.2 -A>94.40
E xIvMeasured Mass Ion Ex#Structure Data MH 1 MH½ 348
"N ' 961.35
349
~~ 972.40
3503
N,)"'a4.~t976.35
351 N .NN \J v~"'
3-2
N:,C
7 7>4"N'N,.993.25
Measured Mass Ion Ex#Structure Data MH 1 MH½ 353
978.35
35~4
NN
960.35
'355
N'l
"N" " N990.45
NV' 990.4
-- ------ ------------------------ 3 -------------------------------- -----------------------------------------------------------
N ,'N <N 'N . 289
Measured Mass Ion Ex#Structure Data MH 1 MH½ 358
t.;':xN.994.10
.' KxN~~'N950.20
)360
N. "<"4978.20
361
Wv>'>'992.20
362
N' . 977.25
Measured Mass Ion Ex#Structure Data MH 1 MH½ 363
994.4.0
364
988.40
'36
366
102.20
366
994.40
E xIvMeasured Mass Ion Ex#Structure Data MH 1 MH½ 368
N'. 978.30
369
960.30
371'
372
983.5
-- - ---- ----- ----- ----- ----- ------------------- ------ ----- ----- ----- ----- ------ ----- ---------- ----- --
994.4
Measured Mass Ion Ex#Structure Data MH 1 MH½
3'74
'375N
.' 'N1034.30
1089.30
E xIvMeasured Mass Ion Ex#Structure Data MH 1 MH½
3-11
~ 4 NS~CV » ,1032.34
379
.- ..... ---
105.30
3817
102.O
NN
1026.1.6
----------- -------------------------------------------------------------------------------------------------------------------------- ~ -' --------------- ----------------
Measured Mass Ion Ex#Structure Data MH 1 MH½ 383
.- e
1025.30
384
1041.30
385 i
991.26 993.26
386
1011.30
38'7 N IN
927.37 929.37
Measured Mass Ion Ex#Structure Data MH 1 MH½ 388
'951.23 953.23
389
1055.10
391 Z
~ N 1022.15
392
9430933
Measured Mass Ion Ex#Structure Data MH 1 MH½
954.31 956.31
394
988.37 990.37
'395 '
N~' 1045.35
396
~K 1012.15
39'7
'N 'rUN1012.1.5
Measured Mass Ion Ex#Structure Data MH 1 MH½ 398 .8
968.32 970.32
399
1026.15
400 '.8
1042.20
401
1040.35
402
'N -,1021.20
Measured Mass Ion Ex#Structure Data MH 1 MH½ 403
'N 1040.15
404 Q
NI
980.52 982.52
405
989.40 991.40
406 <
'a989.40 991.40
920.58 922.58
Measured Mass Ion Ex#Structure Data M I MH½ 408 N
1040.10
954.38 956.38
410
966.37 968.41
411
-N 938.44 940.44
412
.966.42 968.42
Measured Mass Ion Ex#Structure Data MH 1 MH½ 413N
NH
1006.30
4151
0" NN
918.34 433
41$7
'-----N00 .3 .1.005.39N N ~-
Measured Mass Ion Ex#Structure Data MH 1 MH½ 418
7 12< ~ ii'1045.38 419
1045.38
420
7: *"... ..
-, 1050.39
421
1023 '1044.39
-)
Measured Mass Ion Ex#Structure Data M I MH½ 424
~'K 1064.36
425
4" &\N~¾.986.46 988.46
426
-~ 0'-1064.37
M14.
427
'4 ~ ~ K '.41030.38
418
-, ~ .................-. 'N4 -1030.38
44]l9 7
""--4 N,"4'- .$..,:N..,'Y41067.38
4 . NN & ' 0c
Measured Mass Ion Ex#Structure Data MH+ 1 MH½ 430
"~'3 ct N1066.38
431 w
N\ IA .-- NSr 1016.37
432
¾ - ~\1004.38 1006.38
433
4.>t 41074.45 1076.45
434.
\.-. 1029.39
435
N.'~'' -"N1029.39
Measured Mass Ion Ex#Structure Data MH 1 MH½ 436
'N ~ .4975.40 977.40
437
-41 975.40 977.40
438
~K995.46 997.46
439
N.-- 1036.40
440
H. Ni '0- 1030.38
441
1004.30 1064
Measured Mass Ion Ex#Structure Data MH 1 MH½
981.40 983.40
443
445,
44'
985.43 987.43
Measured Mass Ion Ex#Structure Data MH 1 MH½
N ''~"'~ ¾ Y~ ¶1003.30 1005.40 -4A,.
449
.* Y't..~~>.986.40 988.40
4-50s
N.1003.40 1005.40
6 c.....'.'' ~ 'V967.43
451 N
........................ N~~N .N.N N -1017.45
------------S-- ------------------------------------------- - -----------------------------------------------
453
1021.39
30-q
Measured Mass Ion Ex#Structure Data MH 1 MH½ 454
968.45 970.4
~s968.45 970.45
994.55 996.45
NI
96835 97.3
.2 ~''74 ~968.35 970.35
Measured Mass Ion Ex# Structure Data MH 1 MH½;2 460 N
41 1096.43 1098.43
N
461
1065.38 1067.38
462
1166.46 1168.46
463
S1067.40 1069.40
464
1003.50
465
1038.50 1040.50
Measured Mass Ion Ex#Structure Data MH 1 MH½ 466
1038.55 1040.55
467 2
1025.36 1027.36
468
"'...' 1038.37 1040.37
469
yY>>>1010.34 1012.35
470
S1012.35 '1014.35
4717
8 81012.35 1014.36
Measured Mass Ion Ex#Structure Data MH 1 MH½
~~Q 5: t 1037.25 1039.24
473
~S'.982.35 984.35
984.33 986.33
475
Z.984.33 986.33
476
477i
\~ ~ ... 7 .... ...... 927.30
Measured Mass Ion Ex#Structure Data
----- --- --- ----- - --- --- --- -----
~1.995.30 997.30
479 K
4 952.30
480
8 . ~881.34 883.34
481 >
" 4"989.28 991.28
969.33 971.33
483 '
V s"" '.~.W xi
1002.33 1004.33
Measured Mass Ion Ex#Structure Data MH 1 MH½ 484
988.31 990.31
485
K~NrS~t't~'N."¾"\ ~ " /968.83 970.83
486
-~969.33 971.33
48'7
--- ~/>~~~%k--¾"' ~940.30
4 8
J
489
NJ 912629 928293
Nkt&" 13
Measured Mass Ion Ex#Structure Data MH I MH 4-90
898.26 900.26
491
.).0i
.. '. 1003.60
492
(~ ~882.26 884.26
) NJ
494 > .j
104.3 '1042.35
494
104.35 104.35
Measured Mass Ion Ex#Structure Data MH 1 MH½ 496
912.28 914.28
~~ 1003.45
NN
'3 N' ~897.27 899.27
499H -M44 938.27 940.37
500
N' NN 916.31 918.31
----------------N------------------------------------------------------------------------
501
N
Measured Mass Ion Ex#Structure Data MH 1 MH½
'YN 984.30 986.30
503
955.32 957.32
504
'N ~942.33 944.33
505Z
5075
'N' '4 NN'782.37 97.36
-3 1
Measured Mass Ion Ex#Structure Data MH 1 MH½ 508
998.36 1000.36
509
769.27 771.27
5 10
912.35 914.35
5~11 .....N NN
914.36 916.36
Measured Mass Ion Ex#Structure Data MH 1 MH½ 514
998.34 1000.34
NM
517
518 I
ii
IN
3:1
Measured Mass Ion Ex#Structure Data MH 1 MH½
)868.34 870.34
521
965.34 96.34
522
887.37 889.37
523'
A883.35 885.35
5214
.~Nc >~C\W.~JX2i NV~916.34 918.34
'S
980.37 982.37
Measured Mass Ion Ex#Structure Data MH 1 MH½ 52
m925.43 927.43
527
.>925.44 927.43
529
N ' .~925.43 927.43
l k
Measured Mass Ion Ex#Structure Data MH 1 MH½ 53
936.44 938.44
IN
535 ' '
936.44 938.44
..... . ...
N .:.- .. . 7 ~>936.44 938.44
.. ~935435 937435
N 3
Measured Mass Ion Ex#Structure Data MH 1 MH½ 538
955.41 957.41
N<
539 . 1. .
A' NM .f V 4
"m' 883.41 885.41
5~40
N' t"N\K N917.39 919.39
541 N0
896.43 898.43
541
o882.41 884.41
--- ------ ----- - -----------------------------------------------------------------------------------------------------------------
543
1025.38 1027.38
Measured Mass Ion Ex#Structure Data MH 1 MH½ 544
0981.43 983.43
545
-46 (~
1055.30
5347 A
868.40 870.40
548
H .~tN..3883.40 885.40
~..-.. .. ~.931.86 933.86
Measured Mass Ion Ex#Structure Data MH 1 MH½ 550
o'N 8 917.38 899.38
551
554<
5555
'8.4N824
"«<N N ~v A"~ ~ ~~~3 N"2. 4.'N81.8 833
Measured Mass Ion Ex#Structure Data MH 1 MH½ 556 N NXA v 9 V982.45 984.45 N
557 N
0883.39 885.39
56 pm0.~.'N '
* 2 '
EY Meiasured Mass Ion Ex#Structure Data
96&.41 970.41
563
973.36 975.36
564
953.37 955.37
565
1036.20 4,....
566
TO--- 1056.15
567 DN
INN 1056.15
N326
Measured Mass Ion Ex#Structure Data MH 1 MH½ 568
-x M, 910.40 912.40
569
N"926.39 928.39
-570 N
-NN' 'N942.36 944.36
5 71
N
-892.35 894.35
5-73
92.4 983
Measured Mass Ion Ex#Structure Data MH 1 MH½ 5'-74
C 1070.15
575
1054M0
576 t" '
1054.20
5377
QN ~ ' -973.63 975.36
58
N
579
3M8
Measured Mass Ion Ex# Structure Data MH 1 MH½2 580
581
-582 N'
583N
NN
584
585
EY Meiasured Mass Ion Ex#Structure Data
586
587
588N
5~89
N Q
59
N-'-1
591
Measured Mass Ion Ex#Structure Data MH I MH
593~'5
[07481 Synthesis ofExample 608 Oc known comnpound0
N~~ ~ 0 ~~I j~ITF I __
0i D)IPEA,-NMP 0 rI)C"4 K CO D-MF I 0
0 0 K
DCN(, D-FA, Ay \IeoiI, H 2 0
DMF
0 0 )
BN, 0)0 WM2 Nl H-N - 0
N N~
[07491 Step 1: Synthesis oftert-utyl 4(5-(methoxycarboni)pyridin--yl)piperazin-1 carboxylate:
0 331N
[0750] A mixture of methyl 6-fluoronicotinate 2.0g13.2 mmol), tert-butyl piperazine-1 carboxylate (2.4 g, 13.2 mmol) and N-ethyli-N-isopropylpropan-2-amine(3.3 g 26.4 mmol) in anhydrous I-methylpyrrolidin-2-one (10 ml) was stirred at 90°C for 12 hours. TLC showed the reaction was complete. The cooled reaction mixture was partitioned between water (10 nl) and ethyl acetate (50 nil). The organic layer was collected, washed with brine (50 ml x 2), dried over anhydrous sodium sulfate. and concentrated under reduced pressure to give a crude residue which was purified by column (eluted with 20% ethyl acetate in hexane) to afford tert-butyl 4-(5 (methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (4.0g.yield 95%) as yellow solid. HNMR (400 MHz, CDCI): 6 1.48 (s, 911), 3.53-3.56 (m,,4H), 3.67-3.69 (m, 4H), 3.87 (s, 3H), 6.58 (d, J= 8.8 Hz, 2H), 8.02-8.05 (m, 1H). 8.79-8.80 (m,IH). Chemical Formula: C6 i 2N 3 4
, Molecular Weight: 321.37.
[0751] Step 2: Synthesis of methyl 6-(piperazin-1-yl)nicotinate
NH N\ N
0
[0752] A mixture of tert-butyl 4-(5-(niethoxvcarbonyl)pyridin-2-y)piperazine-i-carboxylate (4.0 g. 12.4 mol) and 2,,2-trifluoroacetic acid (10 ml) in dichloromethane (10 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up with dichloromethane (50 ml) and washed with aqueous sodium bicarbonate solution (IN, 15 ml), dried over sodium sulfate to give methyl 6-(piperazin--yl)nicotinate (3.8 g. crude) as yellow oil which was used in next step without further purification. I HNMR (400 MHz, DMSO-d): 6 3.13-3.16 (m, 4H), 3.80 (s, 3H), 3.82-3.85 (m, 411), 6.96 (d,l = 9.2 lz, 11), 8.00-8.03 (in,I1), 8.67-8.68 (m, 1H). Chemical Formula: CI1 HiN 30 2 , Molecular Weight: 221.26.
[0753] Step 3: Synthesis of methyl 6-(4-(2(2--(tert-butoxy)-2-oxoethoxy)ethy)piperazin-1- yl)nicotinate.
N N~ N
0
[0754] A mixture of methyl 6-(piperazin--I-yl)nicotinate (500 mg, 2.3 mmol), tert-butyl 2--(2 (tosyloxy)ethoxy)acetate (745 mg, 2.3 mmol) and potassium carbonate (1.2 g, 9.0 mmol) in anhydrous N N-dimethyformamide (10 ml) was stirred at 40°C for 12 hours. TLC showed the reaction was complete. The cooled reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml).The organic layer was collected, washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography elutedd with 20% ethyl acetate in hexane) to afford methyl 6-(4-(2--(2-(tert-butoxy)--2--oxoethoxy)ethyil)piperazin-1-yl)nicotinate (400 mg, yield 46%) as yellow solid.
[0755] Step 4: Synthesis of 2-( -(4-(5--(methoxycarbonyl)pyridin-2-yl)piperazi-1 yli)ethoxy)acetic acid. O
N O
0
[0756] A mixture of methyl 6-(4--(2-(2-(tert--butoxy) -2-oxoethoxy)ethyl)piperazin-1I-yl)nicotinate (150 mg, 0.39 mmol) and 2,2,2-trifluoroacetic acid (1 ml) in dichloromethane (1 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure to afford 2-(2 (4-(5-(methoxycarbonyl)pyridin-2-yl)piperazin 1-yl)ethoxy)acetic acid (150 mg, crude) as yellow oil which was used in next step without further purification. LCMS: (ES'): m/z 324.1 [M+H]+. ta = 1.306 min. Chemical Formula:
C 15 H 1 N 30s; Molecular Weight: 323.34.
[0757] Step5: Synthesis of methyl6-(4-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2--(((S)-1--(4-(4 methylithiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)- 3 ,3 -dimethyl-1-oxobutan-2
yl)amino)-2- oxoethoxy)ethy)piperazin-1- yl)nicotinate.
N N OHN0
N'
[07581 To a stirred solution of2-(2-(4-(5-(metioxycarbonyl)pyridin-2-yl)piperazin-1 yl)ethoxy)acetic acid (150 mg, crude), (2S4R)-I -((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy N-(4-(4-rnethylthiazol-5-yl)beniyl)pyrrolidine-2-carboxamide hydrochloride (230 mg. 0.48 mmol), and N-ethil-N--isopropylpropan-2-amine (260 mg, 1.92mmol) in anhydrous N,N- dimethylformamide (3 ml) was added HATU (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3 tetramethyluronium hexafluorophosphate ) (360 mg, 0.96 mmol) at 0°C, the resulting mixture was allowed to warm to room temperature and stirred for 20 minutes. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml).The organic layer were collected, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 10% methanol in dichloromethane) to afford ethyl 6-(4-(2-(2 (((S)-i-((2S,4R)-4-hydroxy-2-(((S)--(4-(4-methylthiazol-5 yl)phenyi)ethyl)carbamoyI)pyrrolidin-1l-yl)-3,3-dimethyl-I-oxobutan-2--yl)amino)-2 oxoethoxy)ethyli)piperazin-1-yl)nicotinate (130 mgyield 44%) as white solid. LCMS: (ES'): m/z 750.3 [M+H]*. tR= 2.025min.
[0759] Step 6: Synthesis of 6-(4-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-I-(4-(4-methylthiazol 5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-vl)-3,3-dimethyl-1-oxobutan-2-vl)amino)-2 oxoethoxy)ethyl)piperazin-I-yi)nicotinic acid:
I' N! NFi' 0 o HOTI
[0760] A mixture of ethyl 6-(4-(22--(((S)--((2S,4R)-4-hydroxy-2-(((S)-I-(4-(4-methylthiazol 5--y)phenyl)ethyl)carbamoyl)pyrrolidin-I-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 oxoethoxy)ethyil)piperazin-1-.yl)nicotinate (130 mg, 0.173 mmol) and lithium hydroxide monohydrate (14.2m mg 0.35 mmol) in tetrahydrofuran (5 il)-water (2 mil)-methanol (2 ml) was stirred at 40°C overnight. TLC showed the reaction was completed. The mixture solution was cooled to room temperature, acidified with diluted hydrochloride acid (3N) till p-I 3-4, and extracted with dichloromethane (10 ml x 2).The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to afford 6-(4-(2--(2 (((S)-I-((2S,4R)-4-hydroxy-2-(((S)-I-(4-(4-methylthiazol-5 yl)phenyl)ethyl)carbamoyl)pyrrolidin-I-yl)-3,3-dimethyl-I-oxobutan-2-yl)amino)-2 oxoethoxy)ethyli)piperazin-1-yl)nicotinic acid (60 mg, crude) as colorless oil which was used in next step without purification. 10761] Step7: Synthesis of N-((r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6-(4-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-I-(4-(4-methylthiazol-5 yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 oxoethoxy)ethyl)piperazin-1-yl)nicotinamide:
0 0 N N CI N ,N H N
N'
[07621 Toastirredsolutionof-(4-(2-(2-(((S)-I-((2S,4R)-4-hydroxy-2-(((S)-i-(4-(4 methyithiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 yl)amino)-2-oxoethoxy)ethyl)piperazin-1-yl)nicotinic acid (60 mg, crude), 4-((1r,3r)-3-amino 2,2,4,4-tetrameth ylcyclobutoxy)-2-chliorobenzonitrile hydrochloride (25 mg, 0.81 mmol), and N ethyl-N-isopropylpropan-2-amine (40 mg, 0.32mmol) in anhydrous N,N-dimethylformamide (2 ml) was added HATU (2-(7-Aza-1HI-benzotriazole-1-yl)-1,1,3,3-tetrarnethyluronium hexafluorophosphate) (61 mg, 0.16 mmol) at 0°C, the resulting mixture was allowed to warm to room temperature and stirred at room temperature for 20 min. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (5 ml) and water (5 ml). The organic layer was collected, washed with brine (5ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by TLC (eluted with 10 % methanol in dichloromethane) to afford N-((r,3r)-3-(3-chioro-4-cyanophenoxy)- 2.2,4,4-tetramethyleyclobutyl)-6-(4-(2-(2-(((S)-1-((2S.4R)-4-hydroxy-2-(((S)-I-(4-(4 methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 yl)arnino)-2-oxoethoxy)ethyli)piperazin-1-yl)nicotinarnide. (11.5 mg, yield 15%) as white solid. LC_MS: (ES'): m/z 996.4 [M+H]*. tR = 2.442 min. HNMR (400 M1z, CD 3 0D): 6 1.08 (s, 9H). 1.23 (s. 6H), 1.29 (s. 6H), 1.51-1.58 (m, 3H), 1.98-2.06 (m, 1H), 2.18-2.25 (m, 1H), 2.49 (s. 3H). 2.90 (s, 6H), 3.76-3.88 (Im, 811), 4.06-4.15 (in, 31), 4.29 (s, 1H), 4.41-4.46 (s, 11), 4.57-4.26 (m, 1H). 4.71 (s, 1H). 5.01-5.04 (m, 1H), 6.88-7.00 (m. 2H). 7.14 (s. 1H), 7.42-7.45 (m, 4H), 7.74 (d, J= 8.4 Hz,1I),8.00 (d, J= 6.0 Hz, 1), 8.64 (s, 11), 8.89 (s, I1). Chemical Formula: C 5 2 HCiN 9 0 7S, Molecular Weight: 996.65. 10763] Unless otherwise noted, Examples 594-770 were synthesized according to similar procedures described above for the synthesis of Example 608, by utilizing corresponding starting materials and reagents.
10i7641 Table 18: Additional ExemplaryCompounds
Measured Mass Ion Data Ex # Structure Compound Name TrY7 (1) -n/Z (2)
N-((1r,3r)-3-(3-ch~oro 4-cyana phenoxy) 2;2,4,4 f ~tetra methyl cyclobuitjl)
((2S,4R)-4-hydroxy-2
594 nethvlthiazol-5- 10114 1013.4 yI)pheny1)ethy1)ca rba rn oyl)pyrroiid i r-1-yI)-3 /cne.-hvl-l-oxobuitan-2-I y1)-1H-pyrazo1i-4- yI)pyridin-2 yI)oxy)azetidn-I _______yl)nicotinamide
N-((1r,3r)-3-(3-chlaro 4-cyanophenoxy) 2,2,4,4 Stet ramet: hy Icy c:Ib ulty )-ii
'~ ~ "((2S,4R)-4-hydroxy-2
methyithiazol-5 y1)pheny'!)ethyI)cprbprn ov1)pyrroiidin-I1-yI)-3 595 ~mc.thyl-oxobutan-2 - 11. yI)-lH-pyrazol-4 yl)pyridin-2 VI)oxV)azetidin-1- yI)nicotinarnide
(2S,4R)-1-((S)-2-(4-(2 ((R)-3-((4-(((ir,3R)-3-(3 chlorot-)4-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)c .. arbamoy1)phenyl)amin o)pyrrolidin-I yl)pyridin-4-yl)-1H 596 pyrazol-1-yl)-3- 1023.5 1025.4 methylbultanoyl)-4 hydroxy-N-((S)-1-( 4 methylthiazol-5 yl)phenyI)ethyl)pyrrolid N ine-2-carboxarnide
N
(2S,4R)-1-((R)-2-(4-(2 ((R)-3-((4-(((.r,3R)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 x tetrarmethylcyclobutyl)c 'e ' ''arbarnoyl)phenyl)amin
o)pyrroiidin-1 yl)pyridin-4-yl)-1H 597 . pyrazol-1-yl)-3- 1023.5 1025.4 methylbutanoyl)-4 hydroxy-N-((S)-1-(4-(4 methylthiazol-5 yl)phenyl)ethyl)pyrrolid } M ine-2-carboxamide
1-(2-(4-((1-(5-(4-(3-(4 cyano-3 (trifluoromnethyl)phenyl & )-5,5-dirnethyl-4-oxo-2 thioxoimidazolidin-1 yl)phenyi)pyridin-2 yI)piperidin-4-yl)oxy) 1H-pyrazol-1--yl)-3 methylbutanoyl)-4 hydroxy-N-(4-(4 methylthiazol-5 yl) benzyl)pyrrolidine-2 598 carboxamide 516.3
(2S,4R)--((R)-2-(4-((1 (5-(4-(3-(4-cyano-3 (trifIuorom ethyl)phenyl )-5,5-dimethyl-4-oxo-2 thioxoimidazolidin-1 yl)phenyl)pyridin-2 yl)piperidin-4-yl)oxy) 1H-pyrazol-1-yl)-3 methylbutanoyl)-4 hydroxy-N-(4-(4 methylthiazol-5 yl)benzyl)pyrrolidine-2 599 AN516.3 carboxamide
'$)-
(triflucror-nethyl)phenyl -Lk .Lo )-5,5-dirnethyl-4-oxo-2 thioxoimidazolidinI1 yl)phenoxy)pentyl)oxy) phenoxy)-lH-pyrazol1-l yI)-3-rnethylbutanoyj'l C>4-hydroxy-N-((S)-1--4 600 ~(4--methythiazoL-5- 034 3 ine-2-carboxamide
(2S, 4R)-I- ((S) -2 -(4- (3 ((51-4j-3-(4-cyaria-3 k ~(trifi uoramethyl)phenyl )-5,5-dimethyl-4-axa-2 th ioxo imni d azoIi d in-I yI1)p he n oxy)pe ntyl1) oxyj p phe naxy)- IH -pyra zo1 y1) -3-m e thyIb u-a n o 4- hyd roxy-N -4--(4 rnethylthiazol-5 601 y1)be nzy1) py rroIiid in e-2- 1049.4 525.2 carboxamide
3W-0
(2S,4R)-1-((R)-2-(4-(3 ((5-(4-(3-(4-cyano-3 triflucrornethyl)phenyl )-5,5-dirnethyl-4-oxo-2 thioxoimidazolidin-1 x, yl)phenoxy)pentyl)oxy) phenoxy)-1H-pyrazol-1 yl)-3-methylbutanoyl) 4-hydroxy-N-(4-(4 rnethylthiazol-5 602 yl)benzyl)pyrrolidine-2- 1049.4 525.2 carboxamide
N-(3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)
xN ((2S,4R)-4-hydroxy-2
methylthiazol-5 yl)phenyl)ethyl)carbam oyl)pyrrolidin-1-yl)-3 methyl-1-oxobutan-2 yl)-1H-pyrazol-4 yl)pyridin-2 603 yl)oxy)azetidin-1- [0214 1014.4 yl)pyrimidine-5 carboxamide
N-(3-(3-chloro-4 cyanophenoxy)-2,24,4 tetrarnethyicyciobutyi)
<N((2S,4R)-4-hydroxy-2
mne*thythiazol-5- yI phenyi)ethyl)carbarn oyi)pyrroi idin-1,-yI)-3 mnet hyl- 1-oxobutan-2-. lI)-iH 1rzi-4 604 1012.4 1Iprdi-- 1014.4 yIhoxy)azetidin-i Ks' yI)pyrimidine-5 ca rbaxamid e
cyano-3 (trifiulorornethyl)phenyl N)-5,5-dimethyl-4-oxo-2
th ioxoirn idazal idin-1 yI)phenoxy)mnethyl)cyc obutyi)rnethoxy)benzof 605 A ur~an-2-carboxamido)- 19. 4. *3;3-d im ethyl buta noylJ 4-hyd roxy-N-(1-(4-(4 rnethylthiazol-5 *yI) phe nyi)ethyl) pyrr I id * ine-2-carboxamide
N-((I r, 3r) -3 -(3-ch Ioro 4-cyanophenoxy) 2;2;4;4 tetra metyl cycIo b UtA) G-(W-(f(2- (((S)-l-j(2S,4 R) 4-hydroxy-2-(((S)-i(.
606 N 21ty-Hii~o 964.6 966.4
V)pheny)etnyl~cara3m
4'N oyl~prroidin-i-y)33 '~ -<& dimethyl-1-oxobutan-2 to yI)amino)-2 oxoethoxyjrnethylippe l ______ _____________________________________________ idin-i--1-yi)nicotinamide ___ ____
N-((lr,3r)-3-(3-chloao 4-cyanophenoxy) 2,2,4,4-. 2K"'\.~N8~K\A 'y*<~tetramethycyclobUtyl) -k6-(5(2((S-(2S,4R) 607 Y2K>,~ 4-hydroxy-2-(((S)-1 970. 67(4merytiaon 97214 yl 'fphienyi)ethyl)carbarn * oyl)pyrraiidin-1--yI)-3,3 *~~ \'Aimethyl-1-aoxabutan-2
< yl)arnina)-2 .. oxa et haxy)p entyl1)amin o)pyridazine-3 >'
carhoxamide
>. N, 4-cyancrheiaxy)- 2,2,4,4 tetrarmethyl cyclahutI)
((2S,4R)-4-hydroxvr-2 608 * c ~ methylthiazal-5--64 994 * wc'~( \~ " ~ Vy)phenyi)ethyl)carbarn st&, oy1)py r raIiid in-1-I3,3 N dirnethyl-1-oxobutn2 -' \ ~~'syl)amino)-2 oxoethaxy)ethyl)pipera zin-i-yI)nicotinamide (2S,4-R)-1 -((S)-2-(4-(2 ((S)-3-(4-(3-(4-cyana-3 N (trilUararnethyl)phenyl '~ ~ -5,5-dim ethyli-4-axa-2 N ~ Nthioxoir-nidazalidiriI N c y 1) lp henxy) py rroid in 609 N- - 1-y1) pyri d in-4-y I)-1 516.5 0 pyrazol-1-yIl)-3 r-n eth yIbu*a n oyi) "hyd roxy-N -((S)-i.-(4(4 rnethylthiazol-5 y1)phenyi0ethy1)pyrrolad ine-2-carhoxamicie (2S,4R)-1-((R)-2-(4-(2 N((S)-3-(4-(3-(4-cyana-3 (trilUararnethyl)phenyl /-'" )-5,5-dim ethyl!-4-oxo-2 N-- K h- hi oxoimni d azoIi d in-1 610 ,~ ~yl)phenaxy)pyrraiidin- 516.3 1-yI)pyridin-4-yI)-1 4'- "Npyrazol-1-yIl)-3
N ~pFr-n ethylIbu*a n oyi)-4 hydroxyN((-i44 N ~ ~~~methylthiazal-5- ________ yl)pheny~)ethyl)pyrrolid ine-2-carboxaniide
((5-(4-(3-(4-cyano3 (trifluorornethyl)phenyl )-5,.5-dimethyI--4-oxo-2 thiamaimidazolidin-l yl) ph e noxy)pe ntyl) oxyj 611 propoxV)-.IH-pyrazolI- 101-23 yI)-3-methylbutanoyl) 4-hydroxy-N-((S)-i(4
(21 eh- IHi~dzl yI)phenyi)et:hyl)pyrrolid ine-2-carboxamide
((5-(4-(3-(4-cyano-3 (trifluorornethyl)phenyl )-5,.5-dimethyI--4-oxo-2 thiamaimidazolidin-I. yl)phenoxy)pentyl)oxy) 612 propoxy)-lH-pyrazol-- 1012.3 I) -3-mnethylbutanoy"j 4-hydroxy-N-((S)-i -4
yI)phenyi)et:hyI)pyrrolid ine-2-carboxamide
cyano-3 (trifluoromethyl)phenvi )-5,.5-dimethyI--4-oxo-2 thiamaimidazolidin-l yl)phenoxy)-3 613 hydroxypentyl!)oxy) pro 5~25.8 Z ~poxy)acetamido)-3,3 . '>K dimethylbUtanoyl)-4
rnethylthiazol-5 yl) phe nV ethyI) pyrro Iid ine-2-carboxamide
2-(((-5-(4 3- (4-cyan o3 (trifIu o rom ethi) p he nl )-5,5-dim ethy 1-4-oxo-2 th ioxo imni d azoIidin-I 614 yI)phenoxy)penty)coxy) 538.2 rne-hvl)m--orpholino)ace ta-Mido)--3,3- ~'dimethylbUtanayl)-d
______ ____________________________________________ rethylthiazol-5- ________
-........-------------- ------------------- - yl)phenyi~ethyl)pyrrolid ine-2-carboxaniide
(2S,4R)-I-((S)-2-(2-(4
chloro-4 cya nophenoxv)-2,24,4 tetra methyl cyclobutyl)c arbarncyI)phenoxy)eth yl)p~perazin-I. 615 ylhacetamido)-3,3- 995.4 997.4 dirnethylbutanoyl)-4 * hydroxy-N-((S)-I.-(4(4 * me-.hylth!iazol-5 yl)phenyi)ethyl)pyrrolid ine-2-carboxarnide
!-(2-(4-((6-(4-(3-(4 cyano-3 (trifiUorormnethyl) p henyl )-5,5.-d im ethy 1-4- cxo)-2. > th ioxoimni da zo Iid in1I 'A~x ~yI)phenoxy)hexp-2,4 616 - diyn-1-yl)oxy)-IH 482.6 pyrazoi-1 -yI)-3 methylbutanoyl)-4 lhvdroxv-N-(4-(4. rne* hylthiazol--5- yI)[benzyl)pyrroi idire-2 ca rboxai d e
cyano-3 (trifiulorornethyl)phenyl )-5,5-dimethyl-4-oxo-2 thioxoirnidazolidin-1 yl)phenoxy)pyrro! din
methylbutanoyl)-4 hvdroxv-N-(l-(4.-(4 mne*hylthiazol--5- yl)ph enyl) ethyl) pyrr I id ine-2-carboxamide
3W-5
(2S,4R)-I-((S)-2-(2-(3 ((5-(f5-(3-(4-cyano-3 (trifluoronnethyl)phenyl )-5,5-dirnethy-4-oxo-2 thioxoimidazolidinI1 yl)pyridin-2 618 yl)amino)pentyl)oxVhpr 5[17. o poxy)Pcetp mnid o)-c33 dimethylbutanoy'l)I ShydroxyN((S)-1-(4(4 r thyithiazok yl)pheny~)ethyl)pyrrolid ine-2-carboxaniide (3S,25R,27S,E)-3-(itert butyl)-14-(2-(4-(3-(4 cyaio-3 (trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2 t h ioxoimni d azoIi d in1-I V1) ylp he noxv) e thV 1) N 1 61 5(Y1-493.8594.3 61 ~methylthiazol-5
N\2.,46,23-tetraoxo 7 152-tetraoxa
acos-19-ene-27 carboxamnide (3S,25R,27S,E)-3-(-ert butyl)-14-f,2-(4-(3-(4 cyano-3 (trifluorornethyl)phenyl )-5,5-dirnethy[-4-oxo-2 thioxoimidazolidin1l ylhphenoxy)ethyl)-N
620 ~methyithazok- z3 yl) ph enyl) ethyl) 2,5,16,23-tetraoxo 7,11;15,24-tetraoxad ~' 1,4 "" diazabicyclo[23.2. 1]oct acos-19--ere-27 carbcxamnide
(93R,95S,I1lS,Z)-ll1
(4cyano-3 (trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2 thloxoirnidazolidin1l N ~x~*~ y)phenoxy)ethy).N-.
621 " rethylthiazol-5- 635.3 VI)pherwi)ethyvl)- 7,10,13,24-tetrao 1iH-8,15,19,23 tetra oxa-12-aza-1-(1,4)
pyrrolidinacyclohexaco saphane-95 carboxamide
2-(((R)-2-((4-(3-(4 cyano-3 (trifi Uorornethyl)phenyl )55-dimethyl-4-oxo-2 thioxoir-nidazol idin1l 1622 .ylhexymtyrnr 10 89.3 pholino)methyl)rnorph iino)acetamid)3 dirnethylbutanoyl)-4
methylthipzol-5 yl)phenyi)ethyl)pyrrolid ine-2-carboxamiclE. (2S,4R)-3 -((S)-2-(2-(4
chloro-4 cyanophenoxv)-2,24,4 tetra methyl cyclobutyl)cI arbarniovl)phenoxy)eth 623 oxy)piperidin- 04 1012.4. yl)acetamido)-3,3 dirnethylbutanoyl)-4 methylthipzol-5 yl)phenyi)ethyl)pyrrolid ine-2-carboxarnide
(2S,4R)-I-((S)-2-(5-((5 ((4-(((1r,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 IN. tetramethylcyclobutyl)c arbamoIy)phenyl)amin 624 o)pentyl)oxy)-1H- 963.4 965.4 7 < pyrazol-i-yl)-3 methylbutanoyl)-4 , hydroxy-N-((S)-1-(4-(4 mnethylthiazol-5 yl)phenyi)ethyl)pyrrolid ine-2-carboxamide (2S,4R)-1-((R)-2-(5-((5 ((4-(((1r,3r)-3-(3-chloro 4-cyanopherioxy) 2,2,4,4 tetrarnethylcycIobutyl)c arbamoy1)phenyl)amin 625 o)pentyl)oxy)-1H- 963.4 965.4 pyraz-1-y)-3 methylbutanoyl)-4 hydroxy-N-((S)-1-(4-(4 rnethylthiazol-5 yl) ph enyl) ethyl)pyrrolid ine-2-carboxamide (2S,4R)-1-((S)-2-(2-(2 (3-(((4-(((ir,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 Ne tetramethylcyclobuyl)c arbamoIy)phenyl)amin o)rnethyl)oxetan-3 yl)ethoxy)acetarndo) 626 996.9 998.5 3,3-dimethylbutanoyl) 4-hydroxy-N-((S)-1-(4 (4-methylthiazol-5 yl)phenyl)ethyl)pyrrolid A8 ine-2-carboxamide
3-8
N 2 ,R--(S--4(6 >((4-(4-(3-(4-cyano-i 't. (tii u oro rnethyl)phenyl '.t%)-5,5-dirnethyl-4-oxo-2
~ ~~>¾"thioxoimidlazolidinIl yI)phenoxy)cyclohexyl) 627 aoxy)pyridin-3-yI)cxyj 58. 1H-pyrpzol-i -yl)-3 methylbUtanoyi)-4 hydroxy-N-((S-1-(4'(4 rnethylthi, 1-5 yl) ph enyi) ethyl) pyrrolIid ine-2-carboxarnide
\(25,4R)->--((RY-2-(4-((6
(tilluoror-nethyl)phenyl ' )-5,5-dirnethyl-4-oxo-2 ~ '~~ A>thioxoimidazol idinI1 yl)phenoxy)cyclohexyl) 628 xy)pyridin-3-yI)cxyj- o---- 538.8 1H-pyrazc1-1-l3 N mnethylbUtanoyi)-4 % <\hydroxy-N'((S)-1-4'(4 \N4- .... rnethylthiazck-5 N yl)phenyi~ethyl)pyrrolid ine-2-carboxaniide
(63R,8S,Z)-8-ltert bultylf.9}-2-.(4-(3-'4 cyana-3 (trifiuoramethyl)phenvl )-S,S-dimethyl-4-oxo-2 thioirnidlazolidinI1 yl)phenoxy)ethy)-N
1629 r-nethylthiazol-5- 635.3
A' '.-................y)phenyi)ethylY
""'N 11H-5,12,l6,20 * tetraoxa-9-aza-1(4,1)
* ~ '4 'N"'pyrrolidinacyciohexaco
saphane-65 carboxamide
3W-9
(2S,4R)-1-((S)-2-(2-(4 ((4'-(((lr,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 tetra methylcyclobutyl)c arbamoyl)-[1,1'
63011015 630 biphenyl]-4--13. 1033.4 yl)oxy)butoxy)acetamid o)-3,3 dimethylbutanov)-4 hydroxy-N-((S)-1-(4-(4 methylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxarnide 1-(2-(4-(6-((1-(5-(3-(4 N cyano-3 4 '(trifluoromethyl)phenyl
)-5,5-dimethyl-4-oxo-2 thioxoimidazolidin-1 yl)pyridin-2 yl)piperidin-4 yl)oxy)pyridin-3-yl)-1H pyrazol-1-yl)-3 m ethylbutanoyl)-4 631 hydroxy-N-(1-(4-(2- 515.3 methvl-IH-imidazol-1 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide
1-(4-(3-(4-cyano-3 : (trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2 thioxoirnidazolidii--I yl)phenoxy)-5-(3-(2 (((S)-1-((2S,4R)-4 632 hydroxy-2-(((S)-1-(4-(4- 565.7 methylthiazol-5 yl)phenyi)ethyl)carbarn oyl)pyrrolidin-1-yl)-3,3 dimethyl-1-oxobutan-2 yl)amino)-2 oxoethoxy)propoxy)pe intan-3-y! pent-4-ynoate |
(2S,4R)-I-((S)-2-(2-(3 ((S-(4-(3-(4-cyano-i (triflucrornethyl)phenyl )-5,5-dirnethyl-4-oxo-2 thioxoimidazolidinI1 yl)phenoxy)pentyl)oxy) 633 propoxy)acetarnido)- 994.7 k3;3-d im ethylhbuta nolJ 4-hydroxy-N-((3-(4 '~' ~\~ ~ rnerhyloxazok * "2 -yI)mnethyl) pyrroId'e 2-carboxamide (25,4R)-1-((S)-2-(2-(((k) 1-(4-(4-(((Ir,3R)-3-[3 chloro-.4- '0cyanophenoxy)-2,244 * .tC~t.'¼'tetra methyl cyclobutyljc ~~ .arba moyi!)phenyl)pi per "34 -1azm-yI)propan-2- [009.4 1011.5 "JyI) oxy) aceta m ido)-3 dirn ethylIbuta noyl)C1 dN cthydroxy-N-(f(S)-1-(4'(4 VN rnethylthiazo[-5 yl)ph enyi) ethyl)pyrrolid ine-2-carboxarnide (25,4R)-1-((S)-2-(2-(3 &'
chloro-4 canophenoxy)-2,24,4 q C ~ tetramethylcyclobuly~c a rba moyi!)phenoxy) pen tyl)oxy)opro poxy)aceta rn 635 N ~ 'ido)-3,3- 11027.5 1029.4 dirnethylbutanoyi)-C <Nhydroxy-N-((S)-1-(C-(4-I
N' 'Nll-ehylIt hia zol1-5 <""NtyI)phenyi)ethyl)pyrrolid
ine-2-carboxarnide
N-((lr,3 R)-3-(3-ch loroa X "" 4-cyanophenoxy) '...........¾2,2,4,4
tetra methyl cyclobutyl4
636 1~ I-((2S, 4R) -4- hyd roxy -2-1 1008.4 1010.3
<methylthiazol-3 yhiphenyi)ethyl)carbam
_____ ________________________________________dirnethyl-1-oxobutan-2
3' 51 yl)am!;no)-2 oxoethoxy)ethyl)-2,5 diazabicyclo[22i1.hept an-2.'y)ncotinarnide
N-((lr,3S)-3-(3-chloro 4-cyanaohenoxy) 22,4,4 tetrarnethylcvclobutyl)
i--((2S54R)--4-hydroxy-2 (((S-114(4.'1010.4 637 me-.hylth!azol-5- 1008.5 .... yI)pheny'Oethyl)carbarn coyl)pyrro:ioin-1.-y)3,3 dimie.hyI-i-oxobutn2 yl)am!ino)-2.' oxoethoxy)ethyl)-2,p diazabicyclo[2.2.1] hepl ______an-2-yl)ncotinamide
N-((I r, 3r)-3 -(3 -ch Ioro 4-cyanophenoy)
tetrarnethvlcyclobutyl)
((2 S,4R)-44-hyd roxy-2 ((4-(4--methylthiazol-5 638 982.45 984.45 rrolidin-i--yI)-3,3 dimethyI-l-oxobUt~n-2 VI)amino)--2- OXOethOXy)ethy)pipera zin-1-yI)nicotinarnide
chloro-4 cyariophenoxy)-2,24.4 ~?N~<~'tetra methyl cyclobUtylk: .a .> rba moyi) ph enyl) p iper 639 ~"azin-1-yI)propan-2- 1009.5 1011.4 yII'xylacetarnido)-.3 dirnethylbutanoy)4
~yl) phenyl)ethyl) pyrro Iid ine-2-carboxamide
(2S,4R)-I-((S)-2-(2-(4 (2-(4-(((ir,3r)-3-(4 cyario-3 (trifiuoromethyl)pheno xy)-2,2,4,4 tetra methyl cyclobUtyl)C ardar-noyjpheoxyjetl 640 1030.5 640 W~~k oxyjpperidin-i * >,( ~N ~'\1 ~ > yI)acetamido)-3,3 * ~~ ~ dirnethylbutany) hydraxy-N-(4-(4 methyithiazol-5 yI)benzyl)pyrroiidi'e-2 carhoxaroide (2S,4R)-i--((S)-2-(2-(C (4-(((i-r,3r)-3--(4-cyano 3 (trifiuaromethyl)pheno xy)-2,2,4,4
641 tetra methyl cyclobutyl)c 64 i, arbamay~)phenoxy~oUt 989.5 \ '','" &"N."' '.p , etarnido)-3,3 d i met*hylIb uta n oy ) 4. hyd raxy- N -((S) -1 -(C4-4 methyithiazl-5 yl) phenyi!)ethyl)pyrrolid ine-2-carboxar-nide (2S,4R)-i--((S)-2-(2-(2 (3-(2-((4-(((lr,Br)-3-(3 chloro-4 cyanophenoxy)-2.24 tetra methylcyclobUtAl)C arbar-noyi)phenyl)arnIi.i100. 642 o)ethy')oxetan-3- 1012-5 ~"yl)ethoxy)acetamido) '~ z3,3-d im ethyl buta noyl) .~~4-hydroxy-N-((S)--[4
k.'~k\ (4-mnethylthiazol-.5 yl)phenyi!)ethyl)pyrrolid ine-2-carboxannide
N (2S,4R)-1-((S)-2-(2-(10 (2-(4-(3-(4-cyano-3 (trifluornethyl)phenyl )-5,5-dirnethyl-4-oxo-2 thioxoimidazolidin-1 yl) phenoxy)ethyi)-1,7 N \dioxa-4,10
diazacyciododecan-4 yl)acetamido)-3,3 dimethylbutanovi)-4 hydroxy-N-((S)-1-(4-(4 methylthiazol-5 643 1090.4 yl)phenyl)ethyl)pyrrolid 1 ine-2-carboxarnide
\
N-((1r,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl) 6-(4-(4-(2-(((S)-1 .x N. ox 7 ((2S,4R)-4-hydroxy-2
644 . F", ^... methylthiazol-5- 1029.4 1031.4 "'k ~~~y1) p he ny )et hy1) c arb am oyl)pyrrolidin-1-y)3,3 dimethyl-1-oxobutan-2 yl)amino)-2 oxoethyl)pyridin-2 yl)piperazin-1 yl)nicotinamide (2S,4R)-1-((S)-2-(2-(4 (2-(4-(((1r,3r)-3-(3 chloro-4 ' " cyanophenoxy)-2,2,4,4 tetrarmethylcyclobutyl)c ararnoyl)phenoxy)eth 645 ..... yl)piperazin-1- 981.4 983.4 yl)acetamido)-3,3 dimethylbutanoyl)-4 hydroxy-N-(4-(4 methylthiazol-5 yl)benzyl)pyrrolidine-2 carboxamide
(2S,4R)-l-((S)-2-(2-(4
cyaio-3 (trifl uoromethyl)pheno xy)-2.,2,4,4 tetra methyl cyclobUtjl)C 646 ~., arbar-noyl)phenoxy)eth 55 .~ yl)piperazin-i yl)acetamido)-3,3 dirneffiylbutany)
-)z methylthiazol-5 yl) be n zl) pyrro idin e-2 carboxamide (2S,4R)-1--((R)-2-(4-(3 (3 -(4 -(4-(3-(4-cya n o-3 (trifIuo romethyl)p h enyl )-5,5-d im ethy 1-4-oxo-2 th ioxoimni d azoIid in1I VI ~ lph eny)-I H -i idazo1 647 1y) p ro poxy) pro po xy) I-N I051.4 1H-pyrazol-1--yl)-3 m ret hylbutanoyi)-4 Shyd roxy- N ((S). 4- (-4 N N' methylthiazol-5 N ~yl)phenyl!)ethyl)pyrrol A ine-2-carboxannide (2S,4R)-1--((S)-2-(4-(3 (3-(4-(4-(3-(4-cyano-3 triflel uororniethyl)phenyl )-5,5-dinethy-4-oxo-2 tlioxoirnidazol idin1l 648\~ H y)pheny!)-IH-irnida!o 64 r)-yI)propcoxy)propcoxy)- 1051.4 N -~ ,~ H-pyrazol-1-yl)-3
S~~~e H ehybtanoyll)4 ~*~Fphydroxy-N-((S)-1l-(4A4 NF\ (~~-methyithazok F ~yl)phenyl!)ethyl)pyrrolidI ine-2-carboxar-nide N, N -(Ir, 3r) -3 -(3 -chIor 4-cyanophenoxy) 2,2,4,4 tetramnethylcyclobulylJ
69((2S,4R)-4-hydroxy-2 100.5
methylthiazol-5 V 3 yl)phenyl!)propyl)carba r-noy'0pyrrolidin--I)
______ __________________________________________oxobutan-2-yl)amino)- ___ ____ oxoethoxy)ethyl)pioera, ______zin-1-yI).nicotinarnide cyano-3 (trifluorornethyl)phenyl )-5,5-dirnethyk4-oxo-2 1) tioxo im id azoi d in - I 650 yIpeoy n Yl)1 1027.3 1029.3 1)u ty l)-l1- i m idazo I 1 yl)-3- rn ethy Ib Linn oy S4-hydroxy-N-(i-(4-(4
S.~.r-nethylthiazoI-5
yI)phenyi)et:hyl)pyrrolid ine-2-carboxamide
4-((L-Iysyl)oxv)-2-(((S)
yl)ph ernl) ethyi)carbam ~ ~oyl)pyrrolidin-i--y)3,3 dimethyl-l-oxobutan-2 y)armio)-2
(4-(3-(4-cyano-3 651 (trifiuoronnethyl)phenyl 654.3 X . )-5,5 -d irnethy 1-4- oxo-2 th ioxo im id azoIidin- 1 yl)phenoxy)pentan3vi
((4-(f(1r,3r)-3-(3-chlora 4-cyanophenoxy) 2,2,4,4 t:et-ra~met:hylcyclobulyl~c arbarnoyl!)phenyl)amin 652 N$o)pentVl)oxy)acetamido 1054.6 5>
methyithiazo[-5 yl) ph enyi) ethyl)ca rbarn oyl)pyrroliidin-3-vI ______ __________________________________________isopropyl carbonate
3 56
((4jf(1(r,3r)-3-(3-chloaro 4-cyanophenoxy) 2,2,4,4 tetra methyl cyclobutylIc arbanioyl)phenyl)amin 653 ~ a)pentyI)oxy~ace ta m do IS6 528 6 dimethylbu anoyl)S5
methyithiazol-5 yl)pheny~)ethyl)carbarn oyl)pyrroliidin-3 yI)oxy)rnethyl isopropyl carbonate N-.((ir,3r)-3-('3-chloro 4-cyanaphenoxy) .j2;2,4,4 tetra methyl cyclobuitjl)
~' . ((2S,4R)-4-hydrox-2 654 1(S- 4(- 996.5 998.4 rnerhylthiazol--5- ~ yl)phery'!)ethyl)carbam oyl)pyrro'idin-i-y)3,3 dimethyl-l-oxobutan-2 N - ~<yl)amio)-2 "No xoethoxy)ethyl)pipera zin-1-yI)picolinarnide ____
(2S,4R)-il-((S)-2-((S)-2
chiaao4 n* N.cy ~ foph-lroxy)-2,24,4 Stetra met:hyl cyclobulyljc arba moyl!)phenaxv)eth ylhpiperazin 11) hydroxypropanar ido) 6553,3-dimethyl bUtianyl) 4-hydroxy-N-((S)-- - -" 1027. (4--enethylthiazl-5 yI)pheny')ethyI)pyrrolid 'N ine-2-carboxamide
-7 \""'
(2S,4R)-I-((S)-2-(2-((5 ((4-(((1r,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl)c arbamoyl)-2 656 ' fluorophenyl)amino)pe 986.4 988.4 3 " ntyl)oxy)acetamido) 3,3-dimethylbutanoyl) 4-hvdroxy-N-((S)-1-(4 (4 methylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide (2S,4R)-1-((S)-2-(2-((5 (4-(((1r,3r)-3-(4-cyano 3 (trifluoromethyl)pheno xy)-2,2,4,4 tetramethylcyclobutyl)c 657 r arbanoyl)phenyl)penty 987.4 e I)oxy)acetamido)-3,3 dimethylbutanoyl)-4 hydroxy-N-((S)-1-(4-(4 methylthiazol-5 yl)phenyi)ethyl)pyrrolid ine-2-carboxamide N-((1r,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetra methylcyclobutyl) 6-(4-(2-((_5-((S)-1 ((2S,4R)-4-hydroxy-2
rnethylthiazol-5 yl)phenyl)ethyl)carbarn 658 "N' oyl)pyrrolidin-1-yl)-3- 992.65 994.65 methyl-1-oxobutan-2 h: c yl)isoxazol-3 4 yl)oxy)ethyl)piperazin
N-((lr,3r)-3-(3-chloao 4-cyanophenoxy) 2,2,4,4-. tetramethylcyclobUty)
"'~((2SA4R)-4- hydroxy-2 mehylthiaza-5 \\\.~ yI)phenyi)ethyl)ca rbam 659 o yl)oyrroiidin -1--yI)-3- 992.45 9941.5 'N '~Nc rethyl-i-axabUtan-2
.N.. yI)roxy)e hyl)piperazn
(2S, 4 R)- ((S)-2..2-.2
7chloro-4 cyanaphenaxy)-2,24,4 tetrarnethylcyclobutyl)c arhamoyi)phenyl)pi per K' azin-1 660 yI~ehoxy)acetamido)- 904i 3-hydraxy-3 ~" $5<V 'N methylhutanoyi)-4 \ ... hydraxy-N-((S)-1-(4-(4 P rnethylthiazal-5 yI)ph enyi)ethyl) pyrralIid ine-2-carboxarnide 1}(2-(2-(3-((.5-44-(3-(4 cyano-3 (trifiuLaorarmethyl)p h enyl )--5,5-d im ethyl1-4-axa)-2. th ioxoirn ida zaIid in1I 661 yl)ph e noxy)pe ntyl)aoxv) 105 '~.N&N- N N' \N~-Nproopoxy)acetarnido)-2 N-
(Oxetan-3-yI)acetyl-4 N' ydroxy-N-(1-(4-(4_ N' ~ \" rethylthiazol-5
ine-2-carhoxamide
3 59
(2S,4R)-N-((Sy-l-f4-(IH imidlazol-il yl)pheny'0ethyl)-1-() 2-(2-(3-((5-(4-(3(4 cyano-3 (trifi~uorornethyl)phenyl 662 )-5,.5-dimethy1--4-oxo-2 [O3 6 thioxoimidazolidin-1 yl)phenoxy)pentl)oxy) ., propoxV)acetarnido) '~ 3.3-dirnethylbutafloylj 4-hydroxypyrroiidine-2 carboxamide (2S,4R)-I-((S)-2-(2-(3 ((5-(4-(3-(4-cyano-3 (trifluoror-nethyl)phenyl )-5,5-dirnethyl-4-oxo-2 thioxoimidazolidinI1 yl)phenoxy)pentl)oxy) [77 663 propoxV)acetarnido) I
" 3.3-dirnethylbutanoyl)
yl) phenyi) ethyl)pyrrolid ine-2-carboxarnide (2S,4R)-I-((S)-2-((S-2
> ...... ,chloro-4 H cyanophenoxy)-2,24,4 BC m tetramethylcyclobtyljc . ..... arbanioy!,phenyl)piper azin-I 64yl)ethoxy)propanamido i 1009.4 1011.4
di'methylbutanoy)-4
m eth y11:h azol1-5 ylhphenyI)ethyl)pyrrolid ine-2-carboxannide
36 0
(2S,4R)-1-((S)-2-(2-(4 (3-(4-(((ir,3r)-3-(4 cyano-3 (trifluoromethyl)pheno xy)-2,2,4,4 tetramethylcyclobutyl)c arbarnoyl)phenyl)propy 665 I)piperazin-1- 1027.5 yl)acetamido)-3,3 dimethylbutanovl)-4 hydroxy-N-((S)-1-(4-(4 methylthiazol-5 yl)pheny1)ethyl)pyrrolid ... ine-2-carboxarnide
(2S,4R)-1-((S)-2-(2-((5 ((3-(((lr,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl)c arbamoyi)bicyclo111] K Npentan-1 960.4 666 1958.5 yl)arnino)pentyl)oxy)ac9 - ~etamido)-3,3 dimethylbutanoyl)-4 hydroxy-N-((S)-1-(4-(4 methylthiazol-5 yl)phenyi)ethyl)pyrrolid ine-2-carboxamide (2S,4R)-1-((S)-2-(2-((S) 2-(((R)-2-((4-(3-(4 cyan-o-3 (trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2 thioxoirnidazolidin-1 66> yl)phenoxy)methylrnor 1667 10903 5453 pholino)methyl)morph olino)acetamido)-3,3 dirnethylbutanay)-4 hydroxy-N-((S)-1t-(4-(4 methylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide
N -((lr,3R)-3-(3-chloro 4-cyanophenoxy) * 2,2,4,4-. * tetramethylcyclobUtyl) 6-((IR,4R)-5-(2-(2-((S) 1-((2S,4 R)-4-hydroxy-2
(hydroxy meth v )th ia zo I
yI)pherwi)ethyl)carbdrn oyl)pyrrolidin---y)3,3 * direthy-l-xbutan2 668 yl)amino)-2- 11024.5 1026.5 \ ~o xoethoxy)ethyl)-2,5 d!;azabicyco[22.IbeptI '-~ \ n-2-YI)nicotinamide
N-(Ir,3 R)-3-(3-chlIao 4-cyanaphenaxy) 2,2,4,4 tetra methyl cyclobutI) 6-((2S,4R)-4-(-ydra(2 <-X:((-(4-ARnethyhiazal5 669 94.6 996.4 )lbny~araa~y~ rrolidin-1-yIl)-3,3 d i dm et hy[I-i1-0 XO) abn -2 yl)amino)-2 oxoethaxy)ethyl)-2,5 diazabicycla[2.2.1]nhpt an-2-yl)nicatnarnde N(lr,3r)-3-(3-chloro 4-cyanaohenoxy) 2;2,4,4 tetra methyl cyclobuitjl) 5-((5--(2--(((S)-1l-((2S,4R) 4-hydroxy-2-(((S)-.I.-( 670 (4-m,.ethylthiazol-5- 955.4 957T4 yl)phenyl!)ethyl)carbam '~~~~ ayl)pyr.raiidin---y) "'s' methyl M" - 1-oxobu ta n2
- o xoethoxy)pentVl)amin ______ ______________________________________________ apicoknamide
36 2
N-((lr,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl) 6-(4-(2-(2-(((2S)-1 ((2S,4R)-4-hydroxy-2 2 ((2-hydroxy-1-(4-(4 671 methylthiazol-5- 1025 114.4 e" . yl)phenyi)ethyl)carbam oyl)pyrrolidin-1-yl)-3,3 dimethyl-1-oxobutan-2 yl)amino)-2 oxoethoxy)ethyl)pipera zin-1-yl)nIicotinarnide
N-((1r,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl) 6-(9-(2-(((S)-1-((2S,4R) 4-hydroxy-2-((4-(4 rnethylthiazol-5 672 , yl)benzyl)carbamoyl)py 1006.5 1008.4 rrolidin-1-yI)-3,3 dirnethyl-oxobutan-2 ....... yl)amino)-2-oxoethyl)
diazaspiro[5.5]undecan -3-yl)nicotinamide
N-((1r,3r)-3-(3-chlIoro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl)
e ((2S,4R)-4-hydroxy-2 (((S)-1t-(4-(4 (hydroxymethyl)thiazol -5
673 Cyl)phenyl)ethyl)carbam 1012.5 1014.4 oyl)pyrrolidin-1-yl)-3,3 dimethyl-1-oxobutan-2 yl)amino)-2 oxoethoxy)ethyl)pipera zin-1-yI)nicatinamide
* (2S,4R)-I-((S)-2-(2-(4
cyario-3 (t r ifluo rom e1:h y1) ph en o
tetra methyl cyclobUtjl)C 674 ~arbarnoi henyl)oxeta 16. n3-yl)ethyl)piperazin-i ~ -yI)acetamido)-3,3 ~ dirnethylbutanoy!)-4
methylthiazol-5 yl)phenyl!)ethyl)pyrrolid ine-2-carboxar-nide
2-(((S)-2-((4-(3-f4 cyario-3. (trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2
675 yI)phenoxy)mn.ethyrnor
/ pholino)methvl)mrcph olino)acetamidlo)-3,3 dirneffhybutanoy!-4 lhydroxy-N-((S)-it-(i-(4 methylthiazol-5 y1) p he n 10et hyl1) p rro Iid ine- 2 -car bo x;)mid e (2S,4R)- I-((S) -2 -(2 -((S)
cyano-3 (tr if uoro meth y1) phenyI )5,5 -d im e thyl-4 -o xo -2 i ~~ ~~~t h ioxoirnn id azoIi d in--I 67 y)phe 1)~ noxy)methyl)mno r pholino)mnethyl)mnorph Olino)acetamido)-33 dimnethylbutanoyl)-4 hydroxy-N-((S)-l-f.4(4 rneffhlthiazol-5 y1)pheny'Oethy1)pyrrolid ine-2-carboxamide
36 4 benzyl ((2S,3R)-3-((6-(4 (3-(4-cyano-3 (trifluoromethyl)phenyl -5,5-dirnethyl-4-oxo-2 thioxoimidazolidin-1 yl)phenoxy)hexyl)oxy) I-((2S,4R)-4-hydroxy-2
677 methylthiazol-5- 1054.5 yl)phenyi)ethyl)carbam 3 oyl)pyrrolidin-1y)1 oxobuta.n-2 ylicarbamate
N-((Ir,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetra methylcyclobutyl) -5-(3-((2-(2-(((S)-1. ((2S,4R)-4-hydroxy-2
678 m ethylthiazol-5- 983.4 985.4 4*" yl)phenyl)ethyl)carbarn oyl)pyrrolidin-1-yl)-3,3 dimethyl-1-xobutan-2 A yl)arnino)-2 oxoethoxy)ethyl)(meth yl)amino)propyl)picolin amide e (2S,4R)-1-((S)-2-(2-(4 (2-(4-(((1r,3r)-3-(4 cyano-3 (trifluoromethyl)pheno xy)-2,2,4,4 tetramethylcyclobutyl)c arbamoy1)phenoxy)eth yl)piperazin-1-y)-2 oxcacetamido)-3,3 679 t1043.5 1 dirnethylbutanoyl)- hyrx-N-((S-1-(4-(4 mrnethylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide
N-((lr,3r)-3-(4-cyan-3 methylphenoxy) N-~y ,2,2,4,4-.
Stetra)methylcyclobutyl)
N ((2SA4R)-4-hydroxy-2 680 ~(((S)-1-}(4-(4- 966 met.hylthiazol-5 N<C N, Myl)phenyi)ethyl)carbam oy1)pyr ro,iid in -1- y1)-3,3 N? dimethyl-t-oxobUta-n2 """N lI >tyl)ami;no)-2
''~ oxoethoxy)ethyl~lpioer0 ___________________________________________________zin -1-yI).rIicotinarnide N-((lr,3r)-3-(3,4 dicyaniophenoxy) N ~ 2,2,4,4 tetra methyl cyclobutyl)J
(( 2 S,4R)-4- hvdrox- 2
-- Nmethylthiazol-5
N> N..& l'pherwi)ethyl)carbarnI ~ N~,<~ N '' oyl)pyrrai!idin-i-y)3,3 dirnethyl--oxobutn2 yl)amino)-2 \\ ~ oxoethoxy)ethyl)piper'
N-((lr,3r)-3-((5-cyaro N. -methyipyridin-2
tetra methyl cyclobuitl) 6G-W4- (2--(HS)-1 ((25,4R)-4--hydroxy-2 682 'N(((S)1l(4-(4- 9'.507'7N rne-hylthi;azol-5 \ yl)phenyi)ethyl)carbarn
"Ndimethyl-1-oxobutan-2
~ N oxoethoxy)ethyl)pioer:3 zin-1-yI)nicot.inarniide ___
(2S,4R)-1-(N-(2-(4-(2-(4 4 (((1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)c arbamoyI)phenoxy)eth yl)piperazin-1 yl)acetyl)-N-methyl valyl)-4-hydroxy-N-((S) 683 a en 1-(4-(4-methyIthiazol. 995.55 997.5 5 yl)phenyl)ethyl)pyrroIid .x ine-2-carboxamide \$
N-((1r,3r)-3-(4-cyano-3 (trifiuoromethyl)pheno xy)-2,2,4,4 tetramethylcyclobutyl) 6-(4-(2-(2-(((S)-1 ((2S,4R)-4-hydroxy-2
684 nethylthiazol-5- 1031.5 y yl)pheny)ethyl)carbam ovl)pyrrolidin-1-yl)-3,3 dimnethyl-oxobutan-2 yl)arnino)-2 oxoethoxy)ethyl)pipera -i n - I1y)py ri d az ine- 3 carboxamide (2S,4R)-I-((S)-2-(2-((5 (3-(4-(((ir,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)c arbamoyi)phenyl)oxeta n-3 1685 1 009.5 10 11.5 -5yl)pentyl)oxy)acetarnid
x i dimethylbutanoyl)-4 hydroxy-N-((S)-1-(4-(4 methylthiazol-5 yl)phenyi)ethyl)pyrrolid ine-2-carboxamide
(2S,4R)-I-((S)-2-(2-(4
cyana-3 (trifluaramethyl)phena xy)-2,2,4,4 tetra methyl cyclabUtyl)C 4> arbarnay)penyl)arnir a)m-.ethyl)axetan-3 yI)methyl)piperazir-1 686 yI~V)acetamida)--3,3- 187 686 ~ ~dimethylbutanay!)-4- 18.
K, ~hydraxy-N-((S)-1-(4-(4 ~t rnethylthiazal-5 yI) ph enyl) ethyl) pyrralIid -k ine-2-carbaxamide
N'x
N-((lr,3r)--3-(3-chlaIa- 4-cyanaphenaxy) 2,2,4,4 tetra methyl cyclabutyl) ,.>\ 5191((S)-1l-((25,4R-4 hydraxy-2-(((S)-1.-(4-(4 \~~ 'N t rn~ethylthiazal-5- 16. 05 68 4,~ ~~yI)phenyiOethyl)carbarn 10+. "T yl)pyrraoidin-1.-yI)-3, o.~ k.diniethyI-i-axabutprn2 ,,,9 yI)amina)-(4 rnet hylp iperazi n- I-l) § 9. oxo_nxaoanyi) picoIi n armnd e (2S,4R)'1 -((S)-2-(2-((5
4-cyanaphenaxy) 2,2,4,4-. tet ra methyl cycIaob Utyl)c: arbamoyi)phenaxyj 688 ~~~ - 2,2,3,3,4,4- [77 17. 'J-¾t cetamida)-3,3 , . dimethylbunaoyll)I ' hydraxy-N-((S-1-(4(4 3 mnethylthiaza[-5 yl) ph enyi) ethyl)pyrralid L ------------- i-------- ----------------- L ine-2-carbaxarn ide
36 8
N-((lr,3r)-3-(4-cyan-3 (trifiulorornethyl)pheno xy)-2,2.4,4 K>tetramnethylcyclobUtyl)
((2SA4R)-4-hydroxy-2
689 met.hylthiaPzol-5- I031.5 yI) ph enyi) ethyl)ca rba m NNoyl)oyrroiidin-i--y)-3,3
S' ~oxo et hoxy)et h y1)p ioe r
N - (Ir, 3R) -3 -(3 -chIo ro K N,-'4-cyanophenoxy)
2;2,4,4 Itetra methyl cyclobuitl) G-k((IS,3 R).3-((1-.2 (((S)ajt-(2S4R-4
mne*thythiazo-5- y 1I)p heny1) et hy1) ca rbam 690 \-. N.olproii--I~ 1036.4 1038.4
'K d im e-hyI- 1 -oxo b u-a n-2 yI)amino)-2 ox oet hy1)pi De r idin-4 y1) oxy) cycio bu ty1)a min o
'NN
-N ((l1r, 3r) -3 -(3 -c h I or o 4-cyari ophenoxy) 2;2,4,4 V tetrarneth)ylcyclobuty
4--hydroxy-2-.(((S)-1I(4. (4-mnethylthiazol-3 yI)phenyl)ethyI)carb~rn 691 ~ ~ olproii-y) 1:t 962.9 964.4 '~ methyl-1-oxobutan-2 yI)-1-rnethyl-IH 91"' imidazol-5 yI)penty!)ar-nino)pico P
-3) 6mi9
N-UlIr,3r)-3-(3-chlo.ao ..... 4-cyanopheiaxy)- 2,2,4,4 tetrarmethyl cyclahutyI) 5-((5-(o.2-(S)1((S)4 (4-methylthiaza[-5 \\\ NyI)phenyi)ethyl)carbam ayl)opyrrai id in -I-yI)-3 69 reth yI-.i-axa b Utan-2- ii962.4 964.4 yI)-i-rnethyl-1H imidazal-5 y1) pe ntyI) armnela) picaoin '-N amnide
N -((I.r, 3r) -3 -(3- chlaa or 4-cyanaophenaxy) 2,2,4,4-. tetramnethylcyclabUtyl) 5-((E)-9-(((S)-1-((2S,4R) >~ 44-hydraxy-2-(((S)-1-4 N,,,,, x\ (4-methylthiazal-5 yI)phenyi0ethyl)carham N a~yl)pyrraiidin-yI3 dirnethyl-1-axabutdn-2 yI)arn~na)-4 (hydraxyi.mina)-9 693 "o xananyi~picalinaride 1995.6 997.6
~.
-- -- - - -- - -- - -- --
t3
(2S,4R)-1-((S)-2-(2-(16 (4-(((Ir,3r)-3-(3-chiarc 4-cyanopheiaxy) 2,2,4,4 tetrarmethyl cyclohuty[Ic arharnayi)phenyl) 1,410,3-tetraoxa-129 694 7;16- 11t 76 diazacycioactadeca-7 K ~' "" y)acelamido)--3,3- dimethylbutanoyl)-4
rnethylthiazal-5 yI) ph enyi) ethyl) pyrro Iid ine-2-carbaxamide N-((I r, 3r)-3 -(3-chlIaro 4-cyanoehenoxy) 2;2,4,4 tetra metylcyclobityl) 5-((E)-4-(ethaxvirninu) 9-(((S)-1.-((25,4R)-4
x:rnethylthiazal-5 yI)phenyi)ethyl)carham -~\& \\~&\NNNx# yl)pyrra'idinyl3 dimethyl-1-oxobutan-2 695A'yI)aminao)-9- 1025-5 oxanony[Ipicolinarnide- 5
~\
X, ~.
-3)7'
N-((lr,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 k~:' tetramethylcyclobutyl)
(2S,4R) cyanophenyl)ethyl)carb amoyl)-4 hyd.roxypyrrolidin-1-yl1) 696 m et h 3-methylI- oxobutan 920.5 922.45 2-yI)isoxazol-3 C C 4 yl)oxy)ethyl)piperazin Xt1-yl)nicotinamide
N((ir,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl)
S((2S,4R)-2-(((S)-1-(4 cyanophenyl)ethyl)carb anoyl)-4 hydroxypyrrolidin-1-yl) 697 - "\ 't 3-methyl-1-oxobutan- 905 92245 j 2-yl)isoxazoi--3 CH / ""'\ / yl)oxy)ethyl)piperazin 1-yl)nicotinamide
372)
* N-((S)-1-(3-(3-chloro-4 * cyanophenyl)-1H \pyrazai-1l-yI)oropanw2-
yi)-5-((3-(4-(2-(((S)Il. ((2S,4R)-4-hydroxy-2
rnet hYlthiazol--5- yI)phenyi)ethyI)carb~ni
<\\\dirmet hyl-1-oxcbutdan-2 yI)arn)-2 698 996.5~ppeain 998.4 yyI) pro poxy)rmnet hy1) H-I pyrazaie-3 ~ carbaxamide
N-(lr,3r)-3-(3-chloo 4-cyanophenaxy) 2,2,4,4 tetrarnethylcyclcbutyl)
((2S,4R)-4-hydroxy-2 69IN,>,~< (((thylti44-5 [065.4 106-7.4 yl)ph e nyl) ethyI)ca rbP m ~ oyl)pyrrai idin-1,-y)3,3 '
KdinethyI-1-axabudn-2 ',lamina)-2 oxoethaxy)ethyl)(3i 3 triiluarapraoyl)amina)pI ______ __________________________________________rapyl)picoiinamnide N-((lr,3r)-3-(3-chloara 4 -ynopheix) - 2,2,4,4 ter ethyl cyclabutyl)J 700,4 ,,,> *\ r~s ~ >dimet4hyl-I.-((S)-2 ,N~N'. ,,..N'(methylcarbamayi!)pvrr 93I79. >1 aiidin-1-yI)-1-axabutan cx 2-yI)amina)--2 axaethaxy)ethyl) pipe,r * <N.zin-1-yI)nicatinarnide
N-((lr,3r)-3-(3-chloao 4-cyanophenoxy) 2,2,4,4-. tetramethylcyclabutyl) 6-(4-(3-(2-((R)-1 ((2SA4R)-4-hydroxy-2
701 2methylthiazol-5- 1003.4 1005A4 yl)phenyi)ethyl)carbam i aeyl-yroidin-I) K 'lmthl-ehiH
imidazal-5 V)preopyl)piperazin--_ ______ ____________________________________________ l)ni;cotinamide N-I(ir,3r)-3I,3-chloro 4-cyanophenoxy) 2;2,4,4 tetra methyl cyclobuitl)
((2S,4R)-4~-hyd raxy-2
702 rne* hylthiazol-5-- 100314 1005.4 yI)phenyi!)ethyl)carbam X4 s oyl)pyrroiidin -yI) re.hy-i-oxobuitan-2 * KCM.'NA' NM'C yI)-1-rnethyl-1IH * '~'irndazol-3
y)propyl)piperazin-l _______yI)ni;cotinamide
N-((ir,3r)-3-(4-cyano-3 (ifluorornethyl)pheno xy)-2,2,4,4- tetramethylcyclohutl')
((2S,4R)-4-hydroxy-2 703 'N"Ck~((4-(4-methylthiazolS5 <'~ yI) benzyl)carba my 130 'N,'
CC' H"' ?"'C 'N~\""\ N"'CX.rrolidin-1-yIl)-3,3
dirnethyl1-oxobutan-2 K \V' ~..yI)arni;no)-2 oxoethaxy)ethyl)-2 * oxopiperazin-i _____________________________________________________ I)picoliriarnide ________
37 4.
N-((lr,3r)-3-(4-cyan-3 (trifiulorornethyl)pheno xv)-2,2.4.4 "'N"% ~tetra methy cycaobUtyi)
((2SA4R)-4- hvdroxv-2 ''' 1072.6 704 methylthiaPzol-5 ,~\c& "' yI)phenyi)(oxetan-3 VI) methyl)ca rba m oyI) py .... rraiidin-.-yI)-3,3 'Ndirnethyl--oxobutn2
yI)amino)-2 * exoethoxy)ethyi)pipera ______ ______________________________________________zin-1-yI)nicotinarnide N-(ir,3r)-3-('4-cyano-3 ,~(trifiuoramethyi)phena
" ~<tetra methvlicvciobuitl)
705 me* u~ 1026azl-5 N.yI)1phenyi!)(axei an-3
N""""'.rroiidin--yvI)-3,3
d irmethy1 -oxo b uta n2 yi)arni;no)-2 oxoethaxy)ethyi)pioer0 _____zin-1-yI)nicotinamide
* 'N(2S,4R)-1.-((S)-2(2-4
\ \cvanaphenoxv-2.24,4 S tetrarnethvlcvclobutvl)c MN ~Narbamovi>)2
706 '- K N vIacetamido)-3,3
hvyd roxv- N -((S) -- (4'4 mehylthiapo-5 '~ ~ ~ ~e vIphnvzehlpvrl
~j,~$' Nne-2-ca rboxa midr.
.. NN4 7-5
N-((lr,3r)-3-(4-cyano-3 e A (trifiuoromethyl)pheno xy)-2,2,4,4 tetramethylcyclobutyl) 6-(4-(3-(4-(2-(((S)-1 ((2S,4R)-4-hydroxy-2
707 methylthiazol-5- 1112.9 7 yl)phenyl)ethyl)carbam oyl)pyrrolidin-1--yl).-3,3 dimethyl-1-oxobutan-2 yl)amino)-2 oxoethyl)piperazin-1 C yl)propyl)piperazin- yl)nicotinamide
cyano-3 (trifIuoro methyl)pheno Sxy)-2,2,4,4
tetramethylcyclobutyl)c arbamoyl)phenyl)propy 7 I)piperazin-1 yl)acetamido)-3,3- 1041.5 dimethylbutanoyl) methoxy-N-((S)-1-(4-(4 Srnethylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide
N-((1r,3r)-3-(4-cyano-3 (trifluoromethyl)pheno xy)-2,2,4,4 tetramethylcyclobutyl) 5-((5-(2-(((S)-1-((2S,4R) 4-methoxy-2 (rnethyl(4-44 methylthiazol-5 709 yl)benzyl)carbamoyl)py 1059.7 N Nrrolidin-1-yl)-3,3
K dimethyl-1-oxobutan-2 yl)(methyl)amino)-2 oxoethoxy)pentyl)(met hyl)anino)-N methylpicolinamide
(2S,4R)-l-((S)-2-(2-(4
cyaio-3 (trifluoromethyl)pheno xy)-2,2,4,4 tetra methyl cyclobuitjl)C arbar-noyl)phenyl)-IH 710 1,2,3-triazol-4-5 yl)propyl)piperazin- dimaethyibutanoy3)4 hydroxy-N-(4-(4 '~ ~ ~ re-hvlthiazol-5 yI)benzyl)pyrrolidirL-2 ca rboxamide N-((ir,3r)-3-l(4-cyan-3 (trifuoromethyl)pheno
tetra methyl cyclobuitjl)
((S,4R)-4&hydroxy-2
~, V y)benzyl)carbarnv'P
dirnethyl--xbuta2 yl)amino)-2 oxoethoxy)ethyl)-2 oxopiperaziri-l yl)nicotinamide ____
cyano-3 (trifluorornethyl)pheno xy)-2,2,4,4 ...... \tetra methyl cyclobutyl)C arbarnoyi~phenyl)prooj 712 Ipipeazin-1 1069.7
dimehylbutany)a-4 hydroxy-N-((R)-('4-(4 methyl th azaI-5 y1) ph e n y1)(xeta n-3 y1) met h y1)py rroIi d ire-2 carboxamide
3 77
(2S,4R)-1-((S)-2-(2-(4 (3-(4-(((ir,3r)-3-(4 cyano-3 (trifluoromethyl)pheno e xy)-2,2,4,4 tetramethylcycIobutyl)c arbarnoyl)phenyl)propy 713 N I)piperazin-1- 10697 8C xC' \ yl)acetamido)-3,3 dimethylbutanoyl)4 hydroxy-N-((S)-(4-(4 methylthiazol-5
o yl)phenyl)(oxetan-3 yl)methyl)pyrrolidine-2 carboxamide (2S,4R) -- (('5S,85,155). 15-(tert-butyl)-1-(4-(3 (4-cyano-3 (trifluoromethyl)phenyl )-5,5-dimethyl-4-oxo-2 thioxoimidazolidin-I yl)phenoxy)-5,8 714 diisopropyl-3,9- 1187.6 dimethy-4,7,13-trioxo 3,6,9,14 tetraazahexadecan16 Wyl)-4-hydroxy-N-((S) (4-(4-methylthiazoa-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide N-((1r,3r)-3-(3,4 dicyanophenoxy) 2,2,4,4 etetramethylcyclobulyl) 6-(4-(3-(4-(2-(((S)-1 ((2S,4R)-4-hydroxy-2
715 methylthiazol-5- 1069.6 a yl)phenyl)ethyl)carbam ayl)pyrroidin--yl)-3,3 dimethyl-1-oxbutan-2 yl)amino)-2 oxoethyl)piperazin-1 yl)propyl)piperazin-1 yl)nicatinamide
3'78
N-((lr,3r)-3-((5-cyano 6-m ethylipyridi n-2 7'yI)oxy)-2,2,4,4 tetramethylcyclobLutyl)
((2SA4R)-4-hydroxy-2
716 xY>methylthiaPzol-5- 1059.6 \,""tn yi) ph enyi) ethyl)carba m noI~nprridin-i-uyI1 L33
di methyl-1-oxobUtan-2 -. x& yI)ami;no)-2 A ~~~oxoethyl) p ipe ra z in1I
______ ____________________________________________ I)ni;cotinamide NI-(ir,3r)-3-,(3-chIoro ' 4-cy2300phenoxy) 2;2,4,4 tetramethylcyclobuity)
((2,4R)-4--hydroxy-2
717 ' rnet hylthiazoI-5- 108&5 1080.5 yI)phenyi!)ethyl)carbam * Noyl) pyrroi id in-1--yI)-3,3 N~ dimethyl-1-oxobutan-2 X ~ yI)amino)-2 ...... oxoethIl)piperzinI. 'Z'c~i' N ~yI)propyl)piperazin-l _______yI)nicotinamide
\ . ..... N-((lr,3r)-3-(4-cyano-3 N 'N (trifiuorornethyl)pheno xy)-2,2,4,4- 0$ ~>tet ram et:hylIcy c:Io bu ty1)
-N -"'K nethy('4-4 718 mrre'hylthiazol-5-04. 718 ylibenzyl)carbanoyIpyI "'N."'" oidin-1'.-yI)-3,3- dimethyl-i.-oobutn2 yl)(methyi)amino)-2 oxoethoxy)pentyI)(met N c hyI)amino)picolinarnde
(2S,4R)-l-((S)-2-(2-(2
cyario-3 (trifluoromethyl)pheno xy)-2,2,4,4 tetra methyl cyclobUtjl)C 79arbar-noyl)phenyl)-IH- 102.15 1.23-tiazol-4-5
- 4-Iydroxy-N-((S)4.(4
yl)phenyl!)ethyl)pyrrolid ine-2-carboxar-nide N-f(lr,3r)-3-(3-chlo.o NC~ 4-cyanophenox) 2,24,4 tetra methyl cyclobutyl)J
((2S,4 R)-4-fluoro-2 720 (((S)-1t-(4-(4-98 1000~3 N methylthiazol-5- i9 V1) p hernwi )e thyVl)carb a m ~\C.C~:,oyl)pyrrolidin-.-y)3,3 yl)amino)-2 oxoethoxy)ethyl)pipera zin-1-yI)nicotinamidc N(lr,3r)-3-(3-chloro 4-cyarlophenoxy) 2;24,4 tetra methyl cyclobuitjl)
~K((2S,4S)-4-fluoro-2 721N ~N(((S)-l-f4-(4- 1000.3 rneffhlthiazol-5- 9 '"'yl)phlenyl)ethyl)carbarn
dimethyl-l-oxobutan-2 yI)amino)-2 oxoethoxy)ethyl)pi~pera zin-l-yI)nicot.inarniide ___
N-((lr,3r,)-3--(3--chlo~a- 4-cyanophenoxy) 2,2,4,4 tetra methylcyclobutyl) 722~'-6-(12((()-1((()I 933,55 935.45 ((2S,4R)-2-((4 ~N "' ~ ~chlorobenzyl)carbamoy * I-4-hydroxypyrrol idin I.-yI)-1.-oxopropan-2 ________________________________________________yl)amino)-4-m.-ethYl-1 I____
8 0------- oxopentan-2 yl)oxy) ethyl) p ipera zin _______ -yI)nicotinamide (2S,4R)-I--((S)-2-(2-(4 (4-(4-(((lr,3r)-3-(4 cyano-3 (trifilUrornethyl)pheno xv -2,2,4,4 tetra methyl cyclobutVl)cI 723 ~~~ arbamay!)phenyl)butyI) 14. piperazin-I dd rn ethy I b u*an oyl) 4 "N".' hydroxy-N-((S)-I.-(4-(4 mhylthazo-5 yl~phenyI)ethy1)pyrrolid in 2-carboxamide.
S((1r3r)-3-(4-cyano-3 (triflUorornethyl)pheno xy)-2,2,4,4 tetra methyl cyclobutyl)c arbarnovi)phenyl)propV I)piperazin-I 72 ~ylhacetamido)-3,3- 10'1.4 '>3.~dirnethylbut anoyl)-N
me-.hylth!iazol-5 N. '.~yl)phenyi)ethyl)pyrrolid
~f~N {~""ine-2-carboxarnide
A N-((lr,3r)-3-(3-chloroa 4-cya. ophenoxy) 2,2,4,4-. tetramethylcyclobUtyl)
725 4~~~'A,4-diflUoro-2-((() - 063 11.
dirnethyl-1-oxobutan-2 yl)arnino)-2 "" ""'oxoethoxy)ethyl)piperp
______ _____________________________________________zin-1-yI)nico-inamide _____
N-((lr,3r)-3-(3-chloao 4-cyanophenoxy) 2,2,4,4-. tetramethylcyclabutyl) 6-(4-(2-(((S)-1-(((S)1l ((2S,4R)-2-((4 726 ~~chlarobenzyl)carbarnuy 966 936 I)-4-hydraxypyrralidin
oxabutan2-y)ar-nino) AK > 4-me t hyki-axapen tan ¾, "¾'k"- 2 y1)aoxy) ethy1) p ipera z n
4-cyanapheriaxy) 2,2,4,4 tetrarmethyl cyclahutI) 6- (4- (2- (((S) -1- (((S)-1 * N,((2S,4R)2-(4
727 * " ,,chlorabenzyl)carbama (75.6 977.65 N I)-4-hydraxypyrralilin ~ axabutan-2-I)amina) ¾\~.~\ 4-methyi-1-axapentan 2 'N 3yl)axy)ethyl)piperazin
.-yI)nicatinamnide N-((1r,3r)-3-(3-chlara 4-cyar aphenaxy) 2;2,4,4 tetra methyl cyclabUtl) G-(4-(4-(((S)-1{((S)1- ((25,4R)-2-((4 728 chlarahenzyl)carb~rnc'v 974.5 976.5 .~&\ I)-4-hydraxypyrralidin 1-yI)-1-axaprapan-2 N,,-'-:"~'~ ~ 'N, ~yl)arnina)-4-methylI 1 'N4'\''3 xapentan-2-yl)amna) 4-aoxabutyl)oiperazan- yI)ni'catinamide
((4{(1(r,3r)--3-(3-chlc.,a 4-cyanaphenaxy) 2,2,4,4 ~'. ""tetra methylcyclabutyl)c I04 729 .. ,~, a rb amc4) phne n e t h 1 0Il2.3 'N¼ \ethyl)ami;na)prapaxy) N r~.1-((2S,4R)-4-hydraxv-2
'3 methylthiazaI-5 i___ L ______________________________ yI)phenyi)ethyl)carb'ni I________
---------- oyl)pyrrolidin-1-yl)- oxobutan-2 yl)carbarate (2S,4R)-1-(O-(3-((4 (((1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobuyl)c arbamoyl)phenethyl)(m 730 ethyl)amino)propyl)-L- 912.6 914.55 threonyi)-4-hydroxy-N kdA methylthiazol-5 yl)phenyljethyl)pyrrolid ine-2-carboxamide N-((1r,3r)-3-(3-chIoro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl) 6-(4-(2-(((S)-1-(((S)-1 ((2S,4R)-2-((4 731 chlorobenzyl)carbanov 919.5 921.45 I)-4-hydroxypyrrolidin -y)1-yI-Oxopropan-2 yl)amino)-3-methyl-1 oxobutan-2 yl)oxy)ethyl)piperazin 1-yl)nicotinamide N-((lr,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl) 6-(4-(2-.(2-(((k2S,4R)-4-. hydroxy-1-((S)-3 methyl-2-(1 oxoisoindolin-2 yl)butanoyl)pyrrolidine 2 carboxamido)methyl) 5-(4-methylthiazol-5 732 yl)phenoxy)ethyl)piper 1042.5 1044.5 azin-i-yI)nicotinamide
N-((lr,3r)-3-(4-cyano-3 (trifluoromethyl)pheno xy)-2,2.4,4 tetramethylcyclobutyl) 6-(4-(2-(2-(((2S,4R)-4 hyd.roxy-1-((S)-3 nethyl-2-(1 oxoisoindolin-2 yl)butanoyl)pyrrolidine 2 carboxamido)rnethyl) 733 "5-(4-methylthiazol-5- 1076.5 yl)phenoxy)ethyl)piper 5 azin-I-yl)nicotinamide
(2S,4R)-I-(N-acetyl-0 (3-((4-(((1r,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 tetrarnethylcyclobutyl)c arbamoyl)phenethyl)(m 731 954.5; 956.55 ethyl)amino)propyl)-L threonyl)-4-hydroxy-N
s* ' methylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxarnide (2S,4R)-N-(4-chloro-2 (2-(2-(2-(4-(3-(4-cyano 3 (trifiuoromethyl)phenyl K\\ )-5,5-dimethyl-4-oxo-2 thioxoirnidazolidin-1 yl)phenoxy)ethoxy)eth oxy)ethoxy)benzyl)-4 735 hydroxy-i-(3-rnethyl-2- 955.29 957.29 (3-methylisoxazol-5 yl)butanoyl)pyrrolidine 2-carboxamide
N-((lr,3r)-3-(3-chloara 4--yancpheiaxy) 2,2,4,4 tetrarmethyl cyclahutylI)
((2S,4R)-2-((4- 736 ~~~cyanabenzylkcarbamay' 91042 912.42 ~½ )-4-hydroxypyrrolidir
* N'" *.--~-~~*2
* oxoethoxy)ethyl) pipe r0 ______zin 1-yI),ricotina rnide
4-cyanophenoxy) 2,2,4,4 tetrarmethyl cyclahutylI)
((2S,4R)-2-((4- 1737 C1, 1ho r b e nzy1) ca r bamaoy 91938 921t.38
It * s ~~'~~ xobutan-2--yl)arinaj *2 *oxo et haxy) et h y1)p inpera zin-I- y1) riicotin arn id e z___ (2S,4R)!-("(S)-24-(, (4 -(((I-r, 3r)-3- (3 -c h Ioa ~i$ 4-cyariophenaxy) k ""'2;2,4,4
tetrarnethylcyclabuty~c 4arbamany!)phenyl)praay I)piperazin-l-yl)-4 methylpentanayl)-l. alanyi!)-N-((S--4 chlaraophenyl)ethy!,)-4. hydraxypyrralidine-2 738 carbaxamide i9-4.8 946.5
(2S,4R)-1-((S)-2-(2-(4 (3-(4-(((ir,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 tetra methylcyclobutyl)c arbarmoyl)phenyl)propy 739 I)piperazin-1- 930.7 932.5 yl)acetamido)-3,3 dimethylbutanoy)-N ((S)-1-(4 <" chlorophenyl)ethyl)-4 hydroxypyrrolidine-2 carboxamide
(2S,4R)-1-((S)-2-(2-((5 (4- (((1r, 3r).-3 -(3-c hIo ro. 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl)c
740 1arbamoy)p890.3 nenyl)penty 892.4 I)oxy)acetamido)-3,3 \.t dimethylbutanoyl)-N 4:. x. (S)-1-(4 chlorophenyl)ethyl)-4 hydroxypyrrolidine-2 carboxamide (2S,4R)-1-((S)-2-(2-(4 ((3-(4-(((1r,3r)-3-(4 cyano-3 (trifiluoromethyl)pheno xy)-2,2,4,4 tetramethylcyclobutyl)c arbarnoy)benzyl)oxeta n-3 yl)methyl)piperazin-1 11069.4 741 yl)acetamido)-3,3- 1 dimethylbutanoy) C hydroxy-N-((S)-1-(4-(4 methylthiazol-5 yl)phenyI)ethyl)pyrrolid ine-2-carboxamide
N-((lr,3r)-3-(3-chloro 4-cyanophenoxy) 2,2,4,4 tetramethylcyclobutyl) 6-(4-(2-(((S)-1-(((S)1 ((2S,4R)-2-((4 1742 y ees chlorobenzyl)carbarnoy 961.4 963.45 K I)-4-hydroxypyrrolidin 1-yI)-3,3-dimethyl-1 oxobutan-2-y1)anino) 3-methy-1-oxobutan 2 yl)oxy)ethyl)piperazin 1-yI)nicatinamide 6-(4-(2-(5-chloro-2 ((2S,4R)-4-hydroxy-1 ((S)-3-methyl-2-(1 oxoisoindolin-2 yl)butanoyl)pyrrolidine 2 carboxamido) methyl)p henoxy)ethyl)piperazin 1-yl)-N-((lr,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl) 743 rnicotinanide 979.4 981.4
(2S,4R)-1-((S)-2-(2-(4 (2-(3-(4-(((1r,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)c arbamoyl)phenyl)oxeta 744 n-3-yl)ethyl)piperazin- 1035.4 1037.4 W 1-yl)acetamido)-3,3 % dimethyl butanoyllh4 hydroxy-N- ((S)-1-(4-(4 methylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide
H. (2S,4R)-l ('R)-2(2-4
dlcyanophenoxy> 2;2;4;4 ~'tetra methylcyclobUtYI)C arbar-noylilenyl)prooy I)piperazin-i 745 ~yl)acetami:do)-2-9S6 ~>*> (oxetan-3-yil)acetylj-4 hydraxy-N-((S)-i-(C-4 methyithiazl-5 N- ,Nc ci -yI)phenyi!)ethyl)pyrrolidI
ine-2-carboxarnd
N-4
dicyanophenaxy) \k 2,2,4,4 H'tetramnethylcyclohutly)cI arbamoyl)phenyI)propy I)piperazin-1 "''HyI)acetami;do)-2 746 ""S "'~~cmi (oxetan-3-yi)acetylj 984 - hydroxy-N-((S)-i-(C44 rnethylthiazol-5 N.:0OH:,yI)pheny')ethyl)pyrrolid ine-2-carboxamide ....N .k.....
(2S,4R)-I-((S)-2-(4-(4 K'(((ir,3S-3-(3-chloro-4 N- 3.cyaniophenoxy)-2,24.4 tetramethylcyclobutylkc Sarbamoyi)ph enyl)butar'I 1747K arido)-3,3- 895,35 897.4 dimeihylbUtanayl)-4 ~ N- ">vhydroxy-N-((S)-i-(C44 rnethylthiazol-5 yI)phenyi)ethy)l)pyr-rolid I ine-2-carboxamide
(2S,4R)-I-((S)-2-(6-(4 (((lr,3r-3-(3-chlcro-4 'Ncyancophenoxy)--2,24.4
tetramethycycicbUtyk:c ~*a \ "arba moyi)phenyl)hexa nI 1748 .arnido)-3,3- )~23.5 925.55 Rx ~~~ dirmet*h I b uta ncyi)¼4..
rnethylthiazoi-5 I) ph erl) ethyl) pyrro Iid VN ine- 2-ca rboxam ide
(f(1 r,3r)--3I-3-ch I o ro-4 3 3 cya noph e naxy)-2,24,4 N tetra methylcyclobutyl~c arbarncyi)phenyi)hceita 749 "" "'narnida>-3,3- 1931.4 939.45 Kdirnethylbutancyi)-4 N"'~'N~""ihydrcxy-N-((S)-1-(4-(4 ~""\rnet hylthiazol--& yI phe nyi) ethyl) pyrr I id ine-2-carboxamide ''\(2S,4R) -i-(('R)--24.2-(4
Chiloro-4 cyancophenoxy)--2,24.4 tetramnethylcyclabUtylk: MVarbamoyi'pbenyl)prooyI
I)piperazin-i 750 yI)Hacetamidlo)-2- 993. 995.5 (cxeta n-3-yi)acetyl)-4 N hydrcxy-N -((S)-1-(4-(4 *4 N \
yI)phe nyi)ethyl) pyrro Iid &' ine-2-carboxamide
(3-(4-(((ir,3r)-3-(3 A chlor-o-.4 cyanophenaxyY-2,24,4 3-~'-tetra methylcyclobutylJc arbanioyi!)phenyl)propy I)piperazin-1 751 ~yI)acetamidlo)-2- 95 '95 (oxetan-3-yiacetyl)-4 hydroxy--N-((S)- 1- (4'4
'~C CN<yI)phenyi)ethyl)pyrrol id 0,X ine-2-carboxaniide
(2S,4R)-N-(2-(4-(3-(4 (((lr,3r)-3-(3-chloro-4 cyanophenoxy)--2,24,4 tetrmethylcyclohulyc iz, arbamoyl)phenyI)pro~py
~ rnethylthiazo[-5 yI)be-nzyl)-4-hydroxyI, ((S)-3- methyl -2- (1 oxolsomrdolin-2
2-carboxrniide 14. 752 [ 0396O §01. ~5
4'
F39
(2S,4R)-N-(2-(4-(3-(4 (((1r,3r)-3-(4-cyano-3 (trifluorornethyl)pheno xy)-2,2,4,4 tetra methylcyclobutyl)c arbamoyl)phenyl)propy I)piperazin-1I-yl)--4-(4- methylthiazol-5 yl)benzyl)-4-hydroxy-1 ((S)--3-mrethyl-2--(1 oxoisoindolin-2 yl)butanoyl)pyrrolidine- 1075.7 753 107317 2-carboxamide 5
(2S,4R)-N-(4-chloro-2 (4-(3-(4-(((1r,3r)-3-(3 chloro-4 cyanophenoxy)-2,2,4,4 tetra methylcyclobutyl)c arbamoy!)phenyl)propy ) I)piperazin-1-yl)benzyl) 4-hydroxy-1-((S)-3 rnethyl-2-41 oxoisoindolin-2 yl)butanoyl)pyrrolidine 2-carboxamide 754 976.5 978.5
(2S,4R)-l-((S)-2-(3-(4 >'((l,3S)-3-(3-chloro-4 cyaniophenoxy)-2,24.4 tetramethylcyclabUtylk: arbamoyi)pbenyl)pentaI namido)-3,3 dimethylbutanoyi).4. 755N hydroxy-N-((S)-i-(4 909.4 911.45 methylthiazol-5 M< K CKI ..N yl)pherwi)ethyl)pyrrolid ine-2-carbcxamide
(2S,4R)-1.-((S)-2-(9- (((ir;3r)-3-(3-chloro-4 cyanophenoxy)-2 ,24,4 N. L~etrdrmethV yc Icob utyl)c 'N~~ "" arba moyi!)phenyl)nona 756 .. namido)-3,3 965.45 967.45 dirmelhylbutanoyi)-4 hydroxy-N-((S)-i.-(4'(4 me-hylthaPzol-5 yl)phenyi)ethyl)pyrrolid r'.e-2-carbcxarnide N-((lr,3r)-3-(3-chloao 4-cyariacphenoxy) 2;2,4,4 tetramiehylcyclabutyl)
((25,4R)-21-(4 757 ~~cyclaprapylbenzy!)carb 9~4 974
N ~k"'hvdroxvpyrrolidin-1-i N~t~ 3,-dimeIyl 'N. axobutan-2y mino)j 2 oxaethaxy)ethyl)pioera _______zir-1-y)rictinamide
N-((lr,3r)-3-(3-chlara 4-cyanapheiaxvy) 2,2,4,4 tetra methyl cyclabutyl)
((2S,4R)-2-((4 758 cyibtiezlcraI939.46 941.46 ~~rmayi)-4 Shydraxypyrralidin-1-y.,
3.3-dimethyl-1. K,.,. ~oxabutan-2-yi~amina) 2 _________________________________________________________________________ axethaxy)ethyl)pipera ______ ______ zin-1-yl)nicotinarnide N-((ir,3r)-3-(3-chloro 4-cyanophenoxy) 2;2,4,4 tetramethylcyclobutyl) 6-(4-(2-(2-(((S)-1 ((2S,4R)-2-((4 759 cyclopentylbenzyl)carb5 - 953.48 955.48 anoyl)-4 hydroxypyrrolidin-1-yl) 3,3-dimethyl-1 oxobutan-2-yl)amino) oxoethoxy)ethyl)pipera zin-1-yl)nicotinamide N ((Ir,3r)-3-(3-chlo. 4-cyanophenoxy) 2,2,4,4 tetra methylcyclobutyl) 6-(4-(2-(2-(((S)- 1 ((2S,4R)-4-hydroxy-2 ((4-(tetrahydro-2H 969.47 971t .47 760 pyran-4 yl)benzyl)carbamoy)py rrolidin -vl)53 dirnethyl-1-oxobutan-2 yl)arnino)-2 z> \oxoethoxy)ethyl)pipera
---------------------------------------------------------------------------------------------------------------------- zin-1-yl)nicotinamide i -- I-io in m d (2S,4R)-i-((R)-2-(6-(4 (3-(4-(((1r,3r)-3-(4 cyano-3 (trifiluoromethyl)pheno xy)-2,2,4,4 tetra methyl cyclobutyl)cI 761 ~. *'½c'¾" ~ '~ Narbamnoyliphenyl)propiy
I)piperazm-1-yl)-. [0735 761s oxoisoindolin-2-yl)-3- 1 methylbutanoyl)-4 hydroxy-N-(4-(4 methylthiazol-5 yl)benzyl)pyrrolidine-2 carboxamide
(2S,4R)-I-((S)-2-(6-(4 (3-(4-(((ir,3r)-3-(4 cyano-3 (trifluoromethyl)pheno xy)-2,2,4,4 4s~ ~ tetramethylcyclobuty)c arbamoyl)phenyl)propy 762 m I)piperazin-1-yl)-1- 1073.5 oxoisoindolin-2-yi)-3 rmethylbutanoy)-4 hydroxy-N-(4-(4 methylthiazol-5 yI)benzyl)pyrroiidine-2 carboxamide
(2S,4R)-1I-((S)-2-(8-(4 (((1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetra methylcyclobutyl)c arbamoy!)phenyl)octan 763 oaida)-3,3- 951.5 953.5 dimethylbutanoyl)-4 hydrox-N-((S)-1-4(4 me*thylthiazol--5- yI)phenyl)ethyl)pyrroid ine-2-carboxamide (2S,4R)-1(S--1 -4 (((1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)c "' arbamoyi)phenyl)decan 764 amido)-3,3- 979.5 981.45 dimethylbutanoyl)-4 hydroxy-N-((S)-1-(4-4 methylthiazol-5 yl)phenyl)ethyl)pyrrolid ine-2-carboxamide
N-((lr,3r)-3-(3-chloro
cyanophenoxy)cyclobut yl)-6-(4-(2-(2-(((S)-1 ((2S,4R)-4-hydroxy-2
rnethylthiazol-5 yl)phenyi)ethyl)carbam oyl)pyrrolidin-1-yl)-3,3 dimethyl-1-oxobutan-2 yl)arnino)-2 oxoethoxy)ethyl)pipera zin-1-yl)nicotinamide 1765 1 9410.45 9 425
o",4
N N-((S)-1-(3-(4-cvano-3 (trifluoromethyl)phenyl )-iH-pyrazol-1 yl)propan-2-yl)-5-((3-(4 "'oX.(2-(((S)-1-((2S,4R)-4 hydroxy-2-(((S)-1-.(4-.(4 methylthiazol-5 yl)phenyl)ethyl)carbam eyl)pyrrolidin-1-yl)-3,3 dimethyl-1-xobutan-2 yl)amino)-2 766 oxoethyl)piperazin-1- 1029.4 l)propoxy)methyl)-1H-I
carboxamide
N-((S)-1-(3-(5-cyan-6 rnethylpyridin-2-yI)1'1 pyrazai-I-y)ropai.2.
'"((2 S,4R)-4-h yd roxy-2
Ms yI)phenyI)ethyl)carbarn oyl)pyrroiidin-JI-yI)-3,3 dimet hVI-1-oxobutan-2-.
767 oxoethyl)piperazin- 1 6. 'yI) pro poxy)rmnethyl)-' H-I N'"'>': yrazole-3 carbaxamide
N-((lr,3r1-3-(3-chlara 4-cyanaphe.Iaxy)-. 2,2,4,4 tetrarmethylcyclabutI) 6-.(4-(4- (((S)-I((2S,4R) ½4-hyd raxy-2-(((S)- 1(4 768 (4- methylth iazal1-5- 980.4 982.4 S \ yI)ph enyi) ethyl)ca rba m ) J< yl)oyrraIidin-1-yI)-3&3 ~~d 7dmethyl-it-axabutan-2 yI)ami;na)-4 axabutyi)piperazin1l _______~~~~~~~~~~~ ;______________________________ Incobinamnide (2S,4R)-N-(4
(4-cyana-3 N.~ Nsr'N~N..(trifiuararethyl)phena
xy)-2,2,4,4- ..... ,\, tet ra me t:hylIcy c:laob ul' 1) c 004 11. 769~~ % ranyi)phenyl)prapy o~"~N"' 50 II
I)piperazin-1-yl)- y x axisatin dalHn -2-yl1)-3 methylbutanayi)-4 ' N" hydraxypyrralidine-2
carhaxarnide
(2S,4R)-N-(4 chlorobenzyl)-1-((S)2 f ~(6-(4-(3-4((ir3r)-3 (4-cyano-3 N (trifluoromethyl)pheno xy)-2,2,4,4 tetrarnethylcyclobutyl)c 1012.4 770 arbamoyI)phenyl)propy 1010~taram.5 1005 * I)piperazin-1-yi)-1 c oxo iso indolin-2-y)-3 rnethylbutanoyl)-4 hydroxypyrrolidine-2 carboxamide
[0765] Synthesis of Example 786: N 1 0 NBoc NH Tsr N BN TEA NN N"ATE N -N A N. DOC N
HN TEA, DCM DIMSO C 00°C
3 H H
TEAN NOH N N DCIg N'N-NH HN DPEA
00 O4 NN OH
N o N NNN
AEM-26 NC HIN
DIPEA
ExampIe 786 N N
[0766] Step 1: Synthesis of (2S,6R)-tert-butyl 4-(5-(methoxycarbonyi) pyridin-2-yl)-2,6 dimethylpiperazine-1-carboxylate.
Boc NN
0
[07671 A mixture of methyl 6-fluoronicotinate (200 mg, 0.93 mmol), (2S,6R)-tert-butyl 2,6 dimethylpiperazine-1-carboxylate (289 mg, 1.87 mmol) and N-ethyl-N-isopropylpropan-2-amine (362 mg, 2.80 mmol) in dimethyl sulfoxide (2 ml) was stirred at 100°C for 16 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (15 ml x 2). The combined organic layers were washed with brine (10 ml). dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 20-40% ethyl acetate in hexane) to afford (2S6R)-tert-butvl4-(5-(methoxycarbonyl)pyridin-2-yi)-2,6 dimethylpiperazine-1-carboxylate (300mg, yield 92%) as light yellow solid. LCMS: (ESt ): m/z 350.2 [M+H]*. tR 3.020 min.
[0768] Step 2: Synthesis of methyl 6-((3S,5R)-3,5-dimethylpiperazin-1-yl)nicotinate TFA salt.
NH N N
0 10769] A mixture of (2S,6R)-tert-butyl 4-(5-(methoxycarbonyil)pyridin-2-yl)-2,6 dimethylpiperazine -1-carboxylate (300mg, 0.86 mmol) and 22,2-trifluoroacetic acid (2 ml) in dichloromethane (2 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up in dichloromethane (15 ml) and washed with aqueous sodium carbonate (sat, 20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 6-((3S,5R) 3,5-dimethylpiperazin-1-yl) nicotinate (180 mg. yield 84%) as light yellow solid which was used in next step directly without further purification.
[07701 Step 3: Synthesis of methyl 6-((3S, 5R)-4-(-2--(trt-butoxy)-2- oxoethoxy)ethyl)-3,5 dimethylpiperazin-I-yi)nicotinate.
00 NO N N
0
[07711 To a solution of methyl 6-((3S,5R)-3,5-dimethylpiperazin-1-yl)nicotinate(180 mg, 0.72 mmol), triethylamine(146 mg, 1.44 mmol) in acetonitrile (2 nil) was added tert-butyl 2(2 (tosyloxy)ethoxy)acetate (238 mg, 0.72 mmol). The resulting mixture was stirred at 70°C for 16 hours. TLC showed the reaction was complete. To the reaction mixture was added water (20 ml) and ethyl acetate (20 nl). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (10 ml x 2). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluting with 5% methanol in dichloromethane) to afford methyl 6-((3S, 5R)-4-(2-(-(tert-butoxy)-2- oxoethoxy)ethyl-3, 5-dimethylpiperazin-I yl)nicotinate(75mg,yield 25%) as light yellow solid. LCMS: (ES*: m/z 408.3[M+H]*.ta 2.059 min.
[0772] Step 4: Synthesis of methyl 4-(5-(3-aminopropoxy)pentyl)benzoate.
0 N OH
"NJ 0
[0773] A mixture of methyl 6-((35, 5R)-4-(2 (2-(tert-butoxy)-2- oxoethoxy)ethyl)-3, 5 dimethylpiperazi-1-yl)nicotinate (75 mg, 0.18 mmol) and 2,2,2-trifluoroacetic acid (1 nil) in dichloromethane (1 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure to afford methyl 4-(5-(3 aminopropoxy)pentyl)benzoate (64.8 mg.yield 100%) as lightyellow solid which was used to the next step without further purification.
[07741 Step5: Synthesis of methyl 6-((3S,5R)-4-(22-(-(((2S)--((4R)-4-hydroxy -2-(((S)-I-(4 (4-methylthiazol-5-yl)phenyl)ethyli)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2 vl)amino)-2-oxoethoxy)ethy1)-3,5-dimethylpiperazin-I-yl)nicotinate.
OH 0
NH O O N
[0775] To a stirred solution of methyl 4-(5-(3"-amino~propoxy)pentyl)benizoate (64.8 mig, 0.18 mmol), (4R)-1-((S)-2-amino-3,3-dimethylbuitanoyl)-4-hyldroxy-N-((S)-1-(4-(4-meth-ylthiazol-5 yl')phienyl)ethyl)pyrrolidine-2-carb~oxamnide hydrochloride (88.6 mg, 0. 18 mmol), and N-ethyl-N isopropylpropan-2 amine (143 mg, 1. 1 mmol) in anhydrous N,N-dimethylformamide (1 ml) was added HATU (2 -(7-Azai-1Hl-benizotiazole-1-yl)-1,1,3,3-tetramnethyluroniumI hexafluorophosphate,) (139 mng, 0.37 mmol) at 0°C, the resulting mixture was allowed to warmn to
room temperature and stirred for 40 miun. TLC showed the reaction was complete. The mixture
was partitioned between ethyl acetate (25 ml) and water (15 mal). The organic layer was collected, washed with brine (15 ml), dried over anhydrous sodium sulfate, and concentrated under reduced
pressure to give a. crude residue which was purified by silica. gel flash chromatography (eluted with 5 % methanol in dichloromethane) to afford methyl 6-((3iS,5,R)-4-(2-(2f-L-(((2S)-1-((4R,)-4 hydroxy -2-(((S)- 1-(4-(4-miethylthiiazol-5-yl)phienyl)ethyl)carb~amoyl)pyrrolidini- 1-yl)-3,3 dimethyl- 1--oxobutan--2-y l.)amino)--2--oxoethoxy)ethyil)-3,5.-dimethyvlpiperazin-1l-yl)nicotinate (140 mg, yield 98%).
[0776] Step 6: Synthesis of N.-((1r,3R)-.3--(3--chloro--4-cyanophenoxy)--2,2,4t,4. tetram~rethyleyelobutyl')-6-(('3S,5R')-4-(2-(2-(((2 S)-1-((4R)-4-hydroxy-2--(((S)-1-(4-('4
methylthiazo1-5-yl)phenyl ethyl)carbamoyl )pyrroli din-1I-yl')-3,3-dimethyl-1 -oxobutan-2 yl) amino) -2-oxoethoxy)ethyl)- 3,5-d imethylpiperazin-1I- yl'nicotinamide.
OH 0 N N N H O
O N
[07771 A mixture of methyl 6-((3S,5R)-4-(2-(2-(((2S)-I-((4R)-4-hydroxy -2-(((S)-1-(4-(4 methyilthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3.3-dimethyl-1-oxobutan-2 yl)amino)-2-oxoethoxy)ethyl)-3,5-dimethylpiperazin-1-yl)nictinate(140mg,0.18 mmol) and lithium hydroxide monohydrate (15 mg. 0.36 mmol) in tetrahydrofuran (2 ml)-water (0.5 ml) methanol (0.5 ml) was stirred at 45°C overnight. TLC showed the reaction was complete. The mixture solution was concentrated and the residue was acidified with diluted hydrochloride acid
(IN) till pH-5-6, extracted with dichloromethane (10 ml x 3The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated. The residue was taken up in anhydrous NN-dimethylformamide (2 ml), followed by N-ethyli-N-isopropylpropan-2-amine (132 mg, 1.02 mmol), 4-((1r,3r)--amino-2,2,4,4-tetramethylcyclobutoxy)-2-clorobenzonitrile hydrochloride (54 mg, 0.17 mmol), and HATU (2-(7-Aza-H-benzotriazole-1-yl)-1,1,3.3 tetramethyluronium hexafluorophosphate) (129 mg, 0.34 mmol) at 0°C, the resulting mixture was allowed to warm to room temperature and stirred for 20 minutes. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (30 ml) and water (15 ml). The organic layer was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 10% methanol in dichloromethane) to afford N-((r,R)-3-(3 chloro-4-cyanophenoxy)-2,2.4,4- tetramethyicyclobutyl)-6-((3S.5R)-4-(2-(2-(((2S)-I-((4R)-4 hydroxv-2-(((S)-I-(4-(4-methvlthiazol-5-yl)phenyl)ethyl)carbamoyl)pvrrolidin-1-yi)-3, dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethyl)-3.5-dimethylpiperazin-I-yl)nicotinamide
(16.3 mg, yield 9.3%) as white solid. 1H NMR (400 MIz, CD3 OD): 6 0.93 (s, 9H), 1.12 (s, 6H), 1.17 (s, 12H) 1.42-1.44 (m, 3H). 1.87-1.89 (m, IH), 2.05-2.08 (m 1H),2.38 (s. 3H),2.66-2.73 (m, 2H), 2.81 (m, 211), 3.04 (n 211), 3.58-3.65 (in, 31-1), 3.71-3.74 (m, 1H), 3.87-3.91 (m, 2H), 4.04 (m, 1H). 4.12-4.25(m. 3H), 4.32 (s. IH), 4.41-4.51 (in, 1H), 4.60 (m, IH), 4.87-4.93(m,
1H.) 6.74-6.76 (m, IH), 6.86-6.90 (m IH), 7.04 (s. IH), 7.21-7.35 (im, 4H), 7.61-7.62 (dJ - 8.8 Hz, 111), 7.85-7.87 (m, 1H), 8.48 (br, 1-), 8.77 (br, 11), 8.98 (s, 1-1)). Chemical Formula:
C 53 H 6 sCIN 90sS; Molecular Weight: 1026.68.
[07781 Unless otherwise noted, Examples 771-793 were synthesized according to similar procedures described above for the synthesis of Example 786, by utilizing corresponding starting materials and reagents.
107791 Table 19: Additional Exemplary Compounds
Measured Mass Ion Data Ex # Structure Compound Name In/z (1) m/z (2) (2S,4R)-1-((R)-2-(6-(4-(3-(4 (((1r,3r-)-3--(4-cyano--3 (trifluorornethyl)phenoxy) 2,2,4,4 H 0 tetrar.ethylcyclobutyl)carba 77 N . N -r ~- omoyl)phenyl)propyl)piperazi 1001.45 771 N LN n-1-yl)-1-oxoisoindolin-2-y) 3-methylbutanoyl)-N-(4 H' cyanobenzyl)-4 N hydroxypyrrolidine-2 N carboxamide
(2S,4R)-1-((S)-2-(6-(4-(3-(4 (((1r,3r)-3-(4-cyano-3 (trifIuoromethyl)phenoxy) 2,2,4,4 772 O > tetramethylcyclobutyl)carba 772N N01 oyl)phenyl)propyl)piperazi 1001.55 O-4 N rn-1-yI)-1-oxoisoindolin-2-yl) 3-methylbutanoyl)-N-(4 F ~ 0 cyanobenzyl)-4 F N. hydroxypyrrolidine-2 carboxarnide
(((lr-,3r)--3-(3--choro--4 cyanophenoxy)--2,2,4,4A tetra rnethylcyclo butyl)ca rba ~ ;~-~'N r movl)pheriyl)propyl) ierz ~ \~N~-- OH n-1--yi)-1-oxoisoindoin--2--yi) 1094 OI /~- 0~9~ 3-methylbutanoyl)-.4 '
h 0 )- hydroxy-N-(44-4 yI)benzyl)pyrroidine-2 N N1 carboxamide
(2S,4R)-1.-((S)-2-(6-(4-(3-(4 (((l1r,3r)-3-(3--chloro-4 cyanophenoxy)-2,2,4,4 tetra rn ethylcyclo butyl)ca rba H ~'"N~>moyI)phenyI)propyI)piperazi ,0H 1039.5 1041.45 0 N -N!3-rniethylbutanoyl)-4 K> a )-~ hydroxy-N-(4-(4 HN-'C- mnethylthiazol-5 SyI) benzyl) pyrrolIid ine-2 N N~(\carboxarnide
N-((lr,3r)-3-(3-chloro )H cyanophenoxy)-2,2,4,4 C) j( > tetra methylcyclo butyl)6(4 -N (2-(2-(((S)4l-((2S,4R)-2-((2,5 N, N, H 0~ )NH 0 difluorobenzyI~carbarioyI) 775 4-hydroxypyrrolidin-1-yi)- 921.33 923.34 7<0 -/' -F3,3-dimethyl--oxobutan-2
yI)amino)-2 oxoethoxy)ethyl)piperazin N 1-yI)nicotinarnide
6-(4-(2-(2-(((S)-l-((2S,4R)-2 ((4-(tert ~Hbutyl)benzyl)carbarioyl)-4 l) ydroxypyrrolidin-1I-yi)3,3 ,~N K)0 -"NH dimethvi-1-mobutan-2 H 0 776 Iarn)2-941.41 94141. 7/7 y oxoethoxy)ethy)piperzl'n)
L 4-cyanophenoxy)-2,2,4,4 tetra rn ethylcyclo butyl)n icth N namide
40'
(25,4R)-1-((R)-2-(6-(4-(3-(4 (((1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 N 0 tetrarnethylcyclobutyl)carba N--- ,o moyl)phenyl)propyl)piperazi 7717 7n-1-yI)-1-oxoisoindolin-2-1y.)-4 1.053.5 1055.45 HN 3-methylbutanoyl)-4 2 hydroxy-N-((S)-1-(4-(4 * 'methylthiazol-5
yl)phenyI)ethyI)pyrrolidine 2-carboxamide
(2S,4R)-1-((S)-2-(6-(4-(3-(4 (((1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carba N .. H rnoyl)phenyl)propyl)piperazi n-1-yl)-1-oxoisoindolin-2-yl)-I 778 1 1053.5 1055.45 N 3-methylbutanoyl)-4 \ Shydroxy-N-((S)-1-(4-(4 methylthiazol-5 yI)phenyl)ethyl)pyrrolidine 2-carboxamide
10780] Table 20: Exemplary Compounds.
Measured Ex.E Mass Ion Data Structure Compound Name m/z m/z (1) (2) N-((1r,3r)-3-(3-chioro-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobuty)-6-(4 (5-(((S)-1-((2S,4R)-4-hydroxy 2-(((S)-1-(4-(4-methyithiazol 4C"° 5 yI)phenyl)ethyI)carbamoyl)py 779 * rroIidin-1-yl)-3,3-dimethyl-1- 994.4 996.4 .. .oxobutan-2-yI)amino)-5 \ .c*e (Ae oxopentyi)piperazihn-1 yi)nicotinamide
N-((-r,3r)-3--(3-chloro-4 cyan op he noxy) -2,2,4,4 "3
el ternethylcyclobutyl)--(4 (,5-(((S)-'>((2S,4R)-4-hydroxy X 2-(((R)-2-hydroxy-l-(4-(4 methythiazol-5 yi)phernyl)ethyi )car-barnoyl)py 11 78 "l.rroiidin-I-yi)-3,3-dirniethyl-1- 101112.4 oxobutan-2-yl)amino -5 oxoperity!)piperazin-l y!)nicotinamile
N-((i-r,3r)-3--(3-chloro-4 cyanophenoxy)-2,2,4,4 tetra.nethy cyc obuy)--6--4-
2-(((R)-2-hydroxy-l-(4-(4 ~ \* ~met'hylthiazo-5 Syi )phernyl)ethyi )caebarnoyl)py 781 rro iid in-I-y 1) -3,3Airn ethylI-1I- 996.4 998.4 oxobutarv-2-yl)amino)-4 oxobutyl)piperazin-- y)nicotinamidle
N-((i-r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetra-nethy cyciabuy!)--6--4-
hy droxy-2-(((S)-1- (4- (4 methyithiazl-5 y')pheriyl)ethy')carbarnoyl)py 11 782 rroiidin-I-yi)-3,3-dirniethyl-1- 101112.4 Noxobutan-2-yl)amino)-2-4
N\N axoethoxy)ethyl)--1,4 diazepan-l>yI)nicatinamide
(f(lr,3r)-3-(3-chloro-4 cyanophenoxV)--2,2,4,4- t elrarrethicyclobut yl)carba rnoyl)phenyl)propyI)piperazi
dirnethylbutanoyl)-4 783 ~.hdoyNfS-1(-(-993.5 995.. N methylthiazol-5 yi)phernyl)ethyi )pyrrolidirne-2- '~~'~'~'carboamrnde
N-((Ir,3r)--3-(3--chIoro--4 cyanophenoxy)-2,2,4,4& tetran .ethy'cyc'obutyI)6-(4
(4-cyano--2 784 niethoxypheny)ethyl)ca rba 9 529 95 3.5 * moyl)-4-hydroxypyrrol idin-i 0i-3,3-dimethyl -1-oxobutan
. .oxop e nty1) pi p era zin -i _____ _____________________________________________ i~cotinarnide
cyp no ph e noxy)-2,2,4,4 tetra m.ethyl!cycIob u-yi)-6-(4
N i~--(4-cypno-2- 9 785 "". methoxyphenyl)ethyl!)carba * 956.36 ~ \"'~rnoyl)-4-hydroxypyrrolidi-1- 6 ' ~ yI!)-3,3-dirniethlyV-1-oxobutan 2-yl)am!inol-2 oxoethoxy)ethyl)piperazin-:- y'Onicotinarnide
cyano ph e noxy) -2,.2A,4 tetrametilty!)L~~i)6
((4R)-4-hydroxy-2-(((S)-1 -(4. (4-methylthiazol-5- 12 786 e nyy) et ,y;) c arb amnoy1) py p.h)" I10f6.4
''oxo butan2--y1) arnin o)-.2- ...... oxohoxy)ethI)-3,5 dirnethyi piperazin-1 yI~nicotinarnide
N-((i-r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetra.methy cyciobuvi)--6-(8
hydroxy-2-(((S)-i--(4-(4 Nmethyl..hiazo-5
yi)phernyl)ethyi )car-barnoyl)py rroiidn--yi)-3,3-dirnethyl-1- 1022. 12. 787 oxobutan-2-yl)amino)-2 oxoethoxy)ethyl)--3,8 'N diazabicyclo[3.2.1 ]actan-3 yi~nicotinamide
\ N-((i-r,3S)-3-(3-chioro-4 cya no p hen oxy) -2,.24,4 tetramety !CYCdobuLty)-6
NM ~ hydroxV-2-(((S)-li(4--(4 788 methylthiazolk5- 1026. 12. yi)phenvl)ethyi!)carbam.-oyl)py 4 '~Noxobutan--2--y)arnino)--2- *'\\ oet hoxy)et hy)-3 ...... (hydroxyrnethyI)piperazin-l vi~nicatinarnide N-((lr,3r)-3-(3-chioro-4 cyanophenoxy)--2,2,4,4- tetLram..ethyicycdobutLy}!6-(4
hydroxy-2-((kS) -- ,4-(4.. 789 ~~ methylthiazol-5- 1064. 106. y')phenyl)ethy')carba....oyl)py 5 rroiidi n-1-yl)-3,3-dime-hl-1 oxobkut:an-2-yl)amin)-2 oxoethyl)piperazin-i yi~ethyl)piperazin- ______________________________________________________yl~nicotinarnide
N-((S)-i_-(3-(3-chloro-4 cyanophenyl)-iH-pyrazol-i
(((S)-I-((2SA4R)-4-hydrox-2
yI)phenyI)ethyl)carbamoy)py rr I'-.n-1- 1, -dirne I 790 oxbtn2y~ric-- 981.4 983.4 oxoethoxy)ethyl)piperazin-:_ yi)rnethyl)-i H-Dyrazole-.3- Carbcnxamide
(2S, 4R) -I-((S)- 2- (2-(f((1S, 2S) 2- (4-(2- (4-(((itr;3 r) -3 -(3 ch Ioro-4- cya n oph enoxy) 2,2,4,4 Let ram e Lh v1cy c1ob u *y 10c arb a 791 ay 1)p h enoxy)et hyl1) Dip era zi 10 097 79 n-1- 7 05. y 1 cyc1oh exy 1) oxy) acetam i d o) -3,3-dirnethylbutanoyl)-4
methylthiazol-5 yi)phenyI)ethvl)pyrrobidine--2 carboxarnilde f2S,4R)-I--((S)-2-(2-(((IR,2R) 2-.(4-(2-('4-(((ilr,3r)-3-(3 clor-o-4-cyanopher"OXY) 2,2,4,4 Letramethicyclobutyl~carba 792 moyI)phenoxy)ethy)piperazi 1093. 19. Cx * yi)cyciohexyl)oxy)aceta.ido) 7
hydroxy-N-((S)-I-(4-(4 rnethylthiazol-5 vi)phenyl)ethvi)pyrrolbdine--2 Carboxarnlde \N-((lr,3r)-3-(3-chIoro-4 cyariophenoxy)-22.44 tetramety;!CYC;!ObuLty!)-6-(4 (2-(2-(((S)-i-f(2S,4R)-4 '"~ hydroxy-2-((2-nethoxy-4-(-F 793 rnethylthazol-5 02 1014.3 \'\yi)ben)zyl)Carbrnoyl)pyrrolidi 3i5 5 n- 1-yi)-3,3-d im ethyl-I oxobutan--2-yI)arnino)-.2- oxoetihcny)etihyI)piperazin-i y)niCOtinamide
[07811 Synthesis of Example 794: NH
HO NN K2C.O Ex>N DIP'EANMP DMF F BNrBGC
BOC
'N'o0- Boc N
N ~ Pd/C, H ~ N ABM-26 N ,N H-Clidioxane
EnO N. HO~ ~ N Di-A'
N N NIABM. Noc
I" ~ MeOHAcOH I
NH HN'
NHN Br N H Cdioxane N ON HCI DIE,, O N N
NN N N -s. OH0
ULM-3 N NO NH HATU, N NNCDA N N
HN Example 794
[0782] Step 1: Synthesis of benzy 6-fluoronicotinate.
Bv() O N..
[0783] A mixture of 6-fluoronicotinic acid (10 g,70.9 mmol), benzyl bromide (18 g.106 mmol) and potassium carbonate (18 2 g. 141 mmol) in N,N-dimethylformamide (100 ml) was stirred at room temperature for 12 hours. TLC showed the reaction was complete. The reaction mixture was
allowed partitoned between water (100 ml) and ehlacetate (100 ml). The organic layer was collected, washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography elutedd with 20% ethyl acetate in hexane) to afford benzyl 6-fluoronicotinate (15 g, yield 93%) as yellow solid. 1 HNMR (400 MIz, CDC 3 ): 6 5.37 (s, 2H), 6.96-6.98(m, I1l), 7.34-7.45 (m, 51-), 8.38-8.43 (in, 1), 8.90-8.91 (i, 1H). Chemical Formula: C 3H1 FNO 2
, Molecular Weight: 231.22.
[0784] Step 2: Synthesis of tert-butyl 4-(5-((benzyloxy)carbonl)pyridin-2-yl)piperazine-1 carboxylate.
^NBoc
BnO l N
[07851 A mixture ofbenzyl6-fluoronicotinate(15g,65miol),di-tert-butylpiperazine-1,4 dicarboxylate (12 g, 65mmol) and N-ethyl-N-isopropylpropan-2-amine (16.6g, 129 mmol) in dry 1-iethylpyrrolidin-2-one (80 ml) was stirred at 80°C for 12 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was collected, washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude residue which was purified by silica gel flash chromatography (eluted with 20-50% ethyl acetate in hexane) to afford tert-butyl 4-(5-((benzyloxy)carbonyl)pyridin-2-yl)piperazine-1-carboxylate (20 g, yield 80%) as white solid.
[07861 Step 3:Synthesis of 6-(4-(tert-butoxycarbonyl)piperazin-1-y)nicotinic acid. NBoc N
FO 0
[07871 A mixture of tert-butyl 4-(5-((benzyloxy)carbonyl)pyridin-2-yl)piperazine-1-carboxylate (2.0 g, 5.03 mmol) and palladium on carbon (10%, 200 mg) in ethanol (20 ml) was stirred at 30°C overnight under hydrogen atmosphere (hydrogen balloon). TLC showed the reaction was complete. Palladium on carbon was removed through filtration and washed with ethanol (20 ml x 2). The combined filtrates were concentrated under reduced pressure to give 6-(4-(tert butoxycarbonyl)piperazin--1-yl)nicotinic acid (1.6 g, crude) as colorless oil which was used in next step without purification.
[0788] Step 4: Synthesis of tert-butyl 4-(5-(((ir,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazine-I-carboxylate.
NBoc N NN
C1 0
[07891 To stirred solution of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinicacid (300 mg, 0.97 mmol), 4-((r,3r)--amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride (306 mg, 0.97 mrnol), and N-ethyli-N-isopropylpropan-2-amine (309 mg, 2.4 nmol) in anhydrous N,N-dimethylformamide (8 ml) was added HATU (2-(7-Aza-IH benzotriazole-1-vl)-1,1,3.3-tetramethyluronium hexafluorophosphate) (684 mg. 1.8 mmol) at0°C, the resulting mixture was allowed to warm to room temperature and stirred for 20 min. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (50 ml) and water (80m). The organic layer was collected, washed with brine (Omil), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was
purified by silica gel flash chromatography (eluted with 10 % methanol in dichloromethane) to afford tert-butyl 4-(5-(((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazine-I-carboxylate (400 mg, yield 72%) as white solid.
[0790] Step 5: Synthesis of N-((r,3r)-3-(3-chloro-4-cyanophenoxy)-2,,4,4 tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide. -NH
C1 N
[0791] A mixture of tert-butyl 4-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-22,4,4 tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazine-I-carboxylate (80 mg, 0.14 mmol) in hydrogen chloride in dioxane solution (4M, 2 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up in dichloromethane (20 ml) and washed with aqueous sodium bicarbonate solution (IN, 5 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by pre-TLC (eluted with 10
% methanol in dichloromethane) to afford [N-((1r3r)-3-(3-chloro-4-canophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (32 mg, yield 50%) as white solid. LC_MS: (ES'): m/z 468.6 [M+H]. tR = 2.285 min. IHNMR (400 MHz, CD 3 0D): 6 1.07-1.38 (in, 12H), 3.12-3.40 (in, 4H), 3.51-3.86 (in. 1H), 3.94 (br, 3H), 4.17-4.30 (in. 2H), 6.99-7.15 (in,
211), 7.74(s, 1H), 8.05(s, 11), 8.48-8.68 (in, 2H). Chemical Formula: C25H-3CAN502; Molecular Weight: 467.99.
[07921 Step 6: Synthesis of tert-butyl 3-(4-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxv)-2,2,4,4 tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazin.-I-yl)azetidine-1-carboxylate. -Nloc N
c o I
[0793] A mixture of tert-butyl 3-oxoazetidine-1-carboxylate (87 mg, 0.51 mmol), N-((1r,3r)-3 (3-chloro-4-cyanophenoxy)-2,,4,.4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (200 mg, 0.43 mmol), acetic acid (45 mg, 0.75 mmol) in methanol (10 ml) was stirred at room temperature for 30 min, followed by addition of sodium cyanoborohydride (53 mg, 0.86 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude residue which was purified by silica gel flash chromatography (eluted with 10 % methanol in dichloromethane) to afford tert-butyl3-(4-(5-(((r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazin-1-yl)azetidine-I carboxylate (143 mg, yield 52%) as white solid.
[07941 Step 7: Synthesisiof 6-(4-(azetidin-3-yl)piperazin-1-yl)-N-((ir,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4.4-tetramethylicyclobutyl)nicotinamide hydrochloride.
4 12
H/'N
[0795] A solution of tert-butyl3-(4-(5-(((r,3r)-3-(3-chloro-4-cyanophenoxy)-22,4,4 tetramethylcyclobutyl)carbaioyI)pyridin-2-yl)piperazin-I-y)azetidine-I -carboxylate (140 mg, 0.22mmol) in hydrogen chloride in 1.4--dioxane (4M, 5 ml) was stirred at room temperature for 6 hours. TLC showed the reaction was complete. The volatiles were removed under reduced pressure to give 6-(4-(azetidin-3-yl)piperazin-1-yl)-N-((Ir,3r)-3-(3-chlioro-4-cyanophenoxy) 2,2,4,4-tetramethylcyclobutyi)nicotinamide hydrochloride (130 mg. crude) as white solid which was used in next step without further purification.
[0796] Step 8: Synthesis of tert-butyl 2-(3--(4-(5-(((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazin-I-yl)azetidin-I-yl)acetate.
-U 0
N N
c/^^ N o ,
[07971 To a stirred solution of 6-(4-(azetidi-3-y)piperazin-1-l)-N-((1r,3r)-3-(3-chlioro-4 cyanophenoxy)-2,2,4,4-tetramethvlcyclobutyl)nicotinamide hydrochloride (130 mg, crude), N etlhyl-N-isopropylpropan-2-amine (148 mg, 1.14 mmol)in acetonitrile (5 ml) was added tert-butyl 2-bromoacetate (45 mg, 0.23 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluted with 10 %
methanol in dichloromethane) to afford tert-butyl 2-(3-(4-(5-((((r,3r)-3-(3-chloro-4 cyanophenoxy)-2.2,4,4-tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)piperazin-1-yl)azetidin-1 yl)acetate (70 mg, yield 49%, over 2 steps) as yellow solid.
[0798] Step 9: Syntihesisiof2-(3-(4-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2.2,4,4 tetramethvlcyclobutyl)carbamoyl)pvridin-2-yl)piperazin-1-yl)azetidin-1-yI)acetic acid.
OH
N ' 0
N- N
10799] A solution of tert-butyl 2-(3-(4-(5-(((1r,3r)-3-(3-chioro-4-cyanophenoxyv)-',2,4,4 tetramethilcyclobutyl)carbamoyl)pyridin-2-yi)piperazin-1-yi)azetidin-1-yl)acetate (65 mg, 0.10 mmol) in hydrogen chloride in 1,4-dioxane (4M, 5 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were removed under reduced pressure to give 2-(3-(4-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-22,4,4 tetramethvlcyclobutyl)carbamoyl)pvridin-2-yl)piperazin-1-yl)azetidii-l-yI)acetic acid (60 mg crude) as white solid which was used in next step without further purification.
[08001 Step 10: Synthesis of N-((r,3r)-3-(3-chioro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6-(4-(I-(2-(((2S)-1-((4R)-4-hydroxy-2-(((S)-I-(4-(4-methvlthiazol-5
yI)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimnethyl-I-oxobutan-2-yl)amino)-2 oxoethyl)azetidin-3-yl)piperazin-1-yl)nicotinamide. cL .o,. b--- NC 1 0
0
NN
[0801] To a stirred solution of2-(3-(4-(5-(((1r3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carbamoyl)pyridin-2 -ylI)piperazin-I-yl)azetidin-I-yl)acetic acid (60 mg, crude), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-I-(4-(4-metiylthiazol 5-yi)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (49 mg, 0.10 mmol), and N-ethyl-N isopropylpropan-2-amine (78 mg, 0.6 mmol) in anhydrous NN-dimnethyformamide (2 ml) was added HATU (2-(7-Aza--IH-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (58 m, 0.15 mmol) at 0°C, the resulting mixture was allowed to warm to room temperature and stirred at room temperature for 20 min. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by prep. HPLC to afford N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyil)-6-(4-(I-(2-(((2S) 1-((4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)pienyl)ethvl)carbamoyl)pyrrolidin-1-yI) 3.3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethyl)azetidin-3-yl)piperazin-1-yl)nicotinamide (15 mg, yield 13.6%, over 2 steps) as white solid. LCMS: (ES'):m/z 1007.5 [M+HI. tR 2.397 min. 'H NMR (400 MHz, CD 30D): 6 0.93, 0.95 (two singles, 9H), 1.12(s, 6H), 1.18 (s, 6H),1.41 1.48 (m, 3H), 1.85-1.94 (in, 2H1), 2.07-2.11 (, 1), 2.22-2.33 (m, 1H), 2.34-2.38 (m,6), 3.01 3.14 (in, 3H), 3.17-3.19 (m,2H), 3.55-3.66 (m,6H), 3.71-3.76 (m, 1H), 4.014.06 (m, 1H), 4.18 (s, 1F), 4.31-4.37 (m, 1H),4.47-4.54 (in, 211), 4.88-4.92 (m, 1H), 6.74 (d,,J= 8.8 Hz, 1H), 6.88 (dd, J= 2.4, 8.8 Hz, 1H), 7.03 (d,J= '2.4 Hz, IH), 7.27-7.36 (m,4H). 7.62 (d, J= 8.8 Hz, 1H),
7.87 (dd,J = 2.0, 9.2 Hz, 1H), 8.51 (d. J= 2.0 Hz,IH), 8.77 (s, H). Chemical Formula:
CH67ClNo00 6S; Molecular Weight: 1007.68.
[08021 Synthesis of Example 795:
0 NaBHCN J Cbh, CH- COOH PN- - .. Cbz'N'\~l N NC CzNP/C. H2: H N: O TA N N' . N O MeOH DMSO N 0
OH N 0 0,
N'N\ OH N N'\ O ' N N 0 2) ANIB26 NN H H
Exanmle795
N H
10803] Step 1:Synthesisofbenzyl3-(4-(2-tert-btoxy-2-oxoethyi)piperazin-1-vl'azetidine-1 carboxylate.
Cbz,
N 0 NO'
10804] To a stirred solution of benzyl3-oxoazetidine-1-carboxylate (300 mg, 1.46 mmol), tert butvl2-(piperazin-1-yl)acetate (307mg, 1.53 mmol) and acetic acid glacial (1 d) in methanol (4 ml) was added sodium cyanoborohydride (276 mg, 4.39 mmol) at room temperature. The mixture was stirred at room temperature for 1.5 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The organic layer was collected, washed with brine (25 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 20-30 % ethyl acetate in hexane) to afford benzyl 3-( 4 -(2-tert butoxy-2-oxoethyl)piperazin-iyl)azetidine-1-carboxylate (145 mg, yield 25%) as white solid. 1H
NMR (400 MHz, CDCis): 6 1.46 (s, 9H). 2.43 (br 4H).2.62 (br, 4H), 3.11 (s.211), 3.13-3.18 (in, 111), 3.87-3.90 (in, 2), 3.99-4.03 (in,21), 5.08 (s, 21), 7.30-7.35 (in, 51). Chemical Formula:
C 2 1 3,N30 4 ;Molecular Weight: 389.49.
[08051 Step 2: Synthesis of tert-butyl2-(4-(azetidin-3-yl)piperazin-I-y)acetate.
H-N) N 0 N O
[08061 A mixture of benzyl3-(4-(2-tert-butoxy-2-oxoethyl)piperazin-1-yl)azetidine-1 carboxylate (145 mg, 0.37 mmol) and palladium hydroxide on carbon (10%, 15 mg) in ethanol (5 ml) was stirred at room temperature overnight under hydrogen atmosphere (hydrogen balloon). TLC showed the reaction was complete. Palladium on carbon was removed through filtration and washed with methanol (5 ml x2). The combined filtrates were concentrated under reduced pressure to give tert-butyl 2-(4-(azetidin-3-yi)piperazin-1-yl)acetate (85 ig, yield 89%) as colorless oil which was used in next step directly without further purification. H NMR (400 Muz, CDC 3 ): 6 1.46 (s. 911), 2.40 (br,411), 2.60 (br, 411), 2.87-2.95 (, 1), 3.09-3.11 (in,211), 3.16-3.27(m, 11-), 3.45-3.50 (in, 111), 3.52-3.56 (in, 1), 3.59-3.63 (in, 1H). Chemical Formula: C13H2 5N 3 0 2 ; Molecular Weight: 255.36.
[0807] Step3: Synthesis of methyl 6-(3-(4-(2-tert-butoxy-2-oxoethyl)piperazin-1-yl)azetidin-1 yl)nicotinate.
N N'
[08081 A mixture of tert-butyl2-(4-(azetidin--3-yl)piperazin-1-yl)acetate (85 mg, 0.33 mmol), methyl 6-fluoronicotinate (103 mg, 0.66 mmol) and triethylamine (135 mg. 1.33 mmol) in dimethyl sulfoxide (2 ml) was stirred at II0°C for 5 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (20 ml) and water(10 m). The organic layer was collected, washed with brine (10 ml). dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 5 % methanol in dichloromethane) to afford methyl 6-(3-(4-(2 tert-butoxy-2-oxoethyl)piperazin-I-yl)azetidin-1-yl)nicotinate (63 mg, yield 48%) as yellow solid. LCMS: (ES'): m/z 391.2 [M+H]*. tR - 1.532 min. H NMR (400 MHz, CDCl 3):6 1.46 (s. 9H), 2.52 (br, 41), 2.64 (br, 411), 3.12 (s, 2H), 3.33-3.40 (, 11), 3.86 (s, 31-1), 3.95-3.99 (n, 2H), 4.13-4.17 (in, 2H), 6.21 (d,,J= 8.8 Hz, 1H), 7.97-7.80 (m, iH), 8.76--877 (m, 1H). Chemical
Formula: C2 0 H3N 404; Molecular Weight: 390.48.
[0809] Step 4: Synthesis of methyl 6-(3-(4-(2-((2S)--((4R)-4-hydroxy-2-((S)-I-(4-(4 methyltlhiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-I-yl)-3,3-dimethyl-I-oxobutan-2-ylamino) 2-oxoethyl)piperazin-1-yl)azetidin-1-yI)nicotinate.
0
N 0 N N N
HN S
10810] A mixture of methyl 6-(3-(4-(2-ert-butoxy-2-oxoethyl)piperazin-I-yl)azetidin-I yl)nicotinate (63 mg, 0.16 mmol) and 2,2,2-trifluoroacetic acid (1 ml) in dichloromethane (1 ml) was stirred at room temperature for 2 hour. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up in anhydrous N,N dimethylformiamide (2 ml), followed by sequentially addition of (2S,4R)-1-((S)-2-amino-3,3 dimethylbutanoyl)-4-hydroxy-N-((S)-I-(4-(4-methylithiazol-5-yl)phenyl)ethyl)pyrrolidine-2 carboxamide hydrochloride (78 mg, 0.16mmol), N-ethyl-N-isopropylpropan--2-amine (104 mg, 0.80 mmol), and HATU (2-(7-Aza-IH-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (184 mg, 0.48 mmol) at 0°C, the resulting mixture was allowed to warm up to room temperature and stirred for 1 hour. LCMS showed formation of desired product. The reaction mixture was partitioned between ethyl acetate (40 ml) and water (20 ml). The organic layer was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography elutedd with 10% methanol in dichloromethane-1% ammonium hydroxide) to afford methyl 6-(3-(4-(2-((2S)-I-((4R)-4-hydroxy-2-((S)-I-(4-(4-methylthiazol-5 yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yi)-3,3-dimethyl-1-oxobutan-2-ylamino)-2 oxoethyl)piperazin-1-yl)azetidin-1-yl)nicotinate (88mg, yield 72%)as yellow solid. LCMS: (ES'): m/z 761.4 [M+H]. tR = 1.893 min. H NMR (400 MIHz, CDCI):6 1.07 (s, 9H), 1.48 (d,J 6.8 Hz, 3H). 1.99-2.11 (m, 2H), 2.50 (br, 4H), 2.54 (s, 3H), 2.63 (br, 4H), 3.01-3.10 (m, 2H), 3.35-3.40 (m, 11-1), 3.49 (s, 11-1), 3.57-3.61 (i, 1H), 3.87 (s, 311). 3.95-3.99 (m, 2H1, 4.15-4.20 (n 3H), 4.45 (d, = 8.4 Hz,I H), 4.51 (br, I H), 4.76 (t, J= 7.6 Hz 1H), 5.04-5.12 (in, I H), 5.22 (d,J 8.8 Hz, 111), 7.36-7.42 (m, 5H). 7.80-7.83 (m,1H), 7.99-8.01 (m, 1-1), 8.68 (s, 1-1), 8.76-8.77 (m, 11-). Chemical Formula: C39 H52 NsO 6S; Molecular Weight: 760.95.
[0811] Step 5: Synthesis of N-((r,3r)-3-(3-chloro-4-cyanophenoxy)-2,,4,4 tetramethylcyclobutyl)-6-(3-(4-(2-((2S)-1-((4R)-4-hvdroxy-..-((S)-1-(4-(4-methylthiazol-5 yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl--oxobutan-2-ylamino)-2 oxoethyl)piperazin-1-yl)azetidin-1-yl)nicotinaiide.
Cl O", 0
NC N N\OH N 0 N N HN I-IN
S
108121] A mixture of methyl 6-(3-(4-(2-((2S)-1-((4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazol-5 yl)phenyi)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-I-oxobutan-2-ylamino)-2 oxoethyl)piperazin-1-yl)azetidin-1-yl)nicotinate(88 mg. 0.12 mmol) and lithium hydroxide monohydrate (10 mg, 0.24 mmol) in tetrahydrofuran (2 ml)-water (0.5 ml)-methanol (0. 5 ml) was stirred at room temperature overnight. TLC showed the reaction was complete. The mixture solution acidified with diluted hydrochloride acid (3N) till pH 5-6. The volatiles were evaporated under reduced pressure.'The residue was taken up in N,N-dimethyiformamide (1 ml), followed by sequentally addition of 4-((1r,3r)-3-amino-2,2,4,4-etramethylcyclobutoxy)-2-chiorobenzonitrile hydrochloride (36 mg, 0.11 mmol), N-ethil-N-isopropylpropan-2-amine (75 mg, 0.58 mmol), and HATU (2-(7-Aza-I1H-benzotriazole-I-y1)-1,1,3,3-tetramethyluronium hexafluorophosphate) (132 mg, 0.35 mmol) at 0°C, the resulting mixture was allowed to warm up to room temperature and stirred at room temperature for 30 minutes. LCMS showed formation of desired product. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was collected, washed with brine (10 ml). dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by pre-HPLC to affordN-((r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(4-(2-((2S)-1 ((4R)-4-hydroxy-2-((S)-I-(4-(4-methylithiazol-5-yl)phenyil)ethylcarbamoy)pyrroIidin-1i-yl)-3,3 dimethyl-1-oxobutan-2-yilamino)-2-oxoethyl)piperazin-1-yl)azetidin-1-yl)nicotinamide (17.2 mg, yield 15%) as white solid. LCMS: (ES): m/z 1007.4 [M+H]. R= 2.365 min. 1H NMR (400 MHz, CD3 0D):6 0.93, 0.95 (two singles, 911), 1.12 (s, 6H), 1.18 (s, 611), 1.41-1.48 (in, 311), 1.82 1.88 (m, 1H), 2.07-2.14 (m, 1H). 2.38 (s, 3H). 2.50-2.59 (in, 8H), 3.03 (s, 2H), 3.32-3.35 (m, 1H),
3.63-3.67 (in, 1H), 3.75-3.77 (m. 1H), 3.86-3.89 (m, 2H). 4.03-4.05 (m, 1H), 4.09-4.12 (m 2H). 4.18 (s. 1),,4.34 (br, 1H), 4.45-4.49 (m, IH), 4.54 (s, IH), 4.90-4.93 (m, H), 6.36 (d, J= 8.8 Hz, 1H), 6.87--6.90 (m, 1H), 7.02-7.03 (m, 1H), 7.27--7.36 (m, 4H), 7.58--7.63 (mn, 2H), 7.86-.7.88 (in, 1H), 8.11 (br, 1H), 8.44 (s, 1H), 8.50 (d, J= 7.6 Hz, 1H), 8.78 (s, 1H). Chemical Formula: CHi67CN 1oOS; Molecular Weight: 1007.68.
[08131 Unless otherwise noted, Examples 796-808 were synthesized according to similar procedures described above for the synthesis of Examples 794 and 795, by utilizing corresponding starting materials and reagents.
[08141 Table21: Additional ExemplaryCompounds.
Measured Mass ion Data Ex Structure Compund Name m/z(1) 1/ (2) ek, n N-((1r,3r)-3-(3-chloro-4 N cyanophenoxy)-2,2,4,4 N H tetramethylcydobutyl)-6-(4 N H (1-(2-(((S)-1-((2S,4R)-4 ? hydroxy-2-(((S)-1-(4-(4 N 0 ~methylthiazol-5-. 794 HI yl)phenyl)ethyl)carbamoyl)py 1007.5 1009.4 rrolidin-1-yl)-3,3-dimnethyl-1 oxobutan-2-yl)amino)-2 OXcethyl)azetidin-3 yl~piperazin-1 yI)nicotinamide
ci o-/ n N-((1r,3r)-3-(3-chloro-4 N yanophenoxv)-2,2,4,4 N HN NW Htetramethylcyclobutyl)-6-(3 (4-(2-(((S)-1-((2S,4R)-4 N N hydroxy-2-(((S)-1-(4-(4 methylthiazol-5- 1007.4 7 yl)phenyl)ethyl)carbarnoyl)py rrolidini-1-yl)-3,3-dimet-hyl-1 oxobutan-2-yl)amino)-2 oxoethyl)piperazin-1 Ny2)azetidin-1-yl)nicotinamide
(2S,4R)-1-((S)-2-(3-(4-(3-(4 H (((lrr)-3-(3-chloro-4 oHcyanophenoxy)-2,2,49.4 -~N tet ra methyl cycI ob Utylca rba NH moyl)phenvl)propyl)pi perazi 994 914 N , n- 1-y!)isoxazol-5y)3 -c\ I myethylbutarncyl)--4-hydroxy- N-((S)-l-(4-(4-mnethylthiazoi! N 5-yI)phenyl)ethyl)pyrrolidine 2-carboxamide (2S,4R)-1-((R)-2--(3-(4-(3-(4 H N (((1r,3r)-3-(3-chloro-4 N ~~~OH cyanophenoxy)-2244 JN, tN ra methyl cycI ob Utylca rba 797 ~~moyl)phenvl)propyl)piperaz 8. 914 NH --1-yi)isoxazo-5--y)-3 methylbUtany')-4-hydroxy N-((S)4l-(4-(4-rnetLhylthiazoi' N N 5-yI)phenyl)ethyl)pyrrolidine 2-carboxamide
[0815] 1able 22: Exemplary Compounds
IMeasured Ex.Mass Ion Data Structure Compound Name /i r/ () (2) N- ((ir,3R)-3-(3-chloro-4
X, ~ ~6-((IR4R)-5-(5-((S) y\" ((2S'4R-j-hyuroxy-2IwJ.S)
798 ~yl) p hc'nyl)ethyl) ca rba m yl) 909 92 Sdimetrhy-1-oxobutdn-2
2,5 ndiazabicyclo[2.2.1 ]heptan 2-yI)nicotinamnide
cya n ophe noxv)-2,24,4 tetrarm ethyl cy o b utyfl6
'~ ~((2SAR)-4-hydroxV'2-(((S)- 1030. oc *(4(-meth)yithiazol-54 pyrrolidin-1.-yI)-3,3 dinnethyl-i-oxobutpn-2 yi)ami!no)-5 oxopenty!)piperazin1l yi~nicotinarnide
N-f(lr,3r)-3-(3-chlor-4 cyanophenoxy)-2,24.4 tetra methylcycl bUtyI-6 (4-(2,2-d ifIu oro- 5-(SI ((2S,4R)-4-hydroxy2-((P) "N- ~ ~ ~ 22hydroxy-1l-(4--(4- 06 08 800 methylthiazo-5 1Yl')plhenyl)ethyl)carbarnoy)
li dh-,ethy-t-OXObUtan-2 y~aio-5 oxopentyi~piperazin1l ______ ________________________________________________yl~nicotinannide ____ ____
chloro--4-cyanophenoxy) 2,2,4,4 tetra methylcycl!obUtyl)ca rb arnoyl)phenyl)propy 25 801o'l', diaza)bicycl[221']Ieplan 105 1007. 4 2-yI)acetam.-.ido)-3,3
hyd.oxV-N-((S)-1l-(4(4 '. rnethylthiazol-5 yI)phenyl)ethyl)pyrroldno -2-carboxarnide
(2S,4R)-i_-((2S)-2-(2(3-(3 (4-(((i-r,3r)-34(3-choro-4 H ~ ~~cya n ophe noxy)-2,24,4 't tetrarmeit:hylcyc~iobuiyI)carb Provi) m' phenyl) pro py)3,8 Sdiazabicyclo[3.2.3:]octan-8 y 10a cet arn ido) -3,3 dihylbuta-Nol)-(-4 rnethylthiazol-5- 1019ig 802 "7~ y')pheny)ethy)pyr~n 1021.4 4 * -2-carboxarnide
N-((1r,3r)-3- (3-c h Ioro-4 cyanophenoxy)--2,2,4,4 tetlrame.it:hylcyc~iobulyl)o6 (4-(3-(4-(((S)-1-((2S4R)-4 hydroxy-2-(((S)-1-(4-(4 N7 "' ~ rnethylthiazol-5 803 y!p h en y1) e t:hy1)car b am oy1) *0 1037 x~t, pyrrolidin-l-vI)-3,3 ddirethyl-1-oxo buta n-2. yl)arnino)-4 oxobutyl~oxetan-3 yipiperazin-1 _____ _____________________________________________yi~cotinarnicle_________ N-(flr,3r)-3-(3-chlroa4 cvanophenoxy)-2,24,4 tetlrame.it:hylcyc:'obulyI)o6 (4-(4-(4-(2-(((S)-I--((2S,4R) 4-hydroxy-2-(((S)-1-(4-(4 Srnethylthiazol-5- 19 804 "" Iy)phenyl)ethyI)carbamoyl) 1094.5 pyrrolidin-1-yI)-3,3- 6 d~ im ethyl- 1-oxo but n-2
oxoethyl)piperazifl-3 y!)butyl)piperazin-1 _____ _____________________________________________yoi~cotinarnicle_________
4 23
N-f(lr,3r)-3-(3-chlor-4 cyanophenox)2,2,44 ltetrarnethylcyc'l outyI)-6
~~"\\((2S,4R)-4-hydroxy-2-((S)
Syi )p.hIery)ethy)cabarnoy) pyrrolidin-1-yI)-3,3 85dimethyl-1-oxobutan-2 1108. yl)arnino)-2- 7 axaethyl)piperazin 1yI)ethoxy)ethyl)piperazin LyI)nicotinarnide
(((Ilr,3r)-3-(3-chloro4 cya nopherioxy)-2,24,4 t c1:ramr.e t:hyIcy c:Io buty1) carb
806 ~' \ ~ -zir '.yI)aceta!m-ido)3, 1007.5 'Ndirnethylbutanoyl)-4
- y hd roxy- N(S)1.4- (4 methylthiazol-5
yI)p.heny)ethy)pyrrodne -2-carbxamide (2S,4R)-I-((S)-2-(2
3-(3-chioro-4 cyanophenoxv)-2,2,4,4 tetrarm ethyl cy o b utyl) ca rb ~irayIpheyI~rap)25 1005. 807 d dia z ab ic y cIo[ 2.2. 1] hep t an -1007.4 2-vI)acetamido)-3,3 N - Ntyluta oyl-N
hydroxy-N((S)I-(4-(4
yi)phenyl)ethyl) pyrroldne -2-car'boxarnide
4/24
(2S,4R)-i--((2S)-2-(2-(8-(3
(4-(((ir,3r)-3-(3-choro-4
cyanophenoxy)-2,24,4
tetlrarmeit:hylcyc~iobuiyl)carb
arnovI)phenyl)propyIj 3,8
d iaz ab icyc I o[3.2.1jo cta n -3
yI)acetarnido)-3,3 dhmethylbutanoyjl)e
808 , rnet-hylthiazol-5- 1019. 12) yli)phenyl)et:hyl)pyrold ne J
-2-carboxarnide
[08161 Synthesisof Example 809:
4 25
O HN NE10iH HINO Br OBn NH ----- 0~~- N.O H N 1---NI
Boc);-N -O KZ-025-F-1 - OBn - OBn C -N Boc-N N N dioxane/HCI HN\/\*N NP NaB1H3CN \-/--- DIPEA, NMP, 800 C
G N/ N N\N-\- N/ N ULM-3 ______-N OH-,IN ----- 0 N-- N HATU, DIPEA, DIF 110 HO
60 /0 C) / ~NH OlIN L0H-H 2 OHO0 -H )I
- N
s" HO NC
\I N
ABM-26 0 NII /NH OHN /\\/N N" N
Example 809
S
[0817] Step 1: Synthesis of benzyl 2-(piperazin-I-y)acetate):
HNO 0 OBn
[0818] A mixture of piperazine (5.6 g, 65.4 mmol) and benzyl 2-bromoacetate (5 g, 21.8 mmol) in ethanol (50 ml) was stirred at 45°C for 16 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was collected, washed with brine (30 ml x 2),dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography elutedd with 8% methanol in dichloromethane) to afford benzyl 2-(piperazin-1- yl)acetate (2.5 g, yield 50%) as colorless oil. LCMS: (ES"): m/z 235.4 [M+H]. tR = 1.305 min. 'HNMR (400MHz, CDC3): 2.56 (t, J= 4.8 Hz, 4H), 2.93 (t, J= 5 Hz, 4H), 3.25 (s, 2H) 5.16 (s, 2H), 7.33-7.36 (m, 5H). Chemical Foula: C 13-H 8 N 2 0 2 ; MolecularWeight:234.29.
[08191 Step 2. Synthesis of tert-butyl 6-(4-(2-(benzyloxy)-2-oxoethyl)piperazin-1-y)-2 azaspiro[3.3lheptane-2-carboxylate.
0 OBn Boc-N N N
[0820] A mixture of ter-butyl 6-xo-2-azaspiro[3.3]heptane-2-carboxylate (450 mg, 2.1 mmol), benzyl 2-(piperazin-1-yi)acetate (498 m, 2.1 mmol) and acetic acid (120 mg, 2.0 mrnol) in methanol (15 ml) was stirred at room temperature for 30 minutes, followed by addition of sodium cyanoborohydride (256 mg. 4.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 ml), washed with water (10 ml x 2), brine (10 ml) and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 3-5 % methanol in dichloromethane) to afford tert-butyl 6-(4-(2 (benzyloxy)-2-oxoethyl)piperazin-I-yl)-2-azaspiro(3.3]heptane-2-carboxylate (570 mg, yield 62%) as white solid. LCMS: (ES"): m/z 430.7 [M+H]*. tR =1.917 min. I HNMR (400 MVHz, CDC 3 ): 6 1.42 (s, 9H), 2.07-2.12 (m, 2H), 2.27-2.30 (m, 211), 2.64-2.68 (in,51), 2.89-2.90 (m, 4H), 3.27 (s, 2H), 3.81 (s. 2H), 3.92 (s, 2H), 5.16 (s, 2H), 7.32-7.37 (m, 5H). Chemical Formula: C 2 4 Hs5N 3 0 4 ; Molecular Weight: 429.55.
[0821] Step 3: Synthesis of benzyl 2-(4-(2-azaspiro[3.3heptan-6-yl)piperazin-1-y)acetate hydrochloride:
HCl 0 -x OBn IN N N
[0822] A solution of tert-butyl6-(4-(2-(benzyloxy)-2-oxoethyl)piperazin-1-yl)-2- azaspiro[3.3]heptane-2-carboxyate (570 mg, 1.3 nmol) in hydrogen chloride in 14-dioxane (4M. 5 ml) was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The volatiles were removed under reduced pressure to give the benzy 2-(4-(2-azaspiro[3.3]heptan-6 yl)piperazin-1-yl)acetate hydrochloride (400 mg, crude) as white solid which was used in next step without purification. 10823] Step4: Synthesis ofmethyl 6-(6-(4-(2-(benzyloxy)-2-oxoethyli)piperazin-i-yl)-2 azaspiro[3.3]heptan-2-yl)nicotinate.
N N OBn 0 N
[08241 A mixture of benzyl2-(4-(2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)acetate hydrochloride (400 mg, crude), methyl 6-fluoronicotinate (170 mg, 1 mmol) and N-ethyl-N isopropylpropan-2-amine (282 mg, 2.2 mmol) in dry 1-methyl-2-pyrrolidinone (8 ml) was stirred at 80°C for 16 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (30 ml). The organic layer was collected, washed with brine (10 ml x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 0-8% methanol in dichloromethane) to afford methyl 6-(6-(4-(2-(benzyloxy)-2 oxoethvl)piperazin-1-v)-2-azaspiro(3.3]heptan-2-yl)icotinate (120 mg, yield 23%) as white solid. LCMS: (ES):m/z 465.4 [M+H]*. t = 1.747 min. 'HNMR (400 MHz, CDCis): 6 2.11 2.16 (in, 21), 2.37-2.41 (in, 511), 2.62-2.71 (in, 5), 3.27 (s,21H), 3.86 (s, 3), 4.01 (s,2H]), 4.12 (s, 2H), 5.16 (s. 2H), 6.17 (d,,J= 9.2 Hz, 1H), 7.32-7.36 (in, 6H), 7.96-7.98 (m, 1H), 8.75 (d, J= 2.0 Hz, 1H). Chemical Formula: C 2H 3 2N 4 04; Molecular Weight: 464.56.
[08251 Step;: Synthesisof2-(4-(2-(5-(methoxycaronyl)pyridin-2-yl)-2-azaspiro[3.3]heptan-6
yl)piperazin-1-yl)acetic acid. 0 -O '// N N OH N N SN
[0826] A mixtureofmethyl6-(6-(4-(2-(benzyloxy)-2-oxoethyl)piperazin-1-yl)-2 azaspiro[3.3]heptan-2-yl)nicotinate (120 mg, 0.26 mmol) and palladium on carbon (10%, 10 mg) in methanol (10 ml) was stirred at 40°C for 2 hours under hydrogen atmosphere (hydrogen balloon). TLC showed the reaction was complete. Palladium on carbon was removed through filtration and washed with methanol (10 ml x 2). The filtrate was concentrated under reduced pressure to give 2-(4-(2-(5-(methoxycarbonyl)pyridin-2-yl)-2-azaspiro[3.3]heptan-6-yl)piperazin 1-yl)acetic acid (70 mg, crude) as colorless oil which was used in next step without purification. LCMS: (ES'):m/z 375.2 [M+H]*. tp = 0.975 min. Chemical Formula: C 19H2 6 N4 0 Molecular Weight: 374.43.
[08271 Step6: Synthesis of methyl 6-(6-(4-(2-((S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4 methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3.3-dimethyl-1-oxobutan-2-ylamino) 2-oxoethyl)piperazin-I-yl)-2-azaspiro[3.3]heptan-2-il)nicotinate:
OI N / 0 0 NH O HN\
S\
[08281 Toastirredsolutionof 2-(4-(2-(5-(methoxycarbonyl)pyridin-2-yl)-2-azaspiro[3.3]hepan 6-vl)piperazin-1-y)acetic acid (70 mg, crude), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4 hydroxy-N-((S)-1-(4-(4-rnethyilthiazol-5-yl)phenyi)ethyl)pyrrolidine-2-carboxamide hydrochloride (83 mg. 0.18 mmol), and N-ethyl-N-isopropylpropan-2-amine (69 mg, 0.54 mmol) in anhydrous NN-dimethyformamide (3 nl) was added HATU (2-(7-Aza-1H--benzotriazole-1 yl)-I,1,3,3-tetramethyIuronium hexafluorophosphate) (102 mg, 0.27 mmol) at 0°C, the resulting mixture was allowed to warm to room temperature and stirred at room temperature for 20 mins. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (15 ml x 2). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 8 % methanol in dichloromethane) to afford methyl 6-(6-(4-(2-(.(S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4 methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan--ylamino) 2-oxoethyl)piperazin-1-yl)-2-azaspiro[3.3]hepta-2-yl)nicotinate (110 mg, yield 74%) as white solid. LCMS: (ES): m/z 801.4 [M+H]*. ta = 1.912 min. 'HNMR (400 MHz, CDClI): 6 1.09 (s, 911), 1.50 (d, J= 7.2 H z, 3[), 2.01-2.04 (m,2H), 2.10-2.18 (m, 311),2.24 (t,J7.6Hz, 1H), 2.40-2.44 (m 3H),2.55 (s. 3H),2.60-2.62 (Im, 3H), 2.74 (t,,J= 7.8 Hz, 1H), 3.05 (d,,J= 6.0 Hz, 1H), 3.58-3.62 (m, 1H), 3.88 (s, 3H), 4.03 (s, 2H), 4.13-4.17 (m, 3H), 4.23 (d, J= 11 .6 Hz, H), 4.45-4.53 (in, 2H), 4.78 (t, J= 7.8 Hz, 1H), 5.10 (t,J= 7.2 Hz, 1H), 5.37 (t, J= 4.8 Hz, 1H), 6.20
(d,,J= 8.8 Hz, 1[), 7.38-7.44 (m 4H), 7.85 (d,J= 8.4 Hz,1H), 7.98-8.01 (m, 1H), 8.69 (s, 1H), 8.77 (s. 111). Chemical Formula:C 42Hs6 NsO 6S; Molecular Weight: 801.01.
[0829] Step7: Synthesis of ((6--(4-(2-.(()-1-((2S,4R)-4-hydroxy-2-.((S)-1-(4-(4-methylthiazol 5-yl)phenyil)ethylcarbamoyl)pyrroidin-i-yl)-3.3-dimethyl-1-oxobutan-2-ylamino)-2 oxoethylpiperazin-1-y)-2-azaspiro(3.3]heptan-2-yl)nicotinic acid: HO
N 00
[-10 XNH f -1 N a_ ~N\ N N 0 N
10830] A mixture of methyl 6-(6-(4-(2-((S)--((2S,4R)-4-hydroxy-2-((S)-i-(4-(4-methylthiazol 5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-2 oxoethyli)piperazin-i-yl)-2-azaspiro[3.3]heptan-2-yl)nicotinate (110 mg. crude) and lithium hydroxide monohydrate (30 mg, 0.55 mmol) in tetrahydrofuran (4 ml)-water (1 ml)-methanol (1 ml) was stirred at room temperature for 16 hours. TLC showed the reaction was complete. The mixture solution was acidified with diluted hydrochloride acid (3N) till p-I 3-4, and extracted with dichloromethane (10 ml x 2). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give the 6-(6-(4-(2-((S)-1- ((2S,4R)-4-hydroxy-2-((.S-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamnoyl)pyrroiidin-1-y) 3,3-diiethyl-1-oxobutan-2-ylamino)-2-oxoethyli)piperazin-1-yl)-2-azaspiro[3.3]heptan-2 yl)nicotinic acid (100 mg. crude) as white solid which was used in next step without purification. LCMS: (ES"): mlz 787.5 [M+H], tR = 1.773 min. Chemical Formula: C 41 H5 4 N8 0 6 S; Molecular Weight: 786.98.
[0831] Step 8: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2 ,2,4,4 tetramethvlcyclobutyl)-6-(6-(4-(2-((S)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methyltiiazol-5 yl)phenyl)ethyilcarbamoyl)pyrrolidin-1-yi)-3.3-dimethyl-1-oxobutan-2-ylamino)-2 oxoethyl)piperazin-I-yl)-2-azaspiro[3.3]heptan-2-yl)nicotinamide.
HO N:C
Cl N
0 NH -- -- -NH OHN N\N N 0 -N
N 108321] To a stirred solutionof 6-(6-(4-(2-((S)--((2S,4R)-4-hydroxy-2-((S)--(4-(4 methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-l-yi)-3,3-dimethyl-1-oxobutan-2-ylamino) 2-oxoethyl)piperazin-1-yl)-2-azaspiro[3.3]heptan-2-yl)nicotinic acid (100 mg, crude), 4-((r,3r) 3-amino-,2,4,4-tetramethylcyciobutoxy)-2-chlorobenzonitrile hydrochloride (44 mg, 0.14 mmol), and N-ethyli-N-isopropylpropan-2-amine (72 mg. 0.56 mmol) in anhydrous N,N dimethyifornamide (3 ml) was added HATU (2-(7-Aza-1-1-benzotriazole-1-yi)-1,1,3,3 tetramethyluronium hexafluorophosphate) (79 mg, 0.21 mmol) at 0°C, the resulting mixture was allowed to war to room temperature and stirred for 20 min. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (15 ml x 2). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 8 % methanol in dichloromethane) to afford N ((lr,3r)-3-(3--chioro-4-cyanophenoxy)-2,2,4.4-tetramethyicyclobutyl)-6-(6-(4-(2-((S)-1-((2SAR) 4-hydroxy-2-((S)-1-(4-(4-methylthiazol-5-yi)phenyi)ethylcarbamoyi)pyrrolidin-1-yl)-3,3 dimethyl-1-oxobutan-2-ylamino)-2-oxoethyi)piperazin-1-yl)-2-azaspiro[3.3]heptan-2 yl)nicotinamide (52.5 rg, yield 37%, two steps) as white solid. LCMS: (ES"): m/z 1047.5
[M+H]I .tR 2.385min. 'I-INMR (400MH, CD30D):61.07(s, 9H),1.23(s, 6H),1.30 (s,611), 1.53-1.60 (m, 3H), 1.93-1.99 (m. 1H), 2.22-2.27 (in, IH), 2.49-2.63 (m, 9H), 2.72-3.03 (,in. 8H), 3.19-3.26 (in, 21), 3.48-3.64 (m, 11-), 3.74-3.78 (in, 1H), 3.87 (d,JI= L2 Hz, 1H), 4.09 (s, 2H), 4.15-4.19 (m,3H), 4.31 (s.1H), 4.46 (br, 1H), 4.59 (t, J= 8.4 Hz, 1H). 4.66 (s, 1H). 5.01-5.04 (in, 11), 6.44 (d J= 8.8 Hz, 111). 6.99-7.02 (i, 111), 7.14 (d,,J= 2.0 Hz, 1H), 7.41-7.46 (m, 4H),
7.74 (d, J= 8.8 Hz, 1H), 7.97-8.00 (in, IH), 8.54 (s, IH), 8.90 (s,IH). Chemical Formula:
C5 6 1-1 7ClNIO0 6S; Molecular Weight: 1047.74.
[0833] Unless otherwise noted, Examples 810-812 were synthesized according to similar procedures described above for the synthesis of Example 809, by utilizing corresponding starting materials and reagents.
[08341 Table 23: Additional Exemplary Compounds
Measured Mass Ion Data Ex. Structure Compound Name mf/z (1)mz(2
N-((1r,3r)-3-(3-chlor-4 cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6 (6-(4-(2-(((S)-1-((2S4R)-4 hydroxy-2-(((S)-1-(4-(4 methylthiazol-5 809 yl)phenyl)ethyl)carbamoyl) 1047.5 1049.4 pyrrolidin-1-yl)-3,3- dimethyl-1-oxobutan-2 yl)amnino)-2 oxoethyI)piperazin-1-yi)-2 azaspiro[3.3]heptan-2 yl)nicotinarnide (2S,4R)-1-(2-(3-(2(S)-1 (((S)-1-(4-(4-(((1r,3S)-3-(3 chloro-4-cyanophenoxy) 2,2,4,4 tetra methylcyclobutyl)carb amoyl)phenyl)piperazin-1 yl)-3- methyl-1-oxobutan-2 yl)a mino)-3-methyl-1 810 1203.3 1205. 3 oxobutan-2 yl)(nethyl)am.ino)ethoxv)is oxazol-5-yi)-3
hydroxy-N-((S)-1-(4-(4 -methylthiazol-5 yl)phenyl)ethyl)pyrrolidine -2-carboxamide
.. ... 1-(2-(3-(2-(4-(2-(2-(4-(3 (3-chloro-4 cyanophenoxV)-2,24,4 tetrarnethyicyclo)buly:)carb ar.mOyI)phenoxy)ethOXy~cyc lohexyl)piperazin-1 yI)ethoxy)isoxazol--.v!)-3. .-. ethyl buta noyl)-4 811 hydroxy-N-(i-(-(4- 11336 1135.6 rnethylthiazoI-5 yl)phenyl)ethy!i)pyrroliirwn "~ ~"-2-carboxamide
N N-(r,3r)-3-(3-chro-4 cy n oph e noxy)-2,24,4 '' tetra methyl!cycl ob u-y)6
hyd roxy-2-(((R)-2T hyd roxy I- (4-(4-m ethy lth iazolS-5 812 ~~yl)phenyl)ethyl)carbamoyl) 114 11. ~ pyrrol din-1--yi)-3,3 . ........ ~~ d im et h y i-1-oxob utan 2 yl)amino)-2 oxoethoxV)ethyl)piperazn i.-yI)nicotinarnide
[0835] Synithesis of Example 813:
N Br INbNCHz
t'Y 0NN P/ r~-- s - o~y NHCbz,-SuO N HN .DCM Cbz,'Pd(dba iBuBF MeOH TEA, KJ DMF tB:uNa Toluene 0 0
0 0
STFA. DCMN 0 2.UIM-3 DIPEA N \ N HATUDMF
N
-- YN~ L iOH THF, MeOH, HOH NN 0[4N N DIPEA. HATL',0MA 2%Af3M-26, 2( '~
Example 813 Nii
[08361 Step 1: Synthesis of (35R)-benzyl 3,5-dimethylpiperazine--carboxylate.
rNH Cbz-N"
[08371 To a stirred solution of (2S,6R)-2,6-dimethylpiperazine (32.7 g,291.4 mmol) in dichloromethane (100 ml) was added benzyl (2.5-dioxopyrrolidin-I-yl) carbonate (I Ig, 43.78 mmol) at 0°C. The reaction mixture was stirred at 0 °C for 1 hour. TLC showed the reaction was complete. The resulting reaction mixture was allowed to warm up to room temperature and partitioned between dichloromethane (50 ml) and water (60 ml); the organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 10-50 % ethyl acetate in hexane) to afford (3S,5R)-benzyl 3,5-dimethylpiperazine-1 carboxylate (6 g, yield 55%) as colorless oil. 1H NMR (400 MHz, CDCI 3 ): 6 1.06 (d, J= 6.0 Hz, 6H), 2.32-2.46 (m, 2H), 2.78-2.80 (m, 2H), 3.95-4.10 (m, 2H), 5.14-5.15 (m, 2H), 7.29-7.38 (m. 5H1-). Chemical Formula: C 1H 20 N 2 O2 ; Molecular Weight: 248.32.
[0838] Step 2: Synthesis of (3S.5R)-benzyl 4-(5-(methoxycarbonyl)pyridin-2-yl)-3,5 dimethylpiperazine-I-carboxylate.
Cbz7
0
[08391 To a stirred solution of (3S,5R)-benzyl 3.5-dimethylpiperazine-1-carboxylate (1.0 g, 4.0 mmol), sodium 2-methylpropan-2-olate (768.8 mg, 8.0 mmol) and methyl 6-bromonicotinate (951.7 mg. 4.4 mmol) in toluene (10 ml) was added tri-tert-butylphosphine tetrafluoroborate (115.6 rg, 0.4 mmol) and Pd 2(dba)3 (Tris(dibenzyideneacetone)dipalladium) (366.3 rg 0.4 mmol) at room temperature under nitrogen atmosphere; the mixture was degassed with nitrogen three times. The reaction mixture was stirred at 100°C for 2 hours. TLC showed the reaction was complete. The resulting reaction mixture was cooled to room temperature and partitioned between ethyl acetate (40 ml) and water (40 ml); the organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 ml x 2).The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate. and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography elutedd with 10-30 % ethyl acetate in hexane) to afford (3S,R)-benzyl4-(5-(methoxycarbonyl)pyridin-2-yl)-3,5. dimethylpiperazine-i-carboxylate (250 mg, yield 16%) as yellow oil. 'H NMR (400 MI-Iz, CDCl3): 6 1.24 (s, 6H), 3.16 (s, 2H), 3.86 (s, 3H), 4.01-4.19 (m 2H), 4.55 (br, 2H), 5.16-5.22 (m, 2H), 6.51 (d,,J= 8.8 iz, 11-1), 7.33-7.39 (i, 51-1). 8.02-8.04 (m, IiH) 8.82 (d, J= 2.0Hz, 1-1). Chemical Formula: C 2 1H2 5N 30 4 ; Molecular Weight: 383.44. LC_MS: (ES+): m/z 384.5[M+H]I.
tR = 2.947 min.
[08401 Step 3: Synthesis ofmethyl 6-((2S,6R)-2,6-dimethylipiperazin-1-yl)nicotinate. *"YNI-I NNH
0
10841] Amixture ofpalladiumon carbon (10%,50mg)and(3S,5R)-benzyl4-(5 (methoxycarbonyil)pyridin-2-yl)-3,5-dimethylpiperazine-I-carboxylate (250 mg, 0.65 mnol) in methanol (30 ml) was stirred at 40°C for 1 hour under hydrogen atmosphere (hydrogen balloon). TLC showed the reaction was complete. Palladium on carbon was removed through filtration and washed with methanol (10 ml x2). The combined filtrates were concentrated under reduced pressure to afford inethyl 6-((2S,6R)-2,6-dimethylipiperazin-1-yl)nicotinate (170 mg, crude) as yellow oil which was used in next step directly without further purification.
[08421 Step 4: Synthesis of methyl 6-((2R,6S)-4-(2-(2-(tert-butoxy)--2-oxoethoxy)ethyl)-2,6 dimethylpiperazin-I-yi)nicotinate.
~o
0
[0843] A mixture of methyl 6-((2S,6R)-2,6-dimethvlpiperazin-1-yl)nicotinate (162 mg. 0.65 mmol), tert-butyl 2-(2-(tosyloxy ethoxy)acetate (257.7 mg, 0.78 mmol), triethylamine (131.3 mg, 1.3 mmol) and potassium iodide (10 mg. 0.06 mmol) in NN-dimethylformamide (6 ml) was stirred at 50°C for 12 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (15 ml x 2). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by which was purified by silica gel flash chromatography (eluted with 0-30% ethyl acetate in hexane) to afford methyl 6-((2R,6S)-4-(2(2 (tert-butoxy)-2-oxoethoxy)ethyl)-2,6-dimethylpiperazin-1-yl)nicotinate (250 mg, crude) as yellow oil which was used in next step directly without further purification.
[08441 Step 5: Synthesis of methyl 6-((2R,6S)-4-(2--(-(((2S)--((4R)-4-hydroxy-2-(((S)-1-(4 (4-methythiazol-5-yl)phenyl)ethyi)carbamoyl)pyrrolidin-I-yl)-3,3-dimethyl-I-oxobutan-2 yl)amino)-2-oxoethoxy)ethyi)-2,6-dimethylpiperazin-I-yl)nicotinate.
N N\K. N'
[0845] A mixture of m methyl 6-((2R,6S)-4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)-2,6 dimethylpiperazin-1-yl)nicotinate (200 mg, 0.49 mmol) and 2,2,2-trifluoroacetic acid (2 ml) in dichloromethane (3 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up in dry N,N-dimethylformamide (2 ml), followed by sequential addition of N-ethyl-N isopropylpropan-2-amine (127.4 mg, 0.98 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl) 4-hydroxy-N-((S)-1-(4-(4-methyIthiazol-5-vl)phenyl)ethyl)pyrroidine-2-carboxamide hydrochloride (235 mg, 0.49 mmol), and HATU (2-(7-Aza-1H-benzotriazole-1-yl)-,1,3,3 tetramethyluronium hexafluorophosphate) (279.5 mg, 0.74 mmol) at 0°C, the resulting mixture was allowed to warm up to room temperature and stirred for 10 minutes. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layers was collected, washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 0-5% methanol in dichloromethane) to afford methyl 6-((2R.6S)-4-(2-(2-(((2S)-I-((4R)-4-hydroxy-2-(((S)-I-(4-(4-methvlthiazol-5 yl)phenyi)ethyl)carbamoy)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 oxoethoxy)ethyl)-2,6-dimethylpiperazin-1-yl)nicotinate (180 mg.yield 47%) as yellow solid. 1H NMR(400 MHz, CDOD): 6 1.03-1.09 (in, 911), 1.35-1.38 (in, 6H), 1.51-1.61 (m, 31), 1.95-2.02 (in, 1IH), 2.20-2.25 (m, IH), 2.36-2.39 (in, 2H). 2.50 (s, 3H). 2.72 (t, J = 5.6 Hz, 2[), 2.91-3.02 (in, 2H), 3.72-3.82 (m, 3H), 3.83-4.03 (m, 4H). 4.05-4.17 (m, 2H), 4.37-4.56 (,in. 3H), 4.57-4.62 (m, 111), 4.72 (s, 1H), 5.00-5.03 (i, 111), 6.69-6.73 (m, 1H), 7.40-7.48 (m, 411), 8.00-8.04 (in, 1H), 8.72 (d, -=2.4 Hz, 1H), 8.89 (s, 1H). Chemical Formula: C 4 0 H5 N 7 0 7 S; Molecular Weight: 777.97. LCMS: (ES,): i/z 778.4 [M+-]. tR =2.155 imi.
[0846] Step 6: Synthesis of [N-((r,3R)-3-(3-chloro-4-cyanophenoxy)-2.2,4,4 tetramethylcyclobutyl)-6-((2R,6S)-4-(2-(2-(((2S)-1-((4R)-4-hydroxy-2-(((S)-i-(4-(4 methlvthiazol-5--yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2
yl)aimino)-2-oxoethoxy)ethyl)-2,6-diiethylpiperazin-I-yl)nicotinanide. OH
o N
S
[08471 A mixture of methyl 6-((2R,6S)-4-(2-(2-(((2S)-1-((4R)-4-hydroxy-2-(((S)-1-(4-(4 methylthiazol-5-yl)phenyl)ethyI)carbaioyl)pyrroIidin-I-yl)-3,3-dimethyl-1-oxobutan-2 yl)amino) -2-oxoethoxy)ethyli)-2,6-dimethylpiperazin-1-yl)nicotinate (170 mg, 0.22 mmol) and lithium hydroxide monohydrate (36.7 mg. 0.88 miiol) in tetrahydrofuran (4 nil)-water (1 ml) methanol (1 nil) was stirred at 40°C for 3 hours. TLC showed the reaction was complete. The reaction mixture was acidified with diluted hydrochloride acid (3N) till p1- 3-4 and evaporated
4 37 under reduced pressure. The residue was taken up in dry NN-dimethyformamide (2 ml), followed by sequential addition of N-ethyli-N-isopropylpropan-2-amine (46.7 mg, 0.33 mmol), 4 ((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride (69.4 mg, 022 mmol), and HATU(2-(7-Aza-H-benzotrazole--y)-11,33-tetramethyluronium hexafluorophosphate) (92.5 mg, 0.33 mmol) at 0°C, the resulting mixture was allowed to warm up to room temperature and stirred at room temperature for 10 minutes. TLC showed the reaction was complete. The mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by preparative TLC (eluted with 10% methanol in dichloromethane) to afford N-((lr.3R)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetramethylcyclobutyil)-6-((2R,6S)-4-(2-(2-(((2S)-I-((4R)-4-hydroxy-2 (((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1 oxobutan-2-yl)amino)-2-oxoethoxy)ethyl)-2.6-dimethylpiperazin-1-yl)nicotinamide (100 mg. 44%) as white solid.HNMR (400 MzCD30D): 6 0.94, 0.95 (two singles, 9H), 1.12 (s, 6H), 1.18 (s, 6H), 1.21-1.29 (m, 6H), 1.40-1.48 (m, 3H), 1.87 (s, 1H), 2.07-2.15 (m, 11H) 2.23-2.31 (m, 211), 2.38 (s, 3), 2.60-2.62 (mn,2H), 285 (dJ = 12.8 Hz, 2H), 3.60-3.79 (m, 411), 3.93-4.06 (m, 3H), 4.18 (s, IH), 4.35-4.39 (m, 3H), 4.45-4.52 (m, 1H). 4.60 (s, 1H), 4.88-4.93 (m, iH), 6.59 6.63 (m, 11), 6.88 (dd, J= 8.8, 2.4Hz, 1H), 7.03 (d, J = 2.4 Hz, I), 7.26-7.36 (m, 41H), 7.49 (d, J 8.8 Hz, IH), 7.62 (d, = 8.8 Hz, IH), 7.82 -7.86 (m, IH), 8.47-8.50 (m. 1H), 8.52 (d, J -- 2.4 Hz, 111), 8.77 (s, 1H). Chemical Formula: CL;HoClN 9 07S; Molecular Weight: 1024.71 LCMS: (ES*): m/z 1024.5 M+H]. tR = 2.548 min.
[0848] Unless otherwise noted, Examples 814-824 were synthesized according to similar procedures described above for the synthesis of Example 813, by utilizing corresponding starting materials and reagents. 10849] Table 24: Exemplary Compounds.
Measured Mass Ion Ex Data Structure Compound Name m/z (1) m/z (2) rvanophnoy-2,2,4,4 lrametiylcyclobutyl)-6-.
((4R)-4-hydroxy-2-((fS)-1 (4-(4-methvlthiazoi-5 813 vl y)phenyI)ethyI)carbarnoy 1024.5 102 6.4 l~~rlii--y.33 dimnethyl-1-oxobutan-2 -X YvI)ar-nino)-.2- N. OXOethO)NY)ethyl)-2,6
yi)n'cotinarnide N-(.,r--( -ho o4 cyanophenoxy)-2,2,4,4 tetra methyl cyc o b Utyl)-6 (4-(2-(2-(((S).-I(2S,4R)-4
mnethythiazol-5 814 V, ip heny1)et hy1) ca rbam oy 10417.8 1049.5
di~ty-1-oxobutan-2 y1)arnino)-2-oxoethyl)-2 azaspirol,33I1heptan-6 yl)piperazin yi~nicotinamide N-((lr,3r)-3--(3--chlo,--4- cya n opINe n o y) -2,2,4,4 tetramnnethyl cylo b utyl)-6 (4-(2-(2 -(((S) . -((2 S,4R)-4
mnethythiazol-5 815 I)phenyl)ethyl)carbamoy V~N 1024.4 1026.4
ss dirnethyI-l.oxobutan-2 yI)amino)-2-oxoethoxy) 2- met hylpropyI)piperazin _____ ______________________________________________ iyI)nicotinam.-.ide_________
43~9
(2S,4R)-l-((S)-2-(2 N
((2R,SS)-4-(3-(4-(((lr,3S) 13-3-chloro-4- N. cyanoaphenox)-2,2,4,4 tetram.-.ethylcyci obutyl)ca r ba moyl) phenyi)propyl) ~~~ ~2,5-d im ethyl piperazirv- l- 2[4 03 816 ~~ yiacetamido)-3,3 dirnethylbutanoyl)-4 hydroxy--N-.((S)-l-(4-('4 N ~ ~~mefhyltiaa[5 y!)phenyl)ethyl) pyrrlidin .... .e-2-carboxarnde
N (2S,4R)- 1-((S)-2-(2 ((2S,SR)-4-('3-(4-k(((Ir, 3R) 3-(3-ch or-4 N cyanoaphenoxv)-2,2,4,4 tetramnethylcycl obutyl)ca r bamay!)phenyl)propyl) 2,54dimethylpiperazin- 1214 02 817 .- yVI)acetarnido)-33 d i reth y Ib utan oy )-4 h y droxy- N -((S)-1.4- (4 N methythiazl-5 yi)phenyl)ethyl)pyrrolid!in ..... -2-carhaxarnde
N-((ir,3r)--3-(3-chloro--4 cya nophenoxy)-2,2,4,4 tetram.-.ethylcyci obutyl)-6
hydroxy--2--((kS)-1-('4-(4 . ~methylthiazol-5 yl) ph enyl)ethyl) ca rba rn oy 1) pyrrolidi--1 -y)-3 818 mehlIaaua-- 990 95 992.95 yl)isoxazol-3 1) p ro py1) p ipera z n- I -~' yl)nicotinarnide
IN
44-0
N-(1lr,3r)3(3choro-4 l etramethylcyciobutyl)-6- (4-(3-(,5-((R)-I-((2S,4R)Y4 hyd roxy-2-(((S)- 1-(4- (4 'A' ethylthiazol-5 A'' ip h enyl)e thyl)ca rbarmnay 1) lpyrroHidi n-1I-yi)-3 819~~ methyl- 1-oxo buta n-2- 905 925 wA VI~ '' y)isoxazol-3 yi p rapy1) p ipe ra z;n- VA yi)nicotinamide
(2S4R)-lj-(5Y)2-(2-(4(3 (4-(((i-r,3r)-3-(3-chioro-4 cyanophenoxy)-2,2,4,4 letramnethylcyciobutyl)car barnayl)pheny')propyl)pip 1820 .....- y~aeamid) 1009.5 1011.5 ~ hydroxy-N-((R)-2 hydroxy-1-(4-(4 "' methylthiazol-5 yi)phenyl)ethyl)pyrrolidin e-2-carhaxamide N-((lr,3r)-3-(3-chloro-4 cyariophenoxy)-2,2,.4.4 tet ramnethyl cyc'aob Utyl)-6 ....... (8-(2-(2-(((S)-1-((2S,4.R)-4 hydroxy-2-(((R)--2 ~ >"' 'Athydroxy-J4(4-(4
N' " methyithiazol-5 y'penl Nhyrcrbmo 82 >ly)phyrrldethy-l)carbamoy 1039 1041 d imethylI-oxobUta n-2 "4' yi~amino)-2 oxoethoxy)ethy)- 3,8. diazabicycla[3.2.i.]octan * 3-yI~nicatinamnide
44.1
N-(flr,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 '~LetramethVlcyclobutyl)-6
hydroxy-2-(((R)-2 hvdroxy-l-(4-(4
822 yl)phenvl)ethvl)carbarnov 1026.7 1027.7
... dimethVI-1-oxobutan-2 y!)amino)-2 oxoe-thoxy)e-thyl)-i-,4 diazepan-l ylinncotinarnide
(2S,4R)-l-((S)-2-(2-((R)-4 3 -(.(( r, R - -3
chloro-4--cyanophenoxV)- 2,2,4,4 tetram.-.ethylcyci obutyl)ca r bamoyl)phenyi)propyl)-3 (hydroxyr-nethyl)piperazin 823 -1-yI)acetarnido)-3,3- i0 [025.9 dirnethylbutanoyl)-4 h yd roxy-N -(S) -1- (4 - W methylthiazo.-5 yl)p')enyl)ethyl) pyrro Hdi n e-2-carboxarnide
(2S,4R)-l-((S)-2-(2-((S)-4
chlo.-o-4--cyanophenoxV)- 2,2,4,4 tetra -.ethylcyciobutyl)ca r b am oy1) ph e ny0p ro py1) -3 (hydroxyr-nethyI)piperazin 824 -1-yI)aceta rn ido)-3,3- 103 125 d irnethyl buta noyl)-4 Nhyd roxy--N-.((S) -1- (4- W mnethylthiazo-5 yl)phenyl)ethyl)pyrroid!in e-2-carboxarnde
[08501 Synthesis of Example 825.
4 42
NH N N 3" N1 NN2KEx
NC O c BNc NC TFA, DCM NC
K 2CO3 Nal. CHCN. NH ri,' NH 100°C, 24h C:- C>
Intermediate from example 79
N N 2 BrONO 0 ---- ---- 0'FA' DM Ni D:EA,DOM,,15ph NC N . N ... N C NH rt 12h Nh
04
ULM-3 HN
BOP, DIEA. DMF, , 2h
Example 825
N
[08511 Step 1: Synthesis of tert-butyl414-(5-[[(1r3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylicyclobutyl carbamoyl]pyridin-2-yl)piperazin-1-yl]nethylpiperidine-1-carboxylate.
N NN NH.
NC -~ NH
[08521 Into a 20-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-(piperazin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethvlcyclobutvlpyridine-3-carboxamide (260.0 mg, 0.56 mmol, 1.00 equiv), tert-butyl 4 (bromomethyl)piperidine-1-carboxylate (233.0 mg, 0.84 mmol, 1.50 equiv), CH 3 CN (5 mL), potassium carbonate (230.0 mg, 1.66 mmol, .3.00 equiv), NaI (89.0 mg, 1.00 equiv). The resulting solution was stirred for 24 hours ati 0 °C. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 218.0 mg (59%) of tert-butyl 4-[[4[-(5-[[(r.3r)-3-(3-chloro-4-cyanophenoxy)-2,2,.4,4 tetramethylcvclobutyllcarlamoyl]pyridin-2-yl)piperazin-I-yljmethyl]piperidine-I-carboxylate as a yellow solid. LC-MS (ES+):m/z 66565 [(M-+], t = 1.56 min, (1.9 minute run).
[0853] Step 2: Synthesis of 6-[4-(piperidin-4-ylmethyl)piperazin-1-yi]-N-[(1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetramethylcyclobutyllpyridine-3-carboxarnide.
N NN H TFA 0 N
NH
[0854] Into a50-mLround-bottom flask, was placed tert-butyl 4-[[4-(5-[[(1r,3r)-3-(3-chloro-4 cyanophenoxy)-,2.,4,4-tetramethylcyclobutyl]carbamoyl]pyridin-2-yl)piperazin-1 yli]methylpiperidine-1-carboxylate (218.0 mg,0.33 mmol.1.00equiv),dichioromethane(5rmL), trifluoroacetic acid (2 mL). The resulting solution was stirred for I h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 170.0 mg (92%) of 6-[4 (piperidin-4-ylmethyl)piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4.4 tetramethylcyclobutyl]pyridine-3-carboxamide as yellow oil.
[08551 Step 3:Synthesis of tert-butyl 2-(4-[[4-(5-[[(r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylicyclobutyl]carbamoyl]pyridin-2-yl)piperazin-1-yl]meithyl]piperidin-1-yl)acetate.
NW' 0 N N 0
0 IN NC / NH
C NH
[0856] Into a 50-mL round-bottom flask, was placed 6-[4-(piperidin-4-ylmethyl)piperazin-I-yl] N-[(lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyilcyclobutyI pyridine-3-carboxamide (170.0 mg, 0.30 mmol, 1.00 equiv), dichloromethane (5 mL), DIEA (155.0 mg. 1.20 mmol, 4.00 equiv), tert-butyl 2-bromoacetate (117.0 mg, 0.60 mmol, 2.00 equiv). The resulting solution was stirred for 1.5 h at room temperature. The resulting solution was extracted with dichloromethane and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol
(12:1). The collected fractions were combined and concentrated under vacuum. This resulted in 200.0 mg (98%) of tert-butyl 2-(4--[4-(5-[[(r,r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutylicarbamoyl]pyridin-2-yl)piperazin-1-ylI]methylipiperidin-1-yl)acetate as a yellow solid.
[08571 Step4: Synthesisof 2-(4-[[4-(5-[(ir,3r)-3-(3-chlioro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]carbamoyl]pyridin-2-yl)piperazin-I-yl]methyl]piperidin-1-yl)acetic acid.
N 0 N N OH
NC NH
[0858] Into a 100-mL round-bottom flask, was placed tert-butyl 2-(4-[[4-(5-[[(r,3r)-3-(3-chloro 4-cyanophenoxy)-2.2,4,4-tetramethyicyclobutyl]carbamoyl]pyridin-2-yl)piperazin-I
ylmethyl]piperidin-1-yl)acetate (200.0 mg, 0.29 mmol, 1.00 equiv), dichloromethane (57.7 mL), trifluoroacetic acid (21.4mL). The resulting solution was stirred for I overnight at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 170.0 mg (93%) of 2-(4-[[4-(5- [ [(1r,3r)-3-(3-chioro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]carbamoyl]pyridin-2-yl)piperazin-1-yl]methyl]piperidin-1-yl)acetic acid as yellow oil.
[0859] Step5: Synthesisof 6-(4-[[1-([[(2S)-1-[(2S4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyl-1,3 thiazol-5-yl)phenyil]ethyl]carbamoyl]pyrrolidin-1-yl]-3,3-dimethil-1-oxobutan-2 yl]carbamoyl]methyl)piperidin-4-yli]methyl]piperazin-1-yl). N-[(1r,3r)-3-(3-chioro-4 cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide. OH
rN 0K NNN H N OC 0 N 0HN CN
Example 825 N
[08601 Into a 50-mL round-bottom flask, was placed2-(4-.[[4-(5-[(lr,3r)-3-(3-chioro-4 cyanophenoxy)-2,',4,4-tetramethylcyclobutyl]carbamoyilpyridin-2-yi)piperazin-1 yljmethyl]piperidin-1-yl)acetic acid (170.0mg, 0.27 mmol, 1.00equiv),(2S,4R)-1-[(2S)-2 amino-3,3-dimethylbutanoyll-4-hydroxy-N-[(IS)-1-[4-(4-methyl-1,3-thiazol-5 yl)phenyl]ethyl pyrrolidine-2-carboxamide hydrochloride (131.0 mg, 0.27 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), DIEA (169.0 mg, 1.31 mmol, 4.00 equiv), BoP (145.0 mg, 1.20 equiv). The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the water. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RPI8 OBD Column, 5um,19*150mm; mobile phase, Water(IOMMOL/L NH4HCO3) and ACN (52.0% ACN up to 73.0% in 8 min); Detector, UV 254nm. This resulted in 63.0 mg (22%) of 6-(4-[[I1-([[(2S)-I-[(2S.4R)-4-hydroxy--I-[[(IS)-1-[4-(4-methyl-1,3-thiazol-5 yl)phenyl]ethyl]carbamovl]pyrrolidin-1-yl]-3,3-dimethyl-I-oxobutan-2 yl]carbamoyl]methyl)piperidin-4-yl]methyl]piperazin-I-yl)-N-[(1r,3r)-3-(3-chloro-4 cyaiophenoxy)-2,2,4,4-tetramethylcyclobutyl-pvridine-3-carboxamide as a white solid. H-NMR (400 MHz, CD30D) 58.89 (s, 1H), 8.62 (s, 1H), 7.99-7.96 (in. 1), 7.75-7.73 (d,J=8.4Hz, 1H). 7.49-7.36 (m, 4H), 7.14 (s,1H), 7.01-6.94 (in, 11), 6.85-6.83 (m, 111), 5.05-5.00 (in, 1), 4.62 (s. 1H), 4.60-4.41 (m, 2H), 4.29 (s, 11), 4.11 (s, 1H) 4.89-4.85 (in, 1H) 3.78-3.62 (m, 5H), 3.05- 3.01 (in, 21), 2.94-2.84 (m, 2H), 2.58-2.52 (in, 411) 2.43 (s, 311). 2.20-2.18 (i, 51), 2.00-1.81 (in, 311), 1.70-1.50 (in, 411), 1.38-1.30 (i, 21), 1.28 (s, 611), L22 (s, 611), 1.05 (s, 911); LC-MS (ES+): nz 1050.05 [(MH+]. ti = 1.95 min, (3.0 minute run. Chemical Formula:
C 56 1-173 CN1006S. Molecular Weight: 1048.51.
[08611 Synthesis of Example 829:
OH ~OH0ITsHN 0 -------------- 0 --- TsCl, Et 3 N, DMAP_ I K O , Nal Bn -'n ' BnO NP1001I DMF, '1000,16 h D-,r,11 i Y __NO 10C'61 0 0 0
Nr- -4I N.I12H
r.ND ---- ---- ABM-26 N N C NN--\ HAIU, DIEA _0 Pd/OH 2 --N N 0 MeGH rt 4 h 0~ 0-~\ DMF rt I h OBn OH
N N -\_N~N N-- N_
0 U'~LOH 0~~ . I H NC MeOH, H 2 0, ft, 5h NC NH
NHH H
00
N ULM-3 NO . N!J N.NH
HAIU, DIEA I,! 0 OMErt1hExample 829 Sq
[08621 Step 1: Synthesis ofbenzy 6-[4-(hydrox ethyVi~iperi din-- I1.yl] pyridine--3-carloxylate.
No_" OH
BnO~r::' 0
[08631 Into a100-mL round-bottom flask, was placed benzl 6-choropyidine-3-carboxviate (2.0 & 8.08 niniol, 1.00 equiv), N,N-dinethlformamide("30 n L), piperidin-4-ylmethanoi (927.4 mg, 8.05 mmol, 1.00 equiv), potassium carbonate (3.3g&.23.88rnmoi, 3.00 equiv). The resulting
44.7 solution was stirred for 16 hours at 100°C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (v: v = 1: 1). This resulted in 1.72 g (65%) of benzyl 6-[4-(hydroxymethyl)piperidin--I yl]pyridine-3-carboxylate as colorless oil. LC-MS (ES+): i/z 327.30 [MHI+, tR =1.12 rin (3.0 minute run).
[08641 Step 2: Synthesis of benzyl 6-[4-([[(4-methylbenzene)sulfonyl]oxy]methyl)piperidin-1 vIIpyridine-3 -carboxylate.
B OTs
BnO Y
[0865] Into a 100-mL round-bottom flask, was placed benzyl 6-[4-(hydroxymethy)piperidin-1 yl]pyridine-3-carboxylate (7 g 5.21 mmol, 1.00 equiv), dichloromethane (30 mL), triethylamine (L g, 10.87 mmol, 2.00 equiv), 4-methylbenzene-I-sulfonyl chloride (1.2 g 6.29 mmol, 1.20 equiv), 4-dimethylaminopyridine (190.9 mg, 1.56 mmol, 0.30 equiv). The resulting solution was stirred for 16 hours at room temperature.The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (v: v = 1: 2). This resulted in 1.9 g (76%) of benzyl 6-[4-([[(4 methylbenzene)suifonyl]oxy]methyl)piperidin-1-yI]pyridine-3-carboxylate as a white solid. LC-MS (ES+): rn/z 481.35 [MH], R =2.74 min (5.0 minute run).
[0866] Step 3: Synthesis of benzyl 6--(3-(-(4-(2-ethoxy-2-oxoethyl)piperazin-1 yl)ethyl)pyrrolidin-1-yl)nicotinate.
N N0- - -- NN N/\N N-, I - - N-, "
0 oT 0 ----
OBn
[08671 Into a 100-mL round-bottom flask, was placed benzyl 6-[4-([[(4-methyibenzene) sulfonyl]oxy]methyi)piperidin--yl]pyridine-3--carboxylate (8000mg. 1.66 mmol, 1.00 equiv), N-methyl pyrrolidone (10 mL)potassium carbonate (688.6 mg, 4.98 mrnol, 3.00 equiv), ethyl 2 (piperazin-1-yl)acetate (286.1 mg. 1.66 mmol, 1.00 equiv). The resulting solution was stirred for 16 hours at 120° C in an oil bath. The reaction was then quenched by water (50 mL), extracted with ethyl acetate (50 mLx 3), washed with water (50 mL) and brine (50 mL). The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (9/1). This resulted in 450.0 mg (56%) of benzy 6-(3-(2-(4-(2 ethoxy-2-oxoethil)piperazin-1-yl)ethil)pyrrolidin-1-yl)nicotinate as yellow oil. LC-MS (ES*): mz 481.05 [MH], R =2.54 min (4.6 minute run).
[0868] Step 4: Synthesis of 6-(3-(2-(4-(2-ethoxy-2-oxoethyl)piperazin-1-yl)ethyl)pyrrolidin-1 yl)nicotinic acid.
N N N N--
OH 108691 Into a 100-mL round-bottom flask, was placed benzy 6-(3-(2-(4-(2-ethoxy-2 oxoethyl)piperazin-1-yl)ethyl)pyrrolidin-1-Iy)nicotinate (450.0 mg, 0.94 mmol, 1.00 equiv), methanol (10 mL), palladium carbon (400.0 mg). The flask was then vacuumed and flushed with hydrogen. The reaction mixture was hydrogenated at room temperature for'24 hours under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. This resulted in 320.0 mg (88%) of 6-(3-(2-(4-(2-ethoxy-2-oxoethyl)piperazin-1 yl)ethyl)pyrrolidin--vl)nicotinic acid as yellow oil. LC-MS (ES):n/z 391.10M[II,tR ~^0.64 min (2.0 minute run). 108701 Step 5: Synthesis of ethyl 2-(4-(2-(1-(5-(((r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcycIobutyl)carbamoyi)pyridin-2-yl)pyrrolidin--3--yi)ethyl)piperazin-I--y)acetate.
N N 0 o NC NH
[0871] Into a 50-mL round-bottom flask, was placed 6-(3-(2-(4-(2-ethoxy-2-oxoethyl)piperazin 1-yl)ethyl)pyrrolidin-I-yl)nicotinic acid (200.0 mg, 0.51 mmol, 1.00 equiv), N,N dimethyiformamide (5 mL),2-chloro-4--[(1r,3r)-3-amino--2.2,4,4 tetramethylcyclobutoxy]benzonitrile hydrochloride (161.5 mg, 0.51 mmol, 1.0 equiv), N,N,N,N-Tetrarnethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophospate (292.3 mg, 0.77 mmol, 1.50 equiv), N,N--diisopropylethylamine (198.5 mg, 1.54 mmol, 3.00 equiv).The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by water (30 mL), extracted with 3x30 mL of ethyl acetate (30 mLx 3) washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (v: v = 9: 1). This resulted in 300.0 mg (90%) of ethyl 2-(4-(21-5-(((r3r-3-3-chloro-4-cyanophenoxy)-22,4,4 tetramethylcyclobutyl)carbarnoyl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)piperazin-I-yl)acetate as yellow oil. LC-MS (ES): n/z 651.4 [MH], tR =.09 min (2.0 minute run). 10872] Step 6: Synthesis of 2-(4-(2-(I-(5-(((ir,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)ethyi)piperazin-I-yi)acetic acid.
N N NNC NH
C 0 N'
[0873] Into a 50-mL round-bottom flask, was placed ethyl2-(4-(2-(1-(5-(((r,3r)-3-(3-chloro-4 cyanophenoxy)- 2 ,24,4-tetramethylcyclobutyl)carbamoyl)pyridin-2-yl)pyrrolidin-3 yl)ethyl)piperazin-1-yl) (300.0 mg, 0.46 mmol, 1.00 equiv), methanol (10 mL), water (3 mL), lithium hydroxide (110.6 mg, 4.62 mmol, 10.00 equiv). The resulting solution was stirred for 5 h at room temperature. The pH value of the solution was adjusted to 5-6 with I mol/L hydrogen chloride, concentrated under vacuum. The solids were filtered out. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RPI8 013D Column, 5um,19*150mi; mobile phase, water(10 mmol/L ammonium bicarbonate) and acetonitrile (30.0% acetonitrile up to 55.0% in 8 min); Deector, UV 254nm. This resulted in 150.0 mg (52%) of 2-(4-(2-(1-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)carbarnoyl)pyridin-2-vl)pyrrolidin-3-yl)ethyl)piperazin-1-yl)acetic acid as colorless oil. LC-MS (ES`): m 623.60 [MH*], t =0.97 min (1.9 minute run).
[0874] Step 7: Synthesis of N-((1r.3r)-3-(3-chlor-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6-(3-(2-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol
5-yl)phenyl)ethyl)carbamoyi)pyrrolidin-1-yl)-3,3-dimethyl-I-oxobutan-2-yl)amino)-2 oxoethyl)piperazin-I-yl)ethyl)pyrrolidin-1-vi)nicotinamide. HO
N N - O NH HN NCO NH N
[0875] Into a 25-mL round-bottom flask, was placed2-(4-(2-(1-(5-(((ir.3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetramethvlcvclobutyl)carbamoyl)pyridin-2-yl)pyrrolidin-3 yl)ethyli)piperazin-1-yl)acetic acid (140.0 mg, 0.22 mmol, 1.00 equiv), N,N-dimethylformamide (2 mL), (2S,4R)-1-[(2S)-2-amino-3,3-dirnethylbutanovl]-4-hydroxy-N-[(IS)-1-[4-(4-methyl-1,3 thiazol-5-yl)phenyl]ethylpyrrolidine-2-carboxamide hydrochloride (108.1 mg, 0.22 mmol, 1.00 equiv), N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophospae (128.1 mg, 0.34 mnol, 1.50 equiv), N,N-diisopropylethylamine (87.0 mg, 0.67 nmol, 3.00 equiv). The resulting solution was stirred for I hour at room temperature. T The reaction was then quenched by water (20 mL), extracted with ethyl acetate (20mL x 3) and concentrated under vacuum. The solids were filtered out. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RPI80131) Column, 5um, 19*150imm; mobile phase, water (0mmol/L ammonium bicarbonate) and acetonitrile (48.0% acetonitrile up to 63.0% in 8 min); Detector, UV 254nm. This resulted in 76.6mg (32%) of N-((lr.3r)-3-(3-chloro-4-cyanophenoxy) 2,2,4,4-tetramethylcyclobutyl)-6-(3-(2-(4-(2-(((S)-1-((2S4R)-4-hydroxy-2-(((R)-2.hydroxy-1-(4 (4-methylthiazol-5-yl)phenyl)ethyl)carbamoy)pyrrolidin-I-yi)-3,3-dimethyl-1-oxobutan-2 yl)amino)-2-oxoethyl)piperazin-1-yl)ethyl)pyrrolidin1-yIl)nicotinamide as a white solid. H NMR (300 MHz, CD30D): 6 8.56 (s, IH), 8.55 (s, IH), 7.95-7.92 (in. IH), 7.72 (d, J = 8.7 Hz, 11-1), 7.51-7.37 (i, 41), 7.13-7.12 (m, lH), 7.00-6.96 (in, I H), 6.53 (d, J = 8.7 Hiz, 11-1), 5.02-5.00 (in, IH), 4.67-4.36 (m, 3H), 4.28 (s, 1H), 4.14 (s, IH), 3.90-3.55 (m, 4H).3.50-3.40 (m, IH), 3.20-3.08(in, 311), 2.75-2.44 (Im, 131), 2.40-2.17 (in, 311), 2.00-1.90 (in,1), 1.80-1.68 (m, 311), 1.61-1.48 (in, 3H), 1.28-1.22 (in. 12H), 1.05 (s. 9H); LC-MS (ES-'): mnz 1050.50 [MH*]; HPLC: tR =9.78 min (15.0 minute run). Chemical Formula: C5 6 H73 ClNO 6S. Molecular Weight: 1048.51.
[0876] Unless otherwise noted, Examples 826-832 were synthesized according to similar procedures described above for the synthesis of Examples 825 and 829, by utilizing corresponding starting materials and reagents.
[0877] Table 25: Additional Exemplary Compounds
Measured Mass Ex. Ion Data Structure Compound Name m/z m/zz riz(2) mI N-((1r,3r)-3-(3-choro-4 I cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6 (4-((1--(2-(((S)-1-((2S,4 R)-4 hydroxy-2-(((S)-1-(4-(4 methylth azol-5 yI)phenyI)ethyl)carbamoyI) 825 pyrrolidin-1-yi)-3,3- 1050.05 105205 I dirnethyI-1-oxobutan-2 yl)arino)-2 i oxoethyl)piperidin-4 yI)methyI)piperazin-1 o Na yl)nicotnarnide
N-((lr,3R)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetra methylcyclobutyl)-6 c((3S,5 R)-4-(2-(2-(((S)-1I ((2S,4R)-4-hydroxy-2-(((R) 2-hydroxy-1-(4-(4 mnet hyIt hi az ol -5 826 104045 1042.45 yl)phenyl)ethyl)carbamoyl) pyrrolidin-1-yi)-3,3 dirnethyl-1-oxobutan-2 yl)arino)-2 oxoethoxy)ethy)-3,5 dirnethylpiperazin-1 yl1 i)nicatinamide
N-((ir3r)-3-(3-chlora--4 cyanophenoxy)-2,2,4,4 t-etrarnehylcyclobuyl)-
4-hydroxy-2-(((S)-i-(4-(4 imethyithiazoi-5 827 \~yI)phenyl)ethyI)carbarnoyl) ]064.045 1066.05
Idirnethvil-oxobuitan-2 yI)a.rnirio)-2 oxoethyl)pipericlin-4 yI)ethyl)piperpzin-1 ____ ________yI)nicot!inamide
(2S;4R)-1-((2S)-2(21(3-(3 (4-(f(lr,3r)-3-(3-chloro-4 cyano p h enxy) -2,2,4,4 tetr-aM Eth yIcyclIo bu ty1)ca rb Iamoyl)phenyl)propyl)-3,8 I~~ diazabicvdci3.2.l]octan-8 yI)acetarmo)-3.3-. dimetIhyl bUta nayl)-4 hvdroxv-N-((R)-2-hydroxy 828 W 1-k4--(4- rnethylthiazol -5- -)5." 0'14'7 1 yI)phenYl)Et'hyl)pyrro' idine -2-carboxarnde
N-((ir,3r)-3-(3-chlarco-4 cvanophenoxy)-2,2,4,4 tetrarnethylcyclobutyl)-6 (3-(2-(4-(2-( ((S)-1-((2S,4R)-
Imrethylthiazoi-5 829 yI)phenyl)ethyI)ca rba rnoyl) 10419.65 1051.6 py rroH d in -I-y 1) -3,3 -Al dimethyl-I-oxobutan-2
oxoethyl)piperazin-l \,.I~ >~-'yI)ethyl)pyrrolidin-I.
____________________________________________________YI)nicot!inam.-ide ____ ____
4.53
*N-((ir,3r)-3-(3-chloro-4 *cyanophenoxy)-2,2,4,4 I*tetranethylcyclbuyl)-3
hydroxy-2-(((S)---4-(4 830 \\~methylthiazoi-5- 1004.4 10064 y)phenyl)ethyl)carbamany!) NV.. *pyrrolid in-l-yl)--3-rethyl 1-oxobutan-2-yl)isoxazol *3--yI)bultyl)piperazin-i-" _____ ___________________________________________VInicatinamide
cyanaphenaxy)-2,2,4,4 tetramEthylcyclabutyl)-6 (4- (4- (5- ((R) -1- ((2S, 4R) -4
831 .m~...... ~ ~ rethylthiazoi-5- 1004.4 1006.41 X ~..7~'yI)phenyl)ethyl)carbamay0
) Spyrroli'din-1-yi)-3-methyl
I*3-yI)butyI)piperazin-1. * yI)nicatina-mide N -((lr,3r)--3--(3--chlorao-4- * cyanaphenaxy)-2,2,4,4 terrehlcyclabutyl)-6 ((2S,4R)-4-hyjroX"Y-2I((S) 1-(4-(4-rnethylthiazal-5 vI)phe!-yl)e-hvl)carbaniay!) 832 yraii--)3, 1036.95 1038.95 yI)amina)-2 axa e thyI) a irno) cycIaob utao N .~ xy)piper~dn-1. N"" y)nicatina-mide
10878] Synthesof Example 833:
____________, Ts Et 3N. DMAPN !N~O Os HAN O C
i HN , N H C HCB uK2CO,7 DMF Bn. DCM,4h Bnm N K 2C 3 Na:,CH 3CN.100°C,33h 100°`C, 4 h I 0 0
0 Pd/C, H2 0 ABM-26 BN-N N/ AiM-2 - N NH \--N--- - ----------------------- EtCH, 35C, 12 h BOP, DIEA, DMF, rt. 2h
0 \--- ~ ~ 0 LO.-10 \~
N N N -NNN ONJNH O EtOH. rt.,12h NC \ NC Ci1
OH
0N
ULM-3 N N N OHN BOP, DIEA DM.F4,t, 2h
Example 833
N
10879] Step 1: Synthesis of benzyl 6-[4-(2-hydroxyethyl)piperidin-1-yl]pyridine--carboxylate. OH
BnO KN 0
[0880] Into a 100-mL round--bottom flask, was placed benzyl 6-chloropyridine-3-carboxylate (L O g, 4.04 mmol, 1.00 equiv), 2-(piperidin-4-yl)ethan-I-ol (520.0 mg. 4.02 mmol, 1.00 equiv), N,N-dimethylformamide (15 mL), potassium carbonate (1.7 g,12.30 mmol, 3.00 equiv). The resulting solution was stirred for 4 hours at 100°C. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 1.0 g(73%) of benzyl 6-[4-(2-hydroxyethyl)piperidin-1-yIlpyridine-3 carboxylate as a yellow solid. 10881] Step 2: Synthesis of benzy 6-[4-(-[[(4-methibenzenesulfonyloxyethyl)piperidin-1 yljpyridine-3-carboxylate.
OTs
N BnO N
0
[08821 Into a I00-mL round-bottom flask, was placed benzyl 6-[4-(2-hydroxyethyi)piperidin-1
ylpyridine-3-carboxylate (500.0 mg, 1.47 mmol, 1.00 equiv), dichlorornethane (10 mL), TsC1 (419.0 mg, 2.20 mmol, 1.50 equiv).TEA (446.0 mg, 4.41 mmol, 2.00 equiv), 4 dimethylaminopyridine (54.0 mg, 0.44 mmol, 0.20 equiv). The resulting solution was stirred for 4 hours at room temperature. The resulting solution was extracted with dichloromethane and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). The collected fractions were combined and concentrated under vacuum. This resulted in 660.0 rg (91%) of benzy 6-[4-(2-[[(4-methylibenzene)sulfonyl]oxy]ethyl)piperidin-1 yl]pyridine-3-carboxylate as a yellow solid. 10883] Step 3: Synthesis of benzyl 6-(4-[2-[4-(2-ethoxy-2-oxoethyl)piperazin-1 yljethyl]piperidin-1-yl)pyridine-3-carboxylate.
0 0 BnO QN N N
[0884] Into a 100-mL round-bottom flask, was placed benzy 6-[4-(2-[[(4 methvlbenzene)sulfonyl]oxy]ethyl)piperidin-1-yl]pyridine-3-carboxylate (660.0 mg, 1.33 mmol, 1.00 equiv), ethyl 2-(piperazin-1-vDacetate hydrochloride (278.8 mg, 1.34 runol, 1.00 equiv), C[H3CN (10 mL), potassium carbonate (553.0 mg, 4.00 mmol, 3.00 equiv), Nal (200.0 mg, 1.00 equiv). The resulting solution was stirred for 3 hours at 100°C. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (15:1). The collected fractions were combined and concentrated under vacuum. This resulted in 467.0 mg (71%) of benzyl 6-(4-[2-[4-(2-ethoxy-2 oxoethyl)piperazin-l-yl]ethyllpiperidin-1-yl)pyridine-3-carboxylate as yellow oil. LC-MS (ES+): m/z 495.30 [(M-]+], tH = 0.71 min, (1.9 minute run).
[08851 Step4: Synthesis of 6-(4-[2--[4-(2-ethoxy-.2-oxoethyl)piperazin--Iyl]ethyl]piperidin-1
yl)pyridine-3-carboxylic acid. OU N 0 HO N N N
[0886] Into a 50-mL round-bottom flask, was placed benzyl 6-(4-[2-[4-(2-ethoxy-2 oxoethyl)piperazin-i-yl]ethyli]pipeidin-1-yl)pyridine-3-carboxylate (467.0 mg, 0.94 mmol, 1.00 equiv), ethanol (10 mL), Palladium carbon (90.0mg) was added under nitrogen atmosphere, the flask was then vacuumed and flushed with hydrogen. The reaction mixture was hydrogenated at 35°C for 1 overnight under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure. This resulted in 380.0 mg (99%) of 6-(4-2
[4-(2-ethoxy-2-oxoethyl)piperazin-1-yl]ethyl]piperidin-I-yl)pyridine-3-carboxylic acid as a yellow solid.
[08871 Step 5: Synthesis of ethyl 2-(4-[2-[-(5-[[i(r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]carbamoyl]pyridin-2-yl)piperidin-4-yl]ethyl]piperazin-I-yl)acetate. 00
N N N/__ N N 0 HN NC C!
[0888] Into a 50-mLround-bottom flask, was placed 6-(4-[2-[4-(2-ethoxy-2-oxoethyil)piperazin 1-yl]ethyl]piperidin-1-yl)pyridine-3-carboxylic acid (180.0 mg, 0.44 mmnol, 1.00 equiv), 2-chloro
4- [(1r,3r)-3-amino-2,2,44-tetramethylcyclobutoxy]benzonitrile hydrochloride (140.0 mg, 0.44 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), DIEA (230.0 mg, 1.78 mmol, 4.00 equiv), BoP (237.0 mg, 1.20 equiv). The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the water. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (12:1). The collected fractions were combined and concentrated under vacuum.This resulted in 230.0mg (78%) of ethyl 2-(4-2-[-(5-[[(1r,3r)-3-(3-chloro-4
cyanophenoxy)-2.2,4,4-tetramethyleclobutyllcarbamoyl]pyridin-2-yl)piperidin-4 yl]ethyI]piperazin-1-yl)acetate as yellow oil.
[08891 Step6: Synthesisof2-(4-[2-[-(5-[[(r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl carbaioyl]pyridin-2-yl)piperidin-4-yl]ethyl]piperazin-I-yi)aceticacid. 0 0
NN N N 'H H N W NC CI
[0890] Into a 50-mL round--bottom flask, wasplaced ethyl 2--(4-[2-[1--(5-[(r,3r)-3-(3-chloro-4 cyanophenoxy)-,2.,4,4-tetramethylcyclobutyl]carbamoyl]pyridin-2-yl)piperidin-4 yl]ethyl]piperazin-I-vl)acetate (125.0 mg, 0.19 mmol, 1.00 equiv), ethanol (3 mL), LiOH (43.0 mg. 1.80 mmol, 10.00 equiv). water(i mL). The resulting solution was stirred for I overnight at 25°C. The resulting mixture was concentrated under vacuum. This resulted in 110.0 mg (92%) of 2-(4-[2-[1-(5-[[(r,3r)-3-(3-chlioro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutylicarbamoyl]pyridin-2-yi)piperidin-4-yi]ethyl]piperazin-1-yi)acetic acid as yellow oil.
[0891] Step7: Synthesisof 6-(4-[2-[4-([[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(S)--l--[4-(4-methyl 1,3-thiazol-5-yl)phenyl]ethyl]carbamoyllpyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamoyl]methyl)piperazin--1-yl]ethylpiperidin-1-yl)-N-[(r,3r)-3-(3-chloro-4 cyanophenoxy)-2.2.4,4-tetramethylcyclobutyl]pyridine-3-carboxamide. CI
OH
N \\H0N ~N v N H 0OHNN- NC CI
S N
[0892] Into a 50-mL round-bottom flask, was placed.2-(4-[2-[1-(5-[[(1r,3r)--3-(3-chloro-4 cyanophenoxy)-2,',4,4-tetramethylcyclobutyl]carbamoyZlpyridin-2-yi)piperidin-4 yljethyl]piperazin-1-yl)acetic acid (110.0mg, 0.17 mmol, 1.00 equiv), (2S,4R)-1-[(2S)-2-amino
3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5
yl)phenyl ethyl]pyrrolidine-2-carboxamide hydrochloride (83.0 mg, 0.17 mmnol, 1.00 equiv), N.N-dimethylformamide (5 mL), DIEA (89.0 mg,0.69 mmol, 4.00 equiv), BoP (92.0 mg, 1.20 equiv). The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the water. The resulting solution was extracted with ethyl acetate and washed with water. The mixture was dried over anhydrous sodium sulfate. The crude product was purified by Prep-IPLC with the following conditions: Column, XBridge Shield RPI8 013D Column, 5um,19* 150mm; mobile phase, Water(IOMMOL/L NH4HC3) and ACN (55.0% ACN up to 71.0% in 8 min); Detector, UV 254nm. This resulted in 80.0 mg (44%) of 6-(4-[2-[4-([[(2S)-1
[(2S,4R)-4-hydroxy-2-[[(1S)-1-[4-(4-methyil-1,3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin 1-yl]-3,3-dimethyl- I-oxobutan-2-ylJcarbamoyl]methyl)piperazin-1-yl]ethylIpiperidin-I-yl)-N
[(1r,3r)--3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyljpyridine-3-carboxamide as a white solid. H-NMR (400 MHz. CD3 OD )68.88 (s, 1H), 8.59 (s. IH), 7.96-7.93 (m, IH), 7.74 7.72 (m, 11-), 7.47-7.36 (Im, 411), 7.14 (s, 1H), 7.00-6.98 (m, 1H), 6.85-6.83 (m, 1H), 5.05-5.00 (m IH), 4.62 -4.41 (m. 5H), 4.27 (s. IH), 4.12 (s, IH), 3.87-3.72 (m, 2H). 3.05-3.02 (m, 2H), 2.96-2.89 (m, 211), 2.62-2.45 (s, 1311), 2.22-2.16(m, 1), 2.00-1.81 (i, 311),1.60-1.47 (m, 61), 1.27-1.21 (m 14H), 1.04 (s. 9H); LC-MS (ES+): m/z 1063.60 [(MH+], tR 2.87 min, (5.6 minute run). Chemical Formula: C7H-75 CNoO6S. Molecular Weight 1062.53.
[0893] Unless otherwise noted, Examples 834-837 were synthesized according to similar procedures described above for the synthesis of Example 833, by utilizing corresponding starting materials and reagents.
[0894] Table 26: Exemplary Compounds
Measured Mass Ex. Ion Data Structure Compound Name m/z (2)
N-((i-r,3r)-3--(3-chioro-4 cyanophenoxy)-2,2,4,4 tetra.methy' cyc'obut~yi,).6. (4-(2-(4-(2-(((S)-i-((25LlRj) *- 4-hydroxy-2-(((S)-1-(4-(4 methyithiazol-5 833 ~' \yi0phenyl)ethyi)car-barcy) '11063.6 1065.65
py rr oIi d in-I-yI1) -3,3
oxoethyl)piperazin-1. yi!)ethyl)piperidinl-1 _____ ____________________________________________yi~nicotinarnide N-(i'r3r).-3-(3-chi!oro-4 cyanophenoxy)-2,2,4;C tetrarnethyicyciobut~ylj6. (4-(2-(4-(2-(((S)-.i-((25LlRj) 4-hydroxy-2-(((R)-2 1hydroxy-i1-(4-(4
834 1ehlhaoS 108 1. 1 1083.1 ~ . \ yl)phenyl)ethy'i)carb)am-oyI)
poehlipain---l- * N yimethyl-piperazin-1
yarnopno)-224 txetehypicypie rtyz cdn amniolnaphe~uy)
'#4" y()cetrni)-33-lo-4
dirmethylutanotyl)- b
rnet-hylthiazol-5-
~ N -2-carboxamide
(2S,4R)-I-((2S)-2-(2-(3(4 ¾(4-(((1r,3.r)3-(3-chloro-4
CyanophenoxV)--2,2,4,4 tetrarnethyicyclobu.. )ca rnovl)phenyl)butyl)-3,8
' ~ diazabicyclo[3.2.3-]octanV .~~. ~ yIjacetarnido)-3,3- 14. 836 di .. ethyl butanoyl)-4- 1051.47 hyd roxy-N-((R)-2-hyd roxy iI44-(4- methyth ia zo I -S. -2-carboxarnide
N-((Ir,3r)-3-(3-chloro-4 cyanophenoxy)--2,2,4,4 te trame.ithyicyciobuty )-6-' (3-(4-(2-(((S)-1-((2S,4R)-4 hydroxy--2--((kS) -- ,4-(4. methylthiazol-5 yi)phenyl)ethyi)carba. .oyl)
' 837..~ yrolidin-1-yIl)-3,3- 9~94.6 996.55 M climethyki1-oxobutan-2 yl)arnino)-2 s oxoethyl~piperazin-1 yl)propy1)nicotinmd;~
108951 Synthesis of Example 838:
EnO OH Dess-Martin --- n------N------ ------------ PA , I1H20, MeCH DCM rt,
0 Ci CH N" O nO NOH jones agent H2S -4,E~OH -o acetone 0 73C, 2 h KIHCO, DMFIH-O O°Ctort,
BnO __ __ Br 3, DCM TsCI, EtN t B1.10K, THFO -78°CDCM, rt 0CCC +0crt. (D
\-N INH
IntM ediate 01fromexampl eN' 77N-\ NC C! O' -NH N N N- L:OHH-0 SC", 4 z ------------------------------------ rMDH!r C W KCO, NeI.CH 3CN, 60°C, seal tube, N 2
NC CI HN
/ ~T 3P, DIEA, DMF, it \~ NC C:K NC u ExampleC38 N
[0896]1Step 1: Synthesis of3-(benzyoxy)propanal
BnOOH
[08971Into a500-mL 3-necked round-bottom flask purged and maintainedxwih an nrt atmosphere of nitrogen. 'as placed 3-(benzyloxy)propan-1-ol (11.62 g, 69.91 mmol, .00) This was followed equiv), dichloromethane (250 mL).Ho". 462 by the addition of DMP (32.65 g,76.98 mmnol,l1.10)equiv), in portions at 0 C. The resulting solution was stirred for 3hours at 25°C.The resultingmixture was washed with 2x20nmLofNa 2 S 2 03 .The resulting mixture was washed with 1x200 mLof sodium bicarbonate. The mixture was dried over anhydrous sodium sulfte and concentrated under vacuum. The residue 'as applied onto asilica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 10 g(87%) of3-(benzyloxy)propanal as colorless oil.
[0898] Step 2:Synthesisof E)-N-[3-(enzyoxy)propylidene]hydroxylamine.
BnO N'OHN
108991 Into a 250-mL round-bottom flask, was placed N1 2 0H.HC1 (12.51g, 3.00 equiv), H2/MeOH (90/30 mL), NaOAc (14.76 g, 3.00 equiv). This was followed by the addition of a solution of 3-(benzyloxy)propanal (9.84 g, 59.93 mmol, 1.00 equiv) in methanol (10 mL) dropwise with stirring at 0°C in 5 minutes. The resulting solution was stirred for 5 hours at 25°C.
The resulting mixture was concentrated under vacuum. The resulting solution was extracted with
2x150 mL of dichloromethane and the organic layers combined. The resulting mixture was
washed with 1x150 ml of brine. The mixture was dried over anhydrous sodium sulfate. The
resulting mixture was concentrated under vacuum.This resulted in 10 g (93%) of (E)-N-[3
(benzyloxy)propylidene]hydroxylamine as light yellow oil.
[0900] Step 3: Synthesis of (Z)-3-(benzyloxy)-N-hydroxypropcarbonimidoi chloride. CI
BnO N'OH
[0901] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of
nitrogen, was placed (E)-N-[3-(benzyIoxy)propylidene]hvdroxylamine (9 g, 50.22 mmol, 1.00 equiv), N,N-dimethylformamide (60 mL), NCS (8.04 g, 60.21 nmol, 1.20 equiv). The resulting solution was stirred for 3 hours at 25C.The reaction mixture was used to next step without
purification.
[0902] Step 4: Synthesis of (Z)-3-(benzyloxy)-N-hydroxypropcarbonimidoyI chloride.
N'0
BnO OH
[0903] Into a 250--mL round-bottom flask purged and maintained with an inert atmosphere of
nitrogen, was placed (E)-N--[3-(benzyloxy)propylidene]hydroxylamine (9 g, 50.22 mmol, 1.00 equiv), N,N-dimethylformamide (60 mL), NCS (8.04 g, 60.21 mmol, 1.20 equiv). The resulting solution was stirred for 3 hours at 25°C.The reaction mixture was used to next step without
purification.
[0904] Step 5: Synthesis of 2--[3-[2-(benzyloxy)ethyl]-1,2-oxazol--5-yl]acetic acid.
N'0
11 / OH
[0905] Into a 500-mL round-bottom flask, was placed2-[3-[2-(benzyloxy)ethyl]-1,2-oxazol-5 yl ethan-I-ol (6.48 g 26.20 mmol, 1.00 equiv). acetone (120 mL), Jones reagent (8 g CrO3 /80 ml H20/12 ml H2S04). The resulting solution was stirred for 3 hours at 25°C. The reaction was then quenched by the addition of 80 mL of. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 2x100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. This resulted in 6 g crude product(88%) of 2-[3-[2-(benzyloxy)ethyl]-1,2-oxazol 5-yl]acetic acid as yellow oil.
[09061 Step 6: Synthesis of ethyl 2-[3-[2-(benzyloxy)ethyl]-1,2-oxazol-5-yl]acetate.
N-O
BnO 0 O \__
[0907] Into a 250-mL round-bottom flask, was placed 2-[3-[2-(benzyloxy)ethyil]-1,2-oxazol-5 yllacetic acid (5.22 g, 19.98 mmol, 1.00 equiv), ethanol (100 mL), sulfuric acid (2 mL). The resulting solution was stirred for 2 hours at 70°C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with sodium carbonate. The resulting solution was extracted with 2x5() mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuumThe residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 2.5 g (43%) of ethyl 2-[3-[2-(benzyloxy)ethyl]-1,2-oxazol-5-yl]acetate as colorless oil. LC-MS (ES+): m/z 290.00 [MH+], tR= 1.40 min, (2.70 minute run).
[0908] Step 7: Synthesis of ethyl 2 -[3-[2-(benzyloxy)ethyl]-1,2-oxazol-5-yl]-3-methylbutanoate.
N Bno 0 /
0 C
[0909] Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-[3-[2-benzyloxy)ethyil]-1,2-oxazol-5-yl]acetate (347 mg, 1.20 mmol, .00 equiv), tetrahydrofuran (15 mL). This was followed by the addition of t-3uOK (1M in THF)(1.44 mL, 1.20 equiv) dropwise with stirring at 0°. To this was added2 -iodopropane (245 mg, 1.44 mmol, .20 equiv) dropwise with stirring at0°C. The resulting solution was stirred for 10 min at 0°C. The resulting solution was allowed to react. with stirring, for an additional 3 hours at 25C. The reaction was then quenched by the addition of 10 mL of NH4Cl. The resulting solution was extracted with 2x15 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. This resulted in 0.22 g (55%) of ethyl 2-[3-[2-(benzyloxy)ethyl]-1,2-oxazol-5-yl]-3 methylbutanoate as colorless oil.
[0910] Step 8: Synthesis of ethyl 2-[3-(2-hydroxyethyl)-1,2-oxazol-5-yil]-3-methylbtanoate.
HO 0 \
[0911] Into a 25--mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-[3-[2-(benzyloxy)ethyi]-1,2-oxazol-5-yl]-3-methylbutanoate (199 mg, 0.60 mmol, 1.00 equiv), dichloromethane (10 mL). This was followed by the addition of BBr 3 (1 .2 mL, 2.00 equiv) dropwise with stirring at -78°C. The resulting solution was stirred for
20 minutes at -78C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 2x10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 0.13 g (90%) of ethyl 2-[3-(2-hydroxyethyli)-,2-oxazol-5-yl]-3-methylbutanoate as colorless oil.
[0912] Step 9: Synthesis of ethyl 3-methyl-2-[3-(2-[[(4-methylbenzene)sulfonyl] oxy]ethyl)-1,2 oxazol-5-yl]butanoate.
N-O
TsO 0 0 \_
[0913] Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-[3-(2-hydroxvethyl)-1,2-oxazol-5-vl]-3-methylbutanoate (121 mg, 0.50 mmol, 1.00 equiv), dichloromethane (10 mL), triethylamine (152 mg, 1.50 mmol, 3.00 equiv), TsCi (238 mg, 1.25 nmol, 2.50 equiv), 4-dimethylaminopyridine (12 mg, 0.10 mmol, 0.20 equiv). The resulting solution was stirred for 12 hours at 25°C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2x15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with Ix15 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 0.123 g (62%) of ethyl 3-methyl-2-[3-(2-[[(4 methylbenzene)sulfonyl]oxy]ethyl)-1,2-oxazol-5-yl]butanoate as a white solid.
[09141 Step 10: Synthesis of ethyl 3-methyl-2-(3-[2-[4-(5-[[(1r,3r)-3-(3-chloro-4 cyanophenoxy)-,2,4,4-tetramethylcyclobutyl]carbamoyl]pyridin-2-yi)piperazin-I-yl]ethyl]-1,2 oxazol-5-yl)butanoate.
0 N N- N- 0 0 0 NH N NJ
NC CI
[0915] Into a 15-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed. This was followed by the additionof CH 3 CN (6mL), 6-(piperazin-1-yl)-N-[(r,3r) 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylIpyridine-3-carboxamide (152 mg, 0.32 mmol, 1.20 equiv), potassium carbonate (112 mg, 0.81 mmol, 3.00 equiv), The resulting solution was stirred for 2 min at25°C.Ethyl3-methyl-2-[3-(2-[[( methylbenzene)sulfonyl]oxy]ethyl)-1,2-oxazol-5-yl]butanoate (107 mg, 0.27 mmol, 1.00 equiv) and NaI (0.041 g, 100 equiv)was added. The resulting solution was allowed to react, with stirring, for an additional 12 hours at 60°C. The reaction mixture was cooled to 25°C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10/1). This resulted in 0.17 g (91%) of ethyl 3-methvl-2-(3-[2-[4-(5-[[(1r,r)-3-(3--chloro-4--cyanophenoxy)-2,2,44- tetramethylcyclobutyl]carbarnoylIpyridin-2-yl)piperazin-I-yl]ethyl]-1,2-oxazol-5-ylibutanoate as t a white solid. LC-MS (ES+): m/z 691.35 [MH+], R 1.02 min, (1.90 minute run).
[0916] Step 11: Synthesis of 3-methyl-2-(3-[2-[4-(5-[[(r,3r)-3-(3-chloro-4-cyanophenoxy) 2,2,4,4-tetramethylcyclobutyl]carbamoyl~pyridin-2-yl)piperazin-1-yl]ethyl]-1,2-oxazol-5
yl)butanoic acid.
OH
N' N \-/N- 01O
NC CI
[0917] Into a 25-mL round-bottom flask, was placed ethyl 3-methyl-2(3-[2-[4-(5-[[(1r3r)-3-(3 chlioro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoypyridin-2-y)piperazin-1 yl]ethyl]-1,2-oxazol-5-yl)butanoate (159 mg, 0.23 mmol, 1.00 equiv), MeOH/H 2 (5ml/0.5ml). LiCH (17 mg, 0.71 mmol, 3.00 equiv). The resulting solution was stirred for 12 hours at 25°C.
The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel
column with dichlioromethane/methanol (1/5). This resulted in 0.133 g(87%) of3-methyl-2-(3
[2-[4-(5-[[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethyleyclobutyl]carbamoyl]pyridin-2-yl)piperazin-1-y]ethyl]-1,2-oxazol-5-yl)butanoic acid as a white solid. LC-MS (ES+): m/z 663.30 [MH+], tR = 0.94 min, (1.90 minute run).
[0918] Step 12: Synthesis of 6-[4-[2-(5-[1-[(2S4R)-4-hydroxy-2-[[(1S)-I-[4-(4-methyl-1,3 thiazol-5-yl)phenyl]ethyl]carbamoyllpyrrolidin-1-yl]-3-methyl--oxobutan-2-yl]-1,2-oxazol-3 yl)ethyl]piperazin-1-yl]-N-[(ir,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]pyridine-3-carboxamide.
OH N
N N--N N' 0 H O1' NH N
NC CI N
[0919] Into a25-mL round-bottom flask purged and maintained with an inert atmosphere of
nitrogen, was placed 3-methyl-2-(3-[2-[4-(5-[[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-.2.4,4 tetramethylcyclobutyli]carbamoyl]pyridin-2-yl)piperazin-1-yl]ethyl]-1,2-oxazol-5-yl)butanoic acid (133 mg, 0.20 mmol, 1.00 equiv), NN-dimethylformamide (5 mL). T3P (50%in EA)(0.254 g, 2.00 equiv), DIEA (77 mg, 0.60 mmol,3.00 equiv), (2S,4R)-4-hvdroxy-N-[(IS)-1-[4-(4 methyl-1,3-thiazol-5-yl)phenyll ethyIlpyrrolidine-2-carboxamide (79 mg, 0.24 mmol, 1.20 equiv). The resulting solution was stirred for 12 hours at 25C. The solids were filtered out. The crude product (mL) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 5um.19*150mm;Mobile Phase A:Water(IOMMOL/L NH4HCO), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 46% Bto 64% B in 8 min; 220 nm; R: 7.58 min): This resulted in 0.0363 g (19%) of 6-[4-[2-(5-[1-[(2S,4R)-4-hvdroxy-2
[[(1S)-I-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyljcarbamoyl]pyrrolidin-1-y]-3-methyl-1 oxobutan-2-yl]-1,2-oxazol-3-yl)ethylipiperazin-1-yl]-N-[(ir,3r)-3-(3-chloro-4-cyanophenoxy) 2,2,4,4-tetrarnethycyclobutyl.pyridine-3-carboxamide as a white solid. 1 1NMR (300 M-z, CDCl 3 ): 6 8.66 (s, 1H), 8.56-8.55(m, 1H), 7.91-7.87 (m, 1H), 7.52-7.60 (m, 1H), 7.46-7.30 (m, 5H). 6.97-6.96 (m, 1H), 6.82-6.78 (m. 1H), 6.70-6.58 (m, 1H), 6.18 (d.IH.J = 8.7 Hz), 6.06 (dI1H,J = 8.1 Hz),5.14-4.85 (m, 1H), 4.84-4.52 (n 211), 4.14(d, IH,J = 8.1 Hz),4.04 (s, 1I), 3.81-3.42 (m, 7H). 3.05-2.81 (m, 3H), 2.80-2.55 (m 5H), 2.54-2.36 (m, 5H), 2.25-2.10 (m, 1H), 2.03-1.88 (in, 1H), 1.52-1.33 (in, 3H), L.30-1.14 (m, 12H), 1.08-1.01 (m, 3H), 0.92-0.89 (mu, 3H); LC-MS (ES*): mAz 976.40 [MH*], t = 1.51 min, (3.00 minute run). Chemical Formula:
Cs 2 H62ClN 9 0 6S [975.42/977.42].
[0920] Unless otherwise noted, Examples 839-840 were synthesized according to similar procedures described above for the synthesis of Example 838, by utilizing corresponding starting materials and reagents.
[0921] Table 27: Additional Exemplary Compounds
Measured Ex, Mass Ion Data Structure CompoundName m/z m/z (1) (2) N-((1r,3r)-3-(3-chloro-4 cvanophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6-(4 (2-(5-(1-((2S,4R)-4-hydroxy
838 5- 976.4 978.45 yl)phenyl)ethyl)carbamoyl)py rrolidin-1-yl)-3-methyl-1 oxobutan-2-yl)isoxazol-3 yl)ethy)piperazin-1 yl)nicotinamide
N-((lr;3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 anethylcyclobutyl)-43 aIet
\ hydroxy-2-(((S)-1-f4-(4 methythiazol-5 * "'~'-~ ' -~cyI)phenyl)ethyl)carbamoyl)py 839 N' rrolkdi)-l-vi)-3,3-dimethy1 1009 oxobutan-2-vI)amino)-21029 oxoethyl)-3..8 dia)zabicyc43.2..ioctan-3 yI1)pro py1) n icot in am ide
* V cya rlohe noxy) -2,2,4,4 .etra MEth~~tlllCC )LY )-6-(4 - "(8-(2-(((S)-l-((2S,4R)-4- i hydroxy-2-(((S)-I1-(4-(4 methylthiazo-5 ~. ""~~yI)phenyl)ethvl)carbamoyl)py
rroHdin-1-yl)-3,3-dimethy1-l 840 '\~oxobultan-.2--y)an.ino)-2- 1 13
N~ " ~diazabicyc'o[3.2.1'octan-3
109221 Synthesis of Example84-1: OH
0H 0 ",, 0 II OH NH 6H~~
C-HA7.-D A --- NC Example841 NC :Omedate forn example 829
[0923] Step 1: N-((l rl3r)-3 -(3 -chi oro4-cy'noplhenoxy)-' ,2.,4,4-tetramyethyi1cycobutv1)-6-(3 -(2 '4--(2-(((S)--.-((S,4)--4-hydrox-'--(((R)2hydroxy- I-(44.4--methylthiazol- -, yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yi)-3,3-dimethyl-1-oxobutan-2-y)amino)-2 oxoethyl)piperazin-I-yi)ethyi)pyrrolidin-I-yl)nicotinamide.
NH N 0 ::=N /N HH
C HOHN 0 SOH NC
N
[0924] Into a25-mL round-bottom flask, was placed2-(4-(2-(1-(5-(((lr3r)--3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetrarnethylcyclobutyl)carbamoy)pyridin-2-yI)pyrrolidin-3 yl)ethyl)piperazin--1-yl)acetic acid (85.0 mg, 0.14 mmol, 1.00 equiv), N.N-dimethyformamide(2 mL), (2S,4R)-1-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[(IR)-2-hydroxy-1-[4-( 4
methyl-I,3-thiazol-5-yl)phenyl]ethylipyrrolidine-2-carboxamide hydrochloride (67.8 mg, 0.14 mmol 1.00 equiv), N.N.N.N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophospate (77.8 mg, 0.20 mmol, 1.50 equiv), N,N-diisopropylethylamine (52.8 mg, 0.41 mmol, 3.00 equiv). The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by water (20 mL), extracted with ethyl acetate (20 mL x3) and concentrated under vacuum. The solids were filtered out. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep OBD C18 Column, 19*250mm,5um; mobile phase, water (10 mrmol/L ammonium bicarbonate) and acetonitrile (44.0% accionitrile up to 60.0% in 8 min); Detector, UV 254nm. This resulted in 53.2 mg (37%) of N-((Ir,3r)-3-(3-chlioro-4-cvanophenoxy)-2,2,4,4-tetramethvlcyclobutyi)-6-(3-(2-(4-(2-(((S)-1 ((2S.4R)-4-hydroxy-2-(((R)-2-hydroxy-1-(4-(4-methylthiazol-5 yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-y)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2 oxoethyl)piperazin-1-yl)ethyl)pyrrolidin-1-yI)nicotinamide as a light yellow solid. H NMR
(300 MHz, CDOD): 6 8.85 (s, 111), 8.56-8.48 (n, 11), 7.91 (in, ll) 7.69 (d, J = 8.7 liz, 1I), 7.43 (m, 4H), 7.10 (m 1H). 6.95 (m, 1H), 6.50 (d, J = 9.0 Hz, 1H). 5.00 (m, 1H), 4.64-4.52 (m, 2H), 4.43 (s. 1H), 4.24 (s. 1H), 4.10 (s. 1H), 3.93-3.51 (m, 7H), 3.42 (m 1H), 3.15-3.01 (m, 3H)
260 (s, 8H), 2.45 (s,.311),2 38- 2.12 (m,211), 2.04-1.89 (in, 1H), 1.77-1.65 (m, 3H), 1.25 (s,
6H). 1.19 (s. 6H), 1.01 (s, 9H); LC-MS (ES"'): inZ 1065.70[Mffa]it 2.96min (5.2 minute run). Chemical Formula: COH 7 3 C1N 10 0 7 S; Molecular Weighit:1064.5 1.
[0925] Synthesis of Example 845:
~ ----- TAC ,- NTFA0 -- On NJ rr Pd/CKH BnANNaI3H(CAc3, CM 8s. BrO-K4 IKEtcHF, 301c.
Oil,
HCNI CMoC, . A0 , 1, HATLJ, DIEA, DMF Ii"0.5h
IN N, NC , ------- N ----
~ N,,,nNRh20DCc) 4, LCM
N" H (h.~JTFA, DCMA NCN, I
HN
HN 6N4 separation
BOP7 DIEA M OH
NN
<"N
Examoie 845
1-0926]1Step 1: ynthesis of benzyl 6-pprazinl-y)nicotilnate.
NH N
BnO N
0
[0927] A mixture of tert-butyl 4-(5-((benzyloxy)carbonyl)pyridin-2-yl)piperazine-l-carboxylate (20 g, 50.3 nmol) and 2,2,2-trifluoroacetic acid (15 nl) in dichloromethane (50 nl) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure. The residue was taken up in dichloromethane (100 ml) and washed with aqueous sodium bicarbonate (sat. 20 ml x 2).The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give benzyl 6 (piperazin-1-yl)nicotinate (15 g, yield 95%) as yellow solid which was used in next step without further purification. HNMR (400 MHz, CDCI): 2.90-2.92 (m, 4H), 3.60-3.63 (m 4H), 5.31 (s211), 6.54 (d, J= 9.2 Hz, IH), 7.30-7.42(rn, 511), 8.00-8.03 (in, 1H), 8.44 (s, 11). Chemical Formula: C1 7HigN 302.Molecular Weight: 297.35. 10928] Step 2: Synthesis of benzy 6-[4-[3-(benzyloxy)cyclobuty]piperazin-1-y]pyridine-3 carboxylate. OBr
N'
BnO N
0
[0929] Into a 50 mL round-bottom flask, was placed benzyl 6-(piperazin-1-yl)pyridine-3 carboxylate 2.2,2-trifluoroacetate salt (800 mg, 2.02 rmol, 1.00 equiv), dichloromethane (20 mL), 3-(benzyioxy)cyclobutan-1-one (704 mg, 4.00 mmol, 1.50 equiv), sodium triacetoxyborohydride (1.7 g,8.02 mmol, 3.00 equiv). The resulting solution was stirred for 2 hour at room temperature. The reaction was then quenched by the addition of 5 mL water. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was washed with saturate sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). The collected fractions were combined and concentrated under
4 72 vacuum. This resulted in 469mg (51%) of benzyl 6-[4-[3-(benzyloxy)cyclobutyl]piperazin-1 yllpyridine-3-carboxylate as a white solid. LC-MS: (ES'): nz 458.15 [MHI], lR = 0.69min, (1.90 minute run).
[09301 Step 3: Synthesis of 6-[4-[3-(benzyloxy)cyclobutyl]piperazin-1-yljpyridine-3-carboxiic acid. OBn
N N HO, N
[09311 Into a 50mnL round-bottom flask, was placed benzyl 6-[4-[3 (benzyloxy)cyclobutyl]piperazin-1-ylpyridine-3-carboxylate (469 mg, 1.02 mmol, 1.00 equiv), ethanol (20 mL), Palladium carbon (100 mg), hydrogen. The resulting solution was stirred for overnight at 30°C in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 611 mg (162%) of 6-[4-[3 (benzyloxy)cyclobutyl]piperazin-1-vl1pyridine-3-carboxylic acid as a yellow solid.
[0932] Step 4: Synthesis of 6-[4-[3-hydroxycyclobutyl]piperazin-1-yl]pyridine-3-carboxvlic acid. r OH
HO,
0 10933] Into a 50 mL round-bottom flask, was placed 6-[4-[3-(benzyloxy)cyclobutyi]piperazin-1 yl]pyridine-3-carboxylic acid (610 mg1.66 mmol, 1.00 equiv), dichloromethane (10 tmL). This was followed by the addition of a solution of tribromoborane (623 mg, 2.49 mmol, 1.50 equiv) in dichloromethane (2.5 mL) dropwise with stirring at 0°C in 10 min. The resulting solution was stirred for 0.5 hours at room temperature. The reaction was then quenched by the addition of sodium bicarbonate. The resulting solution was diluted with 10 mL of methanol. The solids were filtered out. The crude product ( 460 mg) was purified by Prep-HPLC with the following conditions: Column, 5um,19*150mm; mobile phase, Waer(0mmol/L N-1 1-C0 4 3) and
acetonitrile (48.0% acetonitrile up to 62.0% in 8 min); Detector, UV 220nm. This resulted in 120 mg (26%) of 6-[4-[3-hydroxycclobutyl]piperazin-1-yljpyridine-3-carboxylic acid as a white solid.
[0934] Step5: Synthesis of 6-[4-(3-hydroxycyclobutyl)piperazin--yl]-N-[(ir,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetramethylcyclobutvl]pyridine-3-carboxamide.
N
NC H N-1 N 0
[0935] Into a 50 mL round-bottom flask, was placed 6-[4-[3-(benzyloxy)cyclobutyl]piperazin-1 yl]-N-[(1r,3r)-3-(3-cliioro-4-cyanophenoxy)-2,2,4,4-tetramethyleyclobutylpyridine-3 carboxamide (322 mg, 0.51 mmol, 1.00 equiv), dichloromethane (10 mL). This was followed by the addition of a solution of BBr (190mg, 1.50 equiv) in dichloromethane (4 mL) dropwise with stirring at 0°C in 10 minutes.The resulting solution was stirred for I day at room temperature. The reaction was then quenched by the addition of sodium bicarbonate. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was washed with saturate sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with diclloromnethane/methanol (20:1). The collected fractions were combined and concentrated under vacuum. This resulted in 200 mg (73%) of 6-[4-(3-hydroxycyclobutyl)piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanoplienoxy) 2,2.4,4-tetramethyilcyclobutylpyridine-3-carboxamide as a yellow solid. 10936] Step 6: Synthesis of tert-butyl 2-[3-[4-(5-[[(ir,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]carbamoylipyridin-2-yl)piperazin-I-yl]cyclobutoxy]acetate.
NC NC;
[09371 Into a 50mL round-bottom flask, was placed 6-[4-(3-hydroxycyclobutyl)piperazin-1-y] N-1(1r,3r)-3-(3-chlioro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylIpyridine-3-carboxamide (180 mg. 0.33 mmol, 1.00 equiv) tert-butyl2-diazoacetate (71.4 mg. 0.50 mmol, 1.50 equiv) dichloromethane (20 mL), Rh2(OAc)4 (14.7 mg, 0.10 equiv). The resulting solution was stirred for I overnight at room temperature. The reaction was then quenched by the addition of water. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was washed with saturate sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1).The collected fractions were combined and concentrated under vacuum. This resulted in 150 mg (69%) of tert-butyl 2-[3-[4-(5-[[(ir.3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamovl]pyridin-2-yl)piperazin-1 yl]cyclobutoxy]acetate as a yellow oil. LC-MS: (ES'): inz 652.35 [MH], t R = 1.04min, (1.90 minute run).
[0938] Step 7: Synthesis of2-[3-[ 4 -(5-[[(lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl] carbarnoylIpyridin-2-yl)piperazin-i-ylvcyclobutoxyIacetic acid. 0
Ny NC
[09391 Into a 50 mL round-bottom flask, was placed tert-butyl 2-13-[4-(5-[1r,3r)-3-(3-choro-4 cyanophenoxy)-2,2.4,4-tetramethylcyclobutyl]carbamoyl]pyridin-2-yl)piperazin-1 yl]cyclobutoxy]acetate (150 mg, 0.23 mmol, 1.00 equiv), dichloromethane (10 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for2 hours at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 136 mg (99%) of 2-[3
[4-(5-[[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyleyclobutylcarbamoy]pyridin-2 yl)piperazin-I-yl]cyclobutoxy]acetic acid as yellow oil.
[09401 Step 8: Synthesis of 6-[4-[3-(11(2S)-1-[(2S,4R)-4-hydroxy-2-[[(IS)-I-[4-(4-methy-1,3 thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin-l-yl]-3.3-dimethyl-1-oxobutan-2 yl]carbamoyl]methoxy) cyclobutyllpiperazin-I-yI -N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy) 2.2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide.
OH
H N o HN
, N N \N
[0941] Into a 50 mL round-bottom flask, was placed2- [3-[4--(5-[[(r,3r)-3-(3-chioro-4 cyanophenoxy)-2,24,4-tetramethylcyclobutyl]carbamoyl]pyridin- 2 -yl)piperazin-1 yljcyclobutoxyacetic acid (126 mg, 0.21 mmol, 1.00 equiv),(2S,4R)-1-[(2S)-2-amino-3.3 dirnethylibutanoyl]-4-hydroxy-N-[(IS)-1-[4-(4-methyl- 1,3-thiazol-5-yi)phenyl]ethyl]pyrrolidine 2-carboxamide(94.1 mg, 0.21 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), DIEA (81.9 mg, 0.63 mmol, 3.00 equiv), BOP (93.7 mg. 1.00 equiv). The resulting solution was stirred for I hour at room temperature. The reaction was then quenched by the addition of. The resulting solution was extracted with DCM:MeOH=10: Iand the organic layers combined. The resulting mixture was washed with saturate sodium chloride. The mixture was dried over anhydrous sodium sulfate. The crude product(210 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um,19*150mm; mobile phase, Water(10 mmol/L NH 4HCO3) and acetonitrile (48.0% acetonitrileup to 62.0% in 8 min); Detector, UV 220nm. 50 mg product was obtained and concentrated under vacuum. This resulted in 50 mg (23%) of 6-[4-[3-([[(2S)-1-[(2S,4R)-4-hydroxy-2-[(1S)--1-4-(4-methyl-1,3-thiazol-5 yl)phenyl]ethyl]carbamoyl]pyrrolidin-I-yl]-3,3-dimethyl-1-oxobutan-2 yl]carbamoyl]methoxy)cyclobutyl]piperazin-1-yI]-N-[(1Ir,3r)-3-(3-chloro-4-cyanophenoxy) 2,2.4,4-tetramethylcyclobutyl]pyridine-3-carboxamide as yellow oil. 10942] Step 9: Synthesis of N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]-6-j4-[(1s,3s)-3-([[(2S)-1-[(2S,4R)-4-hydroxy-2-[[(S)-1-4-(4-methyl 1,3-thiazol-5-yl)phenyl]ethyl] carbamoyl] pyrrolidin-I-yl]-3,3-dimethyl-I-oxobutan-2 yl]carbamoyl]methoxy)cyclobutyl]piperazin-1-y]pyridine-3-carboxamide.
HH
N N0 NHN cNNHN
N
[0943] Into a 50 mL round-bottom flask, was placed64[3([[(S)--[(2S,4R)4-hdroxy-2
[[(S)--[4-(4-methyl-1,3-thiazol-5-yl)phenyliethyl]carbamoylipyrrolidin-1-yi]-3,3-dimethyl-1 oxobutan- 2 -ylcarbamoyl]methoxy)cyclobutylipiperazin-1-yi]-N-[(1r,3r)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4-tetrametihylcyclobutyl]pyridine-3-carboxamide (50 mg, 0.05 mmol 1.00 equiv). The resulting solution was stirred for 1 minute at room temperature. The crude product (50 mg) was purified by Chiral-Prep-HPLC with the following conditions: Column, CI-IRALPAK IF, 2*25cm,5um; mobile phase, 2-Methyl-2-methoxy propane and isopropylamine- (hold 45.0% isopropylamine- in 32 min); Detector, UV 220/254nm. 31.5 mg
product was obtained, and concentrated under vacuum. This resulted in 31.5 mg (63%) of N
[(ir,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-6-[4-[(Is,3s)-3-([[(2S)-1
[(2S,4R)-4-hydroxv-2-[[(IS)-I-[4-(4-methyl-1.3-thiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidin I-vil]-3,3-dimethyl-1-oxobutan-2-vl]carbamoyl]methoxy)cyclobutyl-piperazin-1-yllpyridine-3 carboxamide as a white solid. 'H NMR (400 MHz, CD30D) 6 8.87 (s,1H), 8.61- 8.59(m, 1H), 7.98 - 7.92(m, 1H), 7.74- 7.70 (n, 11), 7.57 - 7.38 (in, 41) 7.13- 7.10 (in, 1), 6.99 - 6.96(m, 1H), 6.85 - 6.81(m, 11H), 5.02 - 4.99(m, 11H), 4.72 - 4.66(m, 1H), 4.62- 4.57(m. 1H), 4.46 4.38(m, 1H), 4.27(m, 1H), 4.13(m, 1H), 4.00- 3.88(m, 411), 3.86- 3.67 (, 511), 2.60- 2.42(rn 10H). 2.22- 2.15(m, 1H), 2.02- 1.90(m. 3H), 1.57- 1.46(m, 3H), 1.27- 1.21(d,J= 24.4Hz, 12H), 1.05 - 1.02(S, 9H); LC-MS (ES'): nz 1022.5[MH], Il = 4.294min, (5.60 minute run). Chemical Formula: C 54 1 6 8ClN 90,S; Molecular Weight 1021.47.
[0944] Unless otherwise noted, Examples 842-852 were synthesized according to similar procedures described above for the synthesis of Examples 841 and 845, by utilizing corresponding starting materials and reagents. 10945] Table28: Additional Exemplary Compounds
Ex. Measured Structure Compound Name 7Mass Ion Data cyanophenoxy)-2,2,4,4 tetra rmethyl!cycIo b uty0)-6-(3- (2
In. ~ hydroxV-2-(((R).-2-hydroxy--1-(4- (4- m ethyl th iazok5 841 y) p h enyl) ethyl)ca rbamr.oyl) pyrr 10 65.7 1067.7
oxoethyl~piperazin-1 yi~ethyl)pyrrolidin-1 y:nicotinarnide
Stetra rmethyl!cycI ob utyl)-6- ((2 (3-(2-(((S)-1-f(2S,4R)-4 hydroxy-2-(((S)-.-(4-(4 rnethylthiazol-5 yl) ph enyl) ethyl)ca rba moyl) pyrr o lid i--1.-y)-3,3.-d im ethVl- 1 OXO 1)Utan'-2-y I)a m ino)-2 842 oxoeth oxy)a zetid in-i-- 9 82. 85 984.85 yi) ethyl) ami no) nicotina m d e
N-((lr,3S)-3-(3-chioro-4 cyanophenoxy)-2,.2,4,4 Ietramethy!CYCiabu)ty!i)-6-((S)-4 (2-(4-(2-(((S)-1-((2S,4R)-4
rn.ethyl thi azl-5 v 10ph en v )et hy 10c arb ama yl1) pyrr o H d in-1-yi)-3,3 -di met h y I-1 843 K 1)U t,)'- 2-yI)a m ino) -2- 1094.6 19. oxoethyl) p ipera z in---y) ethyl) 3-(hyd roxym ethyl) p iperazin- 1 y)nicotinarIde
4'78
N-((-r,3R)-3--(3-chloro-4 cyanophenoxy)-2,2,4,4 tetramethy cyci obutvi)-6
4-hydroxy-2-(((R)--2-hydroxy-i 84 4- (4-meth yIth iazo 1-5~ ("~ 1040.9 1042.9 0ipheriyl)ethy'i)ca-barnoyl)pyrr 5 ol;din-1-yi!)--3,3-dim.,eth yl-i oxobutan-2-yl)amino)-2 oxoe- hxy)et hyl)-2,6 dimnethyi pperazin-i ____ _________________________________________y!)nicotinamide ________
[0946] Table 29: Additional Exemplary Compounds
Measured Ix Structure ConmpoundiNameMaso at mlz rnlz
N-(fir,3R)-3-(3-chioro-4 cyanophenoxy)--2,2,4,4 tEt'rarmeithy'cyc'abuty!)-6 k-1. (4-((IR;3S)-3-(2-(((S)-l ((2S,4R)-4-hydroxy-2-(((S)
y!)phenyl)ethy!)carbar, .yl) pyrrolidin-1-yIl)-3,3 dirnethyl-1-oxobutan-2 yl~arnino)-2 845 oxoethoxy)cyclobutyl) pipe 10255 1024.6 razin-1-yi~nicotinamide
4,79
N-((i-r,3R)-3-(3-chlioro-4 cyanophenoxy)-2,2,4,4 tetra.methy cyciobuty)-6
((2S.AR)-4-hydroxy-2-(((S) i--(4-(4-methyithiazol-5 yl)ph e ny1) et h yl)c aba r oyI1) py rro Iid in -I-yI1) -3,3
y;0arnino)--2 846 o xo e tho xy)c y c:Io bu ty 1) p i P 022.6 12. razi n- 1-y1)n c ot inamid e
N - (r, 3r) -3 -(3- chioro-4 cya n oph enoxy)-2,2,4; 4 'N .. tetramnethylcycldobuty-6
hydroxy-2-(((R)-2-hvd roxv i-(4-(4-methylth1zo5 847 "Nyl) phenyl)ethyl)ca rba rnyl) '11065.25 1067 3
'' dimiethyl-1-oxobutan-2 Soxoethy)piperidin-4
yi)met.hyl)piperazin-1- _____ ____________________________________________yinicotinarnide N-((.r,3r)-3-(3-chlioro-4 cyanophenoxy)-2,2,4;4 tetramnethylcyciobutyl06-' (4-(21.-(2-((S)-1-(('2S,4R)-4. hydr-oxy-2-(((S)-4-(4-(4- i rnethylthiazl-5- 10586 8481065 yi )phernyl)ethyi )carbam,-oyI) 66 *'\'"~~~*~ pyrrolidirn.y)3rte:il
......oxoisoindolin-5 vi)oxv)ethyl)piperazin1l _____ _______________________________________________yi~nicotinarnide _________
'>< N-((_IS)-3-(3-chloro-4 cyanophenoxy)-2,2 dlimethylcyclobu-yi-6-(4
methylthiazol-5 849 yipenIeyylar~ ) 9)68.42 970.42 pyrrolidin-i_-yI)-3,3
oxoethoxy)ethyl) piperazi ri I yl)nicotinamide ------------ ~~~ ~~~~~--------------------------------------------------------- -( 1,R3(3a 4 cypnophenoxy)-2,2 di!-nethylcyciobutyI)-6-(4
hydroxy-2-(((S)-'I-(4-(4 methylthiazol-5 850 vl)phenyl)ethvl)carbamoyl) 11968.42 970.42 pyrrolidin-.>yI)-3,3 d iim ethyI- 1-oxo butan-
o)xae',th oxy)ethy) pi pe r z n i-yInicotinamide
N - (r, 30-3 -(3- ch 1oro-4 ~ cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl-E - ~ . 4-((3-(2-((fS)-1-(f2S,4R)-4 hydroxy-2-(((S)-I-l-(4 ~~ rn~ethyk hiazol-5--1~. 851 y'!)phenryI)ethy'!)carbamoyI) ' 1022,95 pyrrolidin-i--yI)-3,3 di methy I- -oxo buta n-2 yl~arnino)-2
yl)rne-hvl)piperazin-IL y'Onicotinarnide
f(flr,3r)-3-(3-chloro-4 cyanophenoxy)-2,.2,.4, te ranrethylcyclobu.A~carb amoyl)pyr!idin-2 852 r'~.yl) pip era zin -1-yl1) et 11 xy)-1 1098.95 1100.9 N o xoisindolin2-yl'3 m4(4ethua yl)a-5-( V 0 p ,e n y1) e th )carb a raoyl1) ______pyrrolidin-3-yl acetate
[0947] Synthesis of Example 853: IH OH i HN O
- - Dess-Martin HC1 BnO K 2C0 3, DMF, nO .N DCM, rt, ovemight BnO )K-N 100°C, 20 h Y NaBH(OAcDCM, rt, overnight 0
N' 0 N 0
Pd/C, H 2 N EtOH, rt,2h HO N 0 0
OH
1) Amide bond formation N 2) Hydrolysis of ethyl ester 3) Arnide bond formation NO. N 0 o for example 829 and 833
Example 853
N N
109481 Step 1: Synthesis of benzyl 6-[4-(hydrxymethy)piperidin-1I-ylpyridine-3-carboxylate: OH Nj
BnO N
0
[0949] Into a 100-mL round--bottom flask, was placed benzyl 6-chloropyridine-3-carboxylate
(4.0 g, 16.1 mmol,L00 equiv), N,N-dimethylformamide (30 mL), piperidin-4-yinethanol (1.85 mg, 16.1 mmol, 1.00 equiv). potassium carbonate (6.6 g, 48.0 mmol, 3.00 equiv). The resulting solution was stirred for 16 hours at 100 °C in an oil bath. The resulting solution was extracted with ethyl acetate (100 mL x 2) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 3.42 g (65%) of benzyl 6-[4-(hydroxymethyl)piperidin--vl]pyridine.-3. carboxylate as colorless oil. 109501 Step 2: Synthesis of benzyl 6-(4-formyilpiperidin-1-yi)pyridine-3-carboxylate:
BnO N
0
[09511 Into a 250-mL round-bottom flask, was placed benzy] 6-[4-(hydroxymethyl)piperidin-1 yl]pyridine-3-carboxylate (3.42 g, 10.6 mmol, 1.00 equiv) and 100 mL dichloromethane. 1,1,1 Triacetoxy)-1I-dihydro-1,2-benziodoxol-3(1-1)-one (6.7 g, 15.8 mmol, 1.50 equiv) was added slowly. The resulting solution was stirred for 4 hours at room temperature. The reaction was then
quenched by the addition of 100 mL of saturated Na2 S 2 03 . The resulting solution was extracted
with dichloromethane (100 mL x 2) and the organic layers combined. The mixture was dried
over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. This
resulted in 3.06 g (67%) of benzyl 6-(4-formylpiperidin-I-yl)pyridine-3-carboxvlate as yellow oil.
[09521 Step 3:Synthesis of benzyl 6-(4-[[4-(2-ethoxy-2-oxoethyl)piperazin-I yl]metlhyl]piperidin-1-yl)pyridine-3-carboxylate:
N 0 N N
BnO 80
[0953] Into a 100-mL round-bottom flask, was placed benzy benzyl 6-(4-formylpiperidin-I yl)pyridine-3-carboxyate (3.06 g, 9.44 mmol, 1.00 equiv) and ethyl2-(piperazin-1-yli)acetate hydrochloride (2.0 g, 9.44 mmol, 1.00 equiv). The resulting solution was stirred at room
temperature for 5 minutes and then sodium triacetoxyborohydride (6.0 g, 28.32 mmol, 3.00
equiv) was added. The reaction was then quenched by the addition of 100 mL of water. The
resulting solution was extracted with ethyl acetate (100 mL x 2) and the organic layers combined
and concentrated under vacuum. The residue was applied onto a silica gel column with
dichlioromethane/methanol (9/1). This resulted in 2.3 g (51%) of benzy 6-(4-[[4-(2-ethoxy-2 oxoethyl)piperazin-1-yIImethylipiperidin-1-yl)pyridine-3-carboxylate as yellow oil. LC-MS (ES'): iz 481.50 [MH+], tj 1.25 min (1.9 minute run).
[0954] Step 4: Synthesis of 6-(4-[[4-(2-ethoxy-2-oxoethyl)piperazin-1-ylmethyllpiperidin-1 yl)pyridine-3-carboxylic acid:
N N
HO N HO 0
[09551 To a solution of benzyl 6-(4-[[4-(2-ethoxy-2-oxoethvl)piperazin-1-yimethyl]piperidin-1 yl)pyridine-3-carboxylate (2.3 g, 4.79 mmol, 1.00 equiv) in 100 mLEtOH was added Pd/C (10%, 1.0 g) tinder nitrogen atmosphere in a 250 ml round bottom flask. The flask was then
vacuumed and flushed with hydrogen. The reaction mixture was hydrogenated at room
temperature for 2 hours tinder hydrogen atmosphere using a hydrogen balloon, then filtered
through a Celite pad and concentrated under reduced pressure. This resulted in 1.3251 g (71 %)
of 6-(4-1[4-(2-ethoxy-2-oxoethyli)piperazin-1-yl]methylpiperidin-1-yl)pyridine-3-carboxylic acid as a white solid. 'H NMR (300 MHz. CD 30D): 8.64 (d, J = 2.4 Hz, IH), 7.97 (dd, J = 9.1, 2.4 Hz, 11), 6.75 (d, J = 9.1 Hz. 1l), 4.40 (d, J = 13.3 Hz, 2H), 4.15 (q, J = 7.1 Hz 211), 3.26 (s. 211), 2.92 (td, J = 12.9, 2.6 Iz, 2H), 2.69 (s, 811), 2.41 (d.J = 6.9 Iz, 211), 1.89 (dd, J = 30.6, 10.6 Hz, 3H), 1.29-1.10 (m, 5H); LC-MS (ES+): m/z 391.35 [MH+]. t,,, 0.70 min (3.0 minute run). Chemical Formula: C20H3ON404; Molecular Weight.390.23.
[0956] Steps 5-7: Synthesis of N-((r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl)-6-(4-((4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5 yl)phenyl)ethyl)carbamoyl)pyrroIidin-I--y) --3,3-dimethyl-1-oxobutan-.2-y)amino)-2 oxoethyl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinamide: Steps 5-7 were synthesized
according to similar procedures described above for the synthesis of examples 829 and 833, by
using corresponding starting materials and reagents.
[09571 Synthesis of Example 864:
NHTEA. DMF , s] :x-~ H N H T F_ H N O Brr
O N NH 0 0
2LN--NH EDCIs N H N--NIH
'I, NHOE
-C HP TsOH NHO HI C: N N N NC-R N H N--NH DCM NC - P_2 N NN THH I NaAcBOH
C-N .- N NH -N--( N--N C NHI Na~cTH NC
N N-N
TPNaH- DMF 3' NC
1t OH N O - ~ -1 NH N-NH] N3 N
HATU DEA N) ExarnplseC84
[0958]Step1: SynthiesistofTert-Butyi 2-(4-(2-hydroxyethiyl)piperazin-1-yI)acetate
[ HTEA,DMF HO N NH _ _ ,-N N- P
[0959] Toa solutionof2-(piperazin-1-yethanol(10g0.0T77mol, 1.0 equiv)inTH-F(60nL) were added asolution of tert-butyl 2-bromoacetate (14.9 g,0.077 mol, 1.0 equiv) in THF(10 mL)and TEA0(15.5g,0154mol,2.0equiv) sequentiallyat0C. The souton was stirred at 50°C for 16 hours. The solvent wasconcentrated under reduced pressure. The residuex'as diluted with DCM and washed with saturated aqueous ammoniumnchloride. The combined organic layers were dried (Na 2 SO 4 ),filtered and concentrated under reduced pressure to afford 1007] terts-Butyi 2-(4(2 hydroxyethyl)piperan-1- (16 gy0.c71.85.1% at, yield) as a light yellow liquid. 1H NMR (400 MHz, CDCik): O 3.61 (t,,J= 5.6 Hz, 2H), 3.12 (s, 2H), 2.54-2.60
(m, 81-1), 1.47 (s, 91-1). Chemical Formula: C12H-N 2 O3; Molecular Weight244.33;
[0960] Step 2: Synthesis of Tert-Butyl 2-(4-(2-chloroethyl)piperazin-1-yl)acetate
-4- TsCI I HO- N N - CI-, N\ o //0
109611 To a solution of tert-Butyl 2-(4-(2-hydroxyethyl)piperazin-1-yl)acetate (3 g, 0.012 mol, 1.0 equiv) in DCM (50 mL) were added TEA (3.6 g, 0.036 mol. 3.0 equiv) and TsC (4.7 g, 0.024 tol,2.0 eq). The mixture was stirred at.20°C for 4 hours. The solution was quenched with water, and then extracted with DCM. The combined organic layers were dried (Na 2SO 4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc from 1:0 to 5:1 .and then 1:1) to afford the desired product (1.6 g, 49.5% yield) as alight yellow liquid. 'HNMR (400 MHz, CDC 3 ): 3.58(t,J=7.2Hz,2H), 3.10 (s, 2H), 2.74 (t. J= 7.2 Hz, 2H), 2.60 (s, 8H), 1.46 (s, 9H).Chemical Formula:
C1 2 H23ClN 2 0 2 ; Molecular Weight: 262.78;
[09621 Step 3: Synthesis of 5-Acetyl-IH-pyrazole-3-carboxylic acid
0 0JN- 0 S N 13 HO
2. LiOH N-NH
[09631 To a solution of InC 3 (1.3 g 5.882 mmol, 0.2 equiv) in water (60 rnL) were added 2 ethoxy-2-oxoethanediazonium (4.1 g, 0.0324 mol, 1.1 equiv) and but-3-yn-2-one (2 g 0.0294 mol, 1.0 equiv). The solution was stirred at 25C for 4 hours. The mixture was extracted with EtOAc. The combined organic layers were washed with brine. The organic phase was dried (Na 2SO4), filtered and concentrated under reduced pressure to afford the crude product (3.9 g). Then the crude product (3.9g, 0.0214mol, lequiv) was dissolved inTIHF/1 2 0 (v/v = 10:1, 8OmL). LiOH (3.6 g, 0.0857mol, 4.0 equiv) was added. The mixture was stirred at 25C for 16 hours. The pH of the solution was adjusted to 7-8 with aq.HCl (2M). The solution was concentrated under reduced pressure. The residue was washed with THF. The combined organic layers were concentrated under reduced pressure to afford 5-Acetyl-1H-pyrazole-3-carboxylic acid (3 g, 66.2% yield) as a brown solid. I H NMR (400 MHz, MeOD): ( 7.01 (s, 1H), 2.54 (s,
3H). Chemical Formula: C6 H6 N 2 0 3 ; Molecular Weight: 154.12.
[09641 Step 4: Synthesis of (S)-5-Acetyl-N-(-(3-(3-chloro-4-cyanophenyl)-1H -pyrazol-1 yl)propan.-2-yI)-1H-pyrazole-3-carboxamide Cl j~=\ ' NNH 0 o Nc ci rlNH\\
HO N H N-NH N-NH EDCI, HOBt NC' \
[0965] To a solution of 5-Acetyl-1H-pyrazole-3-carboxylic acid (1.27 g, 70%. 5.76 mmol 1.5 equiv) in DMF (10 mL) were added DIEA (1.5 g, 11.52 mnol, 3.0equiv) and 3-(3-chloro-4 cyanophenyl)-1H-pyrazol (1 g, 3.84 mmol, 1.0 equiv). 5min later, HATU (1.75 g, 4.60 mmol, 1.2 equiv) was added. The mixture was stirred at 25°C for 30 minutes. Then it was quenched with water. The solution was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic phase was dried(Na 2 SO 4 ), filtered and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc 1/1) to afford (S)-5-Acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-IH-pyrazol-1-yl)propan-2-yl)-lH pyrazole-3-carboxamide (350 mg, 22.9% yield) as a grey solid. 1H NMR (400 MI-z, MeOD): Y
7.89 (s, 1H), 7 .77-7.89 (m, IH). 7.70 (s, 1H), 7.69 (s. 1H), 7.24 (s, 1H), 7 76 (d,J .4Hz,1H), 4.31 (s, 1H), 4.07-4.12 (n, 2H), 2.51 (s, 3H), .22-1.28 (m, 3H).
[0966] Chemical Formula: C19 H1 7 CN6 0 2 : Molecular Weight 396.83;
[09671 Step 5: Synthesis of 5-Acetyl-N-((S)--(3-(3-chloro-4-cvanophenyl)-iH-pyrazol- yl)propan-2-yl)-1-(tetrahydro-2H-pyran-2-yi)-I H-pyrazole-3-carboxamide 0,0 I N 'DHP, TsOH
NC H DCPA D0CM N ' N--N THP
[0968] To a solution of (S)-5-Acetyl-N-(1(-(3-(3-chloro-4-cyanophenyl)-IH-pyrazol-1-yl)propan 2-yl)-1-pyrazoe-3-carboxamide (35 mg0.883 mmol, 1.0 equiv) in DCM (10 mL) were added DHP (111 mg, 1.330 mmol. 1.5 equiv) and TsOH (30 mg, 0.0176 mmol, 0.2 equiv). The mixture was stirred at 20°C for 20 hours. The solution was quenched with water and extracted with EtOAc. The combined organic layers were washed with aq.NaHCO3. The organic phase was dried (Na2SO 4 ), filtered and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (PE/EtOAc from 10:1 to 5:1) to afford 5-AcetylN-((S)- (3-(3-chloro-4-cyanophenyl)-IH-pyrazol-1-yl)propan-2-yl)-I-(tetrahydro-2H-pyran-2-yl)-IH pyrazole-3-carboxamide (320 mg, 75.4% yield) as a grey solid.
[0969] H NMR (400 MH z, MeOD): 0Y 7.80 (s, 1H),7.83--7.97 (m, 1H-), 7.75-7.77 (m, 1 H), 7.7 1 (d, J= 2.4 Hz, I1), 7.35 (s, 1[), 6.76 (d,J= 4.4 Hz, 1H), 6.24-6.24 (d, J= 2.0 Hz, 1H), 4.31 (s, 1H), 4.07-4.12 (m. 2H), 3.97-4.02 (m,IH), 3.78-3.81 (m, 1H),2.51 (s, 3H), 2.31-2.41 (m, IH), 1.71-1.72 (m, 2H),1.59-1.61 (in,21) 1.22-1.28 (m, 31).
[0970] Chemical Formula: C 2 4H25 (N 6 O3 ; Molecular Weight: 480.95;
[0971] Step 6: Synthesis of iV-((S)--(3-(3-Chloro-4-yanophenyl)-1H-pyrazol-1-yl)propan 2-yi)-5-((Z)-1-(hydroxyimino)ethyl)-I-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3 carboxamide
NCN NC N HP EO. cO ~NC'N N H FHP
109721 To a solution of5-Acetyl-N-((S)-1-(3-(3-cloro-4-cyanophenyl)-1H-pyrazo1 yl)propan-2 -yl)-1-(tetrahydro-2H-pyran-2-yl)-IH-pyrazole-3-carboxamide (320 mg. 0.665 mmol, 1.0 equiv) in EtOI- (20 mL) were added NaOAc (1.09 g, 13.304 mmol,20 equiv) and NH 2OH-HCI(924 mg, 13.304 mmol,20 equiv). The solution was stirred at 20'C for 20 hours, and then concentrated under reduced pressure. The residue was dissolved in EtOA and washed with brine. The organic layer was dried (Na 2SO 4), filtered and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (DCM/MeOH = 100/1) to afford N-((S)-I--(3-(3-Chloro--4-cyanophenyl)-1H-pyrazol-1--yl)propan-2-yl)-5--((Z)-1 (hydroxyimino)ethyl)-I-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide (100 mg. 30.3% yield) as a white solid.
[0973]1 H NMR (400 MHz, MeOD): d 8.17-8.20 (m, 1H), 7.95 (s, 1H), 7.72-7.79 (m, 1H),
7.68-7.71 (m, 1H). 6.83 (d, J= 2.0 Hz, 1H), 6.71--6.73 (m,I1H), 6.08 (d, J= 1.6 Hz, IH), 4.31 (s, 1H), 4.07---4.12 (m.2H) 3.97-4.02 (m, IH), 3.78-3.81 (m. 1H), 2.09-3.31 (m, 3H), 1.92-1.99 (m, 41-1), 1.58 (s, 3H), 1.21-1.28 (m,3H).
[0974] Chemical Formula: C2 4 H 2 6ClN 70 3 ; Molecular Weight: 495.96;
[0975] Step 7: Synthesis of (S,E)-Tert-Butyl 2-(4-((1-(3-((1-(3-(3-chloro-4-cyanopheiyl) IH-pyrazol-1-yl)propan-2-yl)carbamoyl)-IH-pvrazol-5-yl)ethylidene)amino)oxy)ethyl) piperazin-1-yl)acetate CI O0HO N0N 09 HQ ,~< -- i ~ I~ NC- N NH N-NH ---- ------ --- -------------------- N-N ' NaH, DMF, 3h CI N
THF NC
[0976] To a solution of -((S)-1-(3--(3-Chloro-4-yanophenyl)-1H--pyrazol-1-yl)propan-2-yl)-5 ((Z)-1-(hydroxyirnino)ethyil)--(tetrahydro-2H-pyran-2-yl)-IH-pyrazole-3-carboxamide (100 mg, 0.2016 mmol, 1.0 equiv) was added NaH (15 mg, 0.6048 mmol, 3.0 equiv) at'20C. After 10 min, tert-Butyl 2-(4-(2-chioroethyl)piperazin-1-y)acetate (79.5 ng, 0.3024 nmol, 1.5 equiv) was added. The mixture was stirred at 20°C for 20 hours. The solution was quenched with water, and then extracted with EtOAc. The combined organic layers were washed with brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH = 100:1) to afford (S,E)-tert Butyl 2-(4-(2-(((1-(3-(1-(3-(3-chlioro-4-cyanophenyl)-1H--pyrazol-1-yI)propan-2-yI)carbamoyl) 1H-pyrazol-5-yl)ethylidene)amino)oxy)ethyl)- piperazin-1-yl)acetate (60 mg, 41.2% yield) as a white solid, which was used into the next step without further purification.
[0977] Step 8: Synthesis of N-((S)-1-(3-(3-Chloro-4-eyanophenyl)-1H-pyrazol-1-yl)propan 2-yl)-5-((E)-1-((2-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((SV)-1I-(4-(4-methylthiazol-5 yl)phenyl)ethyl)carbamoyl)pyrrolidi-1-yl)-3,3-dimethyl-1-oxobuta-2-yl)amino)-2 oxoethyl)piperazin-1-yl)etioxv)imino)etiyl)-1H-pyrazole-3-carboxamide
C THP I N' 2. UL~M-3, HATrU, D)IEA' NC' '
Exape 864
[0978] To a solution of (SE )-tert-Butyl 2--(4-((1-(3( -((-(3-(3-choro-4-cyanophenyl)-1H
pyrazol-1-yl)propan-2-yl)carbamoyl)-1H-pyrazol-5-yl)ethylidene)amino)oxy)ethyl)- piperazin 1-yl)acetate (60mg) in dioxane (2 mL) was added HCi-dioxane (4mL. 6N). The mixture was stirred at 20C for 2 hours. The solution was concentrated in vacuo to afford the crude desired product (60 mg). Then the crude product (60 mg, 0.103mmol, I.Oequiv) was dissolved in DMF (5 mL). TEA (208 mg, 2.06 mmol, 20.0 equiv) and ULM-3 (55 mg, 0.124 mmol, 1.2 equiv) were added at 25°C. 5 minutes later, EDCI (197mg, 1.O3mmol, 10 equiv) and1-1013t (139mg, 1.03mmol, 10 equiv) were added. The resulting solution was stirred at 25C for 16 hours. The mixture was quenched with water, and then extracted with EtOAc. The combined organic layers were washed with brine. The organic layer was dried (Na2 SO4), filtered and concentrated under reduced pressure. The residue was purified by Prep.TLC (DCM/MeOH )13:1) to afford N-((S) 1-(3-(3-Chioro-4-cyanophenyl)-111-pyrazol-1-yl)propan-2-yl)-5-((E)-I-((2-(4-(2-((S)-1 ((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-rmethylthiazol-5-il)phenyl)ethyi)carbamoyl)pyrrolidin-1-yl) 3,3-dimethyl-I-oxobutan-2-yl)amino)-2-oxoethyl)piperazin-1-yl)ethoxy)imino)ethyi)-1H pyrazole-3-carboxamide(33.2 mg, 31.9% yield) as a white solid.
[0979] H NMR (400 MHz. MeOD): d 8.86 (s, IH),7.96 (s. IH), 7.96 (s, IH), 7.70-7.78 (m,
1H), 7.69 (s, 1H), 7.39-7.44 (rn,4H), 6.75 (d,,J= 2.4 Hz, 1H), 4.99-5.00 (m, 1H), 4.62 (s, 1H), 4.55-4.56 (In, 311), 4.38-4.43 (in, 511), 3.72-3.89 (m, 2H), 3.07 (s, 111), 2.99 (s, 1H), 2.82-2.86 (m, 311), 2.64-2.67 (m, 711), 2.47 (s, 311), 2.18 (s, 41), 1.91-1.99 (m, 11-), 1.49 (d,- = 7.2 Hz, 2H), 115-1.30 (m 6H), 1.04(s, 9H).
[09801 LC-MS: (ES+): mz 1008.4 [M+H];tR = 3.636 min.
[0981] Chemical Formula: CsH 62ClN 3 0 6S; Molecular Weight: 1008.63; 10982] Unless otherwise noted, Examples 854-863 were synthesized according to similar procedures described above for the synthesis of Examples 853 and 864, by utilizing corresponding starting materials and reagents.
[09831 Table 30: Additional Exemplary Compounds
Measured Mass Ex Ion Data Structure CompoundName m-f/z m/z _______________________________________________(1) (2) N-((Ir,3r)-3-(3-chIoro-4 cyanophenoxy)-2,2,4,4 OH tetramethycyclobutyl) NO 6-(4-(4-(2-(((S)-1 N N N A N ((25,4R)-4-hydroxy-2 H H O NH (((S-I14-(4 methylthiazol-5 853 01049.49 10,51.49 yI)phenyl)ethyl)carbamo yI)pyrroldin-1-yI)-3,3 dimethyl-1-oxobutan-2 CIN yl)amnino)-2 oxoethyl)piperazin-1 yI)rnet:hyI)piperidin-I yl)nicotinamide
N-((Ir,3r)-3-(3-chlara-4 cyanophenoxy)-2,2,4,4 tetramethylcyclabutyl)
N. -, . (25,4R)-4-hydroxy-2 N ~ ~(((R)-2-hydroxy-1-(4-(4 854 H " eh~hao--106549 1067.49 N N H ~ 0 'i~ ~H l)phenyl)ethyl)carbama b yl)pyrralidin--1-yI)-3,3 dimethyi-i-axabutan 2 S yl)amino)-2 oxo aethy1) p ip era z in -I N y1)m eth y1)p iperi di! i ______ _________________________________________________yl)nicatinamide ____
N-((I r, 3r)-3 -(4- cyan o- 3 oj (t rifIuaoremret hy1) p heneox y)-2,2,4,4 N~. tetra methyl cyclobutyl) <'N'" - N6-(4-2-(2-(((S)-i
855 (~~~(2S4R)-4-hydroxy-2- 13.5 1~4 0 methyithiazal-5 Q C $>yl)phenyl)ethyl)carbamo V yl)pyrralidin-i.-yI)-3,3 F dimethyi---axobutan-2 FF yl~lamino)-2 axaethaxy)ethy)l)piperazi n-i-yl)nicatinarnide N-((ir,3r)-3-(3-chloro-4 >- canepher axy)--2,2,4,4- tetramethylcyclabutyl)
-M, ~~ ~ ((25,I4 R) -4 -h ydroxy 2 C"'\ kN~N~.A\~ N ethyithiazal-5
856 V-'-yI)phenyl)ethyl)carbama 8"56yrcii-iy)3 1056,9 058.9 rnmethyi-i-axabutan-2 N'yl)-3oxoisoindo~in-5 eNyl)aoxy) ethy 10pipera ziI--. V)nicatiramide
(3R,5S)-l-f(S)-2-(6-(2-(4
4-cyariophenoxy) 2,2,4,-/ tetra methylcyclobutvl)ca -~ rbarnoyI)pyridin-2 A ... yI)pi,)erazin-1-
87'' oxo iso in d oi n- 2-y1) -3 109 !101 nethylbutanoyly-5(((S)
yl)phenyl)ethyl)carbamo yl)pyrrolidin-3-vl acetate
(2R,4S)-1l-((2S)-2-.(2-(3 (4-(4-((flr,3r)-3-(3 chloro-4 cyano~henoxy)-2,2,4,4 tetrarniehylylCObtyl)ca ~ rbamoyl)phenyl)butyl) rb1 858 1iyl[.1atn 03347 I035.47 diazabcco321otn 8-yl)acetamido)-3,3 ~- dimethyibutanol)-4 hydroxy-N-((S)-1--(4-(4.. methylthiazol-5 yl)ph enyl) ethyl) pyrro Iid i ne-2-carboxamide
(4- (((1ir; 3r)-3- (3--chlIaoro O~ 4-cyanaophenoxy) N 2,2,4,4 N[- ~ ', ~tetra methyl cyclobutl)ca 89N rbamnovl)phenyl)bu-yi)pi 859 perazin--yI-)acetamido)-- 102346 i02546 H ' 3 3-d inethyl bu tanoyl) 4-hydroxy-N-((R)-2 hydroxy-1--(4-(4 S methylthiazol-5 N yl)phenyl)ethyl)pyrrolidi ------------ ----------- -------------------- L-n e -2 -c a rb ox arn ide .........------------L------
4 92)'
N-((Ir;3R)-3-(3-chloro-4 cyanophenoxy)-2,2,4,4 tetrarnethylcyclobutyl) S6-(4((IS,3R)-3-((2-(((S)
H r' r 1-((2S,4R)-4-hydroxV-2 S H 0 0 nthylthiazo-5 80fHN 102143 102'3.43 80 N~ HN> yI)phenyl)ethyl)carbamo yI) 1iyrrolidin-i--yl)-3,3- jfl~ N ~N '-.-/ dirnethyV-amabutav-2 yI)a. .ino)-2 N oxoethyI)arnino)cvclobut yI)piperazini-- ______ ),icotinam-,ide
cyarlophenoxy)-2,2,4,4 tetraMethylCyClObUty) H6-(4((R,3S)-3-((2-(((S) H 9 1\ 1-((2S,4R)-4-hydroxy-2 N (((S)1-41(4 861 0 H 6HN methylthiazol-5- 12.5 1~ N j vI)phe!-yl)ethyl)carbamo yI)pyrroIidin--yI-)--3,3 diMethylVIoxobutan-2 0/ 0 /~*~- ~yI)ar. ino)-2 'Noxoethyi~anino)cyclobut yI)piperazin-3 _____ ________________________________________ --- _ yI)nicotinamidce
chloro-4 cy'anophenoxy)-2,2,4,4 /01
/ trrntylyclbut-2 862 v)piperazin-L NI N 0 ylbethoxy)acetarnido)- ~ 9. H I , HN 3,3-dirnethylbu tanoyl) 0 S- 5(()1-4-4 methylthiazol-5 N y 1) p ~I~he n V )ethy1) ca rbam o oxobutanoic acid
H IDDID D 0 ? s NH Y 'A NHI 4-cynophenoxy) ~-< N DHDIDDDN 2,2,44 9909 86 GI0N *- etrdrnethylcyclobutyl)ca 977.51 [M Na rbarnoyl)phenyl)arnino)p +
/ \ entyl-1,1,2,2,3,3,4;4,5 d9)oxy)acetamido)-3,3 ____________________________________________ hydroxv-N-((S)-1--(4-(4a- _________ methylthiazol-5 yl)phenyl)ethyl1)pyrrolidi ne-2-carboxamide N-((S)-1-(3-(3-Chloro-4 cyanophenyl)-1H pyrazol-1-yl)propan-2 yl)-5-((E)-1-((2-(4-(2 (((S)-1-((2S,4 R)-4 hydroxy-2-(((S)-1-(4-(4 methylthiazol-5- 1030.37 0864N N OH yl)phenyl)ethyl)carbamo [M+Na] r8 N 4 I yl)pyrrolidin-1-yl)-3,3- 100839 ~ N-' 1083
+ --NH N4-NH CI's -'N'N Hdimethyl-I-oxobutan-2 HN yl)amino)-2 N oxoethyl)piperazin-1 yl)ethoxy)irnino)ethyl) S -ipyrazole-3 N carboxamide
109841 In certain embodiments, the description provides a compound having a structure selected
from the group consisting of Examples 1-864 (see Tables 2-30), a salt, a polymorph, and prodrug
thereof. In certain additional embodiments, the description provides a composition comprising at
least one of the compounds of Examples 1-864, including a salt,polymorph,andprodrugthereof.
In still additional embodiments. the description provides a therapeutic composition comprising at
least one of the compounds of Examples 1-864, including a salt, a polymorph, and a prodrug
thereof, and a pharmaceutically acceptable carrier.
[09851 Examples - In vitro and in vivo assays.
[0986] The experimental results presented below are made with reference to theTables and
Figures 1-7. 109871 1. Androgen Receptor ELISA Assay.
[09881 Compounds have been evaluated in this assay in LNCaP and/or VCaP cells utilizing
similar protocols. The protocols used with VCaP cells are described below. The androgen
receptor ELISA assay was performed using PathScan AR ELISA (Cell Signaling
Catalog#12850) according to the following assay steps:
[09891 VCaP cells are seeded at 30,000 cells/well at a volume of 200 pL/well in VCaP assay
medium [Phenol red free RPMI (Gibco Cat#11835-030); 5% Charcoal Stripped (Dextran treated) 113S (Omega Scientific, Cat#FB-04); Pen/Strep Life Technologies (Gibco Cat#: 10378-016); 0.
lnM R1881 (Sigma, Cat# R0908) is added upon the start of the assay, not during initial plating of the cells) in Corning 3904 plates. The cells are grown for a minimum of 3 days.
[0990] First, cells are dosed with compounds diluted in 0.1% DMSO - use a polypropylene plate according to the following protocol: (1)(i) make 1000x stock plate in DMSO; (ii) 20mM stock diluted 1/6.7 with DMSO (5 pL + 28.3 pL DMSO) =3mM into row H; (iii) perform serial dilutions in log doses (10L of PROTAC + 20 pL DMSO) from row H towards row B. Reserve row A for DMSO; (iv) 7 doses total (final concentration in this 1000x plate will be 3 mM, 1 mM, 333 pM, I ltM, etc). (2)(i) Make 1x stock plate in media; (ii) transfer 2.5 pL of the 1000x stock to a new 1x stock plate (use 12 channel pipet, start at A (DMSO control) work thru -. When 247.5 iL of media is added to this plate, it will serve as a lOx stock; (iii) make media + lnM R1881 for making 1x stock plate; (iv) add 247.5 IL of media with I nM R1881 to each well of the 1Ox stock plate, mix.
[09911 Then 22 pL of 1x stock is added to cells and incubated for 24h. Ix Cell Signaling Cell lysis buffer is made (Catalogue #9803; comes with the kit) - prepare for 50 pL/well. Keep on ice. Media is aspirated, and 50 pI lx cell lysis buffer/well is added. The cells are placed on ice for 10 minues. The solution is mixed and transferred to PCR plate, and centrifuged at 4C for 10 minutes at 4000 rpm.
[09921 5 iL is transferred to fresh plate (use immediately or freeze -80C); 115 L ELISA Dilutant is added (0.15ug/ml - 0.075ug/ml; comes with the PathScan ELISA).
[09931 Add 100 lJwell AR Elisa; cover and shake, 37C for 2hrs; dump, tap, wash 4x 200 L ELISA wash buffer; add 100 pL/well mouse AR detection Ab; cover and shake, 37C forI lhr; dump, tap, wash 4 x 200 pL ELISA wash buffer; add 100 pL/well anti-mouse -HRP conjugated Ab (comes with the kit); cover and shake, 37C for 30 min; allow TM13 reagent to come to room temperature; dump, tap, wash 4x 200 pL Elisa wash buffer; tap; add 100 L TMB, shake 5min while watching color. Add the stop reagent when light blue color develops. Add 100 tL Stop solution; shake and read at 450nM.
[0994] Progression of prostate cancer in patients treated with anti-androgen therapy usually involves one of several mechanisms of enhanced Androgen Receptor (AR) signaling, including increased intratumoral androgen synthesis, increased AR expression and AR mutations. PROTACs (PROteolysis TArgeting Chimera), which uses bi-functional molecules that simultaneously bind a target of choice and an E3ligase, cause ubiquitination via induced proximity and degradation of the targeted, pathological protein. As opposed to traditional target inhibition, which is a competitive process, degradation is a progressive process. As such, it is less susceptible to increases in endogenous ligand, target expression, or mutations in the target. Thus this technology seems ideal for addressing the mechanisms of AR resistance in patients with prostate cancer.
[09951 AR PROTACs degrade AR in LNCaP and VCaP cells, with nM to pM potency, and had a >85% reduction in AR concentration(Dax) Degradation was rapid, with 50% of AR lost within 15 minutes and maximal degradation observed by 4 hours. The duration of AR knockdown was long-lasting, with no recovery of AR observed over several days. The degradation process in cells was specific, as PROTACs with an inactive epimer for E3 ligase binding did not degrade AR. AR PROTACs induced rapid apoptosis and cell death in VCaP cells. In LNCap and VCaP cell systems, AR PROTACs were anti-proliferative under conditions in which enzalutamide was inactive, such as increasing concentrations of the AR agonist R1881 and cells containing the ARF876L mutation. AR PROTACs typically had tm values of several hours and bioavailability of >50% after ip or sc injection. In mice, AR PROTACs have shown in vivo activity, including involution of seminal vesicles, reduction of AR protein levels in the prostate, and regression of VCaP tumors.
[0996] The following assay results were generated using the androgen receptor ELISA Assay described above, where compound potencies were characterized in highest percentage of Androgen Receptor degradation (Dmx)observed and compound concentration that caused 50% Androgen Receptor degradation (DC5 0 ).
[09971 Table 31. Androgen Receptor degradation (Dm)observed and compound concentration that caused 50% Androgen Receptor degradation (DC, 5 ). Dax: + (Dm_ ax525%);++(26%5Dax
550%); +++ (51% < Dax' 70%);++++ (71% < Dmax); DCso: A (D 1 50nM); B (51n1M DCO <
500nM); C (50lnM< DCo ).
VCaP Ex LNCaP LNCaP VCaP Dmax Dinax(% DCo (p M) DCO(p M) (%)
4-+++ A4++ A
VCal Ex 1-.NCaP LN(al V~aP Dinax I D~imax( DC% IL(pM) DCs5 0 (riM)
2 A A
4 A..A
5 B
6 A
7A
9 + A
10 ±+--L A A
iiA .. A
12 B A
13 ++A
14 C
15 A
16 ... A
P B
20 B
21 +
22 .. A ++B 23 .. 144 B
24 A
25A ++A 26A 2 A
Ex 1-.NCaP LNCall V~aP Dinax I -4 ihnax( DC% IL(pM) DCs50(riM)
28 AA
29 B..
30 .... ± A
A ... A
3 ... A A
33 A
34 A
37 +-+A
38 A
++ A
4-0 A
41 +-+A 42 A 43 ++A
4-4 A
45 +-+A 46 A
47 ++A
4-8 A
49 A
50 A
51++ A
A .. A
VCal Ex 1-.NCaP LN(al V~aP Dinax I -4 iDmax DC% 1X(pM) DCs5 0 (riM)
54 +c
56 ++
+ 60 ++B 61 B 62C 633 ++ A
64B
65B A 66B -B
61A A
69 .... B ++ B
70 +++ + A A
71 ... A..A
12 +++ B 73AA +--L
74 144 -15+ A
76A ++1 A +A
A A A ... A
80 c 1C ++ B
VCaP Ex L.NCaP LNCaP VCaP Dmax -4 Dmax(%) DC (pM) DCs (tM)
83 B B 184 +++ B
85 ++C
[09981 Table 32. Additional Androgen Receptor degradation (Dm.) observed and compound concentration that caused 50% Androgen Receptor degradation (DCfO). DIla: + (Dmax < 25%); ++
(26% < Dmax <50%); +++ (51% < Dmax <70%); ++++ (71% Dm ); DC5 0: A (D < 50nM); B (51nM<DCS500nM);C(50InM DCso)
VCaP VCaP Ex# Dmax (%) DC5 (p M)
86 ++ A
87 ++ A
88 89 ++++ A
94 ++++ A
95 +++ A
96 +++ A
99 +++ A
100 ++++ A
101 +++ A
102 ++++ A
103 ... A 104 ++++ A
105 +++ B
106 ++++ A
107 .A
VCaP VCaP Ex-# Drnax(% DC ,O(pM)
108 .. A 109 ++-A 110 ... A
1 12 .. A 114 .. A 115 ... A 116 ... A 117 .. A 118 ++-A 119 + A 120 ... A 121 A
123 ... A 124 ++-A 1 25 .. A 126 .. A 127 ... A 128 ++-A N2 A 130 .. A 131 .. 132 ... A 133 +
134 + +++ A-- - - - - - - - - - - - - - - - - - - - 135 +++4 A
136 ... A
VCaP VCaP Ex-# Drnax(% DC ,O(pM)
137 .. A 138 ++-A 139 ... A 140 ... A 141 .. A 142 ++-A 145 ... A 147 ... A 148 .. A 149 ... A 150 ... A 151 ... A 152 ... A 153 ... A 154 ... A 155 ... A 156 ... A 157 .. 158 ... A 159 ... A 160 .. A 161 ++-A 162 ... A 163 ... A 164 .. A 165 ++-A 166 + A 167 ... A
5 02
VCaP VCaP Ex# Dmax(%) DCso (p M)
168 +++ A
169 +++ A
170 ++++ A
171 ++ A
172 +++
173 ++++ A
174 ++++ A
175 +++ A
176 +++ A
177 ++++ A
178 ++ A
180 A
181 +++ A
182 ++++
183 ++++
184 ++++ A
185 +++ A
186 ++++ A
187 ++++ A
188 A
189 +++ A
109991 Table 33. Additional Androgen Receptor degradation(max)observedand compound concentration that caused 50% Androgen Receptor degradation (DCi)). Dmax: +
(Dmax 25%); ++ (26% < Dmax 50%); +++ (51%< Dmx <70%); ++++ (71% <Dmax); DCso: A (Dmax 50nM); B (51nMNDCo5 500nM); C (501nM < DCso.
VCal Ex 1-.NCaP LN(al V~aP DinaxI -4 iDmax( DC% IL(pM) DCs50(riM)
190 A
191 A
192A 193 A 194 A
195 + A
196 +4+A
197 A
198 A
199 A
201 +++A
202 +±+A
203 +-+A 104 +++ A
205 +C
206 .. B 207 ++ B 28 + B
209 ++ C
210 ++ c
211 ++ B
112 .... i C
213 ... B
214 .. B 25 ++ B
504.
VCal Ex 1-.NCaP LN(al V~aP DinaxI -4 ihnax DC% 1X(pM) DCs50(riM)
216 .. B
121-1 4+ A 218 ++
219 ....
220 ..
221 4-+B
222 ++
*2 213 +
224 +
225 -+ A
2'217 ++A
228 .. B
229 4-+ i B
231 .. c 232 + C
233 4-++ C 134 ++ B
235 .. i B 236 + c
123- ++ c B +
239 .. A 240 ... A
241 ++ A
VCal Ex 1-.NCaP LN(al V~aP DinaxI -4 iDmax( DC% IL(pM) DCs 50(riM)
242 + C
243 4-+B 244 + B
245 ++c
246 .... B
24-1 .. AA 18 ++ B
249 .... B
250 .... B
251 4-+B
252 ++B
253 .. B
257 ... B
255 ... B
257 B
259 ... B
260 ... B
263 ++ B
164 + B 265 + B
266 .. B
126-1 4+ B
VCal Ex 1-.NCaP LN(al V~aP DinaxI -4 iDmax( DC% IL(pM) DCs 50(riM)
268 .. c 269 4-+c
27, 1 c
272 + C
273 ++ c
14 ++ B
275 + C
276 + C
27- + B 2178 .... BA
280 + c
281 4-+c
283 .. B 284 + B
285 + C 6 A 287 .. C 288 .... A +A
289 ++ C
NO .4+C
291 + C 292 ... B B
293 .. +
Ex 1-.NCaP LNCaPf a1 V~aP DinaxI -4 Dmx DC%(pM)D~s,)(%)M
294 ++B ++ B
295 .... A A
S29 6 .... B -+A
297 ++
+ 298 B. ++ B
299 .... B
300 A .. A
301 .. A +
302 .... B A
03.... A
304 ++ B
305 .. B 306 .... A +
4-+ B A
308 B .. A 309 ++ +
310 ++C +
[0)10010] Table 34.Additional Androgen Receptor degradation (1) .. observed and compound concentration that caused 50% AndrogenReceptor degradation(DC 5 ). D,,,: +
(D~rK 25%)-,++ (26% <Dl,,, <0%);+..(15 1% <D,,,,70%) ++(71 % <Dl,,,,;DC-: A (Dax<5nM); B(5 IM <IDC-5c<500niM); C(501tM < DC,; 0)).
VCaP Ex VCaP Drnax DCDrM
313 A
VCP Ex VCaP
314 1 + B 3< ++ B
316 1 ++ B
37 ++ B
318 B
319 ++A
320 1 ++ A
321 A
322 +
322)> ++- A
324 1 ++ B
325 1A 329 +A
330 + A
333 1 ++` A
334 1 ++A
335 + A
336 1 .. A
337 1A
338 +- A
339 ++A
340 .. A
341 1 ++` A
342 1 ++A
343 +B
344 1 +B
VCP Ex VCaP
345 + A
346 ++- A
347 ++A
366 A
367 1++- A
368 A
369 A
370 +A
371 1 .. A
372
373 +- A
374 +A
37
376 ++A
377 +- B
378 + A 379 ++ A
380
381 A
382 +A
383 1 .. A
384 A
385 +- A
386 + A
387 1 +
VCP Ex VCaP
388 + A
389 39 o + A
391 +- A
3921
393 1++- A
394
39 +
397 A
398 ++ A
399 +++A
400 + A
401 1 .. A
402 ++A
403 + A
404 + A
405 1 .... A
406 A
407 + A
408 + A 49 ++ A 40 A
411 A
412 ++-+ A
413 1++- A
VCaP Ex VCaP Dmax DCO (piM)
414 + A
415 ++++ A
416 ++ B
417 A
[01001] Table 35. Androgen Receptor degradation (Dmax) observed and compound concentration that caused 50% Androgen Receptor degradation (DC 5 0 ). Dmax:+ (Dax 25%); ++ (26%< Dmax 50%); +++ (51%< Dax 70%); ++++ (71% <Dax); DC: A (Dmax 50nM); B (51nM DCs 500nM); C (501nM DCso )
VCaP VCaP Ex. Dmax(%) DC50 (PM) 418 +++ A 419 ++ A 420 +++ B 421 ++ B 422 ++++ A
423 + C 424 + C 425 ++++ A
426 + C 427 + C 428 + C 429 ++ C 430 + C 431 + C 432 + C
433 +++ A 434 C
435 C 436 ... c 437 C 438 ... A 439 440 4-41
442 ++-A 443 444 ... A 445 ... A 446 ++ C 447 . A 44-8 +4-A 449 ++-A 450 .... 4 A
451 + C 452 + C 453 + C
454 ++ C 455 ... C 456 .... 4 A 457 + C 458 + C
459 ++ C 460 461 ++-A 462 463 464 ... C 465 .... i A
466 ... B 467 468 ++-A
469 A
470 ++-A 471 ++ C 472 ... A 473 ++ A 474 ++ A 475 A 476 ++-A 477
+ 478 ++ B 479 ++
480 ++ C 481 + c 482 ... A 483 ++-A 484 ++-A
495 ++ c 496......A. 497 ++- A
498 ++-A 499 ++ C 500 ++ A-- - - - - - - - - - - - - - - - - - - - 501 ++ A
502 ++ B 503 ... A 504 ... A 505 ++A
506 ... A 507 ++ A 508 ... A 509 ++ B 510 ... A
512 ... B
51.3 A 514 ++ c 515 ... A 516 ... A 517 ... A 518 + c 519 ++ A 520 ++C
521 ... A 522 ++A
523 ++ A 524 ++- A 525 ... C 526 ... A 527 ++ A 528 ++-A
529 + A 530 .... A
531 ++ A 532 ... A 533 ++ A 534 ++A
535 ++ A 536 ++ A 537 ++ A 538 ... C 539 ++A
540 ++-A 541 .... 4 A
542 ... A 543 ... A 544 ... A 545 ... A 546 C
547 +++ A 548 +++ A 549 ++++ A
550 ++++ A
551 +++ A
552 +++ A
553 A
554 +++ A
555 ++++ A
556 ++++ A
559 ++++ A
563 +++ A
564 +++ A
565 ++++ A
566 +++ A
567 ++++ A
568 ++++ A
569 ++++ A
570 +++ A
571 ++++ A
572 ++++ A
573 ++ C 574 ++++ A
575 ++++ A
576 ++++ A
577 ++++ A
Table 36. Additional Androgen Receptor degradation (Dm)observed and compound concentration that caused 50% Androgen Receptor degradation (DC). Dax:+(Dmax 25%);++(26% Dmax <50%); +++ (51% Dmax 70%);++++(71% Dma); DCo: A (D , 50nM); B3(5nM <D50
500nM) C (501nM DCso .
VCaP VCaP Exit Drnax(% DC ,o(pm)
594 + C 595 + A 596 ++ C 597 + C -------- 598 ++ iC 599 ++ C 600 ++ C 601 + c 602 + c 603 + c 604 ++4+ A 605 + c 606 _____ _ A 607! ++ C 608A 609! + C 610 + C 611 + C 61.2 + c 613 ++ C 614 ++ C 615 +++- A 61.6 1+ c 617 + c 618 1 +.. A 619 + C 620 + c 621 + ic 622 + C 623 +++4+ A 624 1+ c 625 ++ C 626 ++ A 627' ++ C 628 ++ C 629 ++ B 630 +++A
631 1+ C 632 ++ C
VCaP VCaP Exit Drnax(% DC ,o(pm)
633 + C 634. ++ A 635 ++4+ A 636 A A++ ------- 637 +++4+ A 63- --------------------------- ------------------------ 638 A
640 +++A
641 +++4+ A 642 +++A
643 + c 644 +++A
645 1 .. A 646 ++ A 647 1 +C 648 + C 649 1 ++ A.. 650 C 651 ++C
652 + C 653 ++A
654 +++A
655 ++C
656 1 +... A 657 ++- A 658 + C 659 +++A
660 ++ C 661 + c 662 ++ C 663 1 + C 664 + A 665 ... A 666 ++ C 667 + C 668 ++ B 669 + A 6 10 ------------------ c --------- J
VCaP VCaP Exit Drnax(% DC ,o(pm)
671 ++-A -7 2-'-- ---------------------- ------------ -- A-- ----------- 673 A
674 +-A 675 1C 676' C
678 C 679 C 680 1 .. A 681! A 682~ A 683 ~ ++ C 684---------- ---------- ---------- ----------- ----------- A-- 685 A
686 1 ++ A 687! ++ B 688 A 689 ++-A 690 ++-A 691 + c 692 + c 693 ++ A 694 + A 695 B 696-----------A 697 ++ A 698------- --------- ------- ---------- -------- ----------- A-- 699 ++ A
700 + C 701 1+ C
51)9
VCaP VCaP Exit Drnax(% DC ,o(pm)
702 + c /03 + c 704 + c 705 ++ A
707 . A
708 + C 709 + C 710 A 711 1 + A 112 + c 713 + A 714 1 + c 715' A 716 ++ C 717 A 718 1 + c -19 A
720 + c 721' + c /22 + c 723 A 724 1 + c 125 1+ c 726 + C 727 1 + c /28 + c 729 + c 730 + c 731!1 + c 732! A .
5 20
VCaP VCaP Exit Drnax(% DC ,o(pm)
733 ++-A 734! + C 735! + C 736!1 ++4+ A 1371 ++ c 738 + c 739 + C 740 ... A 741 + A 742 + C 143 1+ C 744 + C 745 + C 746 + C 747 + C 748 ++ A 749 1 .. A 50 +
__+_
751 ~ + C 752 .. A 753 ... A 754 + C 751 ++ C
156 1++- B
757 ++ C 758 1 + c 159' + C 760 ++ C 761. + c 762 1 + c 763 1 ++ A.
VCaP VCaP Exit Drnax(% DC ,o(pm)
764 .. B 765! + C 766! ++ c 767!1 ++ C 168 1+ C 769 + C
770 + C 771 + C 772 + C 77 3 1+ C 174 1+ C 775' + C 77,+ C
777 + C
778 + C 779 + C
780 1 ++ A 81++ C 78?2++ A
783 +++4+ A
784 + c 785 + A 786 1 .. A 1871 .... A
788 +++A
789 +++A
790' ++ C 791 + C 792. ++ C 793 1 .. A 794!1 + A.
VCaP VCaP Exit Drnax(% DC ,O(pm)
795 ++-A 196 ++ C 797 A 798 1+ C 99 ++ 800++++ A
801 A
802 + A 803 ++ C 804 + A 805 + c 8----------------------------------- A-- --------------------- 807 A 8087+ A 809 ++ A
810 A 811 1 ++4+ A 812 1 +... A
813 +++A
814 ++ A 815 + A 816 +++A
817 A 818 + c 819 +++A
820 +++A
821 +++- A A- 822------------------------------- -------------- -- -------- - 822 A 823 A
825 1 ++ A.
VCaP VCaP Exit Drnax(% DC ,o(pm)
826 +4 A 827 ++ A 828 A 829 1 .. A 830 1+ c 831 1 ++ A.
832 +++4+ A
833 +++- A 834--- ------------------------------ A-- --------------------- 835 A
836 +++A 837--------------------------------- A-- --------------------- 837 A 839 A
840 +++A
841. A 842 1 ++ A 843 1 .. A 844 +++A
845 +++4+ A
846 +++- A
847 +++A
848 A 849 .. A 850 ... A 851 ++ A 852 A 853------------------------------- -------------- A- -------- -- - 854 A
856 + C
VCaP VCaP Ex# Dmax(%) DCso (pM)
857 + C 858 + C 859 A
860 +++ A 861 +++ A 862 ++++ A 863 ++++ A
864 + A
[01002] 2. VCaP Cell Proliferation Assay. 1010031 VCaP cells are plated 7,500/well 200 L/well in VCaP assay medium [Phenol red free RPMl (Gibco Cat#118354-030); 5% Charcoal Stripped (Dextran treated) FBS (Omega Scientific, Cat#FB-04); Pen/Strep Life Technologies (Gibco Cat#: 10378-016); 0. InM R1881 (Sigma, Cat# R0908) is added upon the start of the assay, not during initial plating of the cells).
[01004] The assay was performed as follows: the cells are grown for a minimum of 3 days
to deplete androgens; dosing of PROTACs and R1881 is performed as for AR ELISA; the baseline reading of Cell Titer Glo can be performed on day of dosing.
[01005] VCaP cells with 0.1 nM R1881 will double once in 4 days. Gently draw off 110 VL of media so as not to disturb the adherent cells; add 110 uL of CTG; incubate with slow
shaking for 20 minutes; and read luminescence on a plate reader.
[01006] VCaP anti-proliferation data:
[01007] G1 5 0 definition: A (G5o< 50nM); B (51nMN G1 50 250nM); C (251nM< G15 0 )
[01008] Table 37. Inhibition of VCaP Proliferation.
Ex # Giso 75 B 131 B 134 B 150 A
5 25
156 A 157 A 163 A 169 B 170 A 172 A 174 A 182 A 183 A 194 B 195 B 197 B 201 B 202 B 204 A
[01009] Table 38. Inhibition of VCaP Proliferation.
Ex # Mass Data Giso Observed Observed Mass 1: Mass 2: MH+ MH+ ABM--26 279.11 281.11 B ABM--27 279.30 281.30 C ABM-28 400.14 402.14 ABM-29 379.17 381.16 B ABM-30 398.13 400.12 A ABM-31 400.14 402.14 B ABM-32 400.14 402.14 ABM-33 413.20 415.20 B ABM-34 417.16 419.16 C ABM-35 399.15 401.15 ABM-36 484.16 486.16 A ABM-37 598.29 1 600.29 A
[01010] These results support that both the difunctional compounds (ABM-L-ULM) and androgen receptor binding moieties (ABM-e) inhibit VCaP Proliferation.
[01011] 3. Apoptosis in VCaP cells.
[01012] Figure 2 illustrates that compounds as described herein induce apoptosis in VCaP cells. VCaP cells were cultured in Charcoal Stripped Serum containing media supplemented with 0.1 nM RI1881 for 48 hrs. The degree of apoptosis was ascertained with CaspaseGlo assay (Promega). These results demonstrated that PROTACs are much more potent in inducing apoptosis than an AR antagonist enzalutamide. Further, the degree of AR degradation correlates with theirability to induce apoptosis in VCaP cells.
[01013] 4. Anti-proliferation in LNCaP F876L.
[01014] Figure 3 demonstrates the anti-proliferation in LNCaP F876L cells observed with treatment with a compounds as described herein. LNCaP cells transduced with AR F876L construct were cultured in Charcoal Stripped Serum containing media. Indicated doses of enzalutamide or Example 1 were added for 7 days. CellTiterGlo reagent (Promega) was employed to assess proliferation. As shown, LNCaP cells expressing F876L construct proliferate in response to increasing doses of enzalutamide, whereas Example 1 did not exhibit agonist activity. These results demonstrated that AR PROTACs do not possess agonist activity.
[01015] 5. PSA suppression in LNCaP F876L
[01016] Compounds as described herein also suppress PSA in LNCaP F876L cells (See Figure 4). LNCaP cells transduced with AR F876L construct were cultured in Charcoal Stripped Serum containing media supplemented with 0.1 nM R1881 for 7 days. Secreted PSA in the media was detected by PSA ELISA (Sigma). These results demonstrated that AR PROTAC is able to suppress the transcriptional activity of AR in F876L containing cells.
[01017] 6. Prostate involution in C57B6 mouse model.
[01018] Figure 5 demonstrates that compounds as described herein induce prostate involution in C57136 mouse model. 12-week old male C5713L/6 mice were treated with AR PROTAC Example 163 and its inactive epimer analog Compound A which is unable to bind to VHL Ei3 ligase. Enzalutamide (PO, QD, 30 mpk), Example 163 (IP, QD, I and 3 mpk) and Compound A (IP, QD, I and 3 mpk) were administered for 10 days, upon which the prostates were isolated and weighed. PROTAC Example 163 demonstrated a significant reduction in prostate weights, whereas Compound A showed no significant activity. These results demonstrated that the ability of PROTAC Example 163 to degrade AR leads to significant prostate involution in mice at very low doses.
[01019] 7. Tumor growth inhibition in VCaP xenograft model.
[01020] Figure 6 illustrates tumor growth inhibition in a VCaP xenograft model, which was achieved with compounds as described herein. VCaP cells were implanted into CB17 scid mice subcutaneously. Once the tumors were palpable, the mice were castrated, leading to temporary tumor stasis. Upon regrowth of tumors, the mice were dosed with enzalutamide (PO, QD,30mpk)or AR PROTAC Example163(IP, QD, at 30, 10 and 3 mpk) as indicated. Tumor growth inhibition was observed in all treatmentarms.
[010211 8. AR degradation of PROTAC is E3 ligase dependent.
[01022] Figure 7A and Figure 7B demonsrates that AR degration achieved with compounds as described herein is E3 ligase dependent. For example, in Figure 7A, AR PROTAC Example I was added to LNCaP cells at indicated concentrations for 24 hours in the presence or absence of 10 iM VHL E3 ligase ligand compound B. The presence of compound B competes with AR PROTAC Example 1 in VHL E3 ligase binding and greatly diminishes the AR degradation activity of AR PROTAC Example 1. In Figure 713, LNCaP cells were treated with AR PROTAC Example I and its inactive epimer analog compound C which is unable to bind to VHL E3 ligase. While AR PROTAC Example I led to significant degradation of AR, compound C did not. These results demonstrated that AR PROTAC activity in AR degradation is VHL E3 ligase dependent." 101023] 9. PROTAC prodrug oral pharmacokinetics and PROTAC Subcutaneous phamacokinetics.
[01024] Representative Pharmacokinetic Procedure
[01025] Male CD- Imice (6-8 weeks old, weighing 20-30 g, 3 per study) with free access to food and water were administered with the test article at 10 mg/kg either by oral gavage or sub-cutaneous injection in the formulation specified in tables20 and 21, at 10 mL/kg.
[01026] Approximately 0.04 mL blood samples were collected from the dorsal metatarsal vein serially at 0.25, 0.5, 1, 2, 4, 8 and 24 h timepoints; heparin was used as the anticoagulant. The samples were centrifuged at 4000 g for 5 min at 4 °C then stored at -75 °C prior to analysis.
[01027] The plasma samples were analysed via an LC/MS/MS method quantitating for unchanged, administered test article, and/or a derivative species as appropriate. WinNonlin (Phoenix1) was used for the pharmacokinetic calculations and modeling, to generate parameters such as Ca and AUC.
[01028] Table 39: Examples of PROTAC prodrug pharmacokinetics (ESP-4: 5% EtOH, 5% solutol [IS15 in PBS; ESD-4 5% EtOH, 15% solutol in D5W).
Ex # Dose/Route Plasma Exposure
Prodrug Derivative
Vehicle AUC AUC (max (ng/mL) (ng.h/mL) ng/mL) (ng.h/mL)
464 l0mpk PO ESP-4 48 118 157 571
463 10mpk PO ESP-4 12 49 15 42
462 10mpk PO ESP-4 0 0 178 1479
461 10mpk PO ESP-4 0 0 524 212
468 10mpk PO ESP-4 0 0 209 616
4-70 10mpk PO ESP-4 346 469 565 1600
469 10mnpk PO ESD-4 181 353 528 4279
101029] Table 40: Examples of PROTAC Subcutaneous pharmacokinetics (ELP-1: 5% EtOH, 20% labrasol in PBS; ESD--2: 5% EtOH, 20% solutol in D5W).
CD-1 Mouse Plasma Exposure following a 10 mg/kg SC dose Vehicle Ex #
Cmax (ug/L A C 2 m(ng.h/mL)
ESD-1 1 1.15 15600
ELP-1 80 0.18 2530 ESD-1 150 2. 75 40200 ELP-1 182 1.53 29162
ESD-1 174 1.9 35065
[01030] In summary, PROTACs designed to degrade AR are potent (low nM to pM), specific, rapid (within 2-4 hrs); long-lasting (days); active in vitro and in vivo, and have cellular efficacy superior to enzalutamide. AR PROTACs have efficacy in cell systems and work in vivo (AR degradation in prostate; prostate involution in prostate and seminal vesicle; tumor xenograft models). Thus, targeted degradation of AR may provide a novel mechanism for providing efficacious therapy for patients with prostate cancer for whom current therapies have failed. 1010311 SPECIFIC EMBODIMENTS
[010321 An aspect of the present disclosure provides a compound having the structure:
[ABM]-[L], wherein ABM is an androgen receptor (AR) binding moiety, L is a chemical linker moiety, wherein the ABM comprises a structure selected from the group consisting of:
Y2 R R2
N-N -- NW 2 _Y - - I
ABM-a ABM-b
N Rb
ABM-c , and wherein: W 1 is aryl or heteroaryl, independently substituted by 1 or more halo hydroxyl nitro, CN, C--CH, CF 3 . C -6 alkyl (linear, branched, optionally substituted by I or more halo, C 6
alkoxy), C1_6 alkoxyl (linear, branched, optionally substituted by Ior more halo), C2-6 alkenyl, C 2 _6 alkynyl; Y , Y are each independently NRy, 0, S; 3 4 .5 Y J Y, Y , Y are each independently a bond, O, NR , CR R , C=O, C=S, SO SO 2 ; Q is a 3-6 membered alicyclic oraromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 RQ, each RQ is independently H,OH, C1 6 alkyl (linear, branched, optionally substituted by I or more halo, C 1-6 alkoxvl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); 1 2 1 YlY2 R , R, R. R, R, R are each independently H, OH, C 6 alkyl (linear, branched, t optionally substituted by I or more halo, C 1 6 alkoxyl), or R , R2together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);
W2 is a bond, C 1 _6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl, bicyclic, biaryl, biheteroaryl, biheterocyclic, each optionally substituted by 1, 2 or 3 RW 2 ; and each Rw2 is independently H, halo, C1_6 alkyl (optionally substituted by I or more F), OC1_
3alkyl (optionally substituted by 1 or more F), OH, NH 2. NR R-, CN.
[01033] In any aspect or embodiment described herein, the ABM comprises the structure:
R'
wherein: W1 is aryl or heteroaryl, independently substituted by 1 or more halo, CF3 hydroxyl, nitro, CN, CCH, C1 6alkyl (linear, branched, optionally substituted by I or more halo, C1_6 alkoxyl), C1 -6 alkoxyl (linear, branched, optionally substituted by I or more halo), C>, alkenyl, C.6 alkynyl; 3 4 .5 Y2 YJ 2 Y, Y, Y are each independently a bond, O, NR , CR R , C=O, C=S, SO SO 2 ; Q is a 4 membered alicyclic ring with 0-2heteroatoms, optionally substituted with 0-6 RQ, each RQ is independently H, C1-6 alkyl (linear, branched, optionally substituted by 1 or more halo. C alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R ,R are each independently H. OH. C1 _6 alkyl (linear, branched, optionally substituted by 1 or more halo, C16 alkoxy l) W2 is a bond, C1_ 6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl, bicyclic, biaryl, biheteroaryl,or biheterocyclic, each optionally substituted by 1, 2 or 3 R' ; and each Rw2 is independently H, halo, C 1_ 6 alkyl (optionally substituted by I or more F), OC1_
3alkyl (optionally subsituted by I or more F), OH, NH 2. NR R , CN.
[01034] In any aspect or embodiment described herein, the [ABM]-[L] compound further comprises an E3 ubiquintin ligase binding moiety (ULM) coupled to the ABM or L or both.
[010351 In any aspect or embodiment described herein, the ULM comprises a hydroxyl prolyl moiety that binds Von Hippel-Lindau (VHL) E3 ubiquitin ligase.
[01036] In any aspect or embodiment described herein, the ABM comprises the structure:
W
wherein: W1 is aryl or heteroaryl, independently substituted by I or more halo, hydroxyl. nitro. CN,
CF3, CC-, C. alkyl (linear, branched, optionally substituted by I or more halo, C. alkoxyl), C1- alkoxyl (linear, branched, optionally substituted by I or more halo), C 2-6 alkenyl, C 2 -6alkynyl; each Y3 is independently a bond, 0, NRY, CRY R2, C=O, C=S, SO, SO 2; Q is a 3-6 alicyclic or aromatic membered ring with 0-4heteroatoms, optionally substituted with 0-6 RQ, each RQ is independently H,OH, C1_6 alkyl (linear, branched, optionally substituted by I or more halo, C-6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); Rh, RE are each independently H, OH,C 6 alkyl (linear, branched, optionally substituted by I or more halo, C 6 alkoxyl); W2 is a bond, C1-6 alkyl, alicyclic, heterocyclic, aryl, or heteroaryl, each optionally substituted by 1, 2 or 3 RW2; and each Rw2is independently H,halo, OH, NH2, CN, NR"R, C 1 _ 6 alkyl (optionally substituted
3 alky] (optionally substituted by I or more F). by I or more F),OCs
[010371 In any aspect or embodiment described herein, the ABM comprises the structure:
Y3 (y3 )o- 5
ABM-d' wherein:
W 1 is aryl or heteroaryl, each optionally substituted by 1 or more halo, hydroxyl, nitro, CN, CF 3,C 1- 6 alkyl (linear, branched, optionally substituted by I or more halo. C1 6. alkoxyl), orCi alkoxyl (linear, branched, optionally substituted by I or more halo); each Y isindependently a bond, 0, NR ,CR'Ry, or C=0; each R is independently 1-, OH, C1-6 alkyl (linear, branched, optionally substituted by I or more halo, CJ-6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R , RE are each independently H, OH, orC1-6 alkyl (linear, branched, optionally substituted by 1 or more halo, C 6 alkoxyl); W2 is a bond, C1 6 alkyl, aryl, heteroaryl, alicyclic, heterocyclic, each optionally substituted by 1, 2 or 3 RW; and each R is independently H, 01-1, NI- 2, halo, Ci-6 alkyl (optionally substituted by I or more F). OCtalkyl (optionally substituted by I or more F).
[01038] Another aspect of the present disclosure provides a bifunctional compound comprising the chemical structure: ABM-L-ULM, wherein ABM is an androgen receptor (AR) binding moiety, L is absent (a bond) or a chemical linker, and ULM is an E3 ubiquitin ligase binding moiety,wherein the ABM comprises a structure selected from the group consisting of: rR y2
(aN ABM- , Rand -- Y 5
/53
'herein:
WV is aryl or heteroaryl, independently substituted by 1ornmore halo hydroxyl, nitro, CN, CF3, C-CH, C1 salkyl (linear, branched, optionally substituted by 1or more halo, C1 6 alkoxyl), C1_6 alkoxyl (linear, branched, optionally substituted by I or more halo), C2-6 alkenyl, C 2 - 6 alkynyl; Y , Y are each independently NRY, 0, S; YY 4, Y are each independently a bond, O, NR', CR R, C=, C=S, SO, S02; Q is a.3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 R, each RQ is independently H, OH, C1 6 alkyl (linear, branched, optionally substituted by I or more halo, C1- 6alkoxyD, or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); 1, 2, Y2 br Y Ybanhd R, R , , R R, R ,R are each independently H, Of, C-6 alkyl (linearbranched, optionally substituted by I or more halo, C1 6 alkoxyl), or R , R together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms; W 2 is a bond, C 6 alkyl, aryl, heteroaryl, alicyclic, heterocyclic, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally substituted by 1, 2 or 3 R2; and each Rw is independently H, halo, C6alkyl (optionally substituted by I or more F), OC Yl Y2 3alkyl (optionally substituted by I or more F). OH, NH2, NR R , CN. 1010391 In any aspect or embodiment described herein, the ABM comprises the structure: wherein: W1 is aryl or heteroaryl, independently substituted by 1 or more halo, hydroxyl, nitro, CF3 ,
CN, C--CH, C1 6 alkyl (linear, branched, optionally substituted by I or more halo, Cs 6
alkoxyl), C -6 alkoxyl (linear, branched, optionally substituted by I or more halo), C2-6 alkenyl, C62_ alkynyl; Y, Y, Y5 are each independently a bond, 0, NRY, CR Rx, C=O, C=S, SO, SO 2 ; Q is a 4 membered alicyclic ring with 0-2 heteroatoms, optionally substituted with 0-6 RQ, each R,is independently H. C 1 6 alkyl (linear, branched, optionally substituted by I or morehalo,C 6 alkoxyl),or groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);
R ,R are each independently H, OH,C-6 alkyl (linear, branched, optionally substituted by I or more halo, C1 6 alkoxyl);
W 2 is a bond, C 6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl, bicyclic, biheterocyclic, biaryl. or biheteroaryl. each optionally substituted by 1, 2 or 3 R;and each Rw' is independently H, halo, C 6 alkyl (optionally substituted by I or more F), OC
3alkyl (optionally substituted by I or more F) OH. NH2 , NR R, CN. 1010401 In any aspect or embodiment described herein, the ABM comprises the structure:
W
wherein: W1 is aryl or heteroaryl, independently substituted by I or more halo, hydroxyl, nitro, CN, CF 3, C--CH. C>6 alkyl (linear, branched, optionally substituted by I or more halo, C- 6
alkoxyl), C1_ alkoxyl (linear, branched, optionally substituted by I ormore halo), C 2-6
alkenyl, C 2 _6 alkynyl; each Y3is independently a bond, 0, NR Y2, CRRY2, C=O, C=S, SO SO2 ; Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 RQ, each RQ,is independently H,OH, C 6 alkyl (linear, branched, optionally substituted by I or more halo, C1 6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R, RE2are each independently H-1, -, C alkyl (linear, branched, optionally substituted by 1 or more halo, C- 6 alkoxyl);
W2 is a bond, C1 6 alkyl, alicyclic, heterocyclic, aryl, heteroaryl, each optionally substituted by 1, 2 or 3 RW2; and each R w2is independently H, halo, C16 alkyl (optionally substituted by I or more F), OC YJ Y2 3alkyl (optionally substituted by I or more F), OH, NH 2. CN, NR R
[010411 In any aspect or embodiment described herein, the ABM comprises the structure:
Y3 (Y 3)0- ww 5
ABM-d' wherein: WI isaryl or heteroaryl, each optionally substituted by 1 or more halo, hydroxyl, nitro, CN, CF3 , C1-6 alkyl (linear, branched, optionally substituted by I or more halo, CI-6 alkoxyl), or C- alkoxyl (linear, branched, optionally substituted by I or more halo); eachY is independently a bond, 0, NR2, CR'R", or each RQ is independently H. OH. C> 6 alkyl (linear, branched, optionally substituted by I or more halo, C -6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R , R- are each independently H,1- H, or C 6 alkyl (linear, branched. optionally substituted by 1 or more halo, C1_6 alkoxyl); W 2 is a bond, C1 6 alkyl, aryl, or heteroaryl, each optionally substituted by 1, 2 or 3 Rw2 ; and each Rw2 is independently H, OH, NH 2, halo, C1_ 6 alkyl (optionally substituted by I or more
F), OC>3alkyl (optionally substituted by I or more F).
[01042] In any aspect or embodiment described herein, theULM comprises a hydroxyl prolyl moiety that binds Von Hippel-Lindau (VHL) E3 ubiquitin ligase (VLM) comprising the structure ULM-a:
xN X2
ULM-a wherein: a dashed line indicates the attachment of at least one ABM, another ULM or VLM (i.e., ULM' or VLM'), or a chemical linker moiety coupling at least one ABM. a ULM' or VLM' to the other end of the linker;
X , X are each independently a bond,0, NR CR1 R 4 ,C=O, C=S, SO, SO 2; R R are each-independentlyHinearorbranched C 1_6 alkyl, optionally substituted by I
or more halo, optionally substituted C 1-6 alkoxyl (e.g., optionally substituted with 0-3 RP groups); R is o, 1 or3 groups, each independently-, halo, -OH, Cijalkyl; W3 is an optionally substituted-T-N(R aR b),.-T-Aryl, an optionally substituted-T leteroaryl, an optionally substituted -T--Ieterocycle, an optionally substituted -NR' -T Aryl, an optionally substituted -NRI-T-Heteroaryl or an optionally substituted -NR]-T Heterocycle, where T is covalently bonded to X I Ia l each R , R R is independently H. a C1 -C 6 alkyl group (linear, branched, optionally 3 substituted by I or more halo. -01),R C=0, R3C=S, R S3 SON(R 3 R )C=0, N(RR Y4 )C=S, N(RR 4)SO, N(R 3 Ry')SO2; W is an optionally substituted -NR -T-Aryl, an optionally substituted -NR I-T-Heteroaryl group or an optionally substituted -NR-T-Heterocycle, wherein -NR is covalently bonded to X .R is H or CH 3, preferably H; and T is an optionally substituted -(CH2 ),- group, wherein each one of the methylene groups may be optionally substituted with one or two substituentspreferably selected from halogen, a
C 1-C 6 alkyl group (linear, branched. optionally substituted by 1 or more halogen, -OH) or the sidechain of an amino acid as otherwise described herein, preferably methyl, which may be optionally substituted; and n is 0 to 6, often 0, 1, 2, or 3, preferably 0.
[010431 In any aspect or embodiment described herein, R3 and R 4 are each independently H. C 1 6 alkyl (linear, branched. optionally substituted by I or more halo. C1 6 alkoxyl).
[01044] In any aspect or embodiment described herein, the ULM comprises the structure:
H N
wherein:
W is optionallysubstituted aryl, optionally substituted heteroaryl, or each R9 and Rio is independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; or R 9, RI,, and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R Iis optionally substituted heterocyclic, optionally substituted alkoxy, optionally
substituted heteroaryl, optionally substituted aryl, or
N
R 1 is H or optionally substituted alkyl; RI is H, optionally substituted alkyl, optionally substituted alkylcarbonyl optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R1 4a, R14, is each independently H. haloalkyl, or optionally substituted alkyl;
W5 is a phenyl or a 5-10 membered heteroaryl,
R15is H. halogen, CN, OH, NO ,2 NR14aR14b, OR4, CONR4 aR14, NR1 4 aCOR14,
SO 2 NRI1 4aR,4, NRl4aSO2RJ4I, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl. optionally substituted
R
cycloheteroalkyl, or wherein R12 is H. halo, optionally substituted C3
6 cycloalkyl, optionally substituted CI-6 alkyl, optionally substituted CI-6aikenyl, orC1 6 haloalkyl; Xa is S or 0; each R 16 is independently halo, optionally substituted alkyl, haloalkyl, hydroxy, optionally substituted alkoxy, or haloalkoxy; o is 0, 1. 2, 3, or 4; each Rjis independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; and pis 01, 2, 3, or 4.
[010451 In any aspect or embodiment described herein, the ULM comprises the structure:
HO N R N R.
wherein: R 9 is H; Rio is isopropyl, tert-butyl, see-butyl, cyclopentyl, or cyclohexyl:
Rj is
R12 is H; RI is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkvl)aikyicarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; R 14 a is H. haloalkyl, methyl. ethyl, isopropyl, cyclopropyl, or CI-C6 alkyl (linear, branched, optionally substituted), each optionally substituted with I or more halo, hydroxyl, nitro, CN, C1 -C6 alkyl (linear, branched, optionally substituted), or C1 -C6 alkoxyl (linear, branched, optionally substituted); and
Ris is wherein R1 7 is H, halo, optionally substituted C 6 cycloalkyl, optionally substituted C1_ 6 alkyi, optionally substituted C16alkenyl, or C 1_6 haloalkyl; and Xa is S or 0.
[010461 In any aspect or embodiment described herein, JLM is selected from the group consisting of: (2S,4R)-I-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5 yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-I-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(thiazol-5 vl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5 yl)phenvl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)--((S)-2-amino-3,3-dimethyilbutanoyl)-4-hydroxy-N-(4-(oxazol-5
yl)benzyl)pyrrolidine-2-carboxamide hydrochloride; (2SAR)-I-((S)-2-amino-3.3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5 yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-I-((S)-2-amino-3,3-dimethylbutanoyl)-N-(4-chlorobenzyil)-4-hydroxypyrrolidine-2 carboxamide hydrochloride: (2S,4Ri)-1-((S)-2-amino-3,3-dimethvlbutanoyl)-N-(4-cyanobenzyl)-4-hydroxypyrrolidine-2 carboxamide hydrochloride;
(2S,4R)-1-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5
yl)benzyl)pyrrolidine-2-carboxamide hydrochloride; (2SAR)-1-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(thiazo-5-yl)benzyl)pyrrolidine 2-carboxamide hydrochloride; (2S,4R)-I-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5 yl)benzyl)pyrrolidine-2-carboxamide hydrochloride; (2S,4R)-i-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(i-methyl-I H-pyrazol-5 yl)benzyl)pyrroiidine-2-carboxamide hydrochloride; (2S,4R)-4-tert-butoxy-N-(2-hydroxy-4-(4-rnethylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1 oxoisoindolin-2-yl)butanoyi)pyrrolidine-2--carboxamide; (2S,4R)-4-tert-butoxy-1-((S)-2-(6-fluoro-l-oxoisoindolin-2-y)-3-methylibutanoyl)-N-(2 hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;
(2S,4R)-4-tert-butoxy-1-((S)-2-(7-cyano-1-oxoisoindolin--yl)-3-methylbutanoyl)-N-(2 hvdroxy-4-(4-methylthiazol-5-vl)benzyl)pyrrolidine-2-carboxamide; and (2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4 methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride.
[01047] In any aspect or embodiment described herein, the linker group (L) comprises a chemical structural unit represented by the formula:
wherein: q is an integer greater than 1; and A is independently selected from the group consisting of a bond, CRI R, , S, SO S02. NR", SO2NRI, SONR, CONR, NRLCONR ', NRLSO2NR, CO, CR=R, C-C. SiR R. P(O)R", P(O)OR', NR C(=NCN)NR', NR"C(=NCN), NR'C(=CNO 2 )NR , C 3 _ 1 cycloalkyl optionally substituted with 0-6 R and/or RL 1 and/or R1 groups, aryl groups, C 3_uheteocycyl optionally substituted with 0-6 R optionally substituted with 0-6 R and/orR groups heteroaryl optionally substituted with 0-6 R and/or R Igroups; wherein R. R. R , RU and R are each. independently, selected from the group consisting of H, halo, C1salkyl, OC"_alkyl, SC 1 _salkyl, NHC1_salkyl, N(C1_salkyl) 2, C3 _ ucycloalkyl, aryl, heteroaryl, C -_heterocyclyl, 1 OC1_scycloalkyl, SC-scycloalkyl,
NHCscycloalkyl, N(C1_scycloalkyl)2, N(CGscycloalkyl)(CG 1 salkyl), OH, NH2,
SH, SO 2C1.galkyl, P(O)(OC-sailkyi)(C1-salkyl). P(O)(OCgalky), CC-C1 salkyl, CCH, CH=CH(C1_salkyl), C(C1_salkyl)=CH(C1_salkyl), C(C1salkyl)=C(C1 salkyl) 2 .Si(OH)3 , Si(Cjsalky) 3, Si(OH)(Cjsalkv), COC1_salkyl, CO2, halogen, CN, CF3, CHF2, CH 2 F, N) 2 , SF5 , SO 2 NIHC1salkyl, SO 2 N(C1_salkyl) 2 ,SONHC salkyl, SON(Cisalkyl) 2. CONHCIsalkyl, CON(C.salkyl) 2. N(C< galkyl)CO(NH(Cgalkyl), N(CIsalkvl)CON(C.xsalkyl)2 , NHCONH(C 1 gaikl), NHCON(C>salkyl) 2 . NHCONH2 , N(C 8 alkyi)SO 2 NH(C-salkyl), N(C.salkyi)
SO 2 N(Csalkyl)2, NH SO2NI-(Csalkyl), NI-I SO2N(C-salkyl)2, and NH SO2NH 2 ; and wherein when q is greater than 1, R or R- each, independently, can be linked to another A group to form cycloalkyl and/or heterocyclyl moeity that can be further substituted with 0-4 R groups.
[01048] In any aspect or embodiment described herein, the linker (L) comprises the following chemical structure:
L-2 W1 WL2 n
wherein: WX and W- are each independently a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently a H, halo, 01-, CN, CF3, NH 2 , carboxyl, Cl-C6 alkyl (linear, branched, optionally substituted), C1-C6 alkoxy (linear, branched, optionally substituted), or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; YL is each independently a bond, Ci-C6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with 0; orC-C6 alkoxy (linear, branched, optionally substituted); n is 0-10; and a dashed line indicates the attachment point to the PTM or ULM moieties.
54-2
[01049] In any aspect or embodiment described herein, the linker (L) comprises the following chemical structure:
(yLl), WLLo)6 ; W 10-2 WI QL n/1
wherein: W and WL are each independently aryl, heteroaryl, cyclic, heterocyclic, C1 6 alkyl (linear, branched, optionally substituted), C-C. alkoxy, (linear, branched, optionally substituted), bicyclic, biaryl, biheteroaryl,or biheterocyclic, each optionally substituted with RQ, each R is independently a H, halo, 01-, CN, CF3., hydroxyl, nitro, C - CH, C2_6 alkenyl, C2
alkynyl, C 1-C 6 alkyl (linear, branched, optionally substituted), C1 -C 6 alkoxy (linear, branched, optionally substituted), OC 3alkyl (optionally substituted by I or more F),IO NH 2 , NR-'R, CN, or 2 R groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms; 1 YL is each independently a bond, NR 0,0,S, NR , CR RY", C=0, C=S o, SO 2, C1
C 6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with 0;C1 -C6 alkoxy (linear, branched, optionally substituted);
QL is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, biheterocyclic, or bicylic, optionally bridged, optionally substituted with 0-6 R', each RQ is independently H. C 1 - alkyl (linear, branched, optionally substituted by I or more halo, C1 _- alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); R , Rm are each independentlyCH, 6 ,C alkyl (linear, branched, optionally substituted by 1 or more halo. C 1_6 alkoxyl), or R I, R2 together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); n is 0-10; and a dashed line indicates the attachment point to the PTM or ULM moieties. 1010501 In any aspect or embodiment described herein, the L is selected from the group consisting of:
2-(3-(5-(tosyloxy)pentyloxy)propoxy)acetic acid; 2-(3-(,3-dimethyil-5-(tosyloxy)pentyloxy)propoxy)acetic acid; 2-(3-(3-hydroxy--5-(tosyloxy)pentyloxy)propoxy)acetic acid; 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetic acid; 2-(2((2R,3R)-3-(2-(tosyloxy)ethoxy)butan- 2 -yloxv)ethoxy)acetic acid; 2-(2-(2S,3S)-3-(2-(tosyloxy)ethoxy)butan-2-yloxy)ethoxy)acetic acid; 2-(4-(4--(tosyloxy)butoxy)butoxy)acetic acid; tert-butyl 2-(3-(4-(tosyloxy)butoxy)propoxy)acetate; tert-buty 2-(4-(3-(tosyloxy)propoxy)butoxv)acetate. tert-butyl 2--(6-(tosyloxy)hexa-2,4-diynyloxy)acetate; tert-butyl 3-(6-(tosyloxy)hexa-2,4-diynyloxy)propanoate; tert-butyl 4-(6-(tosyloxy)hexa-2,4-diynyloxy)butanoate; ethyl 2-(2-(2-aminoethoxy)ethoxy)acetate hydrochloride; ethyl 2-(5-aminopentyloxy)acetate; methyl 2-(2-(2 -(methylamino)ethoxy)ethoxy)acetate; ethyl 2-(5-(methylamino)pentyloxy)acetate; 2-(3-(2-(tosyoxy)ethoxy)propoxy)acetic acid; 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate; ethyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate; ethyl 3-(2-(2 -(tosyloxy)ethoxy)ethoxy)propanoate; ethyl 5-(tosyloxy)pentanoate; ethyl 3--(-(tosyloxy)ethoxy)propanoate; ethyl 2-(5-(tosyloxy)pentyloxy)acetate; ethyl 3-(5-(tosyloxy)pentyloxy)propanoate; 5-hydroxypentyl 4-methylbenzenesulfonate; ethyl 2-(5--(tosyloxy)pentyloxy)acetate; ethyl 2-(3-(tosyloxy)propoxy)acetate; ethyl 2-(2-(tosyIoxy)ethoxy)acetate; ethyl 2-(4-(2-(tosyloxy)ethoxy)butoxy)acetate; 2-(2-(2-hvdroxyethoxy)ethoxy)ethyI 4-methylbenzenesulfonate; 2-((2R,3R)-3-(2-hydroxyethoxy)butan-2-yloxy)ethyl 4-methylbenzenesulfonate;
2-(2-piperazin-I--yl)--ethoxy-acetic acid; and methyl 6-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)piperazin-1-yl)nicotinate.
[01051] In any aspect or embodiment described herein, the compound is a member selected from the group consisting of Examples 1-864 (Tables 2-30), a salt, a polymorph, isotopic derivative, and a prodrug thereof.
[01052] In any aspect or embodiment described herein, the compound is selected from the group consisting of: NC
NF
' F F c F
NS N? N -S OH
N NH -NH 1
HO NN FH N HNN N
HN> NH/H0
N N- N OH. N F NH NH -N
54-5
~N r>
NN
NH \=-*
NN H x 2 ~-N--- 0 HI 0
O i-NH
NN
s I
f-\ N
PH
H 0H N,/
H-N
a *-S 0 '
N F FI
I54--
N N N 0- 0
N.K '0-:N0
N <\ NH
00
N HO
N = --
HN 0
0
NN i-s/ ')
0-ao §-5\\
N OH
ja 0 H 'fC
HO N- H
C)NH 0 0
N H NH 0
Nl NN
N 0 0 11H H
OH 0"' NH H r N- N H NH F O
N F F
0
N
54-8
OH N 0 N N NI N N
N .N HN NFN NN NN
ow NH NH 0
NH%(~~~ N 0
H HN
cii
NN OH
N 0 0 0 - NH 0'a NH NN NH'/ N
// C1 NN
OHI
0,0 1 0N
\jJ ~-N N \ 0 N NN
H N 0 H N NCN
o HO Ci HN
H N N N N N
H~ wheein
W 1 is aryl or heteroaryl, independently substituted by 1 or more halo, hydroxyl, nitro, CN, C-, C1- 6alkyl (linear, branched. optionally substituted by 1 or more halo,C. alkoxyl), C 1 6 alkoxyl (linear, branched, optionally substituted by 1 or more halo), C 2-6 alkenyl, C 2 -6alkynyl; 1 2I Y , Y are each independently NR , 0, S; 3 4 5 Y2 Y2 Y , Y Y are each independently a bond. 0, NRY, CR R , C=0. C=S, SO, SO 2 ; Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally substituted with 0-6 RQ, each RQ,is independently H, C16 - alkyl (linear, branched, optionally substituted by I ormore halo, C1 6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); . R, , R, RbR, RN are each independently H, C16 alkyl (linear, branched, optionally 1 2 substituted by 1 or more halo, C1_ 6 alkoxyl), or R, R together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms); W 2 is a bond, C1_6 alkyl, alicyclic, heterocyclic, aryl, or heteroaryl, each optionally substituted by 1, 2 or 3 RW2 ; and each R2is independently H, halo, C 1 .6 alkyl (optionally substituted by 1 or more F), OCI. YJ w 3alkyl (optionally substituted by I or more F), OH, NH 2. NR R-, CN.
[01054] In any aspect or embodiment described herein, the compound is selected from the group consisting of: trans-2-Chloro-4-[3-amino-2,2,4.4-tetramethylcyclobutoxy]benzonitrile; cis-2-Chloro-4-[3-amino-2,2,4.4-tetramethylcyclobutoxy]benzonitrile; trans 6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2.2,4,4-tetramethylcyclobutyl]pyridazine-3 carboxamide; trans tert-Butyl N-[3-(3-choro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate; trans 4-Amino-N-[3-(3-chlioro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty]benzamide; trans 5-Amino-N-[3-(3-chlioro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrazine-2 carboxamide; trans 2-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5 carboxamide; 4-Methoxy-N-[(Ir,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethylcyclobutyl]benzamide; trans 1-(2- Hydroxyethyl) -N-[3-(3-choro-4-cyanophenoxy)-2,2,4,4-tetramethycyclobutyl] IH-pyrazole-4-carboxamide; trans 6-Amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylpyridine-3 carboxamide; trans 4-[(5-1-lydroxypentyl)amino]-N-[3-(3-chioro-4-cyanophenoxy)-2,2,4,4 tetramethvicyclobutyllbenzamide; trans tert-Butyl 2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4 tetramethyilcyclobutyl]carbamoyl}phenyl)aminopentyl oxy)acetate; tert-butyl trans-(3-(3-chioro-4-cyanophenoxy)-2,2-dimethylcyclobutyl)carbamate; and tert-butyl cis-(3-(3-chloro-4-cyanophenoxy)-22--dimethylcycIobutyI)carbamate.
[01055] An additional aspect of the present disclosure provides a composition comprising an effective amount of a bifunctional compound of the present disclosure, and a pharmaceutically acceptable carrier.
[01056] In any aspect or embodiment described herein, the composition further comprises at least one additional bioactive agent. 101057] In any aspect or embodiment described herein, the bioactive agent is an anti cancer agent.
[01058] A yet further aspect of the present disclosure provides a therapeutic composition comprising an effective amount of at least two different bifunctional compounds according to the present disclosure. 1010591 Another aspect of the present disclosure provides a method of treating a disease or disorder in a subject comprising administering a composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the present disclosure to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.
[01060] In any aspect or embodiment described herein, the disease or disorder is cancer or Kennedy's Disease or both.
[01061] In any aspect or embodiment described herein, the cancer is prostate cancer.
[01062] In any aspect or embodiment described herein, the composition further comprises an effective amount of at least one additional anti-cancer agent.

Claims (14)

The claims defining the invention are as follows:
1. A bifunctional compound selected from the group consisting of:
H1 kC
0 d
(598), (599),
*AC KC
(600), " (601), tic M
(602),
NN
0F
HNt CH,
FIN
< ' N
NH N (605),N / O' N HN N
NF (609),
0 NHN
F 0I
N- (610),
CH, NH
1CH N
(611),
CM H N N
CHC * 14 HC 9k 0 0 HN 5
CH,
(612),
0N- NH 0 / 5-~ N \/0 -C LH A (613),
cL
04 (614), 0H
S
N F F FS
(616 (N
HC N HO C
HN HCH N
F N F
(617),
(618), N
H, CH, \ HXOjckif H
H H NHN N
0' (619),
N
NH N H,
N-N
0 (620), o HaC C H
F- F, 0/ HC
0 H N FH F (621), 5C
0 NH
NFY> ' Q OH, ,_tN
H3 0 N HO
N F H, 0 N NN F CH 3
0
F bo0 HOHH, L(2)
CHH CN Ho~o
CH
F NN 00 HN
N HN
CH (627),
0
(628),
NN
HIC HC
(629), (631),
H "0 CNH CH
HN
N C CH,
" 1 " C(632),
............
(633), IIc
oCHI
Nh (643), NN N0 N-HN 0
F
Nh S A-N N
S~H 0
A; F F (648),
"A CCH
CH, (650),
1r1
H1
I
A
(651),
(661),
(662),
(663), HC
HC
0 NH
N CHH
(667), HC
0 NH
N 0H (675),
HC C
0 'NH
4 Nr05-' CNtCH 0 (66)
N-.
F C~ ~.$H1 F F )-N
0
0
HN
0
CH,
.- A (714), N
F F F 0
HH,
HON
0 N' CH,
H 1C C (735),
HNH
NN--N NN N O
HNC _ 0
NH CI N (594)
N (594),
H1 C
HC
(595),
N cI
HC CHD
CH,
\ NH 0 N-N
OH (596), N ci
/~HAC CHA
HC NH
NH/ 0 N-N N 0 CH, H Hc
0H (597), h-CH,
N 0
N-N
NN
CH C~ CH,
HC CHN (603) 6 04)
,NN HHC H N HHC OH,
HO H 0
IHCH
N HN A 0 HC ' HN C HA
H C H
CHH
N (607),
H3C N>
s I
NH
N0
H C H
CH. NH 11 / H1C CH1,
NNN-/ C -
H 3C CH _CN (608), I-4c N
KtC NH
CH HC _W a 0H CHNH N i
H 3C CH,
N
CHCC. o,
OH (623),
N
/ ci ~H 1C CH,
H, C OI~I CH. H ow
CHC
C N N M1 - (624) NN
ci H1
HC CH,
N W N
, H, 5 (625), N
//
- CH,
H-LCI HA
CH NH
'0
HN H CH 3 A
HH
CII
H 0 (630), 565I
N
\_4f \-H OH
HS / HC~ H N-NC CH
MC~ ~ CH,~CM MN N
(634),
H/jkCH,i
0
HO
O MC
NN
(63),
HO H HN 0 N
HN% HN CH 1 0CH C H
CM
N (637), S~N N
/ CH1
NH
HN-.Ct CHI OH
H1 C CH, 0 N NCC
ow NH
ci I \ HC CH,
N (638), N
N MN H C __ H HNN I
NN s4 (639),
(111C- Hj,
H, IF N
H-C CHI
(640),
H, o F OH
OHcN I9 C.
N 1 (641),
ri>H CH LC NHr rNH HC
CHo0 (00jl f COH. 0 N L~NO y0 HN HOH4
H 0 S" (642), N
/ 11 HC CHl A CHI
04D..9 NIs H N HN H, H,C C HJF ~NI N r7) H
HN
CHI
\,, N (644),
~NHN{3 C4OH
HC CH3 0 NHNi
N0N (645),
CH,
N HN{C¶, N
00 N--
F /1: \HC CHI F F N HC N-(646),
HIC N1 s
H,1 C \/
NH
CH N. HCCH 1 NH HAC CH,
.N NN0 (D'l \,>NH
J, C H (649),
P CH, N Nr'' CH,1
iLI0 NH
N H Ci N o
0¾
(652), H;C
CH;H,
pNNcN
o CM 1
(653), H~C
I-1 3C N
s
NHC
NN
OHktCH 0r-CINHK
H3 CXH NN(654),
HC N>
s
NH
0
Cl- NH
N OH
/HCCH~ I (655), HO 0H HJ H, 0
H N--( HNS,3rCH,
5 /CH, H1C4
N CH, H
N (656), CH,
NN
CH, (657),
N= HNC
HN CH,
HO,
N 0C H,
HIC CH Do N N/
0,,--- > NH
cl1 H,C CH,
(658), N
HC
HC cwW,o rN
cI \HC CHI
N C H,
H2 H 0NN N CHC C A'
(659), H3C N
O Va HH N N
HH
NN H
_ HA C NH 1
HC(659),
N
ci11 H3C CH 3
OiI1.. NH N H3C CH 3
/ N,' H ~ HN CH 3
0 CH 3 CH 3 CH 3 0H 3 C CH 3
(664), H~C N
NH
NFF CH NH F T
HaC CH, 00 H..: CH 3 (665), HO bHNN$ 0H
YCHNHIH ) H HC
00
CH, N (666),
AH
CC
(668),
HO CH,
N CH, "'NH
N N 0 cI HX N
OHH
HO
HF N HCH,
H~S-C (J~~ % 670),
HO
NH 0t 0
H- CH, OH
/~ \CHCH
N (671), /zN
CH,
MN HO, C o N CH L CH HN- N¶/7-N OH C Cl
- HN<.i-1
H3C CH 3 (672),
0"0
CHa NH
C 0 CH
HN C
SOH \ -N (673),
OH NH
H~H 0 N H NC C'rCH 0
N F
0 (674), HO0 r N 7 CJHI CHN 0 PCM I H HHN-A* 0 HIC HN HCMCH
N f CH, i
N (678), H3C: N
S
HC
NH 0
Ftc C6 -NaOH ci-t NH
\% / I 0HcO
H~aC~ 7~J(679),
H1 C N>
H, C NH
N
H 1C H1C CH 1 CH1 NH
Hc H'% N (680), H 3C N
NH 09 N CH%N'
N, C CHNHH N ~H1 C CHI1 IN
- N N-/
H3CC% N (681), H4C N>
Hc NH 09 N 0 )
H 1 C CHN H, H 1C CHA H.N N0 ~Q-N~,,yx, N
H 3C H'N (682),
N H3 C s
_N HN -, CH3
"If N-CH3
N "0
H 1C NH I.-; 0
HH
NHc
F ...... HI OH F NHNH Fj HC C HA CH1 oi.. ~~NH 0 0 H3 C< C3 N HC CH NJ(684),
Ho0
S ( CHI N -A
CCH,
CH, (685),
N FHC NH F F 1
o CH, H'HC> NH
CH-I UHN
(686), HO0
N 0 N N- 01
H CiHtH H,C CH I
N CHH
N (687), N
itho CH.cCH
HC CHI§ s-l
OH (688),
H3C N
H1 H
NN
F H,C--j-Z OH F /\ ,CH CHI NH
OII..KJ.SNH N- NN0~ 0
H3C CH U J 3 (689),
N, OH H
00 NIl C11
ci N _N H
CHl
Et~c (690), N
ci/ \H-C COH
NH,
N RIC O N -1OH
NH,
N (691),
N
N>H
NH NCCH
N..... CH,
N
~OH 0
H1,C NH
it (692),
Oili
H~C O~CH.
N (693),
H~C CH,
H. H 4 01 (694),H
H Nc
IH N (695),
N
HA H
H
C H,
01
cI HC CIH,
lip (696), N
0 HO-C
0T" YCH,
CH,
ci \H CHN
(697),
Hill
H
C J C HI %I0
HO~ 0c H1 F FN H N-C 0 N CH, H
HC H NN CH, CH, c.
N (699), HEICI NH
CHI
0 C~ CH HIC CH:1 -o - )
0"il.. NH \ INJN
NI (700),
HIC CH OH
N.,cwCHHICNtCo..-NNHH
N (701), H~CCH~OH
H 1C CH j0 CHI N
H CHI
NHN
CtH
0 C HI OH
H IC CH1 H
N (703),
/ H
CC
NW
wHcH NH ON N Or- IcCHI
F F /; H H F
N (704),
CC
NI
HN CHI ON
F
N (705),
HC OH
HgC 4 H 0`10
ccl NH
N C H- H k N
0 flIc Hl ftc (706),
H, C N)2
H~c NH
KCCH, N 0H HC N H N H H
FN F F HaC CHK F NN
HC CH N(707) L N
HCC
HN C HN '-C H
Hf CH NH N F
/ HSC VCH, CD) 01 NH
H;- CH (708), S H
N CHN
CHCH,
HC 0 N
F F 58 (709) c I
'-1,1 CH-I 0 4H,%~~''T 4-C
CIHI,
uN, (710),
/ CH,
NH 0
NN
H 1 0~ Jm, NHOJ~Wk OH
F~ H/ HCH
N1 (711),
HNCH, OH
\ / 0
F / Hc CH, F
N Hc N'
N HNJ~~~ ,,OH
N 09
F Hc N>,
N C (713),
HaC N
NH
0 HCH %f0l N, r.HOH
00
H CH 7 1 %'V (715), HC N
HC NH
CH, Nr CH4H NS H 0M HCCH /H JvCJ(
NN HCHC CH, N 71) 0,--HC / NNN HS
HC NH
H, 4NOH
NC C NH
H.. >-N 'H N N (717),
N N -tH, CH,
CH, 0
CH,
F I F F
N (718),
H1 CC
H H H r-4 CHIQ. C, OH (719), H3 C
HC NH 0 N 0 ).. CHj%' '~~ H~IC - VNF ' 11 HAC CH, CH NH
X N N N-f H3 C~ N (720),
H 1C N
NN
N CHI'k&
cI H, CH, c NH
N (721), OH
N. -NCH, j4 tN N -4 -, Nit w N
w14C (722),
0-IHC(23)
UII~cc N
M*~ ~M,
HC N,
F NNH
F N F oi..jj NH -N
H 3C C HC (724),
H,C NH
N C
H1 C C~r NH(725), OH H2C CH)
NN
c CHI~ HHN N, HN 0P
HC (727), H" C H3 NI N CH, OH
H H CHH Hwl
H0a c (702728) H2 CH
NN "
N 0 CH H HN
HC (72 ),
OH
CH, N H,
CH, N 0 T N(
N ~"CH N mH CHCQ H
HC HJC N C-4 5 (730), OH
HH 0H N N
HHjC
(732),Z (73)
0 CH592
/ HC CH, CH, 0
N HCAN
keCCH 1
HN
N
(734), CH, N- C - C
NH C
HO CH,, (736),
CH,
I NcwM Hr, CN
H 0 CH,(737), .ci
uc HL
NH
H,c C
0H
(738), cI
HNH
NH
1CCH H cl I H1 CCH, H
oil,,
CH
!NN 0 H H
HN4Q H
CH~ (740),
HC NH
07 "'r OH
Hfc NH HfC -CH)zt~o F N F F
NH
NJH JChNCH
HC CH H C CH
1I (742),
HU
NH.
0
HOH
(7(744)
N4 595
HC N>
s
NH
0
N N NH O
NO I-IC CH,
H-IC CHQ \ / (745),
NH
\\ ,N I-NH
HC CH,
H~C C~l \ /(746), N ci
/ H1C CH,
0w' .c 2 NH
HC CH,
HaC CH$3si
OH (747),
HC CH,
Oi}.NH
H1 CH~ \ NH 0 0 XCH
OH (748),
F-IC ~<CH C
NH CH, OH
N IHN- 6.N HN
CH, CH, HCCH, (749), HaC N
H3 C NH
N NH OH
}NHH
N"'* H3C CF-I \
1) (750),
H3 C N11 I? S
H3C NH o 0
N(
N 0
H3 C CHI \
3 J (751),
H1C
tJ Ho
I (752), nH, (753),
HCH.
F44J
-CH
(754), H 3C N
s
HIC NH
N 0 k cI CH %
H3 HC4 CH 3 H CH 3 NH
II>NH -0
H3 H \ (755), HO
HN~z~ 0 ~HN ~H1 C
CH,, 2CH HC
NN CH1 cl 11z
II N (756),
CH,
½ NH N
HO HCHH
HO CH 2 (757),
CH,
NH NN"tCH
N NN
H0 CH,(75),
CHO,
HO- CH , (760),
NN H
Nil~ N 0,",I, HC
H CH,75)
CH. FHc
H 0 CH(761),)
N
HN
H6' H3 C
CHH
Fl F F
N (762), HCH
H 0 CH
NN
CHI (763),
cMm
(764),
DJH
C H
(765),
c ~ 0C
M.u"
(766),
NIP
HC
(767), N
N N(767-N
HIC CHI
NH N
C N NH N
HH) HH
Hw (768), IC CI
0 NH
60 HO HIC H C CH
CHH3
F F IN N(769), ci
0 NHO
O 0
HO' H3C H CH
CH3
F
F F
N (770), N a N HN 0O F F N--O
N (771), o H N 0 N ON N iO 0 N 0 HN
F N
N (772), 0 N 0
0
N NN
N (773), H N0 N -Y0(D oe 0 NO N N :,O 7 0
N NN
N Ci (774),
QH 0 --- 10 - N N NH 0 NH
HI F&F
cii N (775), PH 0 0"O"' N r ~NJ N N, H 0 NH H0
N (776), H N0
0 ~ H ,ON
-~--~ CI S HNII N l N
(777), H N
0 ,NOH
0\ S~
N N
HC N
S H3Cm> HAC NH
N 0 cIH C H,, 3 a H 1C N OH 7 H3 C CH, CH 3 NH
O0ij%.NH -/ _0-
/ H3C CN CHt \ N N
(779),
HO CHI HO
NH
HN,, ca OH
N N CH
01..- NH - N
HC CH,
N (780), CH
NH 5
N -a H I HC CHO .. >~ NH0N
H
N (781),
KtC
fC NH
0-4,
N IC-\NH
cl HC CI 0
H (782), Etc N>
NH
HC H
N ;NO
HIC CHI
NN
,01 H 1C Hl c NH N
N HN"'1 __H 1C CH,N c' U I CH H
H 3C-- CH 3 N- r U" -H
(784),
/2N
,0 H1 C H1 C
NNH N
/ l H1C CH, HN CH OH
NN
HgC CH N\,$
(785), H 3C N
s
H3 C H 0 N 0 c.I CH, -N H3 C OH H3C CH NH CHI CH,
OlN NH N --r-O O1 H3C H \/ N N H-CH CH, (786), 0 N N 1iC. 'CH3
CH3 H 3C CH
0 CH3 Cl H N
HO HN CH
CHC
S (787),
FH1; N>9
NH 0
N
/ H10 OH CH 1 NH OH,
0.. N N N-NH 0 0
H30 H3~ / N N-'(788),
H-IC C3-1
HCC CH,
NN~W O ~ HOH (789),
N\ NN 0
HN?
(,. CHI" CH3I
N
N (790),
HN ND~ 0k....< NH0 ~
C CHD H1 HACH
CD NH N
H Ci H~~ H C.H, HX CH
N H~C(792),
NHCN
N
c 1 HC CH, CHNH
0 :NH NN-J,/- 1 0 HC H N (793), CI ~0." 0
NN N N pH
ON-N N N H 0 0HN0
N (794), CI 0
N NaO
N 0 N N N H 0 HN0
<N (795),
NN
0 N:-0 -N 0 NH N (~Si
Rh (796),
0 N- 0 N
'-90 NH N S
(797),
HO H Nb HN f oM1 N0
N N0 ,
IH ii::HN CHI
N (798), N
'fl
HIC F
NH C' 0 H 1C CH,
OH (799), HCH
H,,C\ NH
'o.NH N= 0I
cl H, c CH,
N (800),
*OH
HH~
CNH ~ H H, c T1,
(801), HO HaC H3 C CH HN
H.CN /\ HN 0 0 3
NN H ICC
CNCHN
HC
N (802),
H1C / N
N ;-oOH CHI NH H 1 C O#'KN) OHCHjQ.I N N N, H CH1 %
0 (803), l-I$ CtII
NH
0'0
HO NX 0
_4w
(805),
Gd (806),
HC ,fOH H
HIC N CH,
CH~ IA N H c1 (807),
HC
NHl HC OH
43==14CH
CHI CNN (808)
N NI
((809),
CH mI--13
H.1C- C, H -KJ
U-N CIH,
(810), HaC Ci~ 0
HaC}O 0
HC "IHc
s N (811),
HO / CH,
NH 0
HC H OH 0~~~ N CNCH CH,
\Hr CH
CI (812),
HC NH 0/ N0
H1C OH SH 1C CH, CHI NH 01,>KaN H N HSo~
HC 7 CH~ N N--/-
H3 C (813), OH
N (814),
H1 C vCHD't
CH. o3 CH1
N, N
OH (815),
NH
0
N 1,-
HSS
NH
N OHHN
cI / HC OH 3
-l. O H2
HC CH(817),
HN 0 HOC
N oIH
0
N /0CH
VN N__ Oi.---aNHtf
c / Hjl CH7
(818),
HN =:e HN s
HN CH,
0 H~CHn
N H, CH, HC CH A ,A- N N N
c/ H CH NC
(819), CCH3
CH, 0H N O '
HC CH 0 H0 NH
(820), N
HgC CHt / C HN HIC N (2N) N HO
HNN .. 1
HN
OH H 3C
N s (821),
/N CH3
HO NH
NA<NQ OH HICCHOA~> HHC CH, HA H \~H CHH
(822), N' HC N
HC
NH 0
CH. NH N
N oil',<>NH
HC CH3 \ / (823),
H 3C
mNH
i CH. NH N
H 3,CH0 N Oil-,} N H
H~jCCH 3 - (824),
HC N
H3C NH 0 CH,3 N H3C-- t H N CI CH NH
H3C CH3 0
<>C / NN
(825),
Ho H
Or..CN--VHCM
H*C CH CH,
CH, N (826),
~~~scO U ?.~ ~ (827),
HO NH
N aii, HN cl,
N NN
Hc O (
cli, C, (828),
H,C 0 NH
NH CH 0
,,C f4c
H CHV(830),
621H
OH4
NH N
H~Cyy< / /(831),
CH. 0 N
HC N
NH OH
N CHI H
O'"~H,C (832),
H
(833), OH4
(834),
HC
HC NH
0 HOH
CH, HN CH,
HN
HaC CHI
N (835), _N s N CH,
HO NH
N CHN HN CH, SLCI
H-iC CH\ /
N H3C C H, H(836),
H~c N
S
H6C
NH
C N OH CIC N CH. NH
H C CHa
H, /(837),
H~
H,~ ca 0H0C CH,
N (838), HO HC, FiC CH N NI
H C
N (839),
H,,C
H-S NHH
HH HN CH, -I H
HXA CH1
N (840),
OHNH
H2 HA
c~CH
N
HC CHO5 opw <- N H
N (842),1)
I-cCH I~c NN
""4
(84(843)
C1 ? CH H, C CH ,-A CH OH
H0 N 0 NH H0
N
(844),
H HC
C1H NH
H'4 CH, NNHN
H C
(845), (846), CH,
H N CH .OH 0 N N4
\H
NH N (847),
NH
H C MO CH
CH CH N HO H N
CH, (848),
HC 4
NH
N H C N
H4C CH, CH, NH
0- H - N-/
N (849), H C
s
NH
N H
Cl ti~ ~ Hj CH, 'N / HCH,C CH NH -00 $-NH N/ N-ror0
N (850),
H C CH, r N 0C CH, NN N
H1 C CHp N
HN CH,
N H N CH,
(851),
C
CH CH,
N HH Nt 0 JlN N N NCN 0 N Hl INc
00
H N H
N (853), OH
NN) -,N, 0 H IN A- H 0 NHH H 04 0
S ciN 4N N (854), PH 0 r3N N N NNH AN NH
,NN 0 F4
F N (855),
HC -C\ 0
$NH
HO H tC
CH, NN 0
HC
CH,
cI' N (856), NV
HC /y
0 NH
0 0
N N
N N QOC
OIAICH, :H N-_ HIN
N' (858),
C ao)'N JH
H NN 0
HP
"OH
HN
N HN
N (860), PH H 0 N N N
N HN
N (861), 0 0 0 O
W-OYN- N< 0 N H 'H HN Nq p
cl S &'N (862), H DDD D 0 pH N o H DD N
N -.
S
/\N (863),
N N CI0 -- NN H
N (864), and salt forms thereof.
2. The bifunctional compound of claim 1, wherein the compound is selected from the group consisting of:
H3C N
HC NH
N 0
, ci -1 HI 4 OH H CH NH
N N 0 C CH
OH
NNN N N
N HN OH NH C1" 0 S N
N
CNH N OH N 0
N j N Ny H 0 HN 0
S
N
OH H IN HN 0 N 'NU
CI 0"' 0
N) N' HO N ON
N
\0 00 NH N N OH
N \ N OH
N C1 O N N 0 0 HN HH
N CN
N mand HO OH 0 NHN N.N ,N,,)lNN N 0 ~0 C 0" H HN0
S
N
3. A composition comprising an effective amount of abifunctional compound of claim Ior claim 2, and apharmaceutically acceptable carrier.
4. The composition of claim 3, wherein the composition further comprises at least one additional bioactive agent.
5. The composition of claim 4, wherein the bioactive agent is an anti-cancer agent.
6. A therapeutic composition comprising an effective amount of at least two different bifunctional compounds according to claim 1 or claim 2.
7. A method of treating a disease or disorder associated with increased androgen receptor expression or activity in a subject, comprising the steps of administering a composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 1 or claim 2 to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.
8. The method of claim 7, wherein the disease or disorder is cancer or Kennedy's Disease or both.
9. The method of claim 8, wherein the cancer is prostate cancer.
10. The method of claim 9, wherein the composition further comprises an effective amount of at least one additional anti-cancer agent.
11. Use of a compound according to claim 1 or claim 2 in the manufacture of a medicament for treating a disease or disorder associated with increased androgen receptor expression or activity.
12. The use of claim 11, wherein the disease or disorder is cancer or Kennedy's Disease or both.
13. The use of claim 12, wherein the cancer is prostate cancer.
14. The use of claim 13, wherein the medicament further comprises, or is intended for administration with, an effective amount of at least one additional anti-cancer agent.
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