AU2016238925B2

AU2016238925B2 - Anti-viral compounds

Info

Publication number: AU2016238925B2
Application number: AU2016238925A
Authority: AU
Inventors: Mary E. Bellizzi; David A. Betebenner; Jean C. Califano; William A. Carroll; Daniel D. Caspi; David A. Degoey; Pamela L. Donner; Charles A. Flentge; Yi Gao; Charles W. Hutchins; Douglas K. Hutchinson; Tammie K. Jinkerson; Warren M. Kati; Ryan G. Keddy; Allan C. Krueger; Wenke Li; Dachun Liu; Clarence J. Maring; Mark A. Matulenko; Christopher E. Motter
Original assignee: AbbVie Ireland ULC
Current assignee: AbbVie Ireland ULC
Priority date: 2010-10-13
Filing date: 2016-10-07
Publication date: 2018-12-20
Anticipated expiration: 2031-10-12
Also published as: AU2016238925A1; AU2019201940A1; AU2020264358A1

Abstract

ANTI-VIRAL COMPOUNDS Compounds effective in inhibiting replication of Hepatitis C virus ("HCV") are described This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

Description

ANTI-VIRAL COMPOUNDS

This application claims priority from U.S. Patent Application Serial No. 13/100,827 filed May 4, 2011, U.S. Provisional Application Serial No. 61/446,800 filed February 25, 2011, U.S. Patent Application Serial No. 12/964,027 filed December 9, 2010 and U.S. Patent

Application Serial No. 12/903,822 filed October 13, 2010, all of which are incorporated herein by reference in their entireties.

The present application is a divisional of AU2014203655, which is a divisional AU2011316506, the entire specifications of which are incorporated herein by cross-reference.

FIELD io The present invention relates to compounds effective in inhibiting replication of

Hepatitis C 5 virus (“HCV”). The present invention also relates to compositions comprising these compounds and methods of using these compounds to treat HCV infection.

BACKGROUND

HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family.

is The 10 enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein p7, and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and

NS5B. 15

The nonstructural protein NS5A is a membrane-associated phosphoprotein present in basally phosphorylated and hyperphosphorylated forms. It is a critical component of HCV replication and is believed to exert multiple functions at various stages of the viral life cycle. A full-length NS5A protein comprises three domains - namely, Domain I, Domain II, and 25 Domain III. Domain I (residues 1 to 213) contains a zinc-binding motif and an amphipathic N-terminal helix which can promote 20 membrane association. Domain II (residues 250 to 342) has regulatory functions, such as interactions with protein kinase PKR and PI3K, as well as NS5B, and also contains the interferon sensitivity-determining region. Domain III (residues 356 to 447) plays a role in infectious virion assembly, and can be modulated by phosphorylation 30 within the domain. NS5A has been identified as a promising therapeutic target for treating HCV.

2016238925 07 Oct 2016

SUMMARY

The present invention features compounds of Formulae I, Ιχ, Ib, Ic, Id, Ie, If and Ig and pharmaceutically acceptable salts thereof. These compounds and salts can inhibit the replication of

HCV and therefore are useful for treating HCV infection.

The present invention also features compositions comprising the compounds or salts of the present invention. The compositions can also include additional therapeutic agents, such as HCV helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, or internal ribosome entry site (IRES) inhibitors.

The present invention further features methods of using the compounds or salts of the present 0 invention to inhibit HCV replication. The methods comprise contacting cells infected with HCV virus with a compound or salt of the present invention, thereby inhibiting the replication of HCV virus in the cells.

In addition, the present invention features methods of using the compounds or salts of the present invention, or compositions comprising the same, to treat HCV infection. The methods 5 comprise administering a compound or salt of the present invention, or a pharmaceutical composition comprising the same, to a patient in need thereof, thereby reducing the blood or tissue level of HCV virus in the patient.

The present invention also features use of the compounds or salts of the present invention for the manufacture of medicaments for the treatment of HCV infection.

!0 Furthermore, the present invention features processes of making the compounds or salts of the invention.

Other features, objects, and advantages of the present invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating preferred embodiments of the invention, are given by way of illustration only, not 25 limitation. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description.

DETAILED DESCRIPTION

Tellinghuisen et al., NATURE 435:374-379 (2005), describes a crystal structure of the NS5A protein in which two NS5A monomers are packed as a dimer via contacts near the N-terminal ends of the molecules. W02006093867 postulates the use of the crystal structure of the NS5A protein in conjunction of computer modeling to design or select NS5A inhibitors.

To improve interactions with the NS5A protein, many NS5A inhibitors have been designed to have dimeric or dimer-like structures. For instance, WO2006133326 (BMS) describes compounds

2016238925 07 Oct 2016 with the formula:

depicts compounds with the

W02008021927(BMS) shows

F (R%

formula:

with the formula:

compounds ; W02008021927 (BMS) describes compounds with the formula:

; and US20100068176 (BMS) shows compounds with the formula:

, wherein L is selected from aryls (e.g.,

or

), aliphatic groups (e.g·, ), heteroaryls

or

L

I ), or a combination thereof (e.g.,

Certain modifications to the above formulae have also been provided. For instance,

2016238925 07 Oct 2016

W02010065681 (Presidio) discloses the formula:

, wherein B is Q or Q-Q, and each Q is independently selected from cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl, with the proviso that only one Q is a six member aromatic ring when B is Q-Q and with the proviso that if B is Q-Q , any Q is that is polycyclic is connected to the remainder of the molecule through only one cycle of the polycycle; WO2010096777 (Presidio) describes a similar formula:

, wherein B is W-W or W-X”-W, and wherein each W is optionally substituted aryl or heteroaryl, and X” is selected from -O-, -S(O)_k, -N(Rⁿ)- and -CR’₂-;

W02010091413 (Enanta) and US20100266543 (Enanta) show the formula:

(R¹)_u

, wherein A is substituted aryl, heteroaryl, heterocyclic, C₃C₈cycloalkyl or C₃-C₈cycloalkenyl and is optionally substituted with selected substituents; and

US20100221215 (Enanta) depicts the formula:

, wherein A is selected from aryl, heteroaryl, heterocyclic, C₃-C₈cycloalkyl or C₃-C₈cycloalkenyl, each optionally substituted, D is 15 absent or an optionally substituted aliphatic group, T is absent or an optionally substituted linear aliphatic group containing zero to eight carbons, E is absent or independently selected from optionally substituted aryl and optionally substituted heteroaryl, and wherein one or two of D, E, and T are absent.

Tables 1-4 compare the antiviral activities of different NS5A compounds. As demonstrated 20 by these tables, several compounds that are generically covered by W02010065681 (Presidio) WO2010096777 (Presidio), WO2010096462 (Enanta), US20100266543 (Enanta), WO2010096462 (Enanta) and US20100266543 (Enanta) appear to have comparable or worse anti-HCV activities than the corresponding compounds described in the BMS applications. W02010065681 (Presidio)

WO2010096777 (Presidio), WO2010096462 (Enanta), US20100266543 (Enanta), WO2010096462

2016238925 07 Oct 2016 (Enanta) and US20100266543 (Enanta) also fail to identify any advantage of these compounds over those described in the BMS applications.

linker between the imidazole moieties.

(BMS-790052) employs a biphenyl

See W02008021927(BMS). The EC₅₀ values of BMS790052 against different HCV genotypes were shown by Nettles et al., “BMS-790052 is a First-inclass Potent Hepatitis C Virus (HCV) NS5A Inhibitor for Patients with Chronic HCV Infection: 0 Results from a Proof-of-concept Study”, 59th Annual Meeting of the American Association for the

Study of Liver Diseases (Oct 31-Nov 1 2008, San Francisco, CA;

www.natap.org/2008/AASLD/AASLD_06.htm). Specifically, Nettles et al., observed that the EC₅₀values of BMS-790052 against HCV genotypes la lb, 3a, 4a and 5a were 0.05, 0.009, 0.127, 0.012, and 0.033 nM, respectively. See also Gao et al., NATURE 465:96-100 (2010). The compounds in 5 Table 1 use different linkers between the imidazole moieties. Table 1 depicts the EC₅₀ values of these compounds when tested using respective replicon assays in the presence of 5% (v/v) fetal bovine serum (FBS). As compared to BMS-790052, the replacement of the biphenyl linker with other linkers can significantly reduce the compounds’ activities against various HCV genotypes.

Table 1. Biphenyl linker versus other linkers

	EC₅₀ (nM)
la	lb	2a	2b	3a	4a	5a	6a
ΓΛ 3=0 N rO- foV' (BMS-790052)	see Nettles et al., supra
J-Zu.....< > )=O 99, 1/ N Hr °Ύϊ°'	0.12	0.03	16	0.09	1.5	0.03	0.05	0.5
N—a )-=° Ma/V (isomer 1, in which the cyclohexanyl moiety has a different cis/trans configuration than isomer 2)	0.71	0.06	9.0	0.4	2.3	0.04	0.08	0.5

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N—a O h r γ ^N * (isomer 2, in which the cyclohexanyl moiety has a different cis/trans configuration than isomer 1)

>10

8.5

>100

>10

4.0

>10

Table 2 compares compounds containing unsubstituted benzimidazole to those containing halo-substituted benzimidazole. Anti-viral activities were assessed using wild-type replicons (e.g., lb WT or la WT) as well as replicons containing specific NS5A mutations (e.g., lb L28T, lb Y93H, la 5 L31V, la Y93C, la M28V, or la Q30E) in the absence of FBS. As compared to the reference compound which contains unsubstituted benzimidazole, compounds containing substituted benzimidazole generally exhibited comparable or worse activities against many of these HCV viruses.

Table 2. Unsubstituted benzimidazole versus halo-substituted benzimidazole

	EC_SO (nM)
lb WT	lb L28T	lb Y93H	la WT	la L31V	la Y93C	la M28V	la Q30E
—/ AH Y'N ΐ 4 -HW o < G (reference compound)	0.01	2.7	0.9	0.09	36	40	1.0	40
<r\ YYA uv _____ /. .· ! Y-Z Ν' '<. , % ,γΥο ^σ;;· . N .O	0.003	1.8	0.5	0.14	109	26	2.4	119
F f Hy ,γυ /H ....	0.004	4.3	2.4	0.26	5.5	34	1.8	59
F _k, ..... Γη M1 /- i- N ^f: Y c>	0.005	>10	5.7	0.28	33	103	11.6	306

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f’ v^:K-< “N <0 ο.../ p

0.007

>10

3.6

0.1

80

141

5.8

52

The present invention surprisingly discovered that compounds with halo-substituted

benzimidazole (e.g., ^z ) can have better activity against certain

HCV variants containing NS5A mutations (e.g., la L31V). Similar testing also showed that

and , as compared to the reference compound in Table 2, exhibited significantly improved activity against the HCV la variant containing the NS5A mutation M28T. These improvements have not been described or suggested in any of the above-mentioned BMS, Presidio or Enanta applications. Accordingly, the present invention features methods of using the compounds containing halo-substituted benzimidazole (e.g.,

/·

N'\__/ '-N

or ) to treat HCV variants (e.g., la M28T or la L31V). These methods comprise administering an effective amount of such a compound to a patient infected with such a HCV variant (e.g., la M28T or la L3IV).

It was also found that when the phenyl linker between the benzimidazole moieties was replaced with a pyrrolidinyl link (e.g.,

H

), the process chemistry to introduce halo substitutions to the benzimidazole moieties became extremely difficult. The above-mentioned BMS,

Presidio and Enanta applications do not provide any enable disclosure that would allow halo substitutions on the benzimidazole moieties in a compound in which the phenyl linker is replaced with

2016238925 07 Oct 2016

H

Scheme XXIV and various Example of the present application (e.g., Examples 2.16,

3.35-3.41, 3.46-3.53, 4.26-4.31, 4.37-4.40, 4.42-4.46, and 4.51-4.57) provide an enabling disclosure that allows such substitutions in compounds with substituted pyrrolidinyl linkers.

Table 3 compares compounds with different linkers between the benzimidazole moieties.

Anti-viral activities were determined using la and lb replicon assays. “HP” refers to human plasma.

The compound containing the pyrrolidinyl linker showed significantly worse anti-HCV activities than those containing the pyridinyl linker.

As compared to the phenyl linker (

US20100068176 (BMS), the pyridinyl linker (

) used in or like 6-membered aromatic linkers are expected to provide similar or comparable anti-HCV activities.

Table 3. Non-aromatic heterocyclic linker versus aromatic heterocyclic linker

	EC₅o (ηΜ, in the presence of 5% FBS)	EC₅o (nM, in the presence of 5% FBS and 40% HP)
la	lb	la	lb
—o (' 7 λ-N NI—< ό Vn ^x 77·-<ύ	>250	>250	2500 - 8000	>4500
6	<0.32	<0.32	<3.2	<3.2
....χ Ν._ν-··υ_Λ.-·^:Η ο-	6.8	2.9	83	190
	1.7	1.7	<3.2	6
j._v .-•'’’'t'*;·;	82	73	166	548

2016238925 07 Oct 2016

Table 4 further shows that when the phenyl linker is replaced with a pyrrolidinyl linker, the compound’s activity against HCV can be significantly reduced. The compound in Table 4 contains a pyrrolidinyl linker and has EC₅₀ values of over 200 nM. In comparison, BMS-790052, which contains a biphenyl linker, has EC₅₀ values of no more than 0.2 nM. see Nettles et al., supra.

Therefore, Tables 3 and 4 clearly demonstrate that the use of an unsubstituted pyrrolidinyl linker in a dimeric or dimerdike NS5A inhibitor can lead to poor anti-HCV activities.

2016238925 07 Oct 2016

Table 4. Non-aromatic heterocyclic linker versus aromatic heterocyclic linker

	EC₅o (nM, in the presence of 5% FBS)	EC₅o (nM, in the presence of 5% FBS and 40% HP)
la	lb	la	lb
N. o >--N O -6	290	320	1200	2400
O z~·^ jJ® // % / \ / Ν'' V A' I	> 1000	10	>10000	60

It was unexpectedly discovered that when the nitrogen atom in the pyrrolidinyl linker is substituted with carbocycle or heterocycle, the anti-viral activities of the compound can be drastically 5 improved. Table 5 shows the anti-HCV activities of compounds in which the pyrrolidinyl linker is substituted with substituted carbocycle or heterocycle.

Table 5. Substituted pyrrolidinyl linker

	EC50 (nM, in the presence of 40% HP)	EC₅o (nM, in the absence of HP)
la	lb	2a	2b	3a	4a
x., y . 0 . N \ /				<	<	<
\^>° ' NH OA 0 (Example 109 of U.S. Patent Application Publication No. 2010/0317568)	0.1	0.3	0.2	0.05	0.05	0.05

2016238925 07 Oct 2016

ιΓί ΗΝ—99 Τ Η\^ΝΗ '—Ν ' ' >t° 9 < / νη ην \ ο=( )=° / (Example 163 of U.S. Patent Application Publication No. 2010/0317568)	0.1	0.3	< 0.05	< 0.05	< 0.05	< 0.05
0 . HN—99 T 99 NH '—N ' ' N—' \=° O=( HN—( }—NH Μ 9 \9 (Example 236 of U.S. Patent Application Publication No. 2010/0317568)	0.3	0.8
0 σ’ yb °7 < / 'nh HN ' »=< H o \ / \ (Example 245 of U.S. Patent Application Publication No. 2010/0317568)	0.2	0.4	< 0.05	< 0.05	< 0.05	< 0.05
n—99^F ' 99—n CA®/®/ 9° °~9 /°Λ Ρ ~λ 9 (Example 251 of U.S. Patent Application Publication No. 2010/0317568)	0.1	0.2	< 0.05	< 0.05	< 0.05	< 0.05

2016238925 07 Oct 2016

0 σ’	0.2	0.2	< 0.05	< 0.05	< 0.05	< 0.05
HN— \ / N yl·⁰' NH o / (Example 256			—NH /‘Q S.......( HN ' O \ 511 Publication

of U.S. Patent Applicatii No. 2010/0317568)
	0
		y
HN— \ / N '----N	oy		—NH ./-0 /	0.6	0.3	0.5	< 0.05	< 0.05	< 0.05
v>°			°y......../
/\ ' NH			/ \ HN ' >°
/ \ (Example 257 of U.S. Patent Application Publication No. 2010/0317568)
	0
	Λ
HN— \ / N' ’—N	Γ\ ^·.....ο-		-NH ./-0 X....../	0.4	0.5	0.07	< 0.05	< 0.05	< 0.05
/ \ / \ / nh HN \ o=( )=° /° ^O' (Example 258 of U.S. Patent Application Publication No. 2010/0317568)

2016238925 07 Oct 2016

0 ΰ· η-ΐΡ-ο-Οτ-ο HN-h° °Λ f- \ ₀H / (Example 271 of U.S. Patent Application Publication No. 2010/0317568)	0.1	0.2	< 0.05	< 0.05	< 0.05	< 0.05
tir HN---N / /?--^N\^H yt° ........< / NH ^HN _X ^X o-< / \ (Example 302 of U.S. Patent Application Publication No. 2010/0317568)	0.1	0.1	< 0.05	< 0.05	< 0.05	< 0.05
r \ . ^XN··· ό < ..-: 7 ; >%'·. ' n r \ _i Ρ’Ά y .·' C ' (Example 3.20 described below)	0.5	0.6	< 0.05	< 0.05	< 0.05	< 0.05
< ' ^Z c i i / 7< ' ; N--'^Z / .. _λ / Ό	0.1	0.2

2016238925 07 Oct 2016

(Example 4.3 described below)
	1.5	1.5	0.5	0.5	0.5	0.2
\__ / / \ ⁷ p
(Example 4.25 described below)
il fo-·/ I \ / Ν' ^iz \ —N ., )=O	0.1	0.2	< 0.05	< 0.05	< 0.05	< 0.05
\ / ^z ri
P (Example 5.1 described below)
o o (Example 37 of U.S. Patent Application Publication No. 2010/0317568)	0.2	0.1	< 0.05	< 0.05	< 0.05	< 0.05

2016238925 07 Oct 2016

It is noted that the anti-HCV activity of

Table 5 also demonstrates that additional halo substitution(s) on the carbocycle/heterocycle substituents on the pyrrolidinyl linker can significantly improve the compounds’ anti-HCV activities (e.g., compare Example 4.25 to Example 3.20 or Example 5.1).

The present invention features compounds having Formula I, and pharmaceutically acceptable salts thereof,

D

I

L-3

I Y-A-fo—X—L₂—B—Z

I wherein:

X is C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R_A or R_F;

Lx and L₂ are each independently selected from bond; or Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of which is independently optionally substituted at each 15 occurrence with one or more R_L;

L₃ is bond or -L_s-K-L_s’-, wherein K is selected from bond, -0-, -S-, -N(R_B)-, -C(O)-, S(O)₂- -S(O)-, -OS(O)-, -OS(O)₂- -S(O)₂O- -S(O)O- -C(O)O- -OC(O)-, OC(O)O- -C(O)N(Rb)-> -N(Rb)C(O)-, -N(Rb)C(O)O- -OC(O)N(Rb)-, -N(Rb)S(O)-N(Rb)S(O)₂- -S(O)N(Rb)-> -S(O)₂N(Rb)-, -C(O)N(Rb)C(O)-, -N(Rb)C(O)N(Rb’)-, 20 N(Rb)SO₂N(Rb’)-, or -N(R_B)S(O)N(R_B’)-;

A and B are each independently C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, and are each independently optionally substituted with one or more R_A;

D is C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R_A; or D is C₃-Ci₂carbocycle or 3- to 12-membered heterocycle which is 25 substituted with J and optionally substituted with one or more R_A, where J is C₃16

2016238925 07 Oct 2016

Ci₂carbocycle or 3- to 12-membered heterocycle and is optionally substituted with one or more Ra, or J is -SF₅; or D is hydrogen or R_A;

Y is selected from -T’-C(RiR₂)N(R₅)-T-R_d, -T’-C(R₃R4)C(R₆R₇)-T-R_D, -L_K-T-R_D or L_K-E;

Ri and R₂ are each independently R_c, and R₅ is R_B; or Ri is Rc, and R₂ and R₅, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more R_A;

R₃, R4, R₍,. and R₇ are each independently Rc; or R₃ and Re are each independently Rc, and R4 and R₇, taken together with the atoms to which they are attached, form a 3- to 120 membered carbocycle or heterocycle which is optionally substituted with one or more R_A;

Z is selected from -T’-C(R₈R₉)N(Ri₂)-T-R_d, -T’-C(Ri₀Rii)C(Ri₃Ri4)-T-R_D, -L_K-T-R_D or -L_K-E;

R₈ and R₉ are each independently Rc, and R_i2 is R_B; or Rs is Rc, and R₉ and R_i2, taken together with the atoms to which they are attached, form a 3 - to 12-membered heterocycle which is optionally substituted with one or more R_A;

Rio, Rn, R13, and R|₄ are each independently R_c; or R₁₀ and R_i3 are each independently R_c, and Rn and R|₄. taken together with the atoms to which they are attached, form a 3 - to 12-membered carbocycle or heterocycle which is optionally substituted with one or more Ra;

!0 T and I” are each independently selected at each occurrence from bond, -L_s-, -L_s-M-L_s’-, or -L_s-M-Ls’-M’-L_s”-, wherein M and M’ are each independently selected at each occurrence from bond, -0-, -S-, -N(R_B)-, -C(O)-, -S(O)₂-, -S(O)-, -OS(O)-, OS(O)₂- -S(O)₂O- -S(O)O- -C(O)O- -OC(O)-, -OC(O)O- -C(O)N(R_b)-, N(Rb)C(O)-, -N(R_b)C(O)O- -OC(O)N(R_b)-, -N(R_b)S(O)-, -N(Rb)S(O)₂- 25 S(O)N(R_b)-, -S(O)₂N(R_b)-, -C(O)N(Rb)C(O)-, -N(R_b)C(0)N(R_b’)-, N(R_b)SO₂N(R_b’)-, -N(R_b)S(O)N(R_b’)-, C₃-C₁₂carbocycle or 3- to 12-membered heterocycle, and wherein said C₃-C₁₂carbocycle and 3- to 12-membered heterocycle are each independently optionally substituted at each occurrence with one or more R_A;

L_K is independently selected at each occurrence from bond, -L_S-N(R_B)C(O)-L_S’- or -L_s30 C(O)N(R_b)-L_s’-; or Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of which is independently optionally substituted at each occurrence with one or more R_L; or C₃C₁₂carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more R_A;

E is independently selected at each occurrence from C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, and is independently optionally substituted at each occurrence with one or more R_A;

2016238925 07 Oct 2016

Rd is each independently selected at each occurrence from hydrogen or R_A;

Ra is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_s-Re, wherein two adjacent R_A, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;

R_B and R_B’ are each independently selected at each occurrence from hydrogen; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 60 membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle;

wherein each 3- to 6-membered carbocycle or heterocycle in R_B or R_B’ is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂5 C₆haloalkenyl or C₂-C₆haloalkynyl;

Rc is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or CiC₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, !0 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R_c is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, 25 phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, CiC₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl;

R_E is independently selected at each occurrence from -O-R_s, -S-R_s, -C(O)R_S, -OC(O)R_S, C(O)OR_S, -N(RsRs’), -S(O)R_s, -SO₂R_s, -C(O)N(R_SR_S’), -N(R_S)C(O)R_S’, N(R_s)C(O)N(R_s’Rs”), -N(R_s)SO₂R_s’, -SO₂N(R_sR_s’), -N(R_s)SO₂N(R_s’R_s”), 30 N(R_s)S(O)N(R_s’Rs’ ’), -OS(O)-R_s, -OS(O)₂-R_s, -S(O)₂OR_s, -S(O)OR_s, -OC(O)OR_S, N(R_S)C(O)OR_S’, -OC(O)N(RsR_s’)> -N(R_s)S(O)-R_s’, -S(O)N(R_sR_s’), -P(O)(OR_S)₂, or C(O)N(R_S)C(O)-R_S’; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, 35 phosphono, thioxo, formyl or cyano; or C3-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence

2016238925 07 Oct 2016

	with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C2-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C2-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs, or N(RsRs’);
5	R_f is independently selected at each occurrence from Ci-Ci_Oalkyl, C2-Ci₀alkenyl or C₂Ci_Oalkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independently optionally substituted with one or more R_L; or -(R_x-Ry)q-(R_x-Ry’), wherein Q is 0, 1, 2, 3 or 4, and each R_x is independently O, S or N(R_B), wherein each R_Yis independently Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene each of which is
0	independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, and wherein each R_Y’ is independently Ci-C₆alkyl, C₂-C₆alkenyl or C₂C₆alkynyl each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,
.5 !0	phosphonoxy, phosphono, thioxo, formyl or cyano; R_l is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RsRs’), S(O)Rs, -SO₂Rs, -C(O)N(RsRs ) or -N(Rs)C(O)Rs’; or C₃-C₆carbocycle or 3- to 6membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C2-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C2-C₆haloalkenyl or C₂-C₆haloalkynyl; wherein two adjacent R_L, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle
25	or heterocycle; L_s, L_s’ and L_s” are each independently selected at each occurrence from bond; or CiC₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene, each of which is independently optionally substituted at each occurrence with one or more R_L; and R_s, Rs’ and R_s” are each independently selected at each occurrence from hydrogen; Ci-
30	C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -O-Ci-C₆alkyl, -O-Ci-C₆alkylene-O-Ci-C₆alkyl, or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each
35	3- to 6-membered carbocycle or heterocycle in R_s , Rs’ or Rs’ is independently optionally substituted at each occurrence with one or more substituents selected from halogen,

2016238925 07 Oct 2016 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂C₆haloalkynyl.

A and B preferably are independently selected from C₅-C₆carbocycle (e.g., phenyl), 5- to 6membered heterocycle (e.g., pyridinyl or thiazolyl), or 8- to 12-membered bicycles such as

independently selected at each occurrence from O, S, NH or CH₂, Z₂ is independently selected at each occurrence from N or CH, Z₃ is independently selected at each occurrence from N or CH, Z₄ is independently selected at each occurrence from O, S, NH or CH₂, and W_b W₂, W₃, W₄, W₅ and W₆0 are each independently selected at each occurrence from CH or N. A and B are each independently optionally substituted with one or more R_A.

More preferably, A is selected from C₅-C₆carbocycle, 5- to 6-membered heterocycle,

and is optionally substituted with one or more R_A; B is selected from C₅-C₆carbocycle, 5- to 6-membered heterocycle,

and is optionally substituted with one or more R_A; where Z_b Z₂, Z₃, Z₄, W_b W₂,

W₃, W₄, W₅, W₆ are as defined above. Preferably, Z₃ is N and Z₄ is NH. For instance, A can be selected from phenyl (e.g., * \=/ ^), pyridinyl (e.g., * thiazolyl (e.g.,

selected from phenyl

preferably, both A and B are phenyl (e.g., both A and B

). Also highly preferably, A

2016238925 07 Oct 2016

substituted with one or more R_A.

, and A and B are substituted

It was surprisingly discovered that when A and/or B were

Also preferably, A is with one or more halogen, such as F or Cl.

; or A is

), the halo-substituted benzimidazole (e.g., A is compounds of Formula I (as well as compounds of Formula I_A, Ib, Ic, Id, Ie, If or I_G described below, and compounds of each embodiment described thereunder) unexpectedly showed significantly improved pharmacokinetic properties, as compared to compounds with unsubstituted benzimidazole. The improvements in pharmacokinetics can be observed, for instance, as a greater total plasma level exposure, measured as the area under the curve (AUC) over a 24 hour period following oral dosing in mouse (for examples see infra). It was also surprisingly discovered that these compounds with halo5 substituted benzimidazole unexpectedly displayed improved inhibitory activity against certain HCV genotype la variants (e.g., variants containing NS5A mutations L31M, Y93H, or Y93N). Accordingly, the present invention contemplates methods of using such compounds to treat HCV genotype la variant infection (e.g., L31M, Y93H, or Y93N la variant infection). These methods comprise administering such a compound to a patient having HCV genotype la variant (e.g., L31M, 20 Y93H, or Y93N la variant). The present invention also contemplates the use of such compounds for the manufacture of a medicament for the treatment of genotype la variant infection (e.g., L31M, Y93H, orY93N la variant infection).

D preferably is selected from C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12membered bicycles, and is optionally substituted with one or more R_A. D can also be preferably 25 selected from Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionally substituted with one or more substituents selected from R_L. More preferably, D is C₅-C₆carbocycle (e.g., phenyl), 5- to 6membered heterocycle (e.g., pyridinyl, pyrimidinyl, thiazolyl), or 6- to 12-membered bicycles (e.g., indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl), and is substituted with one or more R_M, where R_M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_s-Re. Also preferably, D is phenyl, and is optionally substituted with one or more

Ra. More preferably, D is phenyl, and is substituted with one or more R_M, wherein R_M is as defined

2016238925 07 Oct 2016

Jvyv , wherein R_M is as defined above, and each above. Highly preferably, D is

R_n is independently selected from R_D and preferably is hydrogen. One or more R_N can also preferably be halo such as F.

more Ra.

is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

Rn , wherein R_M more R_M.

is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen. One or more R_N can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7tetrahydrobenzo[d]thiazolyl, benzo [d]thiazolyl, or indazolyl, and is optionally substituted with one or more R_A. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R_M. Highly preferably, D

uwv , _or , and is optionally substituted with amino, carboxy, nitro, oxo, phosphonoxy, mercapto,

C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is

Preferably, R_M is halogen, hydroxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more

2016238925 07 Oct 2016 substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, R_M is

Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_M is -L_s-Re, wherein L_s is a bond or Ci-C₆alkylene, and R_E is N(RsRs’), -O-Rs, -C(O)R_S, -C(O)OR_S, -C(O)N(R_SR_S’), -N(R_S)C(O)R_S’, -N(R_S)C(O)OR_S’, N(R_s)SO₂R_s’, -SO₂Rs, -SR_s, or -P(O)(OR_S)₂, wherein R_s and R_s’ can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C₆alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Ci-C₆alkyl or 3- to 6-membered heterocycle; or R_M is Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or R_m is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)ORs, or N(RsRs’)· More preferably, R_M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C₆alkyl (e.g., methyl, isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents !0 selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example R_M is CF₃, C(CF₃)₂-OH, -C(CH₃)₂-CN, -C(CH₃)₂-CH₂OH, or -C(CH₃)₂-CH₂NH₂. Also preferably R_M is -LsRe where L_s is a bond and R_E is -N(RsRs), -O-Rs, -N(Rs)C(O)ORs’, -N(Rs)SO₂Rs’, -SO₂Rs, or SRs. For example where L_s is a bond, R_E is -N(Ci-C₆alkyl)₂ (e.g., -NMe₂); -N(Ci-C₆alkylene-O-CiC₆alkyl)₂ (e.g. -N(CH₂CH₂OMe)₂); -NiCrCealkyljiCrCealkylene-O-CrCealkyl) (e.g. 25 N(CH₃)(CH₂CH₂OMe));—O-Ci-C₆alkyl (e.g., -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-nhexyl); -O-Ci-C₆haloalkyl (e.g., - OCF₃, -OCH₂CF₃); -O-Ci-C₆alkylene-piperidine (e.g., -OCH₂CH₂-1-piperidyl); -NiQ-CsalkyljCiOjOCrCgalkyl (e.g., -N(CH₃)C(O)O-CH₂CH(CH₃)₂), N(C₁-C₆alkyl)SO₂C₁-C₆alkyl (e.g., -N(CH₃)SO₂CH₃); -SO₂C!-C₆alkyl (e.g., -SO₂Me); -SO₂C,C₆haloalkyl (e.g., -SO₂CF₃); or -S-Ci-C₆haloalkyl (e.g., SCF₃). Also preferably R_M is -L_S-R_E where 30 L_s is Cx-Cgalkylene (e.g., -CH₂- -C(CH₃)₂- -C(CH₃)₂-CH₂-) and R_E is -O-R_s, -C(O)OR_S, N(R_S)C(O)OR_S’, or -P(O)(OR_S)₂. For example R_M is -Ci-C₆alkylene-O-R_s (e g., -C(CH₃)₂-CH₂OMe); -Q-Cealkylene-CXOjORs (e.g., -C(CH₃)₂-C(O)OMe); -CrQalkylene-NiRsjCiOjORs’ (e.g, -C(CH₃)₂-CH₂-NHC(O)OCH₃); or -Ci-C₆alkylene-P(O)(ORs)₂ (e.g, -CH₂-P(O)(OEt)₂). Also more preferably R_M is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently 35 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci23

2016238925 07 Oct 2016

C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs, or -N(RsRs’)· For example R_M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-lmethylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-15 yl, piperidin-l-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, R_Mis Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered 0 bicycle and is substituted with J and optionally substituted with one or more R_A, wherein J is C₃C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6membered heterocycle, wherein said C₃-C₆carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, 5 mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or N(RsRs’), and J can also be optionally substituted with one or more R_A. Also preferably, D is C₅C₆carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally !0 substituted with one or more R_A, and preferably, J is at least substituted with a C₃-C₆carbocycle or 3to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or -N(R_sRs) Also preferably, D is C₅-C₆carbocycle or 25 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more

R_a, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R_A. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle 30 or 6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or 24

2016238925 07 Oct 2016

N(RsRs’)· Highly preferably, D is

, wherein each R_N is independently selected from

R_d and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or

6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or N(R_sRs’)· Also preferably, D is wherein each R_N is independently selected from R_D and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and 0 is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or N(RsRs’), and J can also be optionally substituted with one or more R_A Also preferably, D is , and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,

C(O)OR_S or-N(RsRs’).

It was surprisingly discovered that when D contains a halo-substituted carbocycle or heterocycle (e.g., a halo-substituted 5-6 membered carbocycle or heterocycle directly linked to X), the compound of Formula I (as well as compounds of Formula I_A, I_B, Ic, Id, Ie, If or I_G described below, and compounds of each embodiment described thereunder) can exhibit significantly improved 25 inhibitory activity against HCV genotypes 2a, 2b, 3a or 4a and/or improved pharmacokinetic properties. Therefore, the present invention contemplates methods of using such compounds to treat HCV genotype 2a, 2b, 3a or 4a infection. These methods comprise administering such a compound to a patient having HCV genotype 2a, 2b, 3a or 4a. The present invention also contemplates the use of such compounds for the manufacture of a medicament for the treatment of HCV genotypes 2a, 2b, 3a

2016238925 07 Oct 2016

Ri

Rt as described above, wherein at least one R_N is halo such as fluorine. Specific examples of suitable D

R, include, but are not limited to, _ ^RM and , wherein R_N, R_M and J are as described above.

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is optionally substituted with one or more R_A or R_F. X can also be C₅-C₆carbocycle or 0 5- to 6-membered heterocycle which is optionally substituted with one or more R_A or R_F, wherein two adjacent R_A on X, taken together with the ring atoms to which they are attached, optionally form a 5Xto 6-membered carbocycle or heterocycle. Also preferably, X is , wherein X₃ is

C(H) or preferably N and is directly appended to -L₃-D; X₄ is C₂-C₄alkylene, C₂-C₄alkenylene or C₂C₄alkynylene, each of which optionally contains one or two heteroatoms selected from O, S orN; and

X is optionally substituted with one or more R_A or R_F, and two adjacent R_A on X, taken together with the ring atoms to which they are attached, can optionally form a 5- to 6-membered carbocycle or

X,Xheterocycle. In addition, X can be or , wherein X₃ is C and is directly linked to -L₃-D, X₄ is C2-C₄alkylene, C2-C₄alkenylene or C₂-C₄alkynylene each of which optionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted with one or more R_A or R_F, and two adjacent R_A on X, taken together with the ring atoms to which

2016238925 07 Oct 2016 they are attached, optionally form a 5 - to 6-membered carbocycle or heterocycle. Moreover, X can be

wherein N is directly linked to L₃-D, X₄ is C₂-C₄alkylene, C₂-C₄alkenylene or C₂C₄alkynylene each of which optionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted with one or more R_A or R_F, and two adjacent R_A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

JWV'

For instance, X can be

X1-X1 x₂—x₂

X-I—x₂ x₂ x₂ s/vw*

I σννν*

I ϋλΛΛΤ

I ^xi~ Xi

X-ι X₂

X₂ X₂ x₂ x₂ or

X1-X1 wherein Χχ is independently selected at each occurrence from CH₂, O, S or NH, X₂ is independently selected at each occurrence from CH or N, X₃ is N and is directly linked to -L₃-D, and X₃’ is C and is directly linked to -L₃-D; and X is optionally substituted with one or more R_A or R_F, and two adjacent R_A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

For another example, X is jvw

5 5 jwir

X₂^ /X₂x₂

X₂ ^X₂ Xi_x ^Xi xf , x; ,

UWV'

Mm

Xi_x /X₂

Xi jvw

X₂^ /Xi X₂ λλλγ

Xi_x ®₂x₂ | jvw J

W ^X2«s /^X2 ^XW /^X1 ^X1\_v<<^X2

X-2 Xi jvw ^X2^^X1 or ^χ ₂ , wherein Χχ is independently selected at each occurrence from CH₂, O, S or NH, X₂ is independently selected at each occurrence from CH or

N, X₃ is N and is directly linked to -L₃-D, and X₃’ is C and is directly linked to -L₃-D; and wherein

X is optionally substituted with one or more Ra or R_F, and two adjacent R_A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or

2016238925 07 Oct 2016 heterocycle.

Highly preferably, X is

or N and is directly linked to -L₃-D, X₃’ is C and is directly linked to -L₃-D, and wherein X is optionally substituted with one or more R_A or R_F, and two adjacent R_A on X, taken together with the ring atoms to which they are attached, optionally form a 5 - to 6-membered carbocycle or heterocycle.

More preferably, X₃ is N.

Non-limiting examples of X include:

2016238925 07 Oct 2016

wherein ►” indicates the covalent attachment to -L₃-D. Each X can be optionally substituted with one or more R_A or R_F, and two adjacent R_A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

Non-limiting examples of preferred X include the following pyrrolidine rings, each of which is optionally substituted with one or more R_A or R_F:

As shown, the relative stereochemistry at the 2- and 5-positions of the above pyrrolidine ring may be either cis or trans. The stereochemistries of optional substituents R_A at the 3- or 4-positions of the pyrrolidine may vary relative to any substituent at any other position on the pyrrolidine ring. Depending on the particular substituents attached to the pyrrolidine, the stereochemistry at any carbon may be either (R) or (S).

Non-limiting examples of preferred X also include the following pyrrole, triazole or thiomorpholine rings, each of which is optionally substituted with one or more R_A or R_F:

2016238925 07 Oct 2016

As shown, the relative stereochemistry at the 3- and 5-positions of the thiomorpholine ring may be either cis or trans. Depending on the particular substituents attached to the thiomorpholine, the stereochemistry at any carbon may be either (R) or (S).

Also preferably, X is %A/VV* k/XZL·

wherein X₃ is N and is directly linked to -L₃-D, and X is optionally substituted with one or more R_A or R_F. Preferably, R_F is Ci-Ci_Oalkyl,

C₂-Ci₀alkenyl or C₂-Ci₀alkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O,

S or N and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Also preferably, R_F is Ci-Ci_Oalkyl, C₂-Ci₀alkenyl or C₂-Ci₀alkynyl, each of which contains 0,

1, 2, 3, 4 or 5 O and is independently optionally substituted with one or more R_L. Also preferably, R_F is -(R_x-Ry)q-(R_x-Ry’), wherein Q is 0, 1, 2, 3 or 4; each R_x is independently O, S or N(R_B); each R_Yis independently Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; and each R_Y’ is independently Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Preferably, each R_x is O. More preferably, X is optionally substituted with one or more R_A or R_F, each R_F is independently selected from Ci-Ci_Oalkyl, C₂-Ci₀alkenyl or C₂-Ci₀alkynyl, each of which contains 0, 1, 2 or 3 O and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Also preferably, X is optionally substituted with one or more R_A or R_F, each R_F is independently selected from -(O-Ci-C₆alkylene)Q-(O-Ci-C₆alkyl), wherein Q preferably is 0, 1, 2 or 3.

L| and L₂ are preferably independently bond or Ci-C₆alkylene, L₃ is preferably selected from bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. More preferably, L_b L₂ and L₃ are each independently bond or Ci-C₆alkylene (e.g., 30

CH₂- or -CH₂CH₂-), and are each independently optionally substituted with one or more R_L. Highly preferably, L_b L₂ and L₃ are bond.

Y is preferably selected from -L_s-C(RiR₂)N(R₅)-T-R_d -L_S-C(R₃R₄)C(R<5R₇)-T-R_D, -GC(R₁R₂)N(R₅)-T-R_d. -G-C(R₃R4)C(ReR₇)-T-R_D, -N(R_B)C(O)C(R₁R₂)N(R₅)-T-R_D> 5 N(R_b)C(O)C(R₃R4)C(R,R₇)-T-R_d, -C(O)N(R_b)C(R₁R₂)N(R₅)-T-R_Dj -C(O)N(R_b)C(R₃R₄)C(R₆R₇)T-R_d, -N(R_b)C(O)-L_s-E, or -C(O)N(Rb)-L_s-E. G is C₅-C₆carbocycle or 5- to 6-membered

2016238925 07 Oct 2016 heterocycle, such as

or

, and is optionally substituted with one or more R_A (e.g., one or more chloro or bromo). E preferably is a 7- to 12membered bicycle (such as

, wherein U is independently selected at each occurrence from

-(CH₂)- or -(NH)-; V and Z₂₀ are each independently selected from Ci-C₄alkylene, C₂-C₄alkenylene or

C2-C₄alkynylene, in which at least one carbon atom can be independently optionally replaced with O,

S or N), and is independently optionally substituted with one or more R_A. More preferably, Ri is Rc, and R₂ and R₅, taken together with the atoms to which they are attached, form a 5- to 6-membered

halo (e.g., fluoro), Ci-C₆alkyl (e.g., methyl), or C2-C₆alkenyl (e.g., allyl)); and R₃ and Re are each independently Rc, and R₄ and R₇, taken together with the atoms to which they are attached, form a 5to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R_A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C₆alkyl (e.g., methyl), or C2-C₆alkenyl (e.g., allyl)).

Y can also be selected from -M-C(RiR₂)N(R₅)-C(O)-Ly’-M’-R_d, -M-C(RiR₂)N(R₅)-L_y’M’-Rd, -Ls-C(R₁R₂)N(R₅)-C(O)-L_Y’-M’-R_D, -L_S-C(R₁R₂)N(R₅)-L_Y’-M’-R_D, -mC(R₃R4)C(R6R₇)-C(O)-L_Y’-M’-R_D, -M-CCRsRQCCReRvj-LY’-M’-Rn, -L_S-C(R₃R4)C(R6R₇)-C(O)L_Y’-M’-R_D, or -Ls-C(R₃R4)C(R<5R7)-L_Y’-M’-R_D, wherein M preferably is bond, -C(O)N(R_B)- or 5 N(R_B)C(O)-, M’ preferably is bond, -C(O)N(R_B)-, -N(R_B)C(O)-, -N(R_B)C(O)O2016238925 07 Oct 2016

N(R_B)C(O)N(R_B’)-, -N(R_b)S(O)- or -N(R_B)S(O)₂-, and L_Y’ preferably is Ci-C₆alkylene which is optionally substituted with one or more R_L. L_Y’, for example, is a Ci-C₆alkylene such as, but not

; and the optional R_L is a limited to, substituent such as, but not limited to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon within the group L_Y’ can be either (R) or (S). More preferably, Ri is Rc, and R₂ and R₅, taken together with the atoms to which they are attached, form a 5 - to 6-membered heterocycle or 6- to 12-

membered bicycle (e.g., ) which is optionally substituted with one or more R_A (e.g., one or more hydroxy); and R₃ and Re are each independently Rc, and R4 and R₇, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,

or

) which is optionally substituted with one or more R_A.

Also preferably, Y is selected from -N(R_B)CO-C(RiR₂)N(R₅)-C(O)-L_Y’-N(R_B)C(O)O-R_D, NiRBjCO-CiRiRflNiRsj-CiOj-Ly’-NiRBjCiOj-RD, -N(R_B)CO-C(R₁R₂)N(R₅)-C(O)-L_Y’N(R_B)S(O)₂-R_D, -N(R_B)CO-C(R₁R₂)N(R₅)-C(O)-L_Y’-N(R_BR_B’)-R_D, -NtRQCO-CXRiRflNtRs)20 C(O)-L_Y’-O-R_D, -NtRQCO-QRiRflN^-QOj-LY’-RD, -N(R_B)CO-C(R₁R₂)N(R₅)-R_D, -L_sQRiRflN^-QOj-LY’ff^RQQOjO-RD, -Ls-CiR.R^lNiRd-CiOl-Lv'-NiRQCiOl-Ro. -L_sCiRiRflNiRsj-CiOj-Ly’-NiRBjSiOj.-RD, ffis^’iR.RJNiRd^XOlffiv'-NiRXJ-Ro. -L_sCi^RflNiRsj-CiOj-Ly’-O-RD, -L_S-C(R₁R₂)N(R₅)-C(O)-L_Y’-R_D, -Ls-C^R^N^-Rd, N(R_B)CO-C(R₃R₄)C(R₆R₇)-C(O)-L_Y’-N(R_B)C(O)O-R_D, -N(R_B)CO-C(R₃R₄)C(R₆R₇)-C(O)-L_Y’25 N(Rb)C(O)-R_d, -N(R_B)CO-C(R₃R₄)C(R₆R₇)-C(O)-L_Y’-N(R_B)S(O)₂-R_D, -N(R_b)COC(R₃R4)C(R<5R₇)-C(O)-L_Y’-N(R_BR_B’)-R_D, -N(R_B)CO-C(R₃R₄)C(R₆R₇)-C(O)-L_Y’-O-R_D, N(R_B)CO-C(R₃R4)C(R<5R₇)-C(O)-L_Y’-R_D, -N(R_B)CO-C(R₃R₄)C(R₆R₇)-R_D, -L_S-C(R₃R4)C(R6R₇)C(O)-L_y’-N(R_b)C(O)O-R_d, -L_S-C(R₃R₄)C(R₆R₇)-C(O)-L_Y’-N(R_B)C(O)-R_D, -LsC(R₃R₄)C(R₆R₇)-C(O)-L_Y’-N(R_B)S(O)₂-R_D, -L_S-C(R₃R₄)C(R₆R₇)-C(O)-L_Y’-N(R_BR_B’)-R_D, -Ls32

C(R₃R₄)C(R₆R₇)-C(O)-L_y’-O-R_d, -L_s-C(R₃R₄)C(R₆R₇)-C(O)-L_y’-R_d, or -Ls-C(R₃R4)C(ReR₇)R_d, wherein L_Y’ preferably is Ci-C₆alkylene which is optionally substituted with one or more R_L. Ri may be Rc, and R₂ and R₅, taken together with the atoms to which they are attached, may form a 5- to

2016238925 07 Oct 2016 .5

6-membered heterocycle or 6- to 12-membered bicycle (e.g., ) which is optionally substituted with one or more R_A; and R₃ and Rs may be each independently R_c. and R4 and R₇, taken together with the atoms to which they are attached, may form a 5- to 6-membered

) which is carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., optionally substituted with one or more R_A.

Highly preferably, Y is selected from -N(R_b”)CO-C(RiR₂)N(R₅)-C(O)-L_y-N(R_b”)C(O)L_s-R_e or -C(R₁R₂)N(R₅)-C(O)-L_y-N(R_b”)C(O)-L_s-R_e, or Y is -Θ-(3(^₂)Ν(^)-(2(Ο)-Ε_ΥN(R_b”)C(O)-L_s-R_e, wherein L_Y is Ci-C₆alkylene optionally substituted with one or more R_L, and R_b” is each independently R_B. R_B” and Ri are each preferably hydrogen or Ci-C₆alkyl, and R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered

heterocycle or 6- to 12-membered bicycle (e.g., ) which is optionally substituted with one or more R_A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C₆alkyl (e.g., methyl), or C₂-C₆alkenyl (e.g., allyl)). Preferably, L_Y is Ci-C₆alkylene substituted with one or more R_L such as a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. Highly preferably,

L_Y is a Ci-C₆alkylene such as, but not limited to,

I (stereochemistry at a carbon within the group L_Y can be either (R) or (S)), L_Y is independently optionally substituted with one or more R_L (e.g., one or more phenyl or methoxy), G

2016238925 07 Oct 2016 preferably is

H

R_b” is hydrogen; -C(RiR₂)N(R₅)- is

; L_s is a bond; and R_E is methoxy.

wherein T and R_D are as defined herein. T, for example, can be -L_s-M-L_s’-M’-L_s”- where L_s is a bond; M is C(O); L_s’ is Ci-C₆alkylene such as, but not limited to,

, where L_s’ is independently optionally substituted with one or more R_L; R_L is a substituent such as, but not limited to phenyl or methoxy; M’ is -NHC(O)- or -NMeC(O)-; and

L_s” is a bond. Any stereochemistry at a carbon within the group L_s’ can be either (R) or (S). R_D, for example is methoxy. T-R_D includes, but is not limited to:

uwv

2016238925 07 Oct 2016

1/VW

or

T-R_d may also include certain stereochemical configurations; thus T-R_D includes,

JWV JVW

but is not limited to:

JWV

Non-limiting examples of preferred Y also include:

O

2016238925 07 Oct 2016

Z is preferably selected from -L_S-C(R₈R₉)N(R|₂)-T-R_D. -L_s-C(Ri₀Rn)C(Ri₃Ri4)-T-R_D, G-C(R₈R₉)N(R₁₂)-T-R_D, -G-C(R₁₀R_n)C(R₁₃R₁₄)-T-R_D, -N(R_B)C(O)C(R₈R₉)N(R₁₂)-T-R_D, 5 N(R_b)C(O)C(R₁₀R₁₁)C(R₁₃R₁₄)-T-R_d,

-C(O)N(R_b)C(R₈R₉)N(R₁₂)-T-R_d,

C(O)N(R_b)C(R₁₀Rh)C(R₁₃R₁₄)-T-R_d, -N(R_B)C(O)-L_S-E, or -C(O)N(R_B)-L_S-E. G is C₅-

HN-n

HAy r , and is optionally substituted with one or more R_A (e.g., one or more chloro or bromo). A rr

E preferably is a 8- to 12-membered bicycle (such as ^2o^u . wherein U is independently selected at each occurrence from -(CH₂)- or -(NH)-; and V and Z₂₀ are each independently selected from Ci-C₄alkylene, C₂-C₄alkenylene or C₂-C₄alkynylene, in which at least one carbon atom is independently optionally replaced with O, S or N), and is independently optionally substituted with one or more R_A. More preferably, Rs is Rc, and R₉ and R_i2, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

2016238925 07 Oct 2016 .5 ) ) which is optionally substituted with one or more R_A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C₆alkyl (e.g., methyl), or C₂-C₆alkenyl (e.g., allyl)); and R₁₀ and R₁₃ are each independently Rc, and Rn and , taken together with the atoms to which they are attached, form a 5- to 6-membered

carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., ) which is optionally substituted with one or more R_A (such as, but not limited to hydroxy, halo (e.g., fluoro), Cp C₆alkyl (e.g., methyl), or C₂-C₆alkenyl (e.g., allyl)).

Z can also be selected from -M-C(R₈R₉)N(R₁₂)-C(O)-L_Y’-M’-R_D, -M-CCR^NCR^-Ly’Μ’-Rd, -L_s-C(R₈R₉)N(R₁₂)-C(O)-L_y’-M’-R_d, -L_s-C(R₈R₉)N(R₁₂)-L_y’-M’-R_d, -MC(R₁₀Rn)C(R₁₃R₁₄)-C(O)-L_Y’-M’-R_D, -M-C(R₁₀Rn)C(R₁₃R₁₄)-L_Y’-M’-R_D, -L_sC(RioRn)C(Ri₃Ri₄)-C(0)-L_Y’-M’-R_D, or -L_s-C(Ri₀Rn)C(Ri₃Ri₄)-L_Y’-M’-R_D, wherein M preferably is bond, -C(O)N(R_B)- or -N(R_B)C(O)-, M’ preferably is bond, -C(O)N(R_B)-, N(Rb)C(O)-, -N(Rb)C(O)O- N(Rb)C(O)N(R_b’)-, -N(R_b)S(O)- or -N(R_B)S(O)₂- and L_Y’ preferably is Ci-C₆alkylene which is independently optionally substituted with one or more R_L. L_Y’, for example, is a Ci-C₆alkylene such as, but not limited to, , ' , ,

; and the optional R_L is a substituent such as, but not limited to phenyl, SMe, or methoxy. Any stereochemistry at a carbon within the group L_Y’ can be either (R) or (S). More preferably, R₈ is Rc, and R₉ and R₁₂, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

) which is optionally substituted with one or more R_A (e.g., one or more hydroxy); and

Rio and R_i3 are each independently R_c, and Rn and R|₄. taken together with the atoms to which they

2016238925 07 Oct 2016 are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e.g.,

A A or ) which is optionally substituted with one or more R_A.

Also preferably, Z is selected from -N(R_b)CO-C(R₈R₉)N(Ri2)-C(O)-L_y’-N(R_b)C(O)O-Rd,

-N(Rb)CO-C(R₈R₉)N(R₁₂)-C(O)-L_y’-N(Rb)C(O)-R_d, -N(Rb)CO-C(R₈R₉)N(R₁₂)-C(O)-L_y’5 N(Rb)S(O)₂-Rd, -N(Rb)CO-C(R₈R₉)N(R₁₂)-C(O)-L_y’-N(R_bRb’)-Rd, -N(R_b)CO-C(RsR9)N(R₁₂)C(O)-L_y’-O-R_d, -NiRBjCO-CiRsRQNiRnj-CiOj-LY’-RD, -N(R_B)CO-C(R₈R₉)N(R₁₂)-R_D, -L_sC(R₈R₉)N(R₁₂)-C(O)-L_y’-N(R_b)C(O)O-R_d, -L_s-C(R₈R₉)N(R₁₂)-C(O)-L_y’-N(R_b)C(O)-R_d, -L_sC(R₈R₉)N(R₁₂)-C(O)-L_y’-N(Rb)S(O)₂-Rd, -L_s-C(R₈R₉)N(R₁₂)-C(O)-L_y’-N(R_bR_b’)-Rd, -L_sC(R₈R₉)N(R₁₂)-C(O)-L_y’-O-R_d, -Ls-CiRsRQNiRnj-CXOj-LY’-RD, -L_S-C(R₈R₉)N(R₁₂)-R_D, 0 N(^)CO-C(R₁₀Rii)C(R₁₃R₁₄)-C(O)-L_y’-N(^)C(O)O-^), -N(R_b)CO-C(R₁₀Rii)C(R₁₃R₁₄)-C(O)L_y’-N(R_b)C(O)-R_d, -N(R_b)CO-C(R₁oR₁₁)C(R₁₃R₁₄)-C(0)-L_y’-N(Rb)S(0)2-R_d, -N(R_b)COCiRioRnjCiRBRMj-CiOj-LY’-NiRBRB’j-RD, -N(^)CO-C(R₁₀Rii)C(R₁₃R₁₄)-C(O)-L_y’-O-^), N(^)CO-C(R₁₀Rii)C(R₁₃R₁₄)-C(O)-L_y’-^), -N(R_B)CO-C(R₁₀R₁₁)C(R₁₃R₁₄)-R_D, -L_sC(R₁₀R_n)C(R₁₃R₁₄)-C(O)-L_Y’-N(R_B)C(O)O-R_D, -L_s-C(R₁₀Rn)C(R₁₃R₁₄)-C(O)-L_Y’-N(R_B)C(O)5 R_d, -L_s-C(R₁₀R₁₁)C(R₁₃R₁₄)-C(O)-L_y’-N(R_b)S(O)₂-R_d, -Ls-C(R₁₀R_n)C(R₁₃R₁₄)-C(O)-L_Y’N(R_bR_b’)-Rd, -Ls-C(R₁₀R_n)C(R₁₃R₁₄)-C(O)-L_Y’-O-R_D, -L_s-C(R₁₀R_n)C(R₁₃R₁₄)-C(O)-L_Y’-R_D, or -L_s-C(Ri₀Rh)C(Ri₃Ri₄)-R_d, wherein L_Y’ preferably is Ci-C₆alkylene which is independently optionally substituted with one or more R_L. Rs may be Rc, and R₉ and R_i2, taken together with the atoms to which they are attached, may form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

or

) which is optionally substituted with one or more R_A; and

Rio and R_i3 may be each independently R_c, and Rn and R|₄. taken together with the atoms to which they are attached, may form a 5 - to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle

(e.g., or h- ) which is optionally substituted with one or more R_A.

Highly preferably, Z is selected from -N(Rb”)CO-C(R₈R₉)N(Ri2)-C(O)-Ly-N(R_b”)C(O)25 Ls-Re or -C(R₈R₉)N(R₁₂)-C(O)-L_y-N(R_b”)C(O)-L_s-R_e, or Z is -G-C(R₈R₉)N(R₁₂)-C(O)-L_YN(R_b”)C(O)-L_s-R_e, wherein L_Y is Ci-C₆alkylene optionally substituted with one or more R_L, and R_b” is each independently R_B. R_B” and Rs are each preferably hydrogen or Ci-C₆alkyl, and R₉ and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered

2016238925 07 Oct 2016

L_Y is a Ci-C₆alkylene such as, but not limited to,

(stereochemistry at a carbon within the group L_Y can be either (R) or (S)); L_Y is independently optionally substituted with one or more R_L (e.g., one or more phenyl or methoxy); G preferably is

H

R_b” is hydrogen; -C(R_SR₉)N(R|₂)- is

I

JWV ; L_s is a bond; and R_E is methoxy.

Non-limiting examples of preferred Z include:

2016238925 07 Oct 2016

wherein T and R_D are as defined herein. T, for example, can be -L_s-M-L_s’-M’-L_s”- where L_s is a

bond; M is C(O); L_s’ is Ci-C₆alkylene such as, but not limited to,

, where L_s’ is independently optionally substituted with one or more R_L; the optional R_L is a substituent such as, but not limited to phenyl or methoxy; M’ is -NHC(O)- or NMeC(O)-; and L_s” is a bond. Any stereochemistry at a carbon within the group L_s’ can be either (R) or (S). R_d, for example is methoxy. T-R_D includes, but is not limited to:

k/WW include certain stereochemical configurations; thus T-R_D

includes, limited not is

ΛΛΛΤ

αλλ/’

ΛΛΛΛ ruXAr

ΛΛΛΓ

2016238925 07 Oct 2016

T can be, without limitation, independently selected at each occurrence from -C(O)-L_S’-, C(O)O-L_S’-, -C(O)-L_s’-N(R_b)C(O)-Ls”-, -C(O)-L_s’-N(R_b)C(O)O-L_s”- -N(R_b)C(O)-L_sN(R_b)C(O)-L_s”-, -N(R_b)C(O)-L_s’-N(R_b)C(O)O-L_s”-, or -N(R_B)C(O)-L_S’-N(R_B)-L_S”-.

Preferably, T is independently selected at each occurrence from -C(O)-L_S’-M’-L_S”- or 10 N(R_b)C(O)-Ls’-M’-L_s”-. More preferably, T is independently selected at each occurrence from C(O)-L_s’-N(Rb)C(O)-L_s”- or -C(O)-L_S’-N(R_B)C(O)O-L_S”-.

T can also be, for example, -L_s-M-L_s’-M’-L_s”- where L_s is a bond; M is C(O); L_s’ is CiX X

C₆alkylene (e.g., — ), where L_s’ is independently optionally substituted with R_T; the optional

R_T is a substituent selected from -Ci-C₆alkyl, -C₂-C₆alkenyl, -Ci-C₆alkyl-OH, -Ci-C₆alkyl-O-Ci15 C₆alkyl, 3- to 6-membered heterocycle (e.g., tetrahydrofuranyl), or C₃-C₆carbocyclyl (e.g., phenyl, cyclohexyl); M’ is -NHC(O)-, -N(Et)C(O)- or -N(Me)C(O)-; and L_s” is a bond. R_D preferably is hydrogen, -Ci-C₆alkyl (e.g., methyl), -O-Ci-C₆alkyl (e.g., methoxy, tert-butoxy), methoxymethyl, or

2016238925 07 Oct 2016

-N(Ci-C₆alkyl)₂ (e.g., -NMe₂).

Rd can be either (R) or (S).

T can also be, without limitation, -L_s-M-L_s’- where L_s is a bond; M is C(O); L_s’ is Ci10 C₆alkylene (e.g., — ) where L_s’ is independently optionally substituted with R_T; the optional

R_T is a substituent selected from -Ci-C₆alkyl, -Ci-C₆alkyl-OH, -Ci-C₆alkyl-O-Ci-C₆alkyl, or a C₃C₆carbocyclyl (e.g., phenyl, cyclohexyl). R_D, for example is -OH; -OC(O)Me; -NH(Ci-C₆alkyl) (e.g., -NHMe, -NHEt); -N(Ci-C₆alkyl)₂ (e.g., -NMe₂, -NEt₂); a 3- to 10-membered heterocyclyl (e.g., pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, morpholinyl, piperidinyl) optionally 15 substituted with one or more halogen, oxo; C₃-Ci₀carbocycle (e.g., cyclopentyl) optionally substituted with -OH; -Ci-C₆alkyl (e.g., isopropyl, 3-pentyl) optionally substituted with -OH; or NHR_T where R_T is a 3- to 6-membered heterocyclyl (e.g., thiazolyl, pyrimidinyl). T-R_D includes, but is not limited to:

2016238925 07 Oct 2016

5 5 5 5 5

stereochemistry at a carbon within the group T-R_D can be either (R) or (S).

For each compound of Formula I, E_K can also be independently selected at each occurrence from a bond; -L_S’-N(R_B)C(O)-L_S-; -L_s’-C(O)N(Rb)-L_s-; or Ci-C₆alkylene, C₂-C₆alkenylene, C₂C₆alkynylene, C₃-Ci₀carbocycle or 3- to 10-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, R_T 10 O-R_s, -S-R_s, -N(R_sRs’)> -OC(O)R_S, -C(O)OR_S, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, wherein R_T, R_B, Rs, Rs’, L_s and E_s’ are as defined above.

For Formula I as well as Formulae I_A, Ib, Ic, Id, Ie, If or I_G described below, including each and every embodiment described thereunder, R_A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂15 C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, 20 thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or

C₂-C₆haloalkynyl; or -L_A-O-Rs, -L_A-S-Rs, -L_A-C(O)R_S, -F_A-OC(O)R_S, -F_A-C(O)OR_S, -L_A43

2016238925 07 Oct 2016

N(RsRs’), -L_a-S(O)Rs, -L_a-SO₂Rs, -L_a-C(0)N(RsR_s’), -L_a-N(Rs)C(O)Rs’, -L_aN(Rs)C(O)N(Rs’Rs”), -L_A-N(Rs)SO₂R_s’, -L_A-SO₂N(RsR_s’), -L_A-N(Rs)SO₂N(Rs’Rs ”), -L_aN(Rs)S(O)N(Rs’Rs”), -L_A-OS(O)-R_s, -L_A-OS(O)₂-R_s, -L_A-S(O)₂OR_s, -L_A-S(O)ORs, -L_AOC(O)OR_S, -L_a-N(Rs)C(O)OR_s’, -L_a-OC(O)N(RsRs’), -L_a-N(Rs)S(O)-R_s’, -L_a-S(O)N(RsR_s’) or

-L_a-C(O)N(Rs)C(O)-Rs’, wherein L_A is bond, Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or 0 cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, 5 phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

L_s, L_s’ and L_s” preferably are each independently selected at each occurrence from bond; or !0 Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

A and B can be the same or different. Likewise, Li and L₂, or Y and Z, or Y-A- and Z-B-, or -A-Li- and -B-L₂-, can be the same or different. In some instances, Y-A-Li- is identical to ZB—L₂—. In some other instances, Y-A-Li- is different from Z-B-L₂-.

In one embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as * '\=Z/^> ^), and are each independently optionally substituted with one or more R_A. X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle

ντύ-υ I

, wherein X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_A. Specific examples of X are described hereinabove. D is C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with 30 one or more R_A, or is substituted with J and optionally substituted with one or more R_A, wherein J is

C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂2016238925 07 Oct 2016

C₆haloalkynyl, C(O)ORs or -N(RsRs’), and J can also be optionally substituted with one or more R_A.

Preferably, D is preferably, D is

JVW

JVW , wherein R_M and R_N are as defined above. Also , wherein J and R_N are as defined above. Lx and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. Y is -N(R_b)C(O)C(RiR₂)N(R₅)-T-R_d, or -N(R_B)C(O)C(R₃R₄)C(R₆R₇)-T-R_D, and Z is N(R_b)C(O)C(R₈R₉)N(R₁₂)-T-R_d, or -N(R_B)C(O)C(R₁₀R₁₁)C(R₁₃R₁₄)-T-R_D. Rx is Rc, and R₂ and R₅, taken together with the atoms to which they are attached, form a 5 - to 6-membered heterocyclic ring

) which is optionally substituted with one or more R_A: R₃ and Re are each independently R_c, and R4 and R₇, taken together with the atoms to which they are attached, form a 5-

to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A. R« is Rc, and R₉ and R₁₂, taken together with the atoms to which they are

attached, form a 5- to 6-membered heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A; and R₁₀ and R₁₃ are each independently R_c, and R_n and R₁₄, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A. T is preferably independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”- or -C(O)

L_y’-N(R_b)C(O)O-L_s”-. L_y’ is each independently L_s’ and, preferably, is each independently C₄45

2016238925 07 Oct 2016

selected from R_L. T can also be, without limitation, selected from -C(O)-L_Y’-L_S”-, -C(O)-L_Y’-OL_s”-, -C(O)-L_y’-N(R_b)-L_s”-, or -C(O)-L_Y’-N(R_B)S(O)₂-L_s”-. In some cases, at least one of Y and Z is, or both Y and Z are independently.

wherein non-limiting examples of R_D include (1) -O-Ci-C₆alkyl, -O-C₂-C₆alkenyl, -O-C₂-C₆alkynyl, Ci-C₆alkyl, C₂C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle; or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which is independently optionally 0 substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; and non-limiting examples of L_Y’ include Ci-C₆alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Ci-C₆alkyl, -O-C₂-C₆alkenyl, -O-C₂-C₆alkynyl, or 3- to 65 membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

substituted with one or more R_A; B is

In another embodiment, A is , and is optionally h , and is optionally substituted with one or more R_A. Z₃ is independently selected at each occurrence from O, S, NH or

CH₂; and Z₂ is independently selected at each occurrence from N or CH. Preferably, A is and A and B are substituted with one or more halogen, such as F or Cl. When A and/or B are halo-substituted benzimidazole (e.g., A is and B is ), the compounds of this embodiment can have significantly improved

2016238925 07 Oct 2016

pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. X is 5- or 6κΛΛ/V* membered carbocycle or heterocycle or 6- to 12-membered bicycle (e.g., '----> or ντύ-υ

J.

, wherein X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_A. Specific examples of X are described hereinabove. D is C₅-C₆carbocycle or 5- to 6membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R_A, or is substituted with J and optionally substituted with one or more R_A, wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_a. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is 0 independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl,

C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs

N(RsRs’), and J also be optionally substituted with one or more R_A. Preferably, can

JUW

JVW bond 'wv , wherein R_M and R_N are as defined above. Also preferably, or

D is

D is 'wv , wherein J and R_N are as defined above. L| and L₂ are each independently or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. Y is Ls-C(R!R₂)N(R₅)-T-R_d or -Ls-C(R₃R4)C(ReR₇)-T-R_D, and Z is -L_S-C(R₈R₉)N(R₁₂)-T-R_D or -L_sC(Ri₀Rh)C(Ri₃Ri₄)-T-R_d. Ri is Rc, and R₂ and R₅, taken together with the atoms to which they are

A attached, form a 5- to 6-membered heterocyclic ring (e.g., *· ) which is optionally substituted with one or more R_A; R₃ and Re are each independently R_c, and R4 and R₇, taken together with the atoms to which they are attached, form a 5 - to 6-membered carbocyclic or heterocyclic ring

A (e.g., ) which is optionally substituted with one or more R_A. Rg is Re, and R₉ and R_i2,

2016238925 07 Oct 2016 taken together with the atoms to which they are attached, form a 5 - to 6-membered heterocyclic ring (e.g·,

) which is optionally substituted with one or more R_A; and Ri₀ and R_i3 are each independently R_c. and Rn and R_i4, taken together with the atoms to which they are attached, form a A

5-to 6-membered carbocyclic or heterocyclic ring (e.g., ^x ) which is optionally substituted with one or more R_A. T is preferably independently selected at each occurrence from -C(O)-L_Y’N(R_B)C(O)-L_S”- or -C(O)-L_Y’-N(R_B)C(O)O-L_S”-. L_y’ is each independently L_s’ and, preferably, is independently Ci-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L. T can also be, without limitation, selected from -C(O)-L_Y’-L_S”-, -C(O)-L_Y’-O0 L_s”-, -C(O)-L_Y’-N(R_B)-L_S”-, or -C(O)-L_Y’-N(R_B)S(O)₂-L_s”-. In some cases, at least one of Y and Z is, or both Y and Z are independently,

, wherein non-limiting examples of R_D include (1) -O-Ci-C₆alkyl, -O-C₂-C₆alkenyl, -O-C₂-C₆alkynyl, Ci-C₆alkyl, C₂C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, .5 phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle;

or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; and non-limiting 20 examples of L_Y’ include Ci-C₆alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Ci-C₆alkyl, -O-C₂-C₆alkenyl, -O-C₂-C₆alkynyl, or 3- to 6membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂25 C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

In still yet another embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as * ^<\==/^> ^), and are each independently optionally substituted with one or more R_A. X is 5- or 6-membered carbocycle

2016238925 07 Oct 2016 or heterocycle or 6- to 12-membered bicycle (e.g., '----' or '----' , wherein X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_A. Specific examples of X are described hereinabove. D can be, for example, C₅-C₆carbocycle or 5- to 6-membered 5 heterocycle (e.g., phenyl), and is optionally substituted with one or more R_A. or is substituted with J and optionally substituted with one or more R_A. wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, 0 mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl,

C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or N(R_sRs ), and J can also be optionally substituted with one or more R_A. Preferably, D is

Ri

Ri , wherein R_M and R_N are as defined above. Also preferably, D is or wherein J and R_N are as defined above. Li and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. Y is G-C(R!R₂)N(R₅)-T-R_d or -G-C(R;R₄)C(R₍,R-)-T-R_lb and Z is -G-C(R«R₉)N(R_I2)-T-R_D or -GC(Ri₀Rh)C(Ri₃Ri₄)-T-R_d. G is independently C₅-C₆carbocycle or 5- to 6-membered heterocycle,

H N.

such as

N or N ' , and is independently optionally substituted with one or more R_A.

R| is Rc, and R₂ and R₅, taken together with the atoms to which they are attached, form a 5- to 6membered heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A;

R₃ and Re are each independently R_c, and R₄ and R₇, taken together with the atoms to which they are

2016238925 07 Oct 2016 attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,

optionally substituted with one or more R_A. Rg is Re, and R₉ and R_i2, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

optionally substituted with one or more R_A; and Ri₀ and R_i3 are each independently R_c. and Rn and

R₁₄, taken together with the atoms to which they are attached, form a 5 - to 6-membered carbocyclic or

A heterocyclic ring (e.g., ^x ) which is optionally substituted with one or more R_A. T is preferably independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”- or -C(O)L_y’-N(R_b)C(O)O-L_s”-. L_y’ is each independently L_s’ and, preferably, is each independently CiC₆alkylene (e.g., -CH₂- or

) and optionally substituted with one or more substituents selected from R_L. T can also be, without limitation, selected from -C(O)-L_Y’-L_S”-, -C(O)-L_Y’-O-

and Z are independently, , wherein non-limiting examples of R_D include (1) -O-Ci-C₆alkyl, -OC₂-C₆alkenyl, -O-C₂-C₆alkynyl, Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle; or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, 20 phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl or C₂-C₆haloalkynyl; and non-limiting examples of L_Y’ include Ci-C₆alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Ci50

C₆alkyl, -O-C₂-C₆alkenyl, -O-C₂-C₆alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono,

2016238925 07 Oct 2016

In yet another embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as \=/ ), and are each independently optionally substituted with one or more R_A. X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle (e.g.

, wherein X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_A. Specific examples of X are described hereinabove. D can be, for example, C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R_A. or is substituted with J and optionally substituted with one or more R_A. wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A.

Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or N(R_sRs ), and J can also be optionally substituted with one or more R_A. Preferably, D is

Ri

Ri , wherein R_M and R_N are as defined above. Also preferably, D is or wherein J and R_N are as defined above. Li and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. Y is N(Rb)C(O)C(R!R₂)N(R₅)-T-R_d or -N(R_B)C(O)C(R₃R₄)C(R₆R₇)-T-R_D, and Z is -G-C(R₈R₉)N(R₁₂)25 T-R_d or -G-C(R|_(IR, i)C’(R| ,R|₄)-T-R_Ib or Y is -G-C(R!R₂)N(R₅)-T-R_D or -G-C(R₃R₄)C(R₆R₇)-TR_d, and Z is -N(R_B)C(O)C(R₈R₉)N(R₁₂)-T-R_D or -N(R_B)C(O)C(R₁₀Rn)C(R₁₃R₁₄)-T-R_D. R₃ is Rc, and R₂ and R₅, taken together with the atoms to which they are attached, form a 5 - to 6-membered

2016238925 07 Oct 2016 heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A; R₃ and Re are each independently R_c, and R4 and R₇, taken together with the atoms to which they are attached,

form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A. R₈ is Rc, and R₉ and R_i2, taken together with the atoms to which

they are attached, form a 5- to 6-membered heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A; and Ri₀ and R_i3 are each independently Rc, and Rn and R_i4, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,

) which is optionally substituted with one or more R_A. G is

independently C₅-C₆carbocycle or 5- to 6-membered heterocycle, such as , and is independently optionally substituted with one or more R_A. T is preferably independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”- or -C(O)-L_Y’-N(R_B)C(O)O-L_S”-.

L_Y’ is each independently L_s’ and, preferably, is each independently Ci-C₆alkylene (e.g., -CH₂- or

) and optionally substituted with one or more substituents selected from R_L. T can also be, without limitation, selected from -C(O)-L_Y’-L_S”-, -C(O)-L_Y’-O-L_S -C(O)-L_Y’-N(R_B)-L_S”-,

In some cases, Y is

or -C(O)-L_y’-N(Rb)S(O)₂-L_s”-.

as described above. In some

2016238925 07 Oct 2016

as described above.

as described above ,

In still another embodiment, A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl

is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as * \==/ ^). A and B are each independently optionally substituted with one or more R_A. Ζχ is independently selected at each occurrence from O, S, NH or CH₂; and Z₂ is independently selected at each occurrence from N or CH.

X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle (e.g.,

or ντύ-υ I

, wherein X₃ is N and is directly linked to -L₃-D) and is optionally substituted with one or more R_A. Specific examples of X are described hereinabove. D is C₅-C₆carbocycle or 5- to 6membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R_A, or is substituted with J and optionally substituted with one or more R_A, wherein J is C₃-C₆carbocycle, 3- to 15 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more

R_a. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or 20 N(R_sRs ), and J can also be optionally substituted with one or more R_A. Preferably, D is ~^nj>ⁿ' , wherein R_M and R_N are as defined above. Also preferably, D is

2016238925 07 Oct 2016

or

J

or •'w , wherein J and R_N are as defined above. Lx and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. When

A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as \=/ ), Y is NiRBlCXOlCXR.RJNiRyT-Ro. -N(R_B)C(O)C(R₃R₄)C(R₆R₇)-T-R_D, -G-C(RiR₂)N(R₅)-T-R_D or G-C(R₃R₄)C(R₆R₇)-T-R_D, and Z is -L_S-C(R₈R₉)N(R₁₂)-T-R_D or -L_s-C(R₁₀Rii)C(R₁₃R₁₄)-T-R_D.

When B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as * ^), Y is -L_sC(R!R₂)N(R₅)-T-R_d or -Ls-C(R₃R4)C(ReR₇)-T-R_D, and Z is -N(R_B)C(O)C(R₈R₉)N(R₁₂)-T-R_D, 0 N(R_B)C(O)C(R₁₀Rn)C(R₁₃R₁₄)-T-R_D, -G-C(R₈R₉)N(R₁₂)-T-R_D or -G-C(R₁₀Rn)C(R₁₃R₁₄)-T-R_D.

Ri is Rc, and R₂ and R₅, taken together with the atoms to which they are attached, form a 5- to 6membered heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A;

R₃ and Re are each independently Rc, and R4 and R₇, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A R« is Rc, and R₉ and R|₂. taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A; and Ri₀ and R_i3 are each independently R_c, and Ru and

R14, taken together with the atoms to which they are attached, form a 5 - to 6-membered carbocyclic or heterocyclic ring (e.g., ) which is optionally substituted with one or more R_A. G is independently C₅-C₆carbocycle or 5- to 6-membered heterocycle, such as , and is independently optionally substituted with one or more R_A T is preferably independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”- or -C(O)-L_Y’-N(R_B)C(O)O-L_S”-.

2016238925 07 Oct 2016

) and optionally substituted with one or more substituents selected from R_L. T can also be, without limitation, selected from -C(O)-F_Y’-F_S”-, -C(O)-F_Y’-O-F_S”-, -C(O)-F_Y’-N(R_B)-F_S”-, or -C(O)-F_y’-N(Rb)S(O)₂-F_s” cases when A is 5- or

6-membered carbocycle or

In some heterocycle (e.g., phenyl

as described above, and Z is as described above.

other cases when B is 5- or 6-membered

D

In some

carbocycle or heterocycle (e.g., phenyl such described above,

D as described above.

The present invention also features compounds of Formulae I, I_A, I_B, Ic and I_D as described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:

2016238925 07 Oct 2016

D is C₃-Ci2carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R_A; or D is C₃-Ci2carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R_A, where J is C₃Ci₅carbocycle or 3- to 15-membered heterocycle (e.g., a 3- to 6-membered monocycle, a

6- to 12-membered fused, bridged or spiro bicycle, a 10- to t5-memberd tricycle containing fused, bridged or spiro rings, or a 13- to 15-membered carbocycle or heterocycle) and is optionally substituted with one or more R_A, or J is -SF₅; or D is hydrogen or R_A;

R_a is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, 0 phosphono, thioxo, cyano, or -L_B-R_E; wherein two adjacent R_A, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;

L_b is independently selected at each occurrence from L_s; or Ci-Ci_Oalkylene, C₂-Ci₀alkenylene or C₂-Ci₀alkynylene, each of which optionally has 1, 2, 3, 4 or 5 carbon atoms 5 independently replaced with O, S or N(R_B), and each of said Ci-Ci_Oalkylene, C₂Ci_Oalkenylene or C₂-Ci₀alkynylene being independently optionally substituted with one or more R_L;

R_e is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, C(O)OR_S, -N(RsRs’), -S(O)R_s, -SO₂R_s, -C(O)N(R_sRs’), -N(R_S)C(O)R_S’, !0 N(Rs)C(O)N(Rs’Rs”), -N(R_s)SO₂R_s’, -SO₂N(RsR_s’), -N(R_s)SO₂N(Rs’Rs”), N(Rs)S(O)N(R_s’Rs”), -OS(O)-Rs, -OS(O)₂-Rs, -S(O)₂ORs, -S(O)OR_s, -OC(O)OR_S, N(Rs)C(O)OR_s’, -OC(O)N(R_sRs’), -N(R_s)S(O)-Rs’, -S(O)N(RsR_s’), -P(O)(ORs)₂, =C(RsRs ), or -C(O)N(Rs)C(O)-Rs’; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more 25 substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-Ci₂carbocycle or 3- to 12-membered heterocycle; or C₃-Ci₂carbocycle or 3- to 12-membered heterocycle (e.g., 7- to 12membered carbocycle or heterocycle), each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 30 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, trimethylsilyl, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl, C₂-C₆haloalkynyl, -O-R_s, -S-R_s, -C(O)R_S, -C(O)OR_S, or-N(R_sRs)

R_l is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RsRs’), 35 S(O)Rs, -SO₂R_s, -C(O)N(R_sRs’) or -N(R_S)C(O)R_S’; or C₃-Ci₂carbocycle or 3- to 12membered heterocycle (e.g., C₃-C₆carbocycle or 3- to 6-membered heterocycle), each of

2016238925 07 Oct 2016 which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; wherein two adjacent R_L, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle.

In one embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (preferably, A and B are each independently phenyl such as \=/ ), and are each independently optionally substituted with one or more Ra (preferably, A and B are each independently 0 substituted with at least one halo such as F). X is 5- or 6-membered carbocycle or heterocycle or 6- to

12-membered bicycle (preferably, X is wherein X₃ is N and is directly linked to -L₃D), and is optionally substituted with one or more Ra. D is a C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is substituted with J and optionally substituted with one or more Ra. J is C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered .5 tricycle, or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more Ra. Preferably, J is substituted with a C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂!0 C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)OR_S or -N(R_sRs ), or (2) trimethylsilyl, -O-R_s, -S-R_s, -C(O)R_S; and J can also be optionally substituted with one or more R_A.

J

Preferably, D is , wherein J is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen or halo such as F. L| and E₂ are each independently bond or Ci-C₆alkylene, and E₃ is bond, Ci-C₆alkylene or -C(O)-, and E_b E₂, and E₃ are each independently optionally substituted with one or more R_L. Preferably, E_b E₂, and E₃ are bond.

Y is -N(Rb)C(O)C(R!R₂)N(R₅)-T-R_d, -N(Rb)C(O)C(R₃R4)C(R6R₇)-T-R_d, -G-C(R!R₂)N(R₅)-T-R_dor -G-C(R₃R4)C(R,R₇)-T-R_d. Z is -N(R_b)C(O)C(RsR₉)N(R₁₂)-T-R_d, N(RB)C(O)C(R₁₀Rn)C(R₁₃R₁₄)-T-R_D, -G-C(R₈R₉)N(R₁₂)-T-R_D or -G-C/RwRujC/RnRuj-T-RD.

Ri is Rc; and R₂ and R₅, taken together with the atoms to which they are attached, form a 5- to 657

2016238925 07 Oct 2016

membered heterocyclic ring (e.g., ) or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R_A; R₃ and Rs are each independently Rc, and R4 and

R₇, taken together with the atoms to which they are attached, form a 5 - to 6-membered carbocyclic or

heterocyclic ring (e.g., ) or 6- to 12-membered bicycle which is optionally substituted with one or more R_A. Rs is Rc; and R₉ and R_i2, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

) or 6- to 12-membered bicycle ) which is optionally substituted with one or more R_A; and Ri₀ and R_i3 are each independently R_c, and Rn and R_i4, taken together with the atoms to which they are attached, form a

5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) or 6- to 12-membered bicycle which is optionally substituted with one or more R_A. G is independently C₅-C₆carbocycle or 5- to 6-

membered heterocycle, such as , and is independently optionally substituted with one or more R_A. T is preferably independently selected at each occurrence from -C(O)-L_Y’N(R_b)C(O)-L_s”- or -C(O)-L_y’-N(Rb)C(O)O-L_s”-. L_y’ is each independently L_s’ and, preferably,

is each independently Ci-C₆alkylene (e.g., -CH₂- or ) and optionally substituted with one or more substituents selected from R_L. T can also be, without limitation, selected from -C(O)-L_Y’-L_S”, -C(O)-L_Y’-O-L_S -C(O)-L_y’-N(Rb)-L_s”- or -C(O)-L_Y’-N(R_B)S(O)₂-L_s”-. In some cases, Y

2016238925 07 Oct 2016 described above.

as described above.

In another embodiment, A is

substituted with one or more R_A; B is substituted with one or more R_A. Z₃ is independently selected at each occurrence from O, S, NH or CH₂; and Z₂ is independently selected at each occurrence from N or CH. Preferably, A and B are each independently substituted with at least one halo such as F. Also preferably, A is

, and A and B are substituted with one or more halogen, such as F or Cl. When A H c

CO and/or B are halo-substituted benzimidazole (e.g., A is

and B is ), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. X is 5- or 6λΑλ?

membered carbocycle or heterocycle or 6- to 12-membered bicycle (preferably, X is wherein X₃ is N and is directly linked to -L₃-D), and is optionally substituted with one or more R_A. D 15 is a C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is substituted with J and

optionally substituted with one or more R_A. J is C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂C₆haloalkynyl, -C(O)ORs or -N(RsRs’), or (2) trimethylsilyl, -O-Rs, -S-Rs, or -C(O)Rs; and J can

2016238925 07 Oct 2016

k/VW

JVW also be optionally substituted with one or more R_A. Preferably, D is wherein J is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen or halo such as F. Lx and L₂ are each independently bond or Cx-C₆alkylene, and L₃ is bond, Cx-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. Y is -L_s-C(RxR₂)N(R₅)-T-R_D or -L_sC(R₃R₄)C(R₆R₇)-T-R_d. Z is -L_s-C(R₈R₉)N(Rx₂)-T-R_d or-L_s-C(Ri₀Rii)C(Ri₃Ri₄)-T-R_D. Rx is Rc; and R₂ and R₅, taken together with the atoms to which they are attached, form a 5 - to 6-membered

heterocyclic ring (e.g., ) or 6- to 12-membered bicycle (e.g., ) which is optionally substituted with one or more R_A; R₃ and Rs are each independently Rc, and Rx and R₇, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or .5

heterocyclic ring (e.g., ) or 6- to 12-membered bicycle which is optionally substituted with one or more R_A. R« is Rc; and R₉ and R|₂. taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

) or 6- to 12-membered bicycle

) which is optionally substituted with one or more R_A; and Ri₀ and R₁₃ are each independently R_c, and Rn and R_b. taken together with the atoms to which they are attached, form a

5- to 6-membered carbocyclic or heterocyclic ring (e.g., ) or 6- to 12-membered bicycle which is optionally substituted with one or more R_A. T is preferably independently selected at each

occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”- or -C(O)-L_Y’-N(R_B)C(O)O-L_S”-. L_Y’ is each

2016238925 07 Oct 2016

D

independently L_s’ and, preferably, is each independently Ci-C₆alkylene (e.g., -CH₂- or ) and optionally substituted with one or more substituents selected from R_L. T can also be, without limitation, selected from -C(O)-L_Y’-L_S”-, -C(O)-L_Y’-O-L_S”-, -C(O)-L_Y’-N(R_B)-L_S”-, or C(O)-L_y’-N(Rb)S(O)₂-L_s”-. In some cases, Y and Z are independently

, wherein non-limiting examples of R_D include (1) -O-Ci-C₆alkyl, -O-C₂C₆alkenyl, -O-C₂-C₆alkynyl, Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle; or (2) C₃-C₆carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl or C₂-C₆haloalkynyl; and non-limiting examples of L_Y’ include Ci-C₆alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-CiC₆alkyl, -O-C₂-C₆alkenyl, -O-C₂-C₆alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or 20 C₂-C₆haloalkynyl.

In another aspect, the present invention features compounds of Formula I_A and pharmaceutically acceptable salts thereof.

D
Rfi o ^{1 R}2 II		? ° 1 II	F	? Rl2 <9 \|
_Rd-Xk		-X-L₂-E0 N		T—r_d
/ Rc'	1 Rnb	1 Rnb	F	?c'

Ia

2016238925 07 Oct 2016 wherein:

R_nb is each independently selected from R_b;

Rc’ is each independently selected from R_c;

Rd’ is each independently selected from R_D;

R₂ and R₅, taken together with the atoms to which they are attached, form a 3- to 12membered heterocycle which is optionally substituted with one or more R_a;

R₉ and R|₂. taken together with the atoms to which they are attached, form a 3- to 12membered heterocycle which is optionally substituted with one or more R_A;

A, B, D, X, L_b L₂, L₃, T, R_a, R_b, Rc, and R_D are as described above in Formula I.

In this aspect, A and B preferably are independently selected from C₅-C₆carbocycle or 5- to 6membered heterocycle, and are each independently optionally substituted with one or more R_a. More preferably, at least one of A and B is phenyl (e.g., * ^==/^ ^), and is optionally substituted with one or more R_a. Highly preferably, both A and B are each independently phenyl (e.g., * ^), and are each independently optionally substituted with one or more R_a.

D preferably is selected from C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 8- to 12membered bicycles, and is optionally substituted with one or more R_a. D can also be preferably selected from Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionally substituted with one or more R_l. More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12membered bicycles, and is substituted with one or more R_m, where R_m is halogen, nitro, oxo, !0 phosphonoxy, phosphono, thioxo, cyano, or -L_s-Re. Also preferably, D is phenyl, and is optionally substituted with one or more R_a. More preferably, D is phenyl, and is substituted with one or more

R_m, wherein R_m is as defined above. Highly preferably, D is

Rm

JVW or

as defined above, and each R_n is independently selected from R_d and preferably is hydrogen. One or more R_n can also preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more R_a. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

Rm
Rnx
Rn^
Rn
more R_m. Highly preferably, D is	1 JVW

is as defined above, and each R_n is independently selected from R_d and preferably is hydrogen. One or more R_n can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,762 tetrahydrobenzo [d]thiazolyl, benzo [d]thiazolyl, or indazolyl, and is optionally substituted with one or more R_A More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R_M. Highly preferably, D

2016238925 07 Oct 2016 is , or , and is optionally substituted with one or more R_M.

Preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or 0 cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂5 C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, R_M is Ci-C₆alkyl which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, !0 phosphono, thioxo, or cyano; or R_M is -L_S-R_E, wherein L_s is a bond or Ci-C₆alkylene, and R_E is N(RsRs’), -O-Rs, -C(O)R_S, -C(O)ORs, -C(O)N(R_sRs’), -N(Rs)C(O)R_s’, -N(R_s)C(O)ORs’, N(Rs)SO₂Rs’, -SO₂Rs, -SRs, or -P(O)(ORs)₂, wherein R_s and Rs’ can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C₆alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Ci-C₆alkyl or 3- to 6-membered 25 heterocycle; or R_M is Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or

R_m is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, 30 mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl,

C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)OR_S, or N(R_sRs’)· More preferably, R_M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C₆alkyl (e.g., methyl, isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each

2016238925 07 Oct 2016 of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example R_M is CF₃, C(CF₃)₂-OH, -C(CH₃)₂-CN, -C(CH₃)₂-CH₂OH, or -C(CH₃)₂-CH₂NH₂. Also preferably R_M is -L_sR_e where L_s is a bond and R_E is -N(RsRs), -O-Rs, -N(Rs)C(O)ORs’, -N(Rs)SO₂Rs’, -SO₂Rs, or 5 SRs. For example where L_s is a bond, R_E is -N(Ci-C₆alkyl)₂ (e.g., -NMe₂); -N(Ci-C₆alkylene-O-CiC₆alkyl)₂ (e.g. -N(CH₂CH₂OMe)₂); -NiCrCealkyOiCx-Cealkylene-O-Cx-Cealkyl) (e.g. N(CH₃)(CH₂CH₂OMe));—O-Ci-C₆alkyl (e.g., -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-nhexyl); -O-Ci-C₆haloalkyl (e.g., - OCF₃, -OCH₂CF₃); -O-Ci-C₆alkylene-piperidine (e.g., -OCH₂CH₂-1-piperidyl); -NiCx-CsalkyljCCOjOCx-Cgalkyl (e.g., -N(CH₃)C(O)O-CH₂CH(CH₃)₂), 0 NiCi-QalkyljSO.Ci-Cealkyl (e.g., -N(CH₃)SO₂CH₃); -SO.Cx-Cealkyl (e.g., -SO₂Me); -SO.CxC₆haloalkyl (e.g., -SO₂CF₃); or -S-Ci-C₆haloalkyl (e.g., SCF₃). Also preferably R_M is -L_S-R_E where L_s is Ci-C₆alkylene (e.g., -CH₂- -C(CH₃)₂- -C(CH₃)₂-CH₂-) and R_E is -O-R_s, -C(O)OR_S, N(R_s)C(0)0R_s’, or -P(O)(OR_S)₂. For example R_M is -Ci-C₆alkylene-O-R_s (e g., -C(CH₃)₂-CH₂OMe); -Cx-Cealkylene-CXOjORs (e.g., -C(CH₃)₂-C(O)OMe); -CrCealkylene-NiRgjCXOjORs’ (e.g,

-C(CH₃)₂-CH₂-NHC(O)OCH₃); or -Ci-C₆alkylene-P(O)(OR_S)₂ (e.g, -CH₂-P(O)(OEt)₂). Also more preferably R_M is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, !0 C(O)ORs, or -N(RsRs’) For example R_M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-lmethylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1yl, piperidin-l-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, R_M25 is Ci-C₆alkyl which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R_A, wherein J is C₃C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally 30 substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6membered heterocycle, wherein said C₃-C₆carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or 35 N(RsRs’), and J can also be optionally substituted with one or more R_A. Also preferably, D is C₅C₆carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted

2016238925 07 Oct 2016 with one or more Ra, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more Ra, and preferably, J is at least substituted with a C₃-C₆carbocycle or 3to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or -N(R_sRs) Also preferably, D is C₅-C₆carbocycle or

5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_a, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally 0 substituted with one or more R_A. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, 5 amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or j

N(RsRs’)· Highly preferably, D is , wherein each R_N is independently selected from

Rd and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or

6- to 12-membered bicycle and is optionally substituted with one or more Ra, and preferably J is at !0 least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or j

N(R_sRs’)· Also preferably, D is •'vw , wherein each R_N is independently selected from R_D and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or 65

2016238925 07 Oct 2016

N(RsRs’), and J can also be optionally substituted with one or more R_A Also preferably, D is , and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or-N(RsRs’).

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered

bicycles (e.g.

, wherein X₃ is N and is directly linked to -L₃-D), and is optionally substituted with one or more R_A or R_F. Non-limiting examples of X are described hereinabove.

Li and L₂ are preferably independently bond or Ci-C₆alkylene, L₃ is preferably selected from bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. More preferably, L_b L₂ and L₃ are each independently bond or Ci-C₆alkylene (e.g., 5 CH₂- or -CH₂CH₂-), and are each independently optionally substituted with one or more R_L. Highly preferably, L_b L₂ and L₃ are bond.

R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5- to 6or ), which is membered heterocycle or 6- to 12-membered bicycle (e.g., or ), which is optionally substituted with one or more R_A.

R₉ and R|₂. taken together with the atoms to which they are attached, preferably form a 5- to or ), which is

6-membered heterocycle or 6-to 12-membered bicycle (e.g., or ), which is optionally substituted with one or more R_A.

-T-R_d’ can be, without limitation, independently selected at each occurrence from -C(O)L_Y’-, -C(O)O-L_y’-R_d’, -C(O)-L_y’-N(Rb)C(O)-L_s”-R_d’, -C(O)-L_y’-N(R_b)C(O)O-L_s”-R_d’, 25 N(Rb)C(O)-L_y’-N(R_b)C(O)-L_s”-R_d’, -N(Rb)C(O)-L_y’-N(R_b)C(O)O-L_s”-R_d’, or -N(R_B)C(O)66

L_Y’—N(R_b)-L_s”-Rd’, wherein L_Y’ is each independently L_s’ and, preferably, is each independently

2016238925 07 Oct 2016

Ci-C₆alkylene (e.g., -CH₂- or ) and optionally substituted with one or more substituents selected from R_L. Preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’M’-L_s”-R_d’ or -N(R_b)C(O)-L_y’-M’-L_s”-R_d’. More preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”-R_D’ or -C(O)-L_Y’-N(R_B)C(O)O-L_S”-R_D’.

Highly preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)R_d’ or -C(O)-L_y’-N(R_b)C(O)O-R_d’, wherein L_Y’ preferably is each independently Ci-C₆alkylene (e.g., -CH₂- or ) and optionally substituted with one or more substituents selected from R_L.

R_nb and Rc’ are preferably hydrogen, and R_D’ preferably is independently selected at each occurrence from R_E. More preferably, R_D’ is independently selected at each occurrence from CiC₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

R_a preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is !0 independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci25 C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_A-

SO₂R_s, -L_a-C(O)N(RsRs’)> -L_a-N(Rs)C(O)Rs’, -L_a-N(Rs)C(O)N(Rs’Rs”), -L_A-N(Rs)SO₂R_s’, L_a-SO₂N(RsR_s’), -L_a-N(Rs)SO₂N(R_s’Rs”), -L_A-N(R_s)S(O)N(R_s’Rs”), -L_A-OS(O)-Rs, -L_AOS(O)₂-R_s, -L_a-S(O)₂ORs, -L_a-S(O)ORs, -L_a-OC(O)ORs, -L_a-N(R_s)C(O)ORs’, -L_a30 OC(O)N(R_sRs’), -L_a-N(R_s)S(O)-Rs’, -L_a-S(O)N(RsR_s’) or -L_A-C(O)N(R_S)C(O)-R_S’, wherein L_A is bond, Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 0 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or

2016238925 07 Oct 2016 cyano.

L_s, L_s’ and L_s” preferably are each independently selected at each occurrence from bond; or

Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

A and B can be the same or different. Likewise, L₃ and L₂ can be the same or different.

In one embodiment of this aspect, A and B are each independently phenyl, and are each independently optionally substituted with one or more R_A; D is phenyl, and is optionally substituted with one or more R_A, or is substituted with J and optionally substituted with one or more R_A, wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6!0 membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂C₆haloalkynyl, C(O)ORs or -N(RsRs’), and J can also be optionally substituted with one or more R_A.

Preferably, D is preferably, D is

i/WW ^nyvv , wherein R_M and R_N are as defined above. Also , wherein J and R_N are as defined above. Lj and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. T-R_d’ is independently selected at each occurrence from -C(O)-L_y’-N(Rb)C(O)-L_s”-Rd’ or-C(O)L_y’-N(R_b)C(O)O-L_s”-Rd’, wherein L_Y’ is Ci-C₆alkylene (e.g., -CH₂-) and optionally substituted 30 with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_D’ can also be,

2016238925 07 Oct 2016 without limitation, selected from -C(O)-L_Y’-L_S’’-Rd’, -C(O)-L_y’-O-L_s”-R_d’, -C(O)-L_y’-N(R_b)L_s”-R_d’, or -C(O)-L_y’-N(R_b)S(O)₂-L_s”-Rd’. Preferably, R₂ and R₅, taken together with the atoms to which they are attached, form which is optionally substituted with one or more R_a; R₉ and Ri₂, taken together with the atoms to which they are attached, form which is optionally substituted with one or more R_A.

which is

In another embodiment of this aspect, A and B are each independently phenyl (e.g., ), and are each independently optionally substituted with one or more R_A (preferably, A and B are each independently substituted with at least one halo such as F). X is '----' , wherein X₃ is N and is directly linked to -L₃-D, and X is optionally substituted with one or more R_A0 or R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_A. J is C₃C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally .5 substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)ORs or -N(RsRs’), or (2) trimethylsilyl, -O-Rs, -S-Rs or -C(O)Rs; and J can also be optionally substituted with one or more

R_A. Preferably, D is wherein J is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen or halo such as F. L| and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”-R_D’ or-C(O)L_Y’-N(R_B)C(O)O-L_S”-R_D’, wherein L_Y’ is Ci-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_d’ can also be, without limitation, selected from -C(O)-L_Y’-L_S’’-Rd’, -C(O)-L_y’-O-L_s”-Rd’, -C(O)-L_y’-N(R_b)69

2016238925 07 Oct 2016

L_s’’-Rd’, or -C(O)-L_y’-N(Rb)S(O)₂-Ls”-R_d’. R₂ and R₅, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

) or 6- to 12membered bicycle (e.g., ) which is optionally substituted with one or more R_A; and R₉ and

R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic

ring (e.g., ) or 6- to 12-membered bicycle (e.g., substituted with one or more R_A.

) which is optionally

In still another aspect, the present pharmaceutically acceptable salts thereof:

invention features compounds of Formula I_B and

I wherein:

Rc’ is each independently selected from R_c;

Rd’ is each independently selected from R_D;

R₂ and R₅, taken together with the atoms to which they are attached, form a 3- to 1215 membered heterocycle which is optionally substituted with one or more R_A;

R₉ and Ri₂, taken together with the atoms to which they are attached, form a 3- to 12membered heterocycle which is optionally substituted with one or more R_A;

A, B, D, X, Li, L₂, L₃, T, R_a, R_c, and R_D are as described above in Formula I.

In this aspect, A and B preferably are independently selected from 8- to 12-membered bicycles such as

or , where Z₄ is independently selected at each occurrence from O, S, NH or CH₂,

Z₂ is independently selected at each occurrence from N or CH, Z₃ is independently selected at each occurrence from N or CH, Z₄ is independently selected at each occurrence from O, S, NH or CH₂, and

Wi, W₂, W₃, W₄, W₅ and W₆ are each independently selected at each occurrence from CH or N. A and B are each independently optionally substituted with one or more R_A.

2016238925 07 Oct 2016

More preferably, A is selected from , and is

optionally substituted with one or more R_A; B is selected from

, and is optionally substituted with one or more R_A, where Z_b Z₂, Z₃, Z₄, W_b W₂,

W₃, W₄, W₅, W₆ are as defined above. Preferably, Z₃ is N and Z₄ is NH. For instance, A can be

6-membered heterocycle, and A and B are independently optionally

C₅-C₆carbocycle or 5- to substituted with one or more R_A.

2016238925 07 Oct 2016

More preferably, A is

and A and B are substituted with one or more halogen, such as F or Cl. When A and/or B are halo-substituted benzimidazole (e.g., A is

and B is

), the compounds of Formula I_B can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole.

D preferably is selected from C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12membered bicycles, and is optionally substituted with one or more R_A. D can also be preferably selected from Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionally substituted with one or 0 more substituents selected from R_L. More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more R_M, where R_M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_S-R_E. Also preferably, D is phenyl, and is optionally substituted with one or more R_A. More preferably, D is phenyl, and is substituted with one or more R_M, wherein R_M is as defined above. Highly preferably, D is

or

Rm

JVW , wherein R_M is as defined above, and each R_N is independently selected from

Rd and preferably is hydrogen. One or more R_N can also preferably be halo such as F.

D is also preferably pyndinyl, pynmidinyl, or thiazolyl, optionally substituted with one or more R_A. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

Rm
Rnx	li 7
Rn^X
Rn
more R_M. Highly preferably, D is	1 »/wv

n^n ^My=N

T ^Rn jvw , _or jvw , wherein R_M is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen. One or more R_N can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7tetrahydrobenzo[d]thiazolyl, benzo [d]thiazolyl, or indazolyl, and is optionally substituted with one or more R_A. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R_M. Highly preferably, D

«Λ/W , or one or more R_M.

Preferably, R_M is halogen, hydroxy, mercapto,

2016238925 07 Oct 2016 .5 «« , and is optionally substituted with amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, R_M is Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_M is -L_S-R_E, wherein L_s is a bond or Ci-C₆alkylene, and R_E is N(RsRs’), -O-R_s, -C(O)R_S, -C(O)OR_S, -C(O)N(R_SR_S’), -N(R_S)C(O)R_S’, -N(R_S)C(O)OR_S’, N(R_s)SO₂R_s’, -SO₂R_s, -SR_s, or -P(O)(OR_S)₂, wherein R_s and R_s’ can be, for example, each !0 independently selected at each occurrence from (1) hydrogen or (2) Ci-C₆alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Ci-C₆alkyl or 3- to 6-membered heterocycle; or R_M is Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or 25 R_m is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)ORs, or N(R_sRs’)· More preferably, R_M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, 30 amino, carboxy, or Ci-C₆alkyl (e.g., methyl, isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example R_M is CF₃, C(CF₃)₂-OH, -C(CH₃)₂-CN, -C(CH₃)₂-CH₂OH, or -C(CH₃)₂-CH₂NH₂. Also preferably R_M is -L_s73

2016238925 07 Oct 2016

R_e where L_s is a bond and R_E is -N(RsRs), -O-Rs, -N(Rs)C(O)ORs’, -N(Rs)SO₂Rs’, -SO₂Rs, or SRs. For example where L_s is a bond, R_E is -N(Ci-C₆alkyl)₂ (e.g., -NMe₂); -N(Ci-C₆alkylene-O-CiC₆alkyl)₂ (e.g. -N(CH₂CH₂OMe)₂); -N(Ci-C₆alkyl)(Ci-C₆alkylene-O-Ci-C₆alkyl) (e.g. N(CH₃)(CH₂CH₂OMe));—O-Ci-C₆alkyl (e.g., -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n5 hexyl); -O-Ci-C₆haloalkyl (e.g., - OCF₃, -OCH₂CF₃); -O-Ci-C₆alkylene-piperidine (e.g., -OCH₂CH₂-1-piperidyl); -NiQ-CsalkyljCiOjOCj-Csalkyl (e.g., -N(CH₃)C(O)O-CH₂CH(CH₃)₂), N(C₁-C₆alkyl)SO₂C₁-C₆alkyl (e.g., -N(CH₃)SO₂CH₃); -SO.Ci-Cealkyl (e.g., -SO₂Me); -SO₂CjC₆haloalkyl (e.g., -SO₂CF₃); or -S-Ci-C₆haloalkyl (e.g., SCF₃). Also preferably R_M is -L_S-R_E where L_s is Ci-C₆alkylene (e.g., -CH₂- -C(CH₃)₂- -C(CH₃)₂-CH₂-) and R_E is -O-R_s, -C(O)OR_S, 0 N(R_S)C(O)OR_S’, or -P(O)(OR_S)₂. For example R_M is -Ci-C₆alkylene-O-R_s (e g., -C(CH₃)₂-CH₂OMe); -Cj-Cealkylene-CXOjORs (e.g., -C(CH₃)₂-C(O)OMe); -CrCsalkylene-NiRgjCXOjORs’ (e.g, -C(CH₃)₂-CH₂-NHC(O)OCH₃); or -Ci-C₆alkylene-P(O)(OR_S)₂ (e.g, -CH₂-P(O)(OEt)₂). Also more preferably R_M is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs, or -N(RsRs’)· For example R_M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-lmethylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1!0 yl, piperidin-l-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, R_Mis Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered 25 bicycle and is substituted with J and optionally substituted with one or more R_A, wherein J is C₃C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6membered heterocycle, wherein said C₃-C₆carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, 30 mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or N(R_sRs ), and J can also be optionally substituted with one or more R_A. Also preferably, D is C₅C₆carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally 35 substituted with one or more R_A, and preferably, J is at least substituted with a C₃-C₆carbocycle or 3to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy,

2016238925 07 Oct 2016

C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or -N(RsRs’) Also preferably, D is C₅-C₆carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more 5 R_A, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R_A. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at 0 least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or N(R_sRs’)· Highly preferably, D is wherein each R_N is independently selected from

6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂!0 C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or N(R_sRs’)· Also preferably, D is wherein each R_N is independently selected from R_D and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, 25 amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or N(RsRs’), and J can also be optionally substituted with one or more R_A. Also preferably, D is vyw

2016238925 07 Oct 2016 and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or-N(RsRs’).

I X.

bicycles (e.g.

Lx and L₂ are preferably independently bond or Cx-C₆alkylene, L₃ is preferably selected from bond, Cx-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. More preferably, L_b L₂ and L₃ are each independently bond or Cx-C₆alkylene (e.g., CH₂- or —CH₂CH₂—), and are each independently optionally substituted with one or more R_L. Highly 5 preferably, Lx, L₂ and L₃ are bond.

R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5- to 6membered heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more R_A. R₉ and R₁₂, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., or or ~ ) which is optionally substituted with one or more R_A.

-T-R_d’ can be, without limitation, independently selected at each occurrence from -C(O)L_y’-R_d’, -C(O)O-L_y’-R_d’, -C(O)-L_y’-N(Rb)C(O)-L_s”-R_d’, -C(O)-L_y’-N(Rb)C(O)O-L_s”-R_d’, N(Rb)C(O)-L_y’-N(Rb)C(O)-L_s”-R_d’, -N(Rb)C(O)-L_y’~N(Rb)C(O)O-L_s”-R_d’, or -N(R_b)C(O)L_Y’—N(R_b)-L_s”-Rd’, wherein L_Y’ is each independently L_s’ and, preferably, is each independently

Cx-C₆alkylene (e.g., -CH₂- or ) and optionally substituted with one or more substituents selected from R_L. Preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’M’-L_s”-R_d’ or -N(R_b)C(O)-L_y’-M’-L_s”-R_d’. More preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_y’-N(Rb)C(O)-L_s”-Rd’ or -C(O)-L_y’-N(R_b)C(O)O-L_s”-Rd’.

Highly preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)R_d’ or -C(O)-L_y’-N(R_b)C(O)O-Rd’, wherein L_Y’ preferably is each independently Ci-C₆alkylene

2016238925 07 Oct 2016 (e.g., -CH₂- or ' ) and optionally substituted with one or more substituents selected from R_L.

Rc’ is preferably hydrogen, and R_D’ preferably is independently selected at each occurrence from R_e. More preferably, R_D’ is independently selected at each occurrence from Ci-C₆alkyl, C₂C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle; 0 or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Ra preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, !0 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_A-

SO₂R_s, -L_a-C(O)N(R_sR_s’)> -L_a-N(Rs)C(O)R_s’, -L_a-N(R_s)C(O)N(R_s’R_s”), -L_a-N(R_s)SO₂R_s’, L_a-SO₂N(R_sR_s’), -L_a-N(R_s)SO₂N(R_s’Rs”), -L_A-N(R_s)S(O)N(R_s’Rs”), -L_A-OS(O)-R_s, -L_A25 OS(O)₂-R_s, -L_a-S(O)₂OR_s, -L_a-S(O)OR_s, -L_a-OC(O)OR_s, -L_a-N(R_s)C(O)OR_s’, -L_aOC(O)N(R_SR_S’), -L_a-N(R_s)S(O)-Rs’> -L_a-S(O)N(R_sR_s’) or -L_A-C(O)N(R_S)C(O)-R_S’, wherein L_Ais bond, Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which 30 is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci35 C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, Ra is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

2016238925 07 Oct 2016

Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

A and B can be the same or different. Likewise, Lx and L₂ can be the same or different.

optionally substituted with one or more Ra; and D is C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more Ra, or is substituted with J and optionally substituted with one or more Ra, wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more Ra. .5 Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl,

C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or N(RsRs’), and J can also be optionally substituted with one or more Ra. Preferably, D is

each occurrence from O, S, NH or CH₂; and Z₂ is independently selected at each occurrence from N or CH. Preferably, A is

one or more halogen, such as F or Cl. When A and/or B are halo-substituted benzimidazole (e.g., A is

2016238925 07 Oct 2016

), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. L| and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, CiC₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. -T-R_D’ is independently selected at each occurrence from -C(O)-L_y’-N(R_b)C(O)-L_s”-R_d’ or -C(O)-L_Y’-N(R_B)C(O)O-L_S”-R_D’, wherein L_Y’ is C_rC₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_D’ can also be, without limitation, selected from -C(O)-L_Y’-L_S”R_d’, -C(O)-L_y’-O-L_s”-R_d’, -C(O)-L_y’-N(Rb)-L_s”-Rd’, or-C(O)-L_Y’-N(R_B)S(O)₂-L_s”-R_D’.

.5 or more R_A (e.g., halogen); and D is C₅-C₆carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R_A, or is substituted with J and optionally substituted with one or more R_A, wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, CiC₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or -N(RsR_s ), and J can also be optionally substituted with one or more R_A. Preferably, D is

jyw ⁿ<^vv , wherein R_M and R_n are as defined above. Also preferably, D is

J

JVW

N or

J

-''c™ , wherein J and R_N are

2016238925 07 Oct 2016 as defined above. When A and/or B are halo-substituted benzimidazole (e.g., A is

and B is and B is ), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. Lx and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. -T-R_d’ is independently selected at each occurrence from -C(O)-L_y’-N(Rb)C(O)-L_s”-Rd’ or -C(O)-L_y’-N(R_b)C(O)O-L_s”-Rd’, wherein L_Y’ is Ci-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_D’ can 0 also be, without limitation, selected from -C(O)-L_y’-L_s”-Rd’, -C(O)-L_y’-O-L_s”-Rd’, -C(O)-L_y’N(R_b)-L_s”-Rd’, or -C(O)-L_y’-N(Rb)S(O)₂-L_s”-Rd’. R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more R_A. R₉ and R_i2, taken together with the atoms to which they are attached, preferably form a 5 - to 6-membered .5 heterocycle or 6- to 12-membered bicycle (e.g., or ) which is optionally substituted with one or more R_A. More preferably, R₂ and R₅, taken together with the atoms to which they are attached, form which is optionally substituted with one or more R_A: R₉ and R|₂.

taken together with the atoms to which they are attached, form substituted with one or more R_A.

which is optionally

N

In still another embodiment of this aspect, A is H and optionally substituted with one or more R_A (preferably, A is substituted with at least one halogen such as F); B is

2016238925 07 Oct 2016 , and is optionally substituted with one or more R_A (preferably, B is substituted «ΛΛΛΓ

I

with at least one halogen such as F). X is , wherein X₃ is N and is directly linked to L₃-D, and X is optionally substituted with one or more R_A or R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_A. J is C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)OR_S or -N(R_sRs), or (2) trimethylsilyl, -O-R_s, -S-R_s or C(O)R_S; and J

JVW

-s, can also be optionally substituted with one or more R_A. Preferably, D is J .5 'wv , wherein J is as defined above, and each R_N is independently selected from and preferably is hydrogen or halo such as F. Li and L₂ are each independently bond or CiC₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. -T-R_D’ is independently selected at each occurrence from -C(O)-L_y’-N(Rb)C(O)-L_s”-Rd’ or -C(O)-L_Y’N(Rb)C(O)O-L_s”-Rd’, wherein L_Y’ is Ci-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_D’ can also be, without limitation, selected from -C(O)-L_Y’-L_S”-R_D’, -C(O)-L_Y’-O-L_S”-R_D’, -C(O)-L_Y’-N(R_B)-L_S”Rd

R_D’, or -C(O)-L_y’-N(R_b)S(O)₂-L_s”-Rd’. R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

or 7. ) which is optionally substituted with one or more R_A. R₉ and R_i2, taken together with the atoms to which they are attached, preferably form a 5 - to 6-membered heterocycle or

2016238925 07 Oct 2016

6-to 12-membered bicycle (e.g.,

or ) which is optionally substituted with one or more R_A. More preferably, R₂ and R₅, taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R_A; R₉ and R_i2, taken together with the atoms to which they are attached, form or more R_A.

which is optionally substituted with one invention (preferably a compound of Formula

The present invention unexpectedly found that a compound according to this aspect of the I_B or a pharmaceutically acceptable salt thereof, wherein A is

, and A and B are independently optionally substituted with one or more R_A such as one or more halo) showed significantly improved activities against different HCV genotypes and variants. For instance, when tested against HCV replicons of different genotypes in stable cell lines (in the presence of 5% FBS), and as compared to Example 37 of U.S. Patent Application Publication No. 2010/0317568, the EC₅₀ values of the compounds of Examples 3.48, 3.52, 4.38, and 5.1 were at least about 6-fold less than that of Example 37 against genotype la, at least about 3-fold less against genotype 3a, at least about 50-fold less against genotype

6a, and significantly less against genotype 2a. In addition, when tested against HCV genotype la replicons containing certain NS5A mutations in transient transfection assays, and as compared to Example 37 of U.S. Patent Application Publication No. 2010/0317568, the EC₅₀ values of the compounds of Examples 3.48, 3.52, 4.38, and 5.1 were at least about 130-fold less than that of Example 37 against the L31V variant, at least about 7,500 fold less against the M28T variant, at least about 80-fold less against the M28V variant, at least about 500-fold less against the Q30E variant, at least about 300-fold less against the Q30R variant, at least about 800-fold less against the Y93C variant, at least about 1,500-fold less against the Y93H variant, and significantly less against the Q30H variant. Likewise, when tested against HCV genotype lb replicons containing certain NS5A mutations in transient transfection assays, and as compared to Example 37 of U.S. Patent Application

Publication No. 2010/0317568, the EC₅₀ value of the compound of Example 5.1 was at least about 10fold less than that of Example 37 against the Y93H variant.

Accordingly, the present invention features methods of treating different HCV genotype or variant infection. The methods comprise administering a compound of Formula I_B, or a

2016238925 07 Oct 2016 pharmaceutically acceptable salt thereof, to a patient infected with HCV genotype la, lb, 2a, 2b, 3a,

4a, 5a or 6a, or infected with one of the variants described above. Preferably, A is

B is

, and A and B are independently optionally substituted with one or more R_Asuch as one or more halo. Other compounds described in this aspect of the invention or any embodiment thereunder, as well as the title compounds in the Examples described below, may also be used. In one embodiment, the patient being treated is infected with HCV genotype 1, such as la. In another embodiment, the patient being treated is infected with HCV genotype 2, such as 2a. In still another embodiment, the patient being treated is infected with HCV genotype 3, such as 3a. In another embodiment, the patient being treated is infected with HCV genotype 4, such as 4a. In a further embodiment, the patient being treated is infected with HCV genotype 5, such as 5a. In yet another embodiment, the patient being treated is infected with HCV genotype 6, such as 6a.

In yet another aspect, the present invention further features compounds of Formula I_c and pharmaceutically acceptable salts thereof.

.5

I wherein:

Rnb is R_b;

Rc’ is each independently selected from R_c;

R_d’ is each independently selected from R_D;

In this aspect, A preferably is C₅-C₆carbocycle or 5- to 6-membered heterocycle, and is optionally substituted with one or more R_A; and B preferably is 8- to 12-membered bicycle (such as

or

), and is optionally substituted with one or more

2016238925 07 Oct 2016

W₄, W₅ and W₆ are each independently selected from CH or N.

More preferably, A is phenyl (e.g., * ^), and is optionally substituted with one or more R_A; and B is

and is optionally substituted with one or more R_A, where Z_b Z₂, Z₃, Z₄, W_b W₂, W₃, W₄, W₅, W₆ are as defined above. Preferably, Z₃ is N

with one or more R_A.

from C₅-C₆carbocycle or 5- to 6-membered heterocycle. A and B are independently optionally substituted with one or more R_A.

D preferably is selected from C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12membered bicycles, and is optionally substituted with one or more R_A. D can also be preferably 5 selected from Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionally substituted with one or more substituents selected from R_L. More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more R_M, where R_M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_s-Re. Also preferably, D is phenyl, and is optionally substituted with one or more R_A. More preferably, D is phenyl, and is 20 substituted with one or more R_M, wherein R_M is as defined above. Highly preferably, D is

Rm , wherein R_M is as defined above, and each R_N is independently selected from

, wherein R_M

2016238925 07 Oct 2016 .5 more R_M. Highly preferably, D is is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen. One or more R_N can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7tetrahydrobenzo[d]thiazolyl, benzo [d]thiazolyl, or indazolyl, and is optionally substituted with one or more R_A. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R_M. Highly preferably, D

«/VW «/VW , and is optionally substituted with ^vw , _or one or more R_M.

Preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, R_M is 20 Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_M is -L_S-R_E, wherein L_s is a bond or Ci-C₆alkylene, and R_E is N(RsRs’), -O-Rs, -C(O)R_S, -C(O)ORs, -C(O)N(R_sRs’), -N(Rs)C(O)R_s’, -N(R_s)C(O)ORs’, 25 N(R_s)SO₂R_s’, -SO₂R_s, -SR_s, or -P(O)(OR_S)₂, wherein R_s and R_s’ can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C₆alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Ci-C₆alkyl or 3- to 6-membered heterocycle; or R_M is Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or

R_m is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy,

2016238925 07 Oct 2016

N(RsRs’)· More preferably, R_M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C₆alkyl (e.g., methyl, isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example R_M is CF₃, C(CF₃)₂-OH, -C(CH₃)₂-CN, -C(CH₃)₂-CH₂OH, or -C(CH₃)₂-CH₂NH₂. Also preferably R_M is -F_s0 R_e where F_s is a bond and R_E is -N(R_sRs), -O-R_s, -N(R_S)C(O)OR_S’, -N(R_s)SO₂R_s’, -SO₂R_s, or SR_s. For example where F_s is a bond, R_E is -N(Ci-C₆alkyl)₂ (e.g., -NMe₂); -N(Ci-C₆alkylene-O-CiC₆alkyl)₂ (e.g. -N(CH₂CH₂OMe)₂); -NiCpCealkyOiCrCealkylene-O-CrCealkyl) (e.g. N(CH₃)(CH₂CH₂OMe));—O-Ci-C₆alkyl (e.g., -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-nhexyl); -O-Ci-C₆haloalkyl (e.g., - OCF₃, -OCH₂CF₃); -O-Ci-C₆alkylene-piperidine (e.g., -O5 CH₂CH₂-1-piperidyl); -N(Ci-C₆alkyl)C(O)OCi-C₆alkyl (e.g., -N(CH₃)C(O)O-CH₂CH(CH₃)₂), N(Ci-C₆alkyl)SO₂Ci-C₆alkyl (e.g., -N(CH₃)SO₂CH₃); -SO₂Ci-C₆alkyl (e.g., -SO₂Me); -SO₂CiC₆haloalkyl (e.g., -SO₂CF₃); or -S-Ci-C₆haloalkyl (e.g., SCF₃). Also preferably R_M is -L_S-R_E where F_s is Ci-C₆alkylene (e.g., -CH₂- -C(CH₃)₂- -C(CH₃)₂-CH₂-) and R_E is -O-Rs, -C(O)OR_S, N(Rs)C(O)ORs’, or -P(O)(ORs)₂. For example R_M is -Ci-C₆alkylene-O-Rs (e g., -C(CH₃)₂-CH₂!0 OMe); -Ci-C₆alkylene-C(O)OR_S (e.g., -C(CH₃)₂-C(O)OMe); -Ci-C₆alkylene-N(Rs)C(O)OR_s’ (e.g, -C(CH₃)₂-CH₂-NHC(O)OCH₃); or -Ci-C₆alkylene-P(O)(ORs)₂ (e.g, -CH₂-P(O)(OEt)₂). Also more preferably R_M is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci25 C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S, or -N(R_sRs’)· For example R_M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-lmethylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1yl, piperidin-l-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 30 tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, R_Mis Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R_A, wherein J is C₃35 C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 686

2016238925 07 Oct 2016 membered heterocycle, wherein said C₃-C₆carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl,

C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or 5 N(RsRs’), and J can also be optionally substituted with one or more R_A Also preferably, D is C₅C₆carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R_A, and preferably, J is at least substituted with a C₃-C₆carbocycle or 3to 6-membered heterocycle which is independently optionally substituted with one or more 0 substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or -N(R_sRs) Also preferably, D is C₅-C₆carbocycle or

5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_a, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R_A. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently !0 optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or N(RsRs’)· Highly preferably, D is

Bn

Rn , wherein each R_N is independently selected from

6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl,

N(RsRs’). Also preferably, D is

C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or Rn , wherein each R_N is independently selected from R_D and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂2016238925 07 Oct 2016

C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or N(R_sRs ), and J can also be optionally substituted with one or more R_A.

Also preferably, D is

J

jvw and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or-N(RsRs’).

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles (e.g.,

I

, wherein X₃ is N and is directly linked to -L₃-D), and .5 is optionally substituted with one or more R_A or R_F. Non-limiting examples of X are described hereinabove.

Li and L₂ are preferably independently bond or Ci-C₆alkylene, L₃ is preferably selected from bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. More preferably, L_b L₂ and L₃ are each independently bond or Ci-C₆alkylene (e.g., 20 CH₂- or —CH₂CH₂—), and are each independently optionally substituted with one or more R_L. Highly preferably, L_b L₂ and L₃ are bond. Lx and L₂ can be the same or different.

R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5 - to 6membered heterocycle or 6- to 12-membered bicycle (e.g.,

optionally substituted with one or more R_A R₉ and R₁₂, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., p/.

or ) which is optionally substituted with one or more R_A

-T-R_d’ can be, without limitation, independently selected at each occurrence from -C(O)L_y’-R_d’, -C(O)O-L_y’-R_d’, -C(O)-L_y’-N(R_b)C(O)-L_s”-R_d’, -C(O)-L_y’-N(R_b)C(O)O-L_s”-R_d’, 5 N(Rb)C(O)-L_y’-N(R_b)C(O)-L_s”-R_d’, -N(R_b)C(O)-L_y’-N(R_b)C(O)O-L_s”-R_d’, or -N(R_b)C(O)2016238925 07 Oct 2016

L_Y’—N(R_b)-L_s”-R_d’, wherein L_Y’ is each independently L_s’ and, preferably, is each independently

Ci-C₆alkylene (e.g., -CH₂- or ) and optionally substituted with one or more substituents selected from R_l. Preferably, -T-R_d’ is independently selected at each occurrence from -C(O)-L_Y’M’-L_s”-Rd’ or -N(R_b)C(O)-L_y’-M’-L_s’’-Rd’· More preferably, -T-R_d’ is independently selected at each occurrence from -C(O)-L_y’-N(R_b)C(O)-L_s”-Rd’ or -C(O)-L_y’-N(R_b)C(O)O-L_s”-Rd’.

Highly preferably, -T-R_d’ is independently selected at each occurrence from -C(O)-L_y’-N(R_b)C(O)R_d’ or -C(O)-L_y’-N(R_b)C(O)O-R_d’, wherein L_Y’ preferably is each independently Ci-C₆alkylene

	g
(e.g., -CH₂- or /	i ) and optionally substituted with one or more substituents selected from R_l.

R_nb and Rc’ are preferably hydrogen, and R_d’ preferably is independently selected at each .5 occurrence from R_e. More preferably, R_d’ is independently selected at each occurrence from CiC₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Ra preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is 25 independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci30 C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_A89

2016238925 07 Oct 2016

O-Rs, -La-S-Rs, -L_a-C(O)Rs, -L_a-0C(0)R_s, -L_a-C(0)0R_s, -L_a-N(R_sR_s’), -L_a-S(O)R_s, -L_aSO₂R_s, -L_a-C(O)N(RsRs’)> -L_a-N(Rs)C(O)Rs’, -L_A-N(Rs)C(O)N(Rs’Rs”), -L_A-N(Rs)SO₂R_s’, L_a-SO₂N(RsR_s’), -L_a-N(Rs)SO₂N(Rs’R_s”), -L_a-N(R_s)S(O)N(R_s’Rs”), -L_a-OS(O)-Rs, -L_aOS(O)₂-R_s, -L_a-S(O)₂ORs, -L_a-S(O)ORs, -L_a-OC(O)ORs, -L_a-N(R_s)C(O)ORs’, -L_a5 OC(O)N(R_sRs’), -L_a-N(R_s)S(O)-Rs’, -L_a-S(O)N(RsR_s’) or -L_A-C(O)N(R_S)C(O)-R_S’, wherein L_Ais bond, Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

More preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 0 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

Highly preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

!0 L_s, L_s’ and L_s” preferably are each independently selected at each occurrence from bond; or

Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

In one embodiment of this aspect, A is phenyl, and is optionally substituted with one or more

more R_A, wherein Z₃ is O, S, NH or CH₂; and Z₂ is N or CH. D is C₅-C₆carbocycle or 5- to 625 membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R_A, or is substituted with J and optionally substituted with one or more R_A, wherein J is C₃-C₆carbocycle, 3- to

6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more

R_a. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or N(RsRs’), and J can also be optionally substituted with one or more R_A. Preferably, D is ~^nj>ⁿ' , wherein R_M and R_N are as defined above. Also preferably, D is

2016238925 07 Oct 2016

or

J

or •'w , wherein J and R_N are as defined above. Lx and L₂ are each independently bond or Ci-C₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. -T5 R_D’ is independently selected at each occurrence from -C(O)-L_y’-N(Rb)C(O)-L_s”-Rd’ or -C(O)L_y’-N(R_b)C(O)O-L_s”-Rd’, wherein L_Y’ is Ci-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_D’ can also be, without limitation, selected from -C(O)-L_Y’-L_S’’-Rd’, -C(O)-L_y’-O-L_s”-Rd’, -C(O)-L_y’-N(R_b)Ls’-Rd’, or -C(O)-L_y’-N(R_b)S(O)₂-L_s”-Rd’· Preferably, R₂ and R₅, taken together with the atoms to which they are attached, form which is optionally substituted with one or more R_A; R9 and Ri₂, taken together with the atoms to which they are attached, form optionally substituted with one or more R_A.

which is

In another embodiment of this aspect, A is phenyl (e.g., \=/ ), and is optionally substituted with one or more R_A (preferably, A is substituted with at least one halogen such as F); and

B is

N

H , and is optionally substituted with one or more R_A (preferably, B is substituted with at least one halogen such as F). X is wherein X₃ is N and is directly linked to -L₃-D, and X is optionally substituted with one or more R_A or R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_A. J is C₃-C₆carbocycle, 3- to 6membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 1520 membered carbocycle/heterocycle, and J is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 791 to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, CiC₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)ORs or -N(RsRs’), or (2) trimethylsilyl, -O2016238925 07 Oct 2016

R_s, -S-Rs or -C(O)Rs; and J can also be optionally substituted with one or more R_A. Preferably, D is j

or , wherein J is as defined above, and each R_N is independently selected from

R_d and preferably is hydrogen or halo such as F. Lx and L₂ are each independently bond or CiC₆alkylene, and L₃ is bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. -T-R_D’ is independently selected at each occurrence from -C(O)-L_y’-N(Rb)C(O)-L_s”-Rd’ or -C(O)-L_Y’N(R_b)C(O)O-L_s”-Rd’, wherein L_Y’ is Ci-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_D’ can also be, without limitation, selected from -C(O)-L_Y’-L_S”-R_D’, -C(O)-L_Y’-O-L_S”-R_D’, -C(O)-L_Y’-N(R_B)-L_S”Rd’, or -C(O)-L_y’-N(Rb)S(O)₂-L_s”-Rd’· Preferably, R₂ and R₅, taken together with the atoms to .5 which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

) or 6- to 12-

membered bicycle (e.g., ) which is optionally substituted with one or more R_A; R₉ and

R_i2, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic

) which is optionally

In yet another aspect, the present invention features compounds of Formula I_D and pharmaceutically acceptable salts thereof.

2016238925 07 Oct 2016 wherein:

D

I

L-3

Id

Gi and G₂ are each independently selected from C₅-C₆carbocycle or 5- to 6-membered 5 heterocycle, and are each independently optionally substituted with one or more R_A;

Rc’ is each independently selected from R_c;

Rd’ is each independently selected from R_D;

R₉ and R_i2, taken together with the atoms to which they are attached, form a 3- to 12membered heterocycle which is optionally substituted with one or more R_A;

A, B, D, X, L_b L₂, L₃, T, R_a, Rc, and R_D are as described above in Formula I.

In this aspect, A and B preferably are independently selected from C₅-C₆carbocycle or 5- to 6membered heterocycle, and are each independently optionally substituted with one or more R_A. More 5 preferably, at least one of A and B is phenyl (e.g., * ^==/^ and is optionally substituted with one or more R_A. Highly preferably, both A and B are each independently phenyl (e.g., * '\==/^> ^), and are each independently optionally substituted with one or more R_A.

D preferably is selected from C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 8- to 12membered bicycles, and is optionally substituted with one or more R_A. D can also be preferably 20 selected from Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, and is optionally substituted with one or more R_L. More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12membered bicycles, and is substituted with one or more R_M, where R_M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_s-Re. Also preferably, D is phenyl, and is optionally substituted with one or more R_A. More preferably, D is phenyl, and is substituted with one or more

R_m, wherein R_M is as defined above.

Highly preferably, D is

Rm

*/vw

Rm

jwv Q]*

2016238925 07 Oct 2016

, wherein R_M is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen. One or more R_N can also preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more R_A. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or more R_M. Highly preferably, D is , or , wherein R_M is as defined above, and each R_N is independently selected from R_D and preferably is hydrogen. One or more R_N can also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7tetrahydrobenzo[d]thiazolyl, benzo [d]thiazolyl, or indazolyl, and is optionally substituted with one or more R_A. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, 0 indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R_M. Highly preferably, D is , or , and is optionally substituted with one or more R_M.

Preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is 5 independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci20 C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl. More preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, R_M is Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, 25 hydroxy, mercapto, amino or carboxy.

Also preferably, R_M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R_M is -L_S-R_E, wherein L_s is a bond or Ci-C₆alkylene, and R_E is 94

2016238925 07 Oct 2016

N(RsRs’), -O-Rs, -C(O)R_S, -C(O)ORs, -C(0)N(R_sRs’), -N(Rs)C(0)R_s’, -N(R_s)C(O)ORs’, N(Rs)SO₂Rs’, -SO₂Rs, -SRs, or -P(O)(ORs)₂, wherein R_s and Rs’ can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C₆alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Ci-C₆alkyl or 3- to 6-membered 5 heterocycle; or R_M is Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or R_m is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, 0 mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl,

C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)OR_S, or N(R_sRs’)· More preferably, R_M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C₆alkyl (e.g., methyl, isopropyl, tert-butyl), C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents .5 selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example R_M is CF₃, C(CF₃)₂-OH, -C(CH₃)₂-CN, -C(CH₃)₂-CH₂OH, or -C(CH₃)₂-CH₂NH₂. Also preferably R_M is -L_sR_e where L_s is a bond and R_E is -N(RsRs), -O-Rs, -N(Rs)C(O)ORs’, -N(Rs)SO₂Rs’, -SO₂Rs, or SRs. For example where L_s is a bond, R_E is -N(Ci-C₆alkyl)₂ (e.g., -NMe₂); -N(Ci-C₆alkylene-O-CiC₆alkyl)₂ (e.g. -N(CH₂CH₂OMe)₂); -N(Ci-C₆alkyl)(Ci-C₆alkylene-O-Ci-C₆alkyl) (e.g. !0 N(CH₃)(CH₂CH₂OMe));—O-Ci-C₆alkyl (e.g., -Ο-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-nhexyl); -O-Ci-C₆haloalkyl (e.g., - OCF₃, -OCH₂CF₃); -O-Ci-C₆alkylene-piperidine (e.g., -OCH₂CH₂-1-piperidyl); -N(Ci-C₆alkyl)C(O)OCi-C₆alkyl (e.g., -N(CH₃)C(O)O-CH₂CH(CH₃)₂), N(Ci-C₆alkyl)SO₂Ci-C₆alkyl (e.g., -N(CH₃)SO₂CH₃); -SO₂Ci-C₆alkyl (e.g., -SO₂Me); -SO₂CiC₆haloalkyl (e.g., -SO₂CF₃); or -S-Ci-C₆haloalkyl (e.g., SCF₃). Also preferably R_M is -L_S-R_E where 25 L_s is Ci-Cgalkylene (e.g., -CH₂- -C(CH₃)₂- -C(CH₃)₂-CH₂-) and R_E is -O-R_s, -C(O)OR_S, N(R_S)C(O)OR_S’, or -P(O)(OR_S)₂. For example R_M is -Ci-C₆alkylene-O-R_s (e g., -C(CH₃)₂-CH₂OMe); -Ci-Cealkylene-CXOjORs (e g., -C(CH₃)₂-C(O)OMe); -CrCealkylene-NiRgjCXOjORs’ (e.g, -C(CH₃)₂-CH₂-NHC(O)OCH₃); or -Ci-C₆alkylene-P(O)(OR_S)₂ (e.g, -CH₂-P(O)(OEt)₂). Also more preferably R_M is C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently 30 optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs, or -N(RsRs’)· For example R_M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-lmethylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,135 dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l-yl, pyrrolidin-1yl, piperidin-l-yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl,

2016238925 07 Oct 2016 tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, R_M is Ci-C₆alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF₃).

More preferably, D is C₅-C₆carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R_A, wherein J is C₃C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃-C₆carbocycle or 3- to 6membered heterocycle, wherein said C₃-C₆carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, 0 mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl,

C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or N(R_sRs ), and J can also be optionally substituted with one or more R_A. Also preferably, D is C₅C₆carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally 5 substituted with one or more R_A, and preferably, J is at least substituted with a C₃-C₆carbocycle or 3to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or -N(RsRs’) Also preferably, D is C₅-C₆carbocycle or !0 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more

R_a, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R_A. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R_A, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle 25 or 6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or j

N(R_sRs’)· Highly preferably, D is •'vw , wherein each R_N is independently selected from

Rd and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)ORs or 2016238925 07 Oct 2016

N(RsRs’)· Also preferably, D is wherein each R_N is independently selected from R_D and preferably is hydrogen or halogen, and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or 0 N(R_sRs ), and J can also be optionally substituted with one or more R_A. Also preferably, D is -'vw . and J is C₃-C₆carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R_A, and preferably J is at least substituted with a C₃-C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or-N(RsRs’).

X preferably is C₅-C₆carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles (e.g.

, wherein X₃ is N and is directly linked to -L₃-D), and is optionally substituted with one or more R_A or R_F. Non-limiting examples of X are described 20 hereinabove.

L| and L₂ are preferably independently bond or Ci-C₆alkylene, L₃ is preferably selected from bond, Ci-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. More preferably, L_b L₂ and L₃ are each independently bond or Ci-C₆alkylene (e.g., CH₂- or -CH₂CH₂-), and are each independently optionally substituted with one or more R_L. Highly 25 preferably, L_b L₂ and L₃ are bond.

R₂ and R₅, taken together with the atoms to which they are attached, preferably form a 5-to 62016238925 07 Oct 2016

), which is optionally substituted with one or more R_A.

R₉ and R1₂. taken together with the atoms to which they are attached, preferably form a 5 - to

6-membered heterocycle or 6- to 12-membered bicycle (e.g., optionally substituted with one or more R_A.

or ), which is

Gi and G₂ preferably are each independently selected from

N

or , and are each independently optionally substituted with one or more H

R_a (e.g., one or more chloro or bromo). More preferably, Gi is

NH (including any tautomer thereof), and G₂ is ^N (including any tautomer thereof), and each Gi and G₂ is independently optionally substituted with one or more R_A (e.g., one or more chloro or bromo).

-T-R_d’ can be, without limitation, independently selected at each occurrence from -C(O)L_Y’- -C(O)O-L_y’-R_d’, -C(O)-L_y’-N(R_b)C(O)-L_s”-R_d’, -C(O)-L_y’-N(R_b)C(O)O-L_s”-R_d’, N(R_b)C(O)-L_y’-N(R_b)C(O)-L_s”-R_d’, -N(R_b)C(O)-L_y’-N(R_b)C(O)O-L_s”-R_d’, or -N(R_B)C(O)15 L_Y’—N(R_b)-L_s”-R_d’, wherein L_Y’ is each independently L_s’ and, preferably, is each independently

Ci-C₆alkylene (e.g., -CH₂- or ) and optionally substituted with one or more substituents selected from R_L. Preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’M’-L_s”-Rd’ or -N(R_b)C(O)-L_y’-M’-L_s”-Rd’· More preferably, -T-R_D’ is independently selected at each occurrence from -C(O)-L_y’-N(R_b)C(O)-L_s”-Rd’ or -C(O)-L_y’-N(R_b)C(O)O-L_s”-Rd’.

) and optionally substituted with one or more substituents selected from R_L.

2016238925 07 Oct 2016

Rc’ is preferably hydrogen, and R_D’ preferably is independently selected at each occurrence from R_e. More preferably, R_D’ is independently selected at each occurrence from Ci-C₆alkyl, C₂C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C₃-C₆carbocycle or 3- to 6-membered heterocycle; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl.

R_a preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-C₆carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, CiC₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl; or -L_AO-Rs, -La-S-Rs, -L_a-C(O)Rs, -L_a-OC(O)R_s, -L_a-C(O)OR_s, -L_a-N(R_sR_s’), -L_a-S(O)R_s, -L_aSO₂R_s, -L_a-C(O)N(R_sR_s’), -L_a-N(Rs)C(O)Rs’, -Ε_α-Ν^)(2(Ο)Ν^^”), -L_a-N(Rs)SO₂R_s’, !0 L_a-SO₂N(RsR_s’), -L_a-N(Rs)SO₂N(Rs’R_s”), -L_A-N(R_s)S(O)N(R_s’Rs”), -L_a-OS(O)-Rs, -L_aOS(O)₂-R_s, -L_a-S(O)₂ORs, -L_a-S(O)ORs, -L_a-OC(O)ORs, -L_a-N(R_s)C(O)ORs’, -L_aOC(O)N(R_sRs’), -L_a-N(R_s)S(O)-Rs’, -L_a-S(O)N(RsR_s’) or -L_A-C(O)N(R_S)C(O)-R_S’, wherein L_Ais bond, Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

Highly preferably, R_A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from 35 halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

Ci-C₆alkylene, C₂-C₆alkenylene or C₂-C₆alkynylene.

2016238925 07 Oct 2016

A and B can be the same or different. Likewise, Li and L₂ can be the same or different.

In one embodiment of this aspect, A and B are each independently phenyl, and are each independently optionally substituted with one or more R_a; D is phenyl, and is independently optionally substituted with one or more R_A, or is substituted with J and optionally substituted with one or more R_A, wherein J is C₃-C₆carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R_A. Preferably, J is substituted with a C₃C₆carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one 0 or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, CiC₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C(O)OR_S or -N(R_sRs ), and J can also be

H N.

NH optionally substituted with one or more R_A; and Gi is N ' , G₂ is ^N , and each Gi and

G₂ is independently optionally substituted with one or more R_A (e.g., one or more chloro or bromo).

Ri

Preferably, D is wherein R_M and R_N are as defined above. Also

Ri

J preferably, D is wherein J and R_N are as defined above. Lx and L₂ are each independently bond or Cx-C₆alkylene, and L₃ is bond, Cx-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. T-R_D’ is independently selected at each occurrence from -C(O)-L_Y’-N(R_B)C(O)-L_S”-R_D’ or-C(O)20 L_y’-N(R_b)C(O)O-L_s”-Rd’, wherein L_Y’ is Cx-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_L, and L_s” preferably is bond. -T-R_D’ can also be, without limitation, selected from -C(O)-L_y’-L_s”-Rd’, -C(O)-L_y’-O-L_s”-Rd’, -C(O)-L_y’-N(R_b)L_s”-Rd’, or -C(O)-L_y’-N(Rb)S(O)₂-L_s”-Rd’. Preferably, R₂ and R₅, taken together with the atoms to which they are attached, form which is optionally substituted with one or more R_a; R₉

100

2016238925 07 Oct 2016 and R12, taken together with the atoms to which they are attached, form

which is optionally substituted with one or more R_A.

In another embodiment of this aspect, A and B are each independently phenyl (e.g., ), and are each independently optionally substituted with one or more R_A (preferably, A and B are each independently substituted with at least one halogen such as F). X is '----' , wherein X₃ is N and is directly linked to -L₃-D, and X is optionally substituted with one or more R_Aor R_F. D is phenyl, and is substituted with J and optionally substituted with one or more R_A. J is C₃C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or 0 more R_A. Preferably, J is substituted with a C₃-C₆carbocycle, 3- to 6-membered heterocycle, 6- to 12membered bicycle or 7- to 12-membered carbocycle/heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -C(O)ORs or -N(RsRs’), or (2) trimethylsilyl, -O-Rs, -S-Rs or -C(O)Rs; and J can also be optionally substituted with one or more

R_a. Preferably, D is wherein J is as defined above, and each R_N is

H N.

independently selected from R_D and preferably is hydrogen or halo such as F. Gi is N ' , G₂ is

^N , and each Gi and G₂ is independently optionally substituted with one or more R_A (e.g., one or more chloro or bromo). Lx and L₂ are each independently bond or Cx-C₆alkylene, and L₃ is 20 bond, Cx-C₆alkylene or -C(O)-, and L_b L₂, and L₃ are each independently optionally substituted with one or more R_L. Preferably, L_b L₂, and L₃ are bond. -T-R_D’ is independently selected at each occurrence from -C(O)-L_y’-N(Rb)C(O)-L_s”-Rd’ or -C(O)-L_y’-N(R_b)C(O)O-L_s”-Rd’, wherein L_Y’ is Cx-C₆alkylene (e.g., -CH₂-) and optionally substituted with one or more substituents selected from R_l, and L_s” preferably is bond. -T-R_D’ can also be, without limitation, selected from -C(O)25

L_y’-L_s”-R_d’, -C(O)-L_y’-O-L_s”-R_d’, -C(O)-L_y’-N(R_b)-L_s”-R_d’, or -C(O)-L_Y’-N(R_B)S(O)₂101

Ls’’-Rd’· Preferably, R₂ and R₅, taken together with the atoms to which they are attached, form a 52016238925 07 Oct 2016 to 6-membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R_A; R₉ and R₁₂, taken together with the atoms to

A which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., ) or 6- to 12-

membered bicycle (e.g., Y ) which is optionally substituted with one or more R_A.

In another aspect, the present invention features compounds having Formula I_E and pharmaceutically acceptable salts thereof,

D

I

L-3

I

Y-A-fo—X—L₂—B—Z

Ie wherein:

X is 4- to 8-membered heterocycle, and is optionally substituted with one or more R_A;

Lx and L₂ are each independently selected from bond or Cx-C₆alkylene which is independently optionally substituted at each occurrence with one or more halo, hydroxy, -O-Cx-C₆alkyl, or -O-Cx-C₆haloalkyl;

L₃ is bond or Cx-C₆alkylene;

A and B are each independently phenyl, pyridinyl, thiazolyl, or

is independently selected at each occurrence from O, S, NH or CH₂, Z₃ is independently selected at each occurrence from N or CH, and W₃, W₂, and W₃ are each independently selected at each occurrence from CH or N; A and B are each independently optionally substituted with one or more R_A.

D is C₆-C₁₀carbocycle or 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R_M;

Y is -T’-C(RxR₂)N(R₅)-T-R_d;

Z is -T’-C(R₈R₉)N(Rx₂)-T-R_d;

102

2016238925 07 Oct 2016

Ri is hydrogen, Ci-C₆alkyl, Ci-C₆haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C₆alkyl, Ci-C₆haloalkyl, -O-Ci-C₆alkyl or -O-Ci-C₆haloalkyl;

R₂ and R₅ are each independently hydrogen, Ci-C₆alkyl, Ci-C₆haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C₆alkyl, Ci-C₆haloalkyl, -O-Ci-C₆alkyl or -O-Ci-C₆haloalkyl; or R₂ and R₅, taken together with the atoms to which they are attached, form a 3- to 120 membered heterocycle which is optionally substituted with one or more R_A (e.g., 1, 2, 3, or 4 R_A);

R₈ is hydrogen, Ci-C₆alkyl, Ci-C₆haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from 5 halogen, Ci-C₆alkyl, Ci-C₆haloalkyl, -O-Ci-C₆alkyl or -O-Ci-C₆haloalkyl;

R₉ and Ri₂ are each independently hydrogen, Ci-C₆alkyl, Ci-C₆haloalkyl, or 3- to 6membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C₆alkyl, Ci-C₆haloalkyl, -O-Ci-C₆alkyl or -O-Ci!0 C₆haloalkyl; or R₉ and R_i2, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more R_A(e.g., 1,2, 3, or 4 R_a);

T is independently selected at each occurrence from bond or -C(O)-L_S’-;

I” is independently selected at each occurrence from bond, -C(O)N(R_B)-, -N(R_B)C(O)-, or

3- to 12-membered heterocycle, wherein said 3- to 12-membered heterocycle is independently optionally substituted at each occurrence with one or more R_A;

R_d is each independently selected at each occurrence from hydrogen or R_A;

R_a is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L_S-R_E;

R_b and R_B’ are each independently selected at each occurrence from hydrogen; or Ci-C₆alkyl which is independently optionally substituted at each occurrence with one or more substituents selected from halogen or 3- to 6-membered carbocycle or heterocycle; or 3to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R_B or R_B’ is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, Ci-C₆alkyl, Ci-C₆haloalkyl, O-Ci-C₆alkyl, or -O-Ci-C₆haloalkyl;

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2016238925 07 Oct 2016

R_e is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, C(O)ORs, -N(RsRs’), -S(O)R_s, -SO₂R_s, -C(O)N(R_sRs’), -N(R_S)C(O)R_S’, N(Rs)C(O)N(Rs’Rs ”), -N(R_s)SO₂R_s’, -SO₂N(RsR_s’), -N(R_s)SO₂N(Rs’Rs”), N(Rs)S(O)N(R_s’Rs”), -OS(O)-Rs, -OS(O)₂-Rs, -S(O)₂ORs, -S(O)OR_s, -OC(O)OR_S, 5 N(Rs)C(O)OR_s’, -OC(O)N(R_sRs ), -N(R_s)S(O)-R_s’, -S(O)N(R_sRs’), -C(O)N(Rs)C(O)R_s’, or =C(R_sRs ); or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl;

R_L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -C(O)ORs, -N(RsRs’), S(O)Rs, -SO₂R_s, -C(O)N(R_sRs’), or -N(R_s)C(O)Rs’; or C₃-Ci₂carbocycle or 3- to 12membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, !0 C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂-C₆haloalkynyl;

L_s is independently selected at each occurrence from bond; or Ci-C₆alkylene, C₂C₆alkenylene or C₂-C₆alkynylene, each independently optionally substituted with halogen;

L_s’ is independently selected at each occurrence from bond; or Ci-C₆alkylene, C₂25 C₆alkenylene or C₂-C₆alkynylene, each of which is independently optionally substituted at each occurrence with one or more R_L;

R_s, Rs’ and R_s” are each independently selected at each occurrence from hydrogen; CiC₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 30 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -O-Ci-C₆alkyl, -O-Ci-C₆haloalkyl, or 3- to 12-membered carbocycle or heterocycle; or 3- to 12-membered carbocycle or heterocycle; wherein each 3- to 12membered carbocycle or heterocycle in R_s , Rs’ or Rs” is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 35 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,

104

2016238925 07 Oct 2016 cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl or C₂C₆haloalkynyl;

R_m is independently selected at each occurrence from:

halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, SF₅, -N(R_sRs’), -O-Rg, -OC(O)R_S, -OC(O)OR_S, -OC(O)N(R_sRs’), C(O)R_S, -C(O)OR_S, -C(O)N(R_SR_S’), -N(R_S)C(O)R_S’, -N(R_S)C(O)OR_S’, N(R_s)SO₂R_s’, -S(O)R_s, -SO₂R_s, -S(O)N(R_sR_s’), -SR_s, -Si(R_s)₃, or -P(O)(OR_S)₂;

Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, 0 hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -N(R_SR_S’), -O-R_s, -OC(O)R_S, -OC(O)OR_S, -OC(O)N(R_SR_S’), C(O)R_S, -C(O)OR_S, -C(O)N(R_SR_S’), -N(R_S)C(O)R_S’, -N(R_S)C(O)OR_S’, N(R_s)SO₂R_s’, -S(O)R_s, -SO₂R_s, -S(O)N(R_sR_s’), -SR_s, or -P(O)(OR_S)₂; or

G₂, wherein G₂ is a C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, each of which is .5 independently optionally substituted at each occurrence with one or more Rq₂, and each R_G2 is independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C₆alkyl, C₂C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -OR_s, -C(O)OR_S, -C(O)R_S, -N(R_sRs’), or -F₄-G₃;

!0 F₄ is a bond, Ci-C₆alkylene, C₂-C₆alkenylene, C₂-C₆alkynylene, -0-, -S-, -N(R_B)-, -C(O)-,

-S(O)₂- -S(O)-, -C(O)O- -OC(O)-, -00(0)0-, -C(0)N(Rb)-> -N(Rb)C(0)-, N(Rb)C(0)0- -0C(0)N(Rb)-> -N(Rb)S(O)-, -N(Rb)S(O)₂- -S(O)N(Rb)-, S(O)₂N(Rb)-, -N(Rb)C(0)N(Rb’)-, -N(Rb)S0₂N(Rb’)-, or-N(R_B)S(O)N(R_B’)-;

G₃ is a C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with 25 one or more Rg₃; and

Rg₃ is each independently, at each occurrence, halogen, -Ci-C₆alkyl, -C(O)Ci-C₆alkyl, -ΟχC₆haloalkyl, -O-Cx-C₆alkyl, -O-Cx-C₆haloalkyl, C₃-C₆carbocycle, or 3- to 6-membered heterocycle.

As described hereinabove for compounds of Formula I_E A and B are each phenyl, pyridinyl, thiazolyl, or

where Ζχ is independently selected at each occurrence from O, S,

NH or CH₂, Z₃ is independently selected at each occurrence from N or CH, and W_b W₂, and W₃ are each independently selected at each occurrence from CH or N; A and B are each independently optionally substituted with one or more R_A.

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2016238925 07 Oct 2016

optionally substituted with one or more R_A.

is optionally substituted with one or more R_A.

Highly preferably, both A and B are phenyl (e.g., both A and B are * ^<C=/^ ^); or A is

substituted with one or more R_A.

wherein each A and B is independently optionally

In certain embodiments of this aspect of the invention, A and B are substituted by one or more R_A, wherein each R_A is independently selected from halogen (e.g., fluoro, chloro), L_S-R_E (where L_s is bond and R_E is -Ci-C₆alkyl (e.g., methyl), -O-R_s (e.g., -O-Ci-C₆alkyl, -OCH₃), or -Ci-C₆alkyl 15 optionally substituted with one or more halogen (e.g., -CF₃)), or L_S-R_E (where L_s is Ci-C₆alkylene and R_e is -O-Rs (e.g., -Ci-C₆alkyl-O-Ci-C₆alkyl, -CH₂OCH₃)). For example, in certain

F

Cl and A is as defined hereinabove. In still

106

2016238925 07 Oct 2016

membered heterocycle optionally substituted by one or more R_M. Preferably, D is C₆-Ci₀aryl (e.g., phenyl, naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl), and D is substituted with one or more R_M. For example, in certain embodiments D is preferably phenyl substituted by one or more R_M, wherein each R_M is independently halogen (e.g., fluoro, chloro, bromo); Ci-C₆alkyl (e.g., tert-butyl); Ci-C₆alkyl substituted with one or more halogen (e.g., CF₃); -ORs such as -O-Ci-C₆alkyl (e.g., -O-CH₂CH₃); or -O-Ci-C₆alkyl substituted at each occurrence with one or more halogen (e.g., -O-CF₃, -O-CH₂CHF₂) or -O-Ci-C₆alkyl (e.g., -O-CH₂CH₂OCH₃); -ORs (e.g., -O-Ci-C₆alkyl, such as -O-CH₂) substituted with 3- to 12-membered heterocycle (e.g., 3ethyloxetan-3-yl, l,3-dioxolan-4-yl); -O-R_s where R_s is an optionally substituted 3- to 12-membered carbocycle or heterocycle (e.g., cyclopentyl, cyclohexyl, phenyl, l,3-dioxan-5-yl); -N(R_S)C(O)R_S’ wherein R_s and R_s’ are each independently Ci-C₆alkyl (e.g., -N(t-Bu)C(O)Me); SF₅; -SO₂R_s wherein R_s is Ci-C₆alkyl (e.g., -SO₂Me); or C₃-Ci₂carbocycle (e.g., cyclopropyl, cyclohexyl, phenyl).

In certain embodiments of this aspect of the invention, D is preferably phenyl or pyridyl and is substituted by one or more R_M where one R_M is G₂. In certain embodiments where D is phenyl or 20 pyridyl, D is substituted by G₂, G₂ is 3- to 12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) and is optionally substituted with one or more halogen (e.g., fluoro, chloro), hydroxy, oxo, cyano, Ci-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl (e.g., CF₃), C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -O-Ci-C₆alkyl (e.g., -O-CH₃), -C(O)ORs (e.g., C(O)OCH₃), -C(O)Rs (e.g., -C(O)CH₃), or -N(RsRs’); and D is further optionally substituted by one or more R_M where R_M is halogen (e.g., fluoro, chloro), Ci-C₆alkyl (e.g., methyl), Ci-C₆haloalkyl (e.g.,

CF₃), or -O-Ci-C₆alkyl (e.g., -O-CH₃). In certain other embodiments D is phenyl or pyridyl and G₂is, for example, a monocyclic 3-8 membered carbocycle or monocyclic 4-8 membered heterocycle substituted with L₄-G₃ and optionally substituted with one or more R_b2 wherein L₄, G₃ and R_b2 are as

107

2016238925 07 Oct 2016 defined herein. L₄, for example is a bond, a Ci-C₆ alkylene (e.g., -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, etc.), -0-, or —S(O)₂—. G₃ is for example a C₃-Ci₂carbocycle optionally substituted with one or more R_G3. Rg2 and R_G3 are each independently at each occurrence halogen, -C(O)Ci-C₆alkyl, -Ci-C₆alkyl,

-Ci-C₆haloalkyl, -O-Ci-C₆alkyl, or -O-Ci-C₆haloalkyl. In certain embodiments G₂ is

wherein Th is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl) attached to the parent molecular moiety through a nitrogen atom and substituted with one or two L₄-G₃ and optionally substituted with one or more R_G2. Thus, in

G₃

certain embodiments where L₄ is a bond G₂ is Th . where Th j_s optionally substituted with G₃

can be, for example, 3-phenylazetidin4-phenylpiperidin-l-yl, 4-phenyl-3,64-acetyl-4-phenylpiperidin-l -yl, 4-(4R_G2 and G₃ is optionally substituted with R_G2. Thus, Th

1-yl, 3-phenylpyrrolidin-l-yl, 4-phenylpiperazin-l-yl, dihydropyridin-1 (2H)-yl, 4,4-diphenylpiperidin-1 -yl, methoxyphenyl)piperidin-l-yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl, and wherein D can be further optionally substituted with one or more R_M (e.g., fluoro, chloro, methyl, methoxy).

In certain other embodiments of this aspect of the invention, L₄ is a Ci-C₆ alkylene, -O-, or -

, where Th is as defined above and is optionally substituted with R_G2G₃ ./ ^l4

and G₃ is as defined above and is optionally substituted with R_G3. Thus, Th _can be, for example, 4-tosylpiperazin-l-yl, 4-phenoxypiperidin-l-yl, 3-phenoxypyrrolidin-l-yl, 4-benzylpiperidin-l-yl, 4phenethylpiperidin-l-yl, or 3-phenylpropyl)piperidin-l-yl.

108

In certain other embodiments of this aspect of the invention, D is phenyl or pyridyl, D is substituted by G₂ and G₂ is a spiro, bridged, or fused bicyclic carbocycle or heterocycle optionally substituted with L₄-G₃ and one or more Rg₂, wherein D is optionally substituted with one or more R_M

2016238925 07 Oct 2016 and R_m, L₄, G₃, and Rg₂ /^N are as defined herein. In certain embodiments G₂ is wherein Th, is a spiro, bridged, or fused bicyclic nitrogen-containing heterocycle (e.g., 3azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2Hisoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H-isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with G₃ and one or more R_G2. Thus, G₂ is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 60 azaspiro [2.5] oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2Hisoindol-2-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; L₄ is a bond and D is optionally substituted with one or more R_M(e.g., fluoro, chloro, methyl, methoxy).

In certain embodiments of this aspect of the invention, D is -ⁿ<^vv wherein R_M is as defined above in connection with Formula I_E, and D is optionally substituted by one or more additional R_M. Rm

For instance, where D is -'vw , R_M can be fluoro, chloro, tert-butyl, -O-CH₂CH₃, -O-CF₃, -OCH₂CHF₂, -O-CH₂CH₂OCH₃, -O-CH₂-(3-ethyloxetan-3-yl), -O-CH₂-(l,3-dioxolan-4-yl), -Ocyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF₅,

-SO₂Me, or -N(t-Bu)C(O)Me and D can be optionally substituted by one or more additional R_Mselected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C₆alkyl (e.g., methyl).

In certain embodiments, D is wherein R_M is fluoro, chloro, tert-butyl, -O-CH₂CH₃, O-CF₃, -O-CH₂CHF₂, -O-CH₂CH₂OCH₃, SF₅, -SO₂Me, or -N(t-Bu)C(O)Me and D is optionally substituted by one or more additional R_M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C₆alkyl (e.g., methyl).

109

2016238925 07 Oct 2016

In certain embodiments, D is wherein R_M is cyclopropyl, cyclohexyl, or phenyl and D is optionally substituted by one or more additional R_M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C₆alkyl (e.g., methyl).

In certain embodiments, D is wherein R_M is -O-CH₂-(3-ethyloxetan-3-yl), -O-CH₂5 (l,3-dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, or -0-(1,3-dioxan-5-yl) and D is optionally substituted by one or more additional R_M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C₆alkyl (e.g., methyl).

In certain embodiments, D is +vw wherein G₂ is pyridinyl (e.g., pyridin-2-yl), piperidin-1yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4-(propan-20 yl)piperidin-l-yl, 4-fluoropiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4-(trifluoromethyl)piperidin-lyl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l-yl, 2-oxopiperidin-l-yl, 3,3-dimethylazetidin-l-yl, or oxazolyl (e.g., l,3-oxazol-2-yl) and D is optionally substituted by one or more additional R_Mselected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C₆alkyl (e.g., methyl).

wherein Gi is N,

N

C-H, or C-R_m; G₂ is ® . wherein ® is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) attached to the parent molecular moiety through a nitrogen atom and substituted by L₄-G₃ and optionally substituted with one or more Rq₂; L₄is a bond, Ci-C₆ alkylene, -O-, or -S(O)₂-; G₃ is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle (e.g., thienyl) wherein each G₃ is optionally substituted with one or more R_b3; Rg2 and R_b3 at each occurrence are each independently halogen, -C(O)Ci-C₆alkyl, -Ci-C₆alkyl, -Ci-C₆haloalkyl, 110

2016238925 07 Oct 2016

O-Ci-C₆alkyl, or -O-Ci-C₆haloalkyl; g is 0, 1, 2, or 3; and R_M is as defined above in connection with ^G3

Formula I_E. In one group of compounds according to this embodiment, D is 'w , wherein

G₃ is phenyl optionally substituted with one or two R_G3; g is 0, 1, or 2; R_M is each independently

fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and Ή and Rq₃ are as

σννχη defined above. In a further subgroup of compounds of this embodiment, D is wherein G₃ is phenyl optionally substituted with one or two Rq₃; R_Mi is each independently hydrogen, fluoro, chloro, or methyl; and R_G2 is an optional substituent as described herein. In another group of

compounds according to this embodiment, D is , wherein L₄ is Ci-C₆ alkylene, -O-, or S(O)₂-; G₃ is phenyl optionally substituted with one or two Rg₃; g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and

and

Rg₃ are as defined above.

111

2016238925 07 Oct 2016

In yet another embodiment of this aspect of the invention, D is

jvw wherein Gi is

N, C-H, or C-R_m; G₂ is TA , wherein TA is _a spiro, bridged, or fused bicyclic nitrogencontaining heterocycle (e.g., 3 -azabicyclo [3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H5 isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with L₄-G₃ and one or more Rq₂; L₄ is a bond, Ci-C₆ alkylene, -0-, or -S(O)₂-; G₃ is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle (e.g., thienyl) wherein each G₃ is optionally substituted with one or more R_b3; Rg2 and Rq₃ at each occurrence are each independently halogen, -C(O)Ci-C₆alkyl, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci0 C₆alkyl, or -O-Ci-C₆haloalkyl; g is 0, 1, 2, or 3; and R_M is as defined above in connection with

Formula I_E. In one group of compounds according to this embodiment, D is

wherein g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy;

is as defined above. In a further subgroup of compounds D is

wherein R_Mi is each independently hydrogen, fluoro, chloro, or methyl, and

defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2-yl, 2azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2Hisoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).

112

2016238925 07 Oct 2016

In still another embodiment of this aspect of the invention, D is

wherein is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R_G2, wherein R_G2 at each occurrence is each independently halogen, -C(O)Ci-C₆alkyl, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, or -O-Ci5 C₆haloalkyl; and R_M is each independently halogen, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, or

Rg2

-O-Ci-C₆haloalkyl. In one group of compounds according to this embodiment, is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two R_G2. wherein R_G2 at each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_M is

each independently fluoro, chloro, or methyl. For example

is 4,4-dimethylpiperidin-l-yl,

4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4-(propan-2-yl)piperidin-l-yl, 4fluoropiperidin-1 -yl, 3,5-dimethylpiperidin-1 -yl, 4-(trifluoromethyl)piperidin-1 -yl, 4-methylpiperidin1-yl, 4-tert-butylpiperidin-l-yl, 2-oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl.

For compounds of Formula I_E

D

I

L-3

I_E attachment of X to the remainder of the molecule can be conveniently depicted by the abbreviated structural Formula X’, wherein the groups attached to X maintain the same relative spatial orientation as drawn in Formula I_E It is understood that in subsequent depictions of the variable group X, the substituents of X will retain the same relative positions and orientation as in Formula I_E and Formula 20 X’.

X'

113

Compounds of Formula I_E include those where the variable X is selected from the group consisting of X-l, X-2, X-3, and X-4 wherein X-l, X-2, X-3, and X-4 retain the same orientation as structure X’ relative to the remainder of the molecule; wherein the presence of = in X-l, X-2, and

X-3 represents single or double bonds, X₃ is Ci-C₂alkylene or C₂alkenylene, X₂ and X₃ are each Ci2016238925 07 Oct 2016

C₂alkylene or C₂alkenylene, and X₄ is C |-C₂ alkylene.

X-1 %/vww

X-2

A/WW*

X-3

JWUW

V⁴vy

X-4

In accordance with the foregoing description, in certain embodiments of this aspect of the invention, X is pyrrolyl and is attached to the remainder of the molecule as shown in Formula

X_A:

Xa . In certain embodiments, X is pyrrolidinyl and is attached to the remainder of the

JVUV I „I\L molecule as shown in Formula X_B:

Xb . Embodiments according to Formula X_B may exist ww

JVW in cis (X_Bi) or trans (X_B2) forms:

Xbi

Χβ2 . Chiral carbon atoms in

Xb, Xbi, and X_B2 may have either the (R) or (S) absolute stereochemistry.

In yet another embodiment of this aspect of the invention, X is pyrrolyl and is attached to the remainder

the molecule

Xc2 as shown in

Formulae

Xci or . In certain embodiments, X is pyrrolidinyl and is

Xc2:

remainder of the molecule as shown in Formulae X_m or X_D2:

vwv

Embodiments according to Formulae X_m or X_D2 may exist

114 in cis or trans forms and chiral carbon atoms in X_Di and X_D2 may have either the (R) or (S) absolute

2016238925 07 Oct 2016 stereochemistry. In certain embodiments, X is azetidinyl and is attached to the remainder of the molecule as shown in Formulae X_Ei or X_E2:

^^E2 . Chiral carbon atoms in X_Ei and X_E2 may independently have either the (R) or (S) absolute stereochemistry.

In certain preferred embodiments of this aspect of the invention, X is X_A, Xb, Xbi, Xb2, Xci, or X_C2 and L_b L₂, and L₃ are each a bond. In certain other embodiments, X is X_Db Xd2, Xei, or X_E2and Li, L₂, and L₃ are each a bond. In another embodiment, X is X_E3 and Li and L₂ are each methylene (i.e. -CH₂-), and L₃ is a bond.

In compounds of Formula I_E, Y is-T’-C(RiR₂)N(R₅)-T-R_D and Z is -T’-C(R₈R₉)N(Ri₂)-T0 R_d; wherein Τ’, R_b R₂, R₅, R₈. R₉, R₁₂, T, and R_D are as defined herein.

Preferably R_b R₂, R₅, R₈, R₉, and R_i2 are each independently hydrogen; Ci-C₆alkyl; or 3- to 6membered carbocycle or heterocycle, wherein each 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen or Ci-C₆alkyl; wherein R₂ and R₅, taken together with the atoms to which they are attached, 5 optionally form a 3- to 12-membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R_A, and R₉and R|₂ taken together with the atoms to which they are attached, optionally form a 3- to 12membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R_A wherein R_A is as defined herein.

In certain embodiments of this aspect of the invention, R₃ is hydrogen and R₂ and R₅, taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (e.g.,

Ra is halogen (e.g., fluoro, chloro); cyano; L_S-R_E where L_s is a single bond and R_E is Ci-C₆alkyl (e.g., methyl, ethyl), -O-Ci-C₆alkyl (e.g., methoxy), or -O-Ci-C₆haloalkyl (e.g., trifluoromethoxy); or L_s-

R_e where L_s is a double bond and R_E is =C(R_sRs ) (e.g., ³). In a preferred

115

2016238925 07 Oct 2016 embodiment R₂ and R₅, taken together with the atoms to which they are attached form a pyrrolidine ring (i.e.,

) substituted with 0 or 1 R_a wherein R_a is fluoro, methoxy, methyl, ethyl, or cyano. In another preferred embodiment R₂ and R₅, taken together with the atoms to which they are attached form a pyrrolidine ring (i.e.,

In certain other embodiments of this aspect of the invention, R₈ is hydrogen and R₉ and R_i2, taken together with the atoms to which they are attached form a 3 - to 12-membered heterocycle (e.g.,

R_a wherein R_a is halogen (e.g., fluoro, chloro); cyano; L_s-R_e where L_s is a single bond and R_e is Ci0 C₆alkyl (e.g., methyl, ethyl), -O-Ci-C₆alkyl (e.g., methoxy), or -O-Ci-C₆haloalkyl (e.g., trifluoromethoxy); or L_s-R_e where L_s is a double bond and R_e is =C(RsRs) (e.g.,

In a preferred embodiment, R₉ and R_i2, taken together with the atoms to which they are attached form a pyrrolidine ring (i.e.,

) substituted with 0 or 1 R_A wherein R_A is fluoro, methoxy, methyl, ethyl, or cyano. In another preferred embodiment R₉ and R_i2, taken together with the atoms to which they are attached form a pyrrolidine ring (i.e.,

116

2016238925 07 Oct 2016

As used herein, a chiral carbon in any rings formed by joining R₂ and R₅ or R₉ and R_i2 may possess either (R) or (S) stereochemistry. A pyrrolidine ring (i.e.,

formed from either R₂ and R₅ or R₉ and R_i2 preferably possesses the (S) stereochemistry (i.e.,

In this aspect of the invention, I” is independently selected at each occurrence from a bond,5 C(O)N(R_b)-, -N(R_b)C(O)-, or 3- to 12-membered heterocycle, and wherein said 3- to 12-membered heterocycle is each independently optionally substituted at each occurrence with one or more R_A, and

R_a and R_b are as described herein. In particular, where I” is -C(O)N(R_B)-, R_B can be hydrogen (i.e.,

I” is -C(O)N(H)-). In certain embodiments, I” is imidazolyl (i.e.,

) optionally substituted at each occurrence with one or more R_A wherein R_A is halogen (e.g., fluoro, chloro), Ci0 C₆alkyl (e.g., methyl, ethyl), or Ci-C₆haloalkyl (e.g., trifluoromethyl). In certain embodiments, I” is imidazolyl (i.e.,

This aspect of the invention contemplates particular combinations of A with Y and B with Z.

Non-limiting examples of preferred Y when A is C₅-C₆carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) and preferred Z when B is C₅-C₆carbocycle (e.g., phenyl) or

5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) include:

117

2016238925 07 Oct 2016

In certain embodiments of this aspect of the invention, A is

substituted with one or more R_A as described herein, or Y-A is and non-limiting

0-/	a/	V/
1 R ^T examples of preferred Y, where I” is a bond, include: ^D ,	5	1 Ro^^T

wherein T and R_D are as defined herein.

In certain embodiments of this aspect of the invention, B is substituted with one or more R _A as described herein, or B-Z is examples of preferred Z, where I” is a bond, include:

and non-limiting

optionally

118

, where L_s’ is optionally substituted with one or more R_L; and R_L is a substituent such as, but not limited to carbocycle (e.g., cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl), methoxy, or heterocycle (e.g., tetrahydrofuranyl, tetrahydropyranyl).

R_d is hydrogen or R_A wherein R_A is as defined herein. Thus R_D includes, but is not limited to, R_a wherein R_A is L_S-R_E, and L_s and R_E are as defined herein. Thus R_D includes, but is not limited to, herein. L_s’ includes, but is not limited to,

2016238925 07 Oct 2016 p

^D wherein T and R_D are as defined herein.

T at each occurrence is independently a bond wherein L_s’ is as defined

L_s-R_e wherein L_s is a bond and R_E is-N(R_sR_s’), -N(R_S)C(O)R_S’, -N(R_s)C(O)N(R_s’Rs”), N(R_s)SO₂R_s’, -N(Rs)SO₂N(R_s’Rs”), -N(R_s)S(O)N(R_s’R_s”), -N(R_s)C(O)OR_s’, or -N(R_s)S(O)R_s’; or C₃-Ci₂carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, cyano, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, or Ci-C₆haloalkyl.

In one embodiment of this aspect of the invention, R_D is L_S-R_E wherein L_s is a bond and R_E is

-N(R_S)C(O)OR_S’ or 3- to 12-membered heterocycle (e.g., pyrrolidine, piperidine, azepanyl) wherein Rs and Rs’ are as defined herein. For example R_D is preferably L_S-R_E wherein L_s is a bond and R_E is -N(H)C(O)OMe.

Thus according to the foregoing description T-R_D includes, but is not limited to:

«ΛΛ/V

5 5 5 5

119

2016238925 07 Oct 2016

JWV

T-R_d may also include particular stereochemical

configurations; thus T-R_D includes, but is not limited to:

etc.

According to this aspect of the invention, non-limiting examples of preferred Y when A is C₅C₆carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) and preferred Z when B is C₅-C₆carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) include:

120

2016238925 07 Oct 2016

121

2016238925 07 Oct 2016

Ο

122

2016238925 07 Oct 2016

In still another aspect, the present invention features compounds of Formula I_F and pharmaceutically acceptable salts thereof:

A—X—B wherein:

123

2016238925 07 Oct 2016 <λλ>

JWLT , wherein X is optionally substituted with one or more more R_A:

or jvw I

B is

more R_A; and

Y, Z, R_a, and D are as described hereinabove (e.g., Y, Z, R_A, and D as described for Formula I, I_A, I_B, Ic, Id, or I_E, preferably as described for Formula I_E).

In one embodiment of this aspect of the invention,

, wherein , wherein B is is optionally substituted with one optionally substituted with one or more R_A:

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2016238925 07 Oct 2016

T^_R ^D; and D, R_A, T and R_D are as defined hereinabove (e.g., as described for Formula I, I_A, I_B,

I_c, Id or I_E, preferably as described for Formula I_E).

In another embodiment according to this aspect of the invention, A or B are optionally substituted with one or more substituents selected from: R_A wherein R_A is each independently halogen 5 (e.g., fluoro, chloro); L_S-R_E where L_s is a single bond, and R_E is -Ci-C₆alkyl (e.g., methyl), -O-Rs (e.g., -O-Ci-C₆alkyl, -OCH₃), or -Ci-C₆alkyl optionally substituted with one or more halogen (e.g., CF₃); or L_S-R_E where L_s is a Ci-C₆alkylene and R_E is -O-Rs (e.g., -Ci-C₆alkyl-O-Ci-C₆alkyl, CH₂OCH₃). This embodiment includes compounds where A and B are both substituted by one R_A; compounds where A and B are both substituted by zero R_A; compounds where A is substituted by one .0

R_A and B is substituted by zero R_A; and compounds where A is substituted by zero R_A and B is

In a further embodiment of this aspect of the invention, T-R_D is independently selected at each occurrence from the group

JWV

JVW

JWV

s/VW

»/vw

consisting of

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2016238925 07 Oct 2016

preferred and wherein D is as defined hereinabove.

In another embodiment, this aspect of the invention features compound of Formula I_F and pharmaceutically acceptable salts thereof, wherein:

	Ck/ N /	Q-/
more R_A; Y	1 R -^T IS ,	1
NO U/		V/
I 5	1 Ro^T 5	1
Ά-· I UN—		H
\| DIN R 10

R MeQ. MeO Η Ο-/ V-/
1 Rd-^T Rd 5	1 1 -T _R ®T ^KD 5 5
Ή
1 ^Ro^^T , or	1 R ; Z is
/ \.N_S 1 HN-\ r_d-^t >	i HN-\ Rd^⁷ >

and D, R_A, T and R_D are as defined hereinabove.

particular subgroup according to this embodiment includes compounds where A is

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2016238925 07 Oct 2016

defined hereinabove.

In yet another embodiment, this aspect of the invention features compounds of Formula I_F and

A and B are pharmaceutically acceptable salts thereof, wherein: X is

and D, T and R_D are as defined hereinabove. A particular subgroup according to this embodiment includes compounds where T-R_d is each independently selected from

JWV

127

«/VW

2016238925 07 Oct 2016

H

Y^N o

According to each of the ; and D is as defined hereinabove.

foregoing embodiments and description of this aspect of the invention of Formula I_F are groups and subgroups of compounds having particular values for D. Included in each of the foregoing embodiments are groups and subgroups of compounds with the following particular values for D:

In certain groups of compounds according to Formula I_F and the foregoing embodiments and Rm

description of this aspect of the invention, D is , where R_M is fluoro, chloro, tert-butyl, -OCH₂CH₃, -O-CF₃, -O-CH₂CHF₂, -O-CH₂CH₂OCH₃, -O-CH₂-(3-ethyloxetan-3-yl), -O-CH₂-(1,3dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF₅, -SO₂Me, or -N(t-Bu)C(O)Me and D is optionally substituted by one or more additional R_M, selected from the group consisting of halogen (e.g., fluoro, chloro) or Ci-C₆alkyl (e.g., methyl).

In other groups of compounds according Formula I_F and the foregoing embodiments and g₂

description of this aspect of the invention, D is +vw wherein G₂ is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4(propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4(trifluoromethyl)piperidin-1 -yl, 4-methylpiperidin-1 -yl, 4-tert-butylpiperidin-1 -yl, 2-oxopiperidin-1 yl, 3,3-dimethylazetidin-l-yl, or oxazolyl (e.g., l,3-oxazol-2-yl) and D is optionally substituted by one or more additional R_M selected from the group consisting of halogen (e.g., fluoro, chloro), or CiC₆alkyl (e.g., methyl). In particular according to these groups are compounds where D is

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2016238925 07 Oct 2016

; G₂ is piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6dimethylpiperidin-1 -yl, 4-(propan-2-yl)piperidin-1 -yl, 4-fluoropiperidin-1 -yl, 3,5 -dimethylpiperidin1-yl, 4-(trifluoromethyl)piperidin-l-yl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l-yl, 2oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl; and R_Mi is each independently hydrogen, fluoro, chloro, or methyl.

In other groups of compounds according Formula I_F and the foregoing embodiments and description of this aspect of the invention, D IS ATW

wherein Gi is N, C-H, or C-R_M; G₂ is

, R_m, and g are as defined hereinabove. In particular according to these groups, R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or G₃ ./ ^l4

trifluoromethoxy; g is 0, 1, or 2; and 7¼. j_{s as} defined hereinabove. In further subgroups L₄ is a bond; G₂ is

; R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or G₃ trifluoromethoxy; and g is 0, 1, or 2. In particular subgroups, is 3-phenylazetidin-l-yl, 3phenylpyrrolidin-l-yl, 4-phenylpiperazin-l-yl, 4-phenylpiperidin-l-yl, 4-phenyl-3,6-dihydropyridin1 (2H)-yl, 4,4-diphenylpiperidin-1 -yl, 4-acetyl-4-phenylpiperidin-1 -yl, 4-(4-methoxyphenyl)piperidin1-yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In other subgroups

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2016238925 07 Oct 2016

L₄ is Ci-C₆ alkylene, -0-, or -S(O)₂-; G₂ is ; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particular subgroups,

is 4-tosylpiperazin-l-yl, 4-phenoxypiperidin-l-yl, 3-phenoxypyrrolidin-l-yl, 4benzylpiperidin-l-yl, 4-phenethylpiperidin-l-yl, or 3-phenylpropyl)piperidin-l-yl; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or ^G3

g

2. In further subgroups of compounds D is . wherein G₃ is phenyl optionally substituted with one or two Rq₃; g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy,

trifluoromethyl, or trifluoromethoxy; and and Rq₃ are as defined above. In other groups of

, wherein L₄ is Ci-C₆ alkylene, -O-, or -S(O)₂-; G₃ is phenyl optionally substituted with one or two R_G3; g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and and Rq₃ are as defined above. In further

130

2016238925 07 Oct 2016 subgroups of compounds D is

wherein G₃ is phenyl optionally substituted with one or two R<}₃ as defined hereinabove; R_Mi is each independently hydrogen, fluoro, chloro, or methyl;

and Rg2 is an optional substituent, as described above, selected from the group consisting of-C(O)CiC₆alkyl, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, and -O-Ci-C₆haloalkyl.

In other groups of compounds according Formula I_F and the foregoing embodiments and description of this aspect of the invention, D IS i/vw*

wherein Gi is N, C-H, or C-R_M; G₂ is

, wherein , R_M, and g are as defined hereinabove. In particular according to these subgroups, R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

trifluoromethoxy; g is 0, 1, or 2; and is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, 1,3-dihydro-2Hisoindol-2-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl. In further subgroups of compounds D is

vvuv wherein g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy,

trifluoromethyl, or trifluoromethoxy; and is as defined above. In further subgroups of

wherein R_Mi is each independently hydrogen, fluoro, chloro, or

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2016238925 07 Oct 2016

Θ

N ^y methyl and is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2Hisoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).

In other groups of compounds according Formula I_F and the foregoing embodiments and description of this aspect of the invention, D is

wherein

is a monocyclic

4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more Rq₂, wherein R_G2 at each occurrence is each independently halogen, -C(O)CiC₆alkyl, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, or -O-Ci-C₆haloalkyl; and R_M is each independently halogen, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, or -O-Ci-C₆haloalkyl. In each

Rg2 group of compounds according to the foregoing embodiments is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two R_G2, wherein R_G2 at each occurrence is each methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_M is each independently fluoro, chloro,

Rg2 or methyl. For example is 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6dimethylpiperidin-1 -yl, 4-(propan-2-yl)piperidin-1 -yl, 4-fluoropiperidin-1 -yl, 3,5 -dimethylpiperidin1-yl, 4-(trifluoromethyl)piperidin-l-yl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l-yl, 2oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl.

In still another aspect, the present invention features compounds of Formula I_G and pharmaceutically acceptable salts thereof,

Ig wherein:

132

2016238925 07 Oct 2016 jvuv

X is

, wherein X is optionally substituted with one or more R_A

A is

, wherein A is optionally substituted with one or more R_A;

more R_A; and

Y, Z, R_a, and D are as described hereinabove (e.g., as described for Formula I, I_A, I_B, Ic, Id, Ie or I_F, preferably as described for Formula I_E).

In one embodiment, this aspect of the invention features compounds of Formula I_G and

pharmaceutically acceptable salts thereof, wherein: X is

Ra is halogen (e.g., fluoro, chloro); F_S-R_E where F_s is a single bond and R_E is -Ci-C₆alkyl (e.g., methyl), -O-Rs (e.g., -O-Ci-C₆alkyl, -OCH₃), or -Ci-C₆alkyl optionally substituted with one or 15 more halogen (e.g., -CF₃); or F_S-R_E where Fs is a Ci-C₆alkylene and R_E is -O-Rs (e.g., -Ci-C₆alkyl-

O-Ci-C₆alkyl, -CH₂OCH₃); Y and Z are each independently

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2016238925 07 Oct 2016

T-R_d is each independently

JWV

uwv

and D is as defined hereinabove.

In another embodiment, this aspect of the invention features compounds of Formula I_G and pharmaceutically acceptable salts thereof, wherein X is

wherein A is optionally substituted with one R_A; B is

, wherein B is optionally substituted with one R_A; R_A is halogen (e.g., fluoro, chloro); L_s-Re where L_s is a single bond and R_Eis -Ci-C₆alkyl (e.g., methyl), -O-Rs (e.g., -O-Ci-C₆alkyl, -OCH₃), or -Ci-C₆alkyl optionally substituted with one or more halogen (e.g., -CF₃); or L_S-R_E where L_s is a Ci-C₆alkylene and R_E is -

O-R_s (e.g., -Ci-C₆alkyl-O-Ci-C₆alkyl, -CH₂OCH₃); Y and Z are each independently

134 is each independently

2016238925 07 Oct 2016

wherein compounds having (S) stereochemistry (e.g..

or particularly contemplated; and D is as defined hereinabove. This subgroup includes compounds where A and B are both substituted by one R_A; compounds where A and B are both substituted by zero R_a; compounds where A is substituted by one R_A and B is substituted by zero R_A; and compounds where A is substituted by zero R_A and B is substituted by one R_A. In particular, according

According to each of the foregoing embodiments and description of this aspect of the invention of Formula I_G are groups and subgroups of compounds having particular values for D. Included in each of the foregoing embodiments are groups and subgroups of compounds with the following particular values for D:

Groups of compounds according to this aspect of the invention include compounds where D is C₆-Ci₀aryl (e.g., phenyl, naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl), and D is substituted with one or more R_M. Particular subgroups according to this aspect and these embodiments include compounds wherein R_M is halogen (e.g., fluoro, chloro, bromo); Ci-C₆alkyl (e.g., tert-butyl); Ci-C₆alkyl substituted with one or more halogen (e.g., CF₃); -O-Ci-C₆alkyl (e.g., O-CH₂CH₃); -O-Ci-C₆alkyl substituted at each occurrence with one or more halogen (e.g., -O-CF₃, -O-CH₂CHF₂) or -O-Ci-C₆alkyl (-O-CH₂CH₂OCH₃); -O-Ci-C₆alkyl (e.g., -O-CH₂) substituted with an optionally substituted 3- to 12-membered heterocycle (e.g., 3-ethyloxetan-3-yl, 1,3-dioxolan135

2016238925 07 Oct 2016

4-yl); -O-Rs where Rs is an optionally substituted 3- to 12-membered carbocycle or heterocycle (e.g., cyclopentyl, cyclohexyl, phenyl, l,3-dioxan-5-yl); -N(Rs)C(O)Rs’ wherein Rs and Rs’ are each independently Ci-C₆alkyl (e.g., -N(t-Bu)C(O)Me); SF₅; -SO₂Rs wherein R_s is Ci-C₆alkyl (e.g., SO₂Me); or C₃-Ci₂carbocycle (e.g., cyclopropyl, cyclohexyl, phenyl). Other subgroups according to this embodiment include compounds wherein D is phenyl substituted by G₂ and optionally substituted by one or more R_M, wherein G₂ is a 3- to 12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, cyano, Ci-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂C₆alkynyl, Ci-C₆haloalkyl (e.g., CF₃), C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -O-Ci-C₆alkyl (e.g., -O0 CH₃), -C(O)OR_s (e.g., -C(O)OCH₃), -C(O)R_s (e.g., -C(O)CH₃), -N(R_SR_S’), or L₄-G₃; R_M is halogen (e.g., fluoro, chloro), alkyl (e.g., methyl), haloalkyl (e.g., CF₃), or -O-Ci-C₆alkyl (e.g., -O-CH₃); and

L₄, G₃, R_s, and R_s’ are as defined hereinabove.

In certain groups of compounds according to Formula I_G and the foregoing embodiments and description of this aspect of the invention, D is

Rm

7WU , where R_M is fluoro, chloro, tert-butyl, -O5 CH₂CH₃, -O-CF₃, -O-CH₂CHF₂, -O-CH₂CH₂OCH₃, -O-CH₂-(3-ethyloxetan-3-yl), -O-CH₂-(1,3dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(1,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF₅, -SO₂Me, or -N(t-Bu)C(O)Me and D is optionally substituted by one or more additional R_M, selected from the group consisting of halogen (e.g., fluoro, chloro) or Ci-C₆alkyl (e.g., methyl).

In other groups of compounds according Formula I_G and the foregoing embodiments and description of this aspect of the invention, D is g₂

lA/W wherein G₂ is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4(propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4(trifluoromethyl)piperidin-1 -yl, 4-methylpiperidin-1 -yl, 4-tert-butylpiperidin-1 -yl, 2-oxopiperidin-1 25 yl, 3,3-dimethylazetidin-l-yl, or oxazolyl (e.g., l,3-oxazol-2-yl) and D is optionally substituted by one or more additional R_M selected from the group consisting of halogen (e.g., fluoro, chloro), or CiC₆alkyl (e.g., methyl). In particular according to these groups are compounds where D is

136

2016238925 07 Oct 2016

In other groups of compounds according Formula I_G and the foregoing embodiments and description of this aspect of the invention, D IS JVW

wherein Gi is N, C-H, or C-R_m; G₂ is

trifluoromethoxy; g is 0, 1, or 2; and is as defined hereinabove. In further subgroups L₄ is a bond; G₂ is

137

2016238925 07 Oct 2016

g

2. In further subgroups of compounds D is , wherein G₃ is phenyl optionally substituted with one or two R<}₃; g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy,

trifluoromethyl, or trifluoromethoxy; and Th, _anc| βθ_{3 are as} defined above. In other groups of

, wherein L₄ is Ci-C₆ alkylene, -O-, or -S(O)₂-; G₃ is phenyl optionally substituted with one or two R_G3; g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and Th, and Rg₃ are as defined above. In further

138

2016238925 07 Oct 2016 subgroups of compounds D is

wherein G₃ is phenyl optionally substituted with one or two Rq₃ as defined hereinabove; R_Mi is each independently hydrogen, fluoro, chloro, or methyl;

and Rg2 is an optional substituent, as described above, selected from the group consisting of -C(O)CiC₆alkyl, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, and -O-Ci-C₆haloalkyl.

In other groups of compounds according Formula k and the foregoing embodiments and description of this aspect of the invention, D IS i/vw*

wherein Gi is N, C-H, or C-R_M; G₂ is

, wherein Tn . R_m, _and g _{are as} defined hereinabove. In particular according to these subgroups, R_m is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

trifluoromethoxy; g is 0, 1, or 2; and Tn is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, 1,3-dihydro-2Hisoindol-2-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl. In further subgroups of compounds D is

«/vuv wherein g is 0, 1, or 2; R_M is each independently fluoro, chloro, methyl, methoxy,

trifluoromethyl, or trifluoromethoxy; and Tn j_{s as} defined above. In further subgroups of

wherein R_Mi is each independently hydrogen, fluoro, chloro, or

139

2016238925 07 Oct 2016

/ methyl and Th- is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2Hisoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).

In other groups of compounds according Formula I_G and the foregoing embodiments and

N /^N wherein

G2 description of this aspect of the invention, D is is a monocyclic

4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R_G2· wherein R_G2 at each occurrence is each independently halogen, -C(O)CiC₆alkyl, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, or -O-Ci-C₆haloalkyl; and R_M is each independently halogen, -Ci-C₆alkyl, -Ci-C₆haloalkyl, -O-Ci-C₆alkyl, or -O-Ci-C₆haloalkyl. In each

G2

N group of compounds according to the foregoing embodiments is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two R_G2, wherein R_G2 at each occurrence is each methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R_M is each independently fluoro, chloro, z^N or methyl. For example is 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6dimethylpiperidin-1 -yl, 4-(propan-2-yl)piperidin-1 -yl, 4-fluoropiperidin-1 -yl, 3,5 -dimethylpiperidin15 1-yl, 4-(trifluoromethyl)piperidin-l-yl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l-yl, 2oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl.

The present invention also features compounds of Formulae I_E, I_E and I_G as described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:

R_e is independently selected at each occurrence from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, C(O)OR_S, -N(RsRs’), -S(O)R_s, -SO₂R_s, -C(O)N(R_sRs’), -N(R_S)C(O)R_S’, N(Rs)C(O)N(Rs’Rs”), -N(R_s)SO₂R_s’, -SO₂N(RsR_s’), -N(R_s)SO₂N(Rs’Rs”), N(Rs)S(O)N(R_s’Rs”), -OS(O)-Rs, -OS(O)₂-Rs, -S(O)₂ORs, -S(O)OR_s, -OC(O)OR_S, N(Rs)C(O)OR_s’, -OC(O)N(RsRs’)> -N(R_s)S(O)-Rs’, -S(O)N(RsR_s’), -P(O)(ORs)₂, =C(RsRs ), or -C(O)N(Rs)C(O)-Rs’; or Ci-C₆alkyl, C₂-C₆alkenyl or C₂-C₆alkynyl, each of which is independently optionally substituted at each occurrence with one or more

140

2016238925 07 Oct 2016 substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C₃-Ci2carbocycle or 3- to 12membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, trimethylsilyl, Ci-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, Ci-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, -O-Rs, -S-R_s, -C(O)R_S, -C(O)OR_S, or-N(R_sR_s’).

The compounds of the present invention can be used in the form of salts. Depending on the particular compound, a salt of a compound may be advantageous due to one or more of the salt’s 0 physical properties, such as enhanced pharmaceutical stability under certain conditions or desired solubility in water or oil. In some instances, a salt of a compound may be useful for the isolation or purification of the compound.

Where a salt is intended to be administered to a patient, the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, base 5 addition salts, and alkali metal salts.

Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Examples of suitable organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, !0 heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethane sulfonate, benzene sulfonate, 25 pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and 30 undecanoate.

Pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts and organic salts. Non-limiting examples of suitable metallic salts include alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other pharmaceutically acceptable metal salts. Such salts may be made, without limitation, from aluminum, calcium, lithium, magnesium, potassium, 35 sodium, or zinc. Non-limiting examples of suitable organic salts can be made from tertiary amines and quaternary amine, such as tromethamine, diethylamine, N,N’-dibenzylethylenediamine,

141 chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quatemized with agents such as alkyl halides (e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

2016238925 07 Oct 2016

The compounds or salts of the present invention may exist in the form of solvates, such as with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to form, respectively, methanolate, ethanolate or acetonitrilate).

The compounds or salts of the present invention may also be used in the form of prodrugs.

Some prodrugs are aliphatic or aromatic esters derived from acidic groups on the compounds of the invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of the invention. Phosphate prodrugs of hydroxyl groups are preferred prodrugs.

The compounds of the invention may comprise asymmetrically substituted carbon atoms known as chiral centers. These compounds may exist, without limitation, as single stereoisomers (e.g., single enantiomers or single diastereomer), mixtures of stereoisomers (e.g. a mixture of enantiomers or diastereomers), or racemic mixtures. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that is substantially free from other stereoisomers (e.g., substantially free from other enantiomers or diastereomers). By “substantially free,” it means that at least 80% of the compound in a composition is the described !0 stereoisomer; preferably, at least 90% of the compound in a composition is the described stereoisomer; and more preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in a composition is the described stereoisomer. Where the stereochemistry of a chiral carbon is not specified in the chemical structure of a compound, the chemical structure is intended to encompass compounds containing either stereoisomer of the chiral center.

Individual stereoisomers of the compounds of this invention can be prepared using a variety of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers followed by chromatographically separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic 30 resolution.

Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or substantial optically pure materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at the chiral centers. Mixtures of stereoisomers of compounds, including racemic mixtures, resulting from a synthetic reaction may be separated, for 35 example, by chromatographic techniques as appreciated by those of ordinary skill in the art.

Chromatographic resolution of enantiomers can be accomplished by using chiral chromatography

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2016238925 07 Oct 2016 resins, many of which are commercially available. In a non-limiting example, racemate is placed in solution and loaded onto the column containing a chiral stationary phase. Enantiomers can then be separated by HPLC.

Resolution of enantiomers can also be accomplished by converting enantiomers in a mixture 5 to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can be separated by column chromatography or crystallization/re-crystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Non-limiting examples of suitable chiral auxiliaries include chirally pure amino acids, organic carboxylic acids or organosulfonic acids. Once the diastereomers 0 are separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.

Enzymes, such as esterases, phosphatases or lipases, can be useful for the resolution of derivatives of enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be treated with an enzyme which selectively hydrolyzes .5 only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.

Alternatively, salts of enantiomers in a mixture can be prepared using any suitable method known in the art, including treatment of the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization/re-crystallization of the !0 enantiomerically pure salts. Methods suitable for the resolution/separation of a mixture of stereoisomers, including racemic mixtures, can be found in ENANTIOMERS, RACEMATES, AND Resolutions (Jacques et al., 1981, John Wiley and Sons, New York, NY).

A compound of this invention may possess one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as the cis (Z) and trans (E) isomers, and mixtures thereof are 25 intended to be encompassed within the scope of a recited compound unless otherwise specified. In addition, where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.

Certain compounds of the invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotations about an asymmetric single bond, 30 for example because of steric hindrance or ring strain, may permit separation of different conformers. The invention encompasses each conformational isomer of these compounds and mixtures thereof.

Certain compounds of the invention may also exist in zwitterionic form and the invention encompasses each zwitterionic form of these compounds and mixtures thereof.

The compounds of the present invention are generally described herein using standard 35 nomenclature. For a recited compound having asymmetric center(s), it should be understood that all of the stereoisomers of the compound and mixtures thereof are encompassed in the present invention

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2016238925 07 Oct 2016 unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-transisomers. Where a recited compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms. Certain compounds are described herein using general formulas that include variables (e.g., A, B, D, X, L_b L₂, L₃, Y, Z, T, R_A or R_B,).

Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. If moieties are described as being “independently” selected from a group, each moiety is selected independently from the other. Each moiety therefore can be identical to or different from the other moiety or moieties.

The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix “C_x-C_y,” where x is the minimum and y is the maximum number of carbon atoms in the moiety. Thus, for example, “Ci-C₆alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C₃-C₆cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms. A prefix attached to a multiple-component substituent only applies to the first component that .5 immediately follows the prefix. To illustrate, the term “carbocyclylalkyl” contains two components: carbocyclyl and alkyl. Thus, for example, C₃-C₆carbocyclylCi-C₆alkyl refers to a C₃-C₆carbocyclyl appended to the parent molecular moiety through a Ci-C₆alkyl group.

Unless otherwise specified, when a linking element links two other elements in a depicted chemical structure, the leftmost-described component of the linking element is bound to the left !0 element in the depicted structure, and the rightmost-described component of the linking element is bound to the right element in the depicted structure. To illustrate, if the chemical structure is -L_s-ML_s’- and M is -N(R_B)S(O)-, then the chemical structure is -L_s-N(R_B)S(O)-L_s’-.

If a linking element in a depicted structure is a bond, then the element left to the linking element is joined directly to the element right to the linking element via a covalent bond. For 25 example, if a chemical structure is depicted as -L_s-M-L_s’- and M is selected as bond, then the chemical structure will be -L_s-L_s’-. If two or more adjacent linking elements in a depicted structure are bonds, then the element left to these linking elements is joined directly to the element right to these linking elements via a covalent bond. For instance, if a chemical structure is depicted as -L_sM-L_s’-M’-L_s”-, and M and L_s’ are selected as bonds, then the chemical structure will be -L_s-M’30 L_s”-. Likewise, if a chemical structure is depicted as -L_s-M-L_s’-M’-L_s”-, and M, L_s’ and M’ are bonds, then the chemical structure will be -L_s-L_s”-.

When a chemical formula is used to describe a moiety, the dash(s) indicates the portion of the moiety that has the free valence(s).

If a moiety is described as being “optionally substituted”, the moiety may be either substituted 35 or unsubstituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either unsubstituted, or substituted by up to that

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2016238925 07 Oct 2016 particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heterocycle optionally substituted with up to three non-hydrogen radicals, then any heterocycle with less than three substitutable positions will be optionally substituted by up to only as many non5 hydrogen radicals as the heterocycle has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) will be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to two non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to two non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to 0 only one non-hydrogen radical.

Where a moiety is substituted with oxo or thioxo, it means that the moiety contains a carbon atom covalently bonded to at least two hydrogens (e.g., CH₂), and the two hydrogen radicals are substituted with oxo or thioxo to form C=O or C=S, respectively.

The term “alkenyl” means a straight or branched hydrocarbyl chain containing one or more 5 double bonds. Each carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.

The term “alkenylene” refers to a divalent unsaturated hydrocarbyl chain which may be linear !0 or branched and which has at least one carbon-carbon double bond. Non-limiting examples of alkenylene groups include —C(H)=C(H)— — C(H)=C(H)—CH₂— — C(H)=C(H)—CH₂—CH₂—

-CH₂-C(H)=C(H)-CH₂- -C(H)=C(H)-CH(CH₃)-, and -CH₂-C(H)=C(H)-CH(CH₂CH₃)The term “alkyl” means a straight or branched saturated hydrocarbyl chain. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t25 butyl, pentyl, iso-amyl, and hexyl.

The term “alkylene” denotes a divalent saturated hydrocarbyl chain which may be linear or branched. Representative examples of alkylene include, but are not limited to, -CH₂-, -CH₂CH₂-, CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, and -CH₂CH(CH₃)CH₂-.

The term “alkynyl” means a straight or branched hydrocarbyl chain containing one or more 30 triple bonds. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

The term “alkynylene” refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon triple bonds. Representative alkynylene groups include, by way of example, —C=C—, —C=C—CH₂— — C=C—CH₂—CH₂—

-CH₂-C<-CH₂- -C<-CH(CH,)- and -CH₂-CHC-CH(CH₂CH₃)145

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The term “carbocycle” or “carbocyclic” or “carbocyclyl” refers to a saturated (e.g., “cycloalkyl”), partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl”) or completely unsaturated (e.g., “aryl”) ring system containing zero heteroatom ring atom. “Ring atoms” or “ring members” are the atoms bound together to form the ring or rings. A carbocyclyl may be, without limitation, a single 5 ring, two fused rings, or bridged or spiro rings. A substituted carbocyclyl may have either cis or trans geometry. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl, 0 and norpinanyl. A carbocycle group can be attached to the parent molecular moiety through any substitutable carbon ring atom. Where a carbocycle group is a divalent moiety linking two other elements in a depicted chemical structure (such as A in Formula I), the carbocycle group can be attached to the two other elements through any two substitutable ring atoms. Likewise, where a carbocycle group is a trivalent moiety linking three other elements in a depicted chemical structure 5 (such as X in Formula I), the carbocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.

The term “carbocyclylalkyl” refers to a carbocyclyl group appended to the parent molecular moiety through an alkylene group. For instance, C₃-C₆carbocyclylCi-C₆alkyl refers to a C₃C₆carbocyclyl group appended to the parent molecular moiety through Ci-C₆alkylene.

!0 The term “cycloalkenyl” refers to a non-aromatic, partially unsaturated carbocyclyl moiety having zero heteroatom ring member. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl.

The term “cycloalkyl” refers to a saturated carbocyclyl group containing zero heteroatom ring member. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, 25 cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.

The prefix “halo” indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, “Ci-C₆haloalkyl” means a Ci-C₆alkyl substituent wherein one or more hydrogen atoms are replaced with independently selected halogen radicals. Non-limiting examples of Ci-C₆haloalkyl include chloromethyl, 1-bromoethyl, 30 fluoromethyl, difluoromethyl, trifluoromethyl, and 1, LI-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).

The term “heterocycle” or “heterocyclo” or “heterocyclyl” refers to a saturated (e.g., “heterocycloalkyl”), partially unsaturated (e.g., “heterocycloalkenyl” or “heterocycloalkynyl”) or 35 completely unsaturated (e.g., “heteroaryl”) ring system where at least one of the ring atoms is a heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms being independently

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2016238925 07 Oct 2016 selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocycle may be, without limitation, a single ring, two fused rings, or bridged or spiro rings. A heterocycle group can be linked to the parent molecular moiety via any substitutable carbon or nitrogen atom(s) in the group. Where a heterocycle group is a divalent moiety that links two other elements in a depicted chemical 5 structure (such as A in Formula I), the heterocycle group can be attached to the two other elements through any two substitutable ring atoms. Fikewise, where a heterocycle group is a trivalent moiety that links three other elements in a depicted chemical structure (such as X in Formula I), the heterocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.

A heterocyclyl may be, without limitation, a monocycle which contains a single ring. Nonlimiting examples of monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as “azoximyl”), 1,2,5-oxadiazolyl (also known as “furazanyl”), and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2dioxazolyl, and 1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also known as “l,2-diazinyl”), !0 pyrimidinyl (also known as “1,3-diazinyl”), and pyrazinyl (also known as “1,4-diazinyl”)), piperazinyl, triazinyl (including s-triazinyl (also known as “1,3,5-triazinyl”), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as “1,2,3-triazinyl), oxazinyl (including 1,2,3-oxazinyl,

1.3.2- oxazinyl, 1,3,6-oxazinyl (also known as “pentoxazolyl”), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and

1.3.5.2- oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, thiomorpholinyl, and diazepinyl.

A heterocyclyl may also be, without limitation, a bicycle containing two fused rings, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, 30 indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl. Other non-limiting examples of fused-ring heterocycles include benzo-fused heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl” or indazolyl), benzazinyl (including quinolinyl (also known as “135 benzazinyl”) and isoquinolinyl (also known as “2-benzazinyl”)), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) and

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2016238925 07 Oct 2016 quinazolinyl (also known as “1,3-benzodiazinyl”)), benzopyranyl (including “chromenyl” and “isochromenyl”), benzothiopyranyl (also known as “thiochromenyl”), benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothienyl (also known as 5 “benzothiophenyl”, “thionaphthenyl”, and “benzothiofuranyl”), isobenzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl”, and “isobenzothiofuranyl”), benzothiazolyl, 4,5,6,7tetrahydrobenzo[d]thiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, and 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl and 1,4-benzisoxazinyl), and tetrahydroisoquinolinyl.

A heterocyclyl may also be, without limitation, a spiro ring system, such as, for example, 1,4dioxa-8 -azaspiro [4.5] decanyl.

A heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom(s) is oxidized to SO or SO₂. The nitrogen heteroatom(s) in a heterocyclyl may or may not be quatemized, and may or may not be oxidized to N-oxide. In addition, the nitrogen 5 heteroatom(s) may or may not be N-protected.

A heterocycle or carbocycle may be further substituted. Unless specified, the term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, hydroxy, protected hydroxy, -NO₂, -N₃, -CN, -NH₂, protected amino, oxo, thioxo, -NH-Ci-Ci₂-alkyl, -NH-C₂-C₈-alkenyl, !0 -NH-C₂-C₈-alkynyl, -NH-C₃-Ci₂-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci₂-alkyl, -O-C₂-C₈-alkenyl, -O-C₂-C₈alkynyl, -O-C₃-Ci₂-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-Ci-Ci₂-alkyl, C(O)-C₂-C₈-alkenyl, -C(O)-C₂-C₈-alkynyl, -C(O)-C₃-Ci₂-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, C(O)-heterocycloalkyl, -CONH₂, -CONH-Ci-Ci₂-alkyl, -CONH-C₂-C₈-alkenyl, -CONH-C₂-C₈25 alkynyl, -CONH-C₃-Ci₂-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, OCO₂-C₁-C₁₂-alkyl, -OCO₂-C₂-C₈-alkenyl, -OCO₂-C₂-C₈-alkynyl, -OCO₂-C₃-C₁₂-cycloalkyl, -OCO₂aryl, -OCO₂-heteroaryl, -OCO₂-heterocycloalkyl, -OCONH₂, -OCONH-Ci-Ci₂-alkyl, -OCONH-C₂C₈-alkenyl, -OCONH-C₂-C₈-alkynyl, -OCONH-C₃-Ci₂-cycloalkyl, -OCONH-aryl, -OCONHheteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-Ci-Ci₂-alkyl, -NHC(O)-C₂-C₈-alkenyl, -NHC(O)30 C₂-C₈-alkynyl, -NHC(O)-C₃-Ci₂-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)heterocycloalkyl, -NHCO₂-Ci-Ci₂-alkyl, -NHCO₂-C₂-C₈-alkenyl, -NHCO₂-C₂-C₈-alkynynl, -NHCO₂C₃-Ci₂-cycloalkyl, -NHCO₂-aryl, -NHCO₂-heteroaryl, -NHCO₂-heterocycloalkyl, -NHC(O)NH₂, NHC(O)NH-Ci-Ci₂-alkyl, -NHC(O)NH-C₂-C₈-alkenyl, -NHC(O)NH-C₂-C₈-alkynyl, -NHC(O)NHC₃-Ci₂-cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, 35 NHC(S)NH₂, -NHC(S)NH-Ci-Ci₂-alkyl, -NHC(S)NH-C₂-C₈-alkenyl, -NHC(S)NH-C₂-C₈-alkynyl, NHC(S)NH-C₃-Ci₂-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH148

2016238925 07 Oct 2016 heterocycloalkyl, -NHC(NH)NH₂, -NHC(NH)NH-Ci-Ci₂-alkyl, -NHC(NH)NH-C₂-C₈-alkenyl, NHC(NH)NH-C₂-C₈-alkynyl, -NHC(NH)NH-C₃-Ci₂-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NHheteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-Ci-Ci₂-alkyl, -NHC(NH)-C₂-C₈-alkenyl, NHC(NH)-C₂-C₈-alkynyl, -NHC(NH)-C₃-Ci₂-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, 5 NHC(NH)-heterocycloalkyl, -C(NH)NH-Ci-Ci₂-alkyl, -C(NH)NH-C₂-C₈-alkenyl, -C(NH)NH-C₂-C₈alkynyl, -C(NH)NH-C₃-Ci₂-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, -SCOj-Ci-C^-alkyl, -S(O)-C₂-C₈-alkenyl, -S(O)-C₂-C₈-alkynyl, -S(O)-C₃-C₁₂cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO₂NH₂, -SO₂NH-Ci-Ci₂-alkyl, SO₂NH-C₂-C₈-alkenyl, -SO₂NH-C₂-C₈-alkynyl, -SO₂NH-C₃-Ci₂-cycloalkyl, -SO₂NH-aryl, -SO₂NH0 heteroaryl, -SO₂NH-heterocycloalkyl, -NHSO₂-Ci-Ci₂-alkyl, -NHSO₂-C₂-C₈-alkenyl, -NHSO₂-C₂-C₈alkynyl, -NHSO₂-C₃-Ci₂-cycloalkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHSO₂-heterocycloalkyl, CH₂NH₂, -CH₂SO₂CH₃, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C₃-Ci₂cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-Ci-Ci₂-alkyl, S-C₂-C₈-alkenyl, -S-C₂-C₈-alkynyl, -S-C₃-Ci₂-cycloalkyl, -S-aryl, -heteroaryl, -S-heterocycloalkyl, or 5 methylthiomethyl. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted.

An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds. Examples of aliphatic groups are !0 functional groups, such as, O, OH, NH, NH₂, C(O), S(O)₂, C(O)O, C(0)NH, OC(O)O, 0C(0)NH, 0C(0)NH₂, S(O)₂NH, S(O)₂NH₂, NHC(0)NH₂, NHC(0)C(0)NH, NHS(0)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂, C(O)NHS(O)₂NH or C(O)NHS(O)2NH₂, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional 25 group. Carbon atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic 30 groups may be optionally substituted. A linear aliphatic group is a non-cyclic aliphatic group. It is to be understood that when a linear aliphatic group is said to “contain” or “include” or “comprise” one or more specified functional groups, the linear aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group. An 35 exemplary linear aliphatic group is an alkyl, alkenyl or alkynyl, each optionally substituted, which is interrupted or terminated by a functional group.

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2016238925 07 Oct 2016 ^:Σ777τ in a chemical formula refers to a single or double bond.

The term “pharmaceutically acceptable” is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.

The term “therapeutically effective amount” refers to the total amount of each active substance that is sufficient to show a meaningful patient benefit, e.g. a reduction in viral load.

The term “prodrug” refers to derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. A prodrug of a compound may be formed in a conventional manner by reaction of a functional group of the 0 compound (such as an amino, hydroxy, carboxy or phosphate group). Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, Bungard, H., DESIGN OF Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound .5 with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amine functional groups within the compounds of the invention, or phosphate esters of the compounds of the invention.

The term “solvate” refers to the physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association often includes !0 hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, and methanolates.

The term “N-protecting group” or “N-protected” refers to those groups capable of protecting 25 an amino group against undesirable reactions. Commonly used N-protecting groups are described in Greene and Wuts, Protecting Groups in Chemical Synthesis (3^rd ed., John Wiley & Sons, NY (1999). Non-limiting examples of N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; 30 sulfonyl groups such as benzene sulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (pmethylphenyl-S (0)-) or t-butylsulfinyl (t-Bu-S(O)-); carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, pnitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,435 dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5150

2016238925 07 Oct 2016 trimethoxybenzyloxycarbonyl, dimethoxybenzyloxycarbonyl, diisopropylmethoxy carbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, dimethyl-3,5benzhydryloxycarbonyl, t-butyloxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloro-ethoxy-carbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl;

alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl; pmethoxyphenyl; and silyl groups such as trimethylsilyl. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boe) and benzyloxy carbonyl (Cbz).

Abbreviations which have been used in the descriptions of the Schemes, Intermediates and

Examples that follow are: Ac for acetyl; APCI for atmospheric pressure chemical ionization; aq or aq. for aqueous; atm for atmosphere; Boe for Z-butoxycarbonyl; Bu for butyl; /-Bn or tert-butyl for tert/ary-butyl; Cbz for benzyloxycarbonyl; dba for dibenzylidineacetone; DCI for desorption chemical ionization; DDQ for 2,3-dichloro-5,6-dicyano-p-benzoquinone; DEPBT for 35 (diethoxyphosphoryloxy)-l, 2, 3-benzotriazin-4(3/f)-one; DIBAL for diisobutylaluminum hydride;

DMA for ΛύΛ'-di methyl acetamide: DME for 1,2-dimethoxy ethane; DMF for A'. A'-di methyl formamide: DMSO for dimethyl sulfoxide; DMPU for l,3-dimethyl-3,4,5,6-tetrahydro-2(127)-pyrimidinone; dppf for l,l'-bis(diphenylphosphino)ferrocene; EDC, EDAC or EDCI for A'-(3-dimcthylaminopropyl)-Aethylcarbodiimide hydrochloride; e.e. for enantiomeric excess; ELSD for evaporative light scattering !0 detector; ESI for electrospray ionization; Et for ethyl; Et₃N for triethylamine; EtOAc for ethyl acetate;

EtOH for ethanol; Et₂O for diethyl ether; eq or equiv for equivalents; Fmoc for 9fluorenylmethoxycarbonyl; HATU for t/-(7-azabcnzotriazol-l-yl)-A'.A'.A'’.A'’-tctramcthyliironiiim hexafluorophosphate; HOBt for 1-hydroxybenzotriazole; HPLC for high performance liquid chromatography; HOBt for 1-hydroxybenzotriazole; LCMS for liquid chromatography/mass 25 spectrometry; mCPBA for m-chloropcroxybcnzoic acid; Me for methyl; MeOH for methanol; OAc for acetate; Ms for methanesulfonyl; OTF for triflate or trifluoromethanesulfonate; PDC for pyridinium dichromate; z-Pr for isopropyl; Ph for phenyl; PPh₃ for triphenylphosphine; psi or psig for pounds per square inch (gas); PTFE for polytetrafluoroethylene; PXPd for [(t-Bu)₂PCl]₂PdCl₂, PyBOP for (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate; SEM for 230 (trimethylsilyl)ethoxymethyl; T3P for propane phosphonic acid anhydride; Tf for trifluoro sulfonyl;

TFA for trifluoroacetic acid; THF for tetrahydrofuran; TLC for thin layer chromatography; Troc for

2,2,2-trichloroethoxycarbonyl; v/v for volume/volume; wt% for weight percent; w/v for weight/volume; w/w for weight/weight; XantPhos for 4,5-bis(diphenylphosphino)-9,9dimethylxanthene;

The compounds of the present invention can be prepared using a variety of methods. As a non-limiting example, the compounds of the present invention can be prepared according to Scheme I

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2016238925 07 Oct 2016 starting from compounds of Formula II (e.g., n = 0 to 8), Formula V (X₄ can be, for example, O or NRa, where R_A is as described hereinabove and is preferably H or R_E as defined above such as ClC6alkyl, 3- to 12-membered carbocycle or heterocycle, -C(O)Rs, -C(O)ORs, -C(O)N(RsRs ), SO₂N(RsRs ), -S(O)₂ORs, -S(O)ORs, -S(O)N(RsRs ), or a suitable protecting group such as Boe or 5 Fmoc), or Formula VIII (E can be, for example, 3- to 7-membered carbocycle or heterocycle and is optionally substituted with one or more R_A), wherein A, B, D, Y, Z and R_A are as described above.

The 1,4-diketones II, V, and VIII can be reduced to the 1,4-diols using the methods described below, and the resultant racemic, enantiomerically enriched, or meso 1,4-diols may be converted to the dimesylates III, VI, or IX, or alternatively to ditriflates, ditosylates, or dihalides by the methods 0 described below. The dimesylates III, VI, and IX, ditriflates, ditosylates, or dihalides may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described below to give the compounds of the invention. Lx and L₂ can be readily introduced to Formulae II, V 5 and VIII, as appreciated by those skilled in the art in light of the present invention. Likewise, D-L₃NH₂ can be used instead of D-NH₂, as appreciated by those skilled in the art.

Scheme I

As another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II and Formula III as shown in Scheme II. The 1,4-diketones

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2016238925 07 Oct 2016 such as Formula IV may be prepared using known methods (see Nevar, et al., Synthesis: 1259-1262 (2000), such as the reaction of α-bromoketones such as Formula II with methyl ketones such as

Formula III in the presence of a suitable Lewis acid such as ZnCl₂ or Ti(OiPr)₄. For example reaction of II (1 equivalent) with III (1.5 equivalents) in the presence of ZnCl₂ (2 equivalents), diethylamine (1.5 equivalents) and tert-butanol (1.5 equivalents) in a solvent such as benzene at around room temperature can provide the diketones IV. The 1,4-diketones IV may be reduced to the 1,4-diols such as V by the action of NaBH₄, LiAlH₄, or DIBAL. Alternatively, enantioselective reduction of 1,4diketones such as Formula IV can be accomplished by analogy with reported methods (see Chong, et al., Tetrahedron: Asymmetry 6:409-418 (1995), Li, et al., Tetrahedron 63:8046-8053 (2007), Aldous, 0 et al., Tetrahedron: Asymmetry 11:2455-2462 (2000), Masui, et al., Synlett:273-274 (1997), Jing, et al., Adv. Synth. Catal. 347:1193-1197 (2005), Sato, et al., Synthesis: 1434-1438 (2004)), such as reduction with (-) or (+)-diisopinocamheylchloroborane (DIP-chloride), with borane and an oxazaborolidine catalyst, or with asymmetric hydrogenation in the presence of a suitable Ruthenium (II) catalyst, such as [RuC12{(R)-BINAP}{(R,R)-DPEN}] (BINAP=2,2’-bis(diarylphosphino)-l,l’5 binaphthyl; DPEN=l,2-diphenylethylenediamine). The diketones IV (1 equivalent) can be reduced by

NaBH4 (3 equivalents) in solvents such as tetrahydrofuran with heating to about 50 °C. The diketones IV (1 equivalent) can be enantioselectively reduced upon addition to a mixture made from A'A'-dicthylanilinc borane (about 2 equivalents), trimethylborate (about 0.2 equivalents) and either (.S) or (R) a,a-diphenyl-2-pyrrolidinemethanol (about 0.17 equivalents) in a solvent such as THF at !0 temperatures ranging from about 10 °C to about 30 °C (Synthesis 2507-2510 (2003)). The resultant racemic, enantiomerically enriched, or meso 1,4-diols V may be reacted with methanesulfonyl chloride or methane sulfonic anhydride to provide the dimesylate Formula VI. For example, diols V (1 equivalent) can be reacted with methane sulfonic anhydride (about 2.5 equivalents) in the presence of a base such as diisopropylethylamine (about 4 equivalents) in a solvent such as tetrahydrofuran or 25 2-methyltetrahydrofuran at temperatures starting from about -15 °C to -25 °C and increasing to about room temperature. Alternatively Formula V may be converted to a ditriflate or ditosylate by the action of p-toluenesulfonyl chloride or triflic anhydride, or to a dihalide such as a dibromide or dichloride by the action of PPh₃ in the presence of CC1₄ or CBr₄, or by the action of SOC1₂, POC1₃, or PBr₃. The dimesylate, ditriflate, ditosylate, or dihalide may be reacted with an amine, such as 430 fluoroaniline (as shown for illustration in Scheme II), with or without a co-solvent such as DMF at room temperature to 100 °C, to give the pyrrolidines such as Formula VII. The dimesylate VI (1 equivalent) (or in the alternative the ditriflate, ditosylate, or dihalide) may be reacted with between 1 to 20 equiv of an amine D-NH₂, such as, for example, a substituted aniline in solvents such as tetrahydrofuran or 2-methyltetrahydrofuran with or without a co-solvent such as DMF, at about room 35 temperature to about 100 °C, to give the pyrrolidines such as Formula VII. Where fewer equivalents of amine D-NH₂ are employed (i.e., 1-2 equivalents), a base such as diisopropylethylamine can be

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2016238925 07 Oct 2016 added to promote the reaction. In certain cases, the amine can be used in a large excess (i.e., as reaction solvent). For example, the reaction of a dimesylate (1 equivalent) with excess aniline (about

6.5 equivalents) can be conducted by heating to 65 °C in 2-methyltetrahydrofuran until completion of the reaction. Numerous substituted anilines can be reacted with the dimesylate Formula VI, including, but not limited to, 3-fluoro-4-(piperidin-l-yl)aniline, 3,5-difluoro-4-(piperidin-l-yl)aniline,

3.5- difluoro-4-(4-phenylpiperidin-1 -yl)aniline, 3 -difluoro-4-(4-phenylpiperidin-1 -yl)aniline, 4-(4phenylpiperidin-1 -yl)aniline, 4-cyclopropylaniline, 4-cyclopropyl-2-fluoroaniline, 4-cyclopropyl-3,5difluoroaniline, 4-cyclohexyl-3-fluoroaniline, biphenyl-4-amine, 4-(pyridin-2-yl)aniline, 3,5-dichloro4-(piperidin-l-yl)aniline, 4-(4,4-dimethylpiperidin-l-yl)-3,5-difluoroaniline, 4-(4,4-fluoropiperidin-Ι-

Ο yl)-3,5-difluoroaniline, 3-methyl-4-(piperidin-l-yl)aniline, 2,5-difluoro-4-(piperidin-l-yl)aniline, 4(3,5 -dimethylpiperidin-1 -yl)-3,5 -difluoroaniline, 4-(2,6-dimethylpiperidin-1 -y 1)-3,5 -difluoroaniline,

2.3.5- trifluoro-4-(piperidin-l-yl)aniline, 3,5-difluoro-4-(4-isopropylpiperidin-l-yl)aniline, 3,5- difluoro-4-(4-methylpiperidin-l-yl)aniline, 3,5-difluoro-4-(4-(trifluoromethyl)piperidin-l-yl)aniline, 4-(4-Zi77-biitylpipcridin-l-yl)-3.5-difliioroanilinc. 3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)aniline, 45 (2-azabicyclo[2.2.2]octan-2-yl)-3,5-difluoroaniline, 4-(3,3-dimethylazetidin-l-yl)-3,5-difluoroaniline,

4-tert-butylaniline, 4-ethoxyaniline, 4-phenoxyaniline, l-(4-aminophenyl)piperidin-2-one, 4(cyclopentyloxy)-3-fluoroaniline, 3-chloro-4-(trifluoromethoxy)aniline, 2,5-difluoro-4(trifluoromethyl)aniline, 4-(2,2-difluoroethoxy)aniline, 4-chloroaniline, 4-(2-methoxyethoxy)aniline, 4-(oxazol-2-yl)aniline, 4-(2-fluoropyridin-4-yl)aniline, 3,4-difluoroaniline, 4-chloro-3-fluoroaniline, !0 3 -fluoro-4-(methylsulfonyl)aniline, 4-(3 -azabicyclo [3.2.0]heptan-3 -y 1)-3,5 -difluoroaniline, 4-((3ethyloxetan-3-yl)methoxy)aniline, 4-cyclopropyl-3,5-difluoroaniline, 4-(l,3-dioxan-5-yloxy)aniline,

3.5- difluoro-4-(octahydroisoindol-2-yl)aniline, 4-((l,3-dioxolan-4-yl)methoxy)aniline, 4-((3- ethyloxetan-3-yl)methoxy)-3,5-difluoroaniline, 4-(pentafluorosulfanyl)aniline, Al-tert-butyl-2fluorobenzene-l,4-diamine, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, allylamine, or anilines that are listed in or can be made using General Procedures 1,

1.1, or 1.2. The dinitro Formula VII may be reduced to the diamino Formula VIII using Fe in the presence of NH₄C1, HC1, or acetic acid, or by treatment with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as BiCl₃, SbCl₃, NiCl₂, Cu₂Cl₂, or CoCl₂) in a solvent such as ethanol or THF. For example compounds VII (1 equivalent) 30 can be reduced to VIII by reaction with iron powder (about 6 equivalents) and ammonium chloride in a 1:1 mix of THF and ethanol with heating to about 60-80 °C. Alternatively, Formula VII can be reduced to the product Formula VIII by hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney-nickel. For example reduction of VII to VIII can be effected by exposure to 30 psig hydrogen gas in the presence of Raney-nickel Grace 2800 in a solvent such as 35 tetrahydrofuran with shaking. The diamine Formula VIII may be reacted with a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be substituted) in the presence of a

154

2016238925 07 Oct 2016 peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU, T3P or DEPBT, in a solvent such as THF, DMF, dichloromethane, ethyl acetate, or DMSO, with or without the addition of an amine base such as Λ'-mcthylmorpholinc. Hunig’s base, pyridine, 2,6-lutidine, or triethylamine, to give Formula IX. For example, reaction of VIII (1 equivalent) with I-(/i77-biitoxycarbonyl)pyrrolidinc-25 carboxylic acid (2.5 equivalents) and HATU (2.5 equivalents) in the presence of diisopropylethylamine (3 equivalents) in DMSO at about room temperature can provide the product IX. Removal of the Boe protecting groups to give X may be accomplished by treatment with an acid, such as TFA, HC1, or formic acid. For example, reaction of IX (1 equivalent) with TFA:CH₂C1₂ (1:1) at room temperature can provide compounds X. Compounds XI may be prepared by coupling of 0 Formula X with an acid of choice using the standard peptide coupling reagents and conditions described above. For example, X(1 equivalent) can be reacted with acids (2 equivalents) such as, but not limited to, 2-(methoxycarbonylamino)-3-methylbutanoic acid, 2-(methoxycarbonylamino)-3,3dimethylbutanoic acid, 2-cyclohexyl-2-(methoxycarbonylamino)acetic acid, 2(methoxycarbonylamino)-2-(tetrahydro-2W-pyran-4-yl)acetic acid, or acids listed under General 5 Procedure 19. Alternately, diamine VIII may be reacted directly with an appropriately A'-substitiitcd proline in the presence of a peptide coupling reagent such as EDAC/HOBT, PyBOP, HATU, T3P, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as Λ'-mcthylmorpholinc. Hunig’s base, pyridine, 2,6-lutidine, or triethylamine, to directly give compounds XI. For example, VIII (1 equivalent) can be reacted directly with 1-(2!0 (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (about 2 equivalents) and

T3P (about 2.8 equivalents) in the presence of diisopropylethylamine (about 5.5 equivalents) in a solvent such as ethyl acetate at temperatures from about 0 °C to about room temperature to provide XI. The foregoing sequence illustrates the synthesis of particular compounds of the invention XI having a substituted proline group at Y and Z (i.e., R₂ and R₅ taken together with the atoms to which 25 they are attached, and R₉ and R_i2 taken together with the atoms to which they are attached, each form a 5-membered heterocycle). It is understood that analogous synthetic procedures can be used to make compounds of the invention where Y, Z, R₂, R₅, R₉, and R_i2 are other than that shown and described in Scheme II. in each Formula within Scheme II can be replaced with where D is defined above, and such compounds can be readily prepared according to the process described in 30 Scheme II (including making compound XI directly from compound VIII). Eikewise, compounds of

Formula XII can be prepared from compounds of Formula X or directly from compounds of Formula VIII.

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2016238925 07 Oct 2016

XII

Scheme II

As yet another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II and Formula III as shown in Scheme III, where A, B, D, Y, and Z are as described above, using conditions similar to those described above for the preparation of IV in Scheme II. Similarly, the resulting 1,4-diketone IV may be reduced to the 1,4-diols V using the

156

2016238925 07 Oct 2016 methods described above for Scheme II. The resultant racemic, enantiomerically enriched, or meso 1,4-diols V may be converted to the dimesylate VI or alternatively to a ditriflate, ditosylate, or dihalide by the methods described above. The dimesylate VI, ditriflate, ditosylate, or dihalide may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 45 fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described above the give the compounds of the invention. Alternatively, compounds such as VIII, where R is a group such as allyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl, may be treated with reagents useful for the removal of the R group (rhodium catalyst such as Rh(Ph₃P)₃Cl for R = allyl, treatment with an 0 acid such as TFA or HC1 for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for R = substituted benzyl) to generate compounds such as IX. Amine IX may be reacted with an aryl halide or triflate such as X (iodide shown for illustration) employing the BuchwaldHartwig reaction in the presence of a palladium catalyst (such as Pd(OAc)₂ or Pd₂(dba)₃) and a phosphine ligand (such as triphenylphosphine or XantPhos) and a base (such as sodium 5 bis(trimethylsilyl)amide, potassium tert-butoxide, or K₃PO₄) to give the compounds of the present invention. Alternatively, the compounds of the present invention may be obtained by reaction of IX with an aldehyde or ketone through reductive amination in the presence of a hydride reducing agent, such as sodium borohydride or sodium cyanoborohydride (with or without the addition of an acid, such as acetic acid) in a solvent such as ethanol, toluene, THF, or dichloromethane. Alternatively the !0 reductive amination may be conducted through the use of hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. Alternatively, amine IX may react with electrophilic reagents, such as alkyl halides, or with aryl electrophiles (suitably electron deficient aryl and heteroaryl halides and triflates) through nucleophilic aromatic substitution reactions to give the compounds of the present invention.

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II

III

R = allyl or substitued benzyl

Scheme III

As a further non-limiting example, the compounds of XIII can be prepared starting from compounds of Formula II and Formula III as shown in Scheme IV, where X₅ in Formula II and Formula III represents a halogen (e.g., Cl, Br, or F) or a nitro group. Additionally, each phenyl ring can be substituted with X_i3, wherein X_i3 is X₅, H, alkyl, haloalkyl, alkoxy, or haloalkoxy. The 1,4diketones such as IV may be prepared using known methods described above for the preparation of IV for Scheme II. The 1,4-diketones IV may be reduced to the 1,4-diols such as V by the action of

NaBH₄, LiAlH₄, or DIBAL. Alternatively, enantioselective reduction of 1,4-diketone such as IV can be accomplished by the methods described above for the preparation of V in Scheme II. As described for Intermediate 20D, the chiral reduction may proceed with lower stereoselectivity with an additional substituent X_i3 on the phenyl ring. The resultant racemic, enantiomerically enriched, or meso 1,4diols V may be reacted with methansulfonyl chloride or methanesulfonic anhydride to provide the dimesylate VI. Alternatively V may be converted to a ditriflate or ditosylate by the methods described above for Scheme II. The dimesylate, ditriflate, ditosylate, or dihalide may be reacted,

158

2016238925 07 Oct 2016 analogously to Scheme II, with an amine D-NH₂ including but not limited to those amines described or referred to in Scheme II to give VII. When X₅ in Formula VII is nitro, the nitro groups may be reduced to the tetraamino product IX using Fe in the presence of NH₄C1, HC1, or acetic acid, or with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as BiCl₃, SbCl₃, NiCl₂, Cu₂Cl₂, or CoCl₂) in a solvent such as ethanol or THF.

Alternatively, VII (X₅ = nitro) can be reduced to the product IX by hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. Alternatively, compounds VII where X₅ = halogen may be reacted with ammonia (R = H) or an amine bearing a suitable protecting group (R = substituted benzyl such as 4-methoxybenzyl or 2,4 dimethoxybenzyl or R = 0 allyl). The resulting products VIII may be treated with a reagent useful for the removal of the R protecting group (rhodium catalyst such as Rh(Ph₃P)₃Cl for R = allyl, treatment with an acid such as TFA or HC1 for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for R = substituted benzyl) to give the product IX. Formula IX may be reacted with a suitably protected proline acid (Boe is shown, although Cbz, Troc, or Fmoc may be substituted) in the presence of a 5 peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU, T3P, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base, such as Nmethylmorpholine, Hunig’s base, pyridine, 2,6-lutidine, or triethylamine, to give X as a mixture of the amide products. Although formula X depicts reaction taking place on a specific NH₂ group, the reaction may take place at either NH₂. Conversion to the benzimidazole compound XI may be !0 accomplished by heating X in acetic acid (50-100 °C). Alternatively, XI may be prepared by reaction of IX with an aldehyde, followed by treatment with an oxidant, such as Cu(OAc)₂ or MnO₂ (see Penning, et al., Bioorg. Med. Chem. 2008, 16, 6965-6975. After removal of the Boe protecting groups from XI (accomplished by treatment with an acid, such as TFA, HC1, or formic acid), the compounds of the present invention may be prepared by coupling of the resulting diamine XII with an 25 acid of choice using the standard peptide coupling reagents and conditions described above for

F

Scheme II to give XIII. in each Formula within Scheme IV can be replaced with where D is defined above, and such compounds can be readily prepared according to the process described in Scheme IV. Compounds of Formula XIV can be similarly prepared from compounds of Formula XII. When subjected to synthetic processes in Scheme IV, enantiomerically enriched diols V 30 may produce mixtures containing varying amounts of stereoisomeric cis and trans pyrrolidines VII.

The stereoisomeric pyrrolidines may be separated according to standard chromatography techniques. Alternatively, such separations may be carried out at a later stage in the synthetic process including the steps of Schemes XIII and XIV, or after the final step.

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Alternatively IX in Scheme IV may be prepared from a compound of Formula II as shown in

Scheme V. Compound VIII from Scheme II may be treated with an acylating agent such as acetyl

160

2016238925 07 Oct 2016 chloride or acetic anhydride to give compound II (Scheme V). Nitration of compound II to provide III may be accomplished using known methods, such as treatment with nitric acid or potassium nitrate in the presence of an acid such as sulfuric acid or treatment with NO₂BF₄. Removal of the acetamide protecting group may be accomplished by treatment with Boe anhydride in the presence of DMAP to give IV, followed by sequential treatment of IV with hydroxide (such as NaOH, KOH, or Li OH) to remove the acetyl group and a strong acid such as TFA or HC1 to remove the Boe protecting group to provide V. The nitro groups in V may be reduced to amino groups using the methods described above

F

for Scheme IV to provide IX. in each Formula within Scheme V can be replaced with ^/vyv’ where D is defined above, and such compounds can be readily prepared according to the process described in Scheme V.

Scheme V

As still another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II as shown in Scheme VI, where A, B, D, Y, and Z are as described above. A 1,4-diketone compound of Formula II (prepared as described in Scheme III) may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl

161 amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under acid catalyzed conditions, such as acetic acid, TFA, formic acid or HC1, to give the compounds of the invention.

2016238925 07 Oct 2016

Scheme VI

As a further non-limiting example, the compounds of the present invention can be prepared from a compound of Formula II as shown in Scheme VII. A compound of Formula II, where R_x is a 0 halogen, such as bromo, chloro, or iodo, or a tritiate or a nonaflate may be converted to a boronic acid or ester such as Formula III, using the chemistry analogous to that of Scheme II to prepare VII (in Scheme II); for example, by starting with 1 -(4-bromophenyl)ethanone and 2-bromo-l-(4bromophenyl)ethanone. A compound of Formula II, where R_x is a halogen, such as bromo, chloro, or iodo, or a tritiate or a nonaflate may be converted to a boronic acid or ester such as Formula III, (e.g., 5 a cyclic pinacolate ester) where R is hydrogen, methyl, ethyl, or a cyclic pinacolate ester. For example a compound of Formula II can be transformed to a compound of III by treatment with pinacol-borane in the presence of a catalyst such as, for example, tris(dibenzylidineacetone)palladium (0), and a ligand such as, for example, tri-t-butylphosphine, in solvents such as, for example, tetrahydrofuran, dioxane, or toluene at temperatures ranging from ambient to about 130°C. !0 Alternatively, compound II can be reacted with bis(pinacolato)diboron in the presence of a catalyst such as, for example, Combiphos-Pd6 (CombiPhos Catalysts, Inc. (NJ, USA), dichloro [1,1'bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct, or palladium acetate in the presence of a ligand such as, for example, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), and a base such as, for example, potassium acetate in solvents such as, for example, toluene, 25 dioxane, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide at temperatures from about 60 to about 130°C to give compound III. Alternatively, a compound of Formula II may be reacted with an organolithium reagent, such an n-BuLi, sec-BuLi, or t-BuLi, followed by reaction with trimethyl borate or triethyl borate, to give a compound of Formula III.

A compound of Formula III in Scheme VII can be coupled with a compound of Formula IV, 30 where R_Y is a halogen, such as bromo, chloro or iodo, under Suzuki reaction conditions to provide a compound of Formula V. Such conditions include, for example, use of a palladium catalyst such as, for example, tris(dibenzylidineacetone)palladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium, or dichloro[l,r-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct; base such as, 35 for example, potassium carbonate, potassium phosphate, potassium t-butoxide, sodium carbonate,

162

2016238925 07 Oct 2016 cesium carbonate, or cesium fluoride; and solvent such as, for example, toluene, ethanol, water, or tetrahydrofuran, or mixtures thereof heated in the temperature range from about 40 to about 130°C.

Removal of the Boe protecting groups from V may be accomplished by treatment with an acid, such as TFA, HCI, or formic acid. Certain compounds of the present invention such as VI may 5 be prepared by coupling the resulting amino compounds with an acid of choice using the standard peptide coupling reagents, such as EDAC/HOBT, PyBOP, HATU, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as Nmethymorpholine, Hunig’s base, pyridine, 2,6-lutidine, or triethylamine. Each R_z is independently L_Y’-M’-R_D (e g., -L_y-N(R_b”)C(O)-L_s-R_e), and D, L₃, R_b R₂, R₅, L_Y, R_B”, L_s, R_E , L_Y’, M’ and R_D are as defined above. Alternatively, the functionality of T-R_D can similarly be introduced following

removal of the Boe protecting groups in V give compounds of Formula VII.
D ^b<yY l₃ γγ^Β·<	OR I , RO'^ByY	D OR L₃ Yy^bor
	γτ	i I
II

IV

VI

Scheme VII

163

2016238925 07 Oct 2016

As another non-limiting example, the compounds of the present invention can be prepared according to Scheme VIII starting from the compound of Formula II, initially cleaving the diol in oxidative fashion followed by subsequent acid hydrolysis of the acetonide. This dialdehyde intermediate is then treated with an aryl boronate or aryl boronic acid (compound IV where A and Y 5 are as described previously, or compound VII) and aniline III (where W is R_M or J, and R_M and J are as defined above) resulting in the formation of Formula V or Formula VIII respectively. Formula V can be derivatized by deprotonating the hydroxyl groups with a strong base such as sodium hydride, butyl lithium, or potassium hydride, followed by alkylation with R_s-halogen. Alternatively Formula VIII can be deprotonated with a strong base (e.g., sodium hydride) and alkylated with R_s-halogen as 0 well, followed by acid hydrolysis of the phenol protecting groups. The sulfonylation of the phenols with nonafluorobutylsulfonyl fluoride in the presence of a neutralizing agent such as potassium carbonate in a polar aprotic solvent such as DMF, followed by heating provides a compound of Formula IX. Boronate of Formula X is produced by heating Formula IX with bis(pinacolato)diboron in the presence of X-phos and a palladium catalyst, such as Pd2(dba)3 and a base such as potassium .5 acetate in an organic solvent such as dioxane. Formula X is further derivatized to final product by heating a suitably substituted heteroarylhalide in the presence of a palladium catalyst such as

PdC12(dppf) in the presence of a base such as sodium carbonate in a mixture of toluene and ethanol.

Rs is as defined above.

w

/vyir in each Formula within Scheme VIII can be replaced with

A/W* where D is defined above, and such compounds can be readily prepared according to the process !0 described in Scheme VIII.

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Y-Br, Pd°

Na₂CO

1:1 toluene/EtOH Δ

Scheme VIII

As yet another nondimiting example, the compounds of the present invention can be 5 prepared according to Scheme IX starting from the compounds of Formula II and Formula III.

Formula III carboxylic acid is activated towards coupling using reagents such as isobutylchloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as diisopropylethylamine. Upon activation, dianiline of Formula II is added to the reaction, with the isolation of an intermediate amide, which is heated in acetic acid, preferably at 60 °C, to yield the 10 compound of Formula IV. The benzimidazole of Formula IV is treated with SEM-C1 in the presence of a base in an aprotic solvent such as THF, yielding two protected benzimidazole regioisomers V. The boronate esters VI are produced by heating Formula V with bis(pinacolato)diboron in the presence of a palladium catalyst, such as PdC12(dppf), X-Phos, and a base such as potassium acetate in an organic solvent such as dioxane. Heating yields both benzimidazole regioisomers VI. Diol VII 15 is cleaved in oxidative fashion followed by subsequent acid hydrolysis of the acetonide. This dialdehyde intermediate is then treated with an aryl boronate VI and aniline VIII (where W is R_M or J, and R_m and J are as defined above) resulting in the formation of the 3 benzimidazole regioisomers of Formula IX. Formula X is produced by deprotonating the hydroxyl groups with a strong base such as sodium hydride, butyl lithium, or potassium hydride, followed by alkylation with R_s-halogen,

165 followed by acid hydrolysis of the pyrrolidine and benzimidazole protecting groups, preferably by treatment with mineral acid, such as hydrochloric acid in an alcoholic solvent such as methanol. The carboxylic acid R_Z-COOH is activated towards coupling using reagents such as

2016238925 07 Oct 2016 isobutylchloroformate, DCC, EDAC, or HATU in the presence of an organic base, such as diisopropylethylamine. Upon activation, Formula X is added to the reaction, with the isolation of

Formula XI.

w

in each Formula within Scheme IX can be replaced with

where D is defined above, and such compounds can be readily prepared according to the process described in

Scheme IX.

1) HATU

DPEA

DMSO

HOAc

(3 regioisomers)

2. HCI, MeOH

HATU. R-rCOOH

1. NaH R_s-Halogen THF/DMF

Scheme IX

62% Overall θ_(^{both re}9^ioisomers)

O

X

B₂PdCI₂(dppf) KOAc Dioxane 90 °C. 1 h (both regioisomers)

Certain compounds of the invention of general formula (8), where R₂o is -L_S’-M’-L_S”-R_Dand D is as described above, can be prepared according to the methods of Scheme X. The bromoalkylketone (1) can be reacted with an arylalkylketone (2) using the Lewis acid mediated conditions, described above in Scheme II, to give the diaryldiketone (3). The diketone (3) can be converted to the bisboronate (4) by reaction with bis(pinacolato)diborane in the presence of a base such as potassium acetate, a catalyst such as PdCl₂(dppf)-CH₂Cl₂, in a solvent such as DMSO, dimethoxyethane or dioxane with heating to between 60-100 °C. Bisboronate (4) can be converted to

166 the intermediate (5) by Suzuki reaction using, in analogous fashion, the Suzuki conditions described in Scheme VII. The intermediate (5) can be converted to (6) by reaction with an amine D-NH₂ under the analogous conditions described in Scheme VI. For example, reaction of (5) with D-NH₂ in the presence of an acid such as, but not limited to, TFA, in a solvent such as, but not limited to, toluene and with heating up to 110 °C can provide intermediates of general structure (6). Compounds (6) can be converted to compounds of general formulas (7) and then (8) using, in analogous fashion, the methods described in Scheme VII. Alternatively, the functionality of T-R_D can be similarly

2016238925 07 Oct 2016

(6) (7)

Scheme X

The intermediates (6) can also be prepared using the route depicted in Scheme XI. The intermediate (3) can be reacted with an amine D-NH₂ using, in analogous fashion, the conditions described in Schemes VI and X to provide intermediates (9), which can be converted to (10) using,

167 analogously, conditions as described above in Scheme X; and (10),in turn, can be converted to * (6)

2016238925 07 Oct 2016 compounds (6) using the Suzuki reaction conditions described in Scheme VII.

Scheme XI

As still another non-limiting example, the compounds of the invention of general formula (15), where R₂₀ is -L_S’-M’-L_S”-R_D and D is as described above, can be prepared as shown in Scheme XII. A 1,4-diketone compound (3) may be reacted with an amine D-NH₂, under acid catalyzed conditions, such as acetic acid, TFA, formic acid or HCI, to give the compounds (11). For 0 example, a diketone (3) (1 equivalent) can be reacted with an aniline (1.2 equivalents) and TFA (2 equivalents) in a solvent such as toluene with heating to between around 80 and 120 °C to provide the compounds (11). Alternatively, a diketone (3) can be reacted with an aniline (about 10 equivalents) with heating in acetic acid to around about 70 °C to provide the compounds (11). Amines that can be reacted according to the foregoing description include but are not limited to, those amines described or referred to in Scheme II as suitable for reacting with intermediate (5). Compounds of formula (11) can be converted to compounds of formula (12) by reduction with iron in the presence of ammonium chloride. For example, reaction of compounds (11)(1 equivalent) with iron powder (about 6 equivalents) in the presence of ammonium chloride (about 3 equivalents) in a mixed solvent of ethanol:THF:water (1:1:0.25) at reflux can provide compounds (12). The conversion of (11) to (12) !0 may also be effected by other methods described above in Scheme II to convert VII to VIII, for example by catalytic hydrogenation. Compounds (12) (1 equivalent) can be converted to compounds (13) using the peptide coupling condition described for the conversion of VIII to IX in Scheme II, for example using EDAC/HOBt (2 equivalents) and an appropriate acid in solvents such as DMF at around room temperature. Compounds (13) can be converted to compounds (14) using TFA/CH₂C1₂25 as described above for converting IX to X in Scheme II. Compounds (14) can be converted to compounds (15) using procedures analogous to those in Scheme II to convert X to XI, such as the coupling procedure to convert (12) to (13). Alternatively, the functionality of T-R_D can be similarly introduced to compounds of Formula (14) to give compounds of Formula (XII-I).

168

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Compounds of general formula (19), where D is as described above, can be prepared according to the methods of Scheme XIII. Compounds of general formula (16) can be converted to compounds of general formula (17) using a Buchwald reaction with tert-butyl-2carbamoylpyrrolidine-1-carboxylate. This Buchwald reaction can be conducted in the presence of a base (e.g., cesium carbonate), a palladium catalyst (e.g., tris(dibenzylideneaeetone)dipalladium(0)), a phosphine ligand (e.g., 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) in solvent such as dioxane with heating to about 80-120 °C. The intermediate (17) can be reduced to (18) and cyclized to (19) using, in analogous fashion, the conditions described generally in Scheme IV. Compounds (19) can be further reacted as illustrated in Scheme IV to provide compounds of the invention. Each phenyl ring in the above structures can be substituted with X_i3, wherein X_i3 is H, halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy. Mixtures of cis and trans stereoisomeric pyrrolidines in Scheme XIII may be separated into the cis and trans isomers using standard chromatographic techniques.

169

Scheme XIII

2016238925 07 Oct 2016

Certain compounds of the invention of general formula (23), where D is as described above, 5 can be prepared according to the methods of Scheme XIV. Compounds (16) can be reacted with compound (20) using a Buchwald reaction as described generally in Scheme XIII to provide compounds (21). Compounds (21) can be reduced to compounds (22) and cyclized to (23) using, in analogous fashion, the conditions described generally in the foregoing Schemes.

Scheme XIV

Certain compounds of the invention of general formula (29), where R₂₀ is -F_s’-M’-F_s ”-R_Dand D is as described above, can be prepared according to the methods of Scheme XV. Compounds of formula (24) can be converted to compounds of formula (25) (Sonogashira reaction) by reaction with trimethylsilylacetylene, a palladium catalyst (e.g., bis(triphenylphosphine)palladium(II)chloride), a copper catalyst (e.g., copper(I)iodide), and abase (e.g., triethylamine) wherein an amine base can also be used as solvent. The compounds (25) can be desilylated to compounds (26) by reaction with a fluoride source (e.g., tetrabutylammonium fluoride) in a solvent such as THF. Compounds (26) can

170

2016238925 07 Oct 2016 be converted to compounds (27) by formation of the dianion of (26) with n-butyllithium and subsequent reaction with a Weinreb amide (e.g., N-(tert-butoxycarbonyl)-L-proline-N’-methoxyN’methylamide). This reaction can be conducted in an appropriate solvent such as THF or dimethoxy ethane. Compounds (27) can be converted to compounds (28) by reaction with hydrazine 5 in a solvent such as ethanol. The compounds (28) can be converted to compounds (29) using the methods described generally in the foregoing Schemes. Alternatively, the functionality of T-R_D can be similarly introduced to compounds of Formula (28) to give compounds of Formula (XV-1).

(XV-1)

Scheme XV ,0

Certain compounds of the invention of general formula (34), where R₂₀ is -L_s’-M’-L_s”-Rd and D is as described above, can be prepared according to the methods of Scheme XVI. Compounds (24) can be converted to compounds (30) by reaction of (24) with CO(g) under pressure (ca. 60 psi) in the presence of a palladium catalyst (e.g., PdCl₂(dppf)) in methanol as solvent and with heating to around 100 °C. Compounds (30) can be converted to compounds (31) by reaction with hydrazine in a solvent such as methanol with heating to about 60-80 °C. Compounds (31) can be converted to compounds (32) by reaction withN-Boc-2-cyano-pyrrolidine in the presence of abase (e.g., potassium carbonate) in a solvent such as butanol and with heating to around 150 °C with irradiation in a microwave reactor. Compounds (32) can be deprotected to compounds (33) and acylated to (34) using, in analogous fashion, the conditions described generally in the foregoing Schemes.

Alternatively, the functionality of T-R_D can be similarly introduced to compounds of Formula (33) to give compounds of Formula (XVI-1).

171

2016238925 07 Oct 2016

(XVI-1)

Scheme XVI

Certain compounds of the invention of general formula (38), where R₂₀ is -L_s’-M’-L_s”-Rd and D is as described above, can be prepared according to the methods of Scheme XVII. Compounds of formula (24) can be converted to compounds (35) by reaction with CuCN in a solvent such as DMF and with heating to about 160 °C with microwave irradiation. Compounds (35) can be converted to compounds (36) by reaction with HCl(g) in anhydrous methanol at 0 °C with warming to room temperature. Compounds (36) can be converted to compounds (37) by reaction with NH₃(g) in anhydrous methanol at 0 °C with warming to room temperature. Compounds (37) can be converted to compounds (38) by reaction with (41) in THF in the presence of a base (e.g., potassium carbonate). Alternatively, the functionality of T-R_D can be similarly introduced to compounds of Formula (33) to give compounds of Formula (XVII-1).

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Rd^Z Rd (XVII-1)

Scheme XVII

Compounds of formula (41), where R₂o is -L_S’-M’-L_S”-R_D, can be prepared using the methods of Scheme XVIII. Compounds (39) can be converted to compounds (40) by sequential reaction of (39) with isobutylchloroformate in THF at 0 °C followed by diazomethane. Compounds (40) can be converted to compounds (41) by reaction with HBr in acetic acid. Similarly, compounds of formula (XVIII-1) can be converted to compounds of formula (XVIII-2) and then (XVIII-3), wherein T-R_D are as defined above.

(XVIII-1) (XVIII-2) (XVIII-3)

Scheme XVIII

Certain compounds of the invention of general formula (48), where R₂₀ is -F_s’-M’-L_s”-Rd and D is as described above, can be prepared according to the methods of Scheme XIX. Compound (42) can be reacted with compound (43) using, in analogous fashion, the Fewis acid mediated conditions described above in Scheme II to provide compound (44). Compound (44) can be

173 converted sequentially to the diol (45), the mesylate (46) and the cyclic intermediate (47) using, in analogous fashion, the conditions of Scheme II. Compounds (47) can be converted to compounds (48) by reaction with (20) under Buchwald conditions such as those referred to Scheme XIV and described in Scheme XIII. Alternatively, the functionality of T-R_D, wherein T and R_D are as defined above, can be similarly introduced to compounds of Formula (47) to give compounds of Formula

2016238925 07 Oct 2016 (XIX-1).

Scheme XIX

Certain compounds of the invention of general formula (55), where R₂₀ is -L_s’-M’-L_s”-Rd and D is as described above, can be prepared according to the methods of Scheme XX. Diethyl meso2,5-dibromoadipate (49) can be reacted with an amine D-NH₂ in a solvent such as THF, dioxane, or dimethoxyethane with heating from 50-100 °C to give compounds (50). Compounds (50) can be converted to (51) by alkaline hydrolysis with a base (e.g., NaOH, KOH) in an alcohol (e.g., methanol, 15 ethanol) and water mixture for solvent. Compounds (51) can be converted to (52) by reaction first with oxalylchloride, and treatment of the intermediate acid chloride with diazomethane at 0 °C. Compounds (52) can be converted to (53) by reaction with aqueous HBr. Compounds (53) can be converted to compounds (54) by reaction with thiourea in ethanol or like solvent. Compounds (54) can be converted to compounds (55) using, in analogous fashion, the conditions described above in 20 Scheme II. Similarly, the functionality of T-R_D, wherein T and R_D are as defined above, can be introduced to compounds of Formula (54) to give compounds of Formula (XX-1).

174

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(50) (51)

(XX-1)

Scheme XX

Certain compounds of the invention of general formula (60), where R₂o is -L_S’-M’-L_S”-R_D and D is as described above, can be prepared according to the methods of Scheme XXI. Compound (56) can be reacted with compound (57) in pyridine with heating to about 135 °C to form compound (58) . Compound (58) can be converted to compounds (59) by reaction of an amine D-NH₂ with POC1₃ followed by addition of (58) and heating at about 200 °C in 1,2-dichlorobenzene. Compounds (59) can be converted to compounds (60) using, in analogous fashion, the conditions described above 10 in Scheme VII. Similarly, the functionality of T-R_D, wherein T and R_D are as defined above, can be introduced to compounds of Formula (59) to give compounds of Formula (XXI-1).

175

2016238925 07 Oct 2016

(60) (XXI-1)

Scheme XXI

Certain compounds of the invention of general formula (66), where R₂o is -L_S’-M’-L_S”-R_D5 and D are as described above, can be prepared according to the methods of Scheme XXII.

Compounds of general formula (61) can be reacted with borontribromide in dichloromethane at 0 °C to give compounds (62), which can be subjected to hydrogenation conditions using platinum(II) oxide to give compounds (63). Coupling between compounds (63) and proline derivatives (64) can be carried out using standard coupling conditions described above to give compounds (65), which can be 0 converted to (66) by the action of diethylazodicarboxylate and triphenylphosphine in THF.

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(66)

Scheme XXII

Certain compounds of the invention of general formula (74), where R₂₀ is -L_s’-M’-L_s”-Rd and D is as described above, can be prepared according to the methods of Scheme XXIII. Compound (67) can be converted to (68) by reduction of the nitro group using tin(II) chloride in ethanol.

Compound (69) can be made from (68) by peptide coupling with Boc-proline, followed by heating of the resulting amide in acetic acid at 80 °C. Compound (69) can be reacted with SEM-C1 and diisopropylethylamine in dichloromethane to give (70), which can be coupled with (71) using a 10 palladium catalyst such as PXPd using a base such as cesium fluoride in a solvent such as N,Ndimethylformamide at 100 °C to give (72). Compound (72) can be converted to (73) by reaction with Selectfluor in a mixture of THF and water, followed by hydrogenation using 3% Pt on carbon in ethylacetate and then reduction using sodium borohydride in methanol. Compound (73) can be reacted with methanesulfonyl chloride and triethylamine in dichloromethane at -10 °C, followed by 15 addition of an amine (H₂N-D) to give an intermediate that can be converted to (74) by deprotection using 4 N HC1 in 1,4-dioxane and then coupling with R₂₀CO₂H using peptide coupling procedures

177 described above. Similarly, the functionality of T-R_D, wherein T and R_D are as defined above, can

2016238925 07 Oct 2016 be introduced to compounds of Formula (73) to give compounds of Formula (XXIII-1).

Scheme XXIII

Certain compounds of the invention of general formula (81), where R₂₀ is -L_s’-M’-L_s”-Rd and D is as described above, can be prepared according to the methods of Scheme XXIV. Compound (75) can be converted to (76) using SnCl₂ in ethanol. Additionally, the phenyl ring of compound (75) can be substituted with X₁₃ at any position substituted with hydrogen or fluorine, wherein X₁₃ is H, alkyl, haloalkyl, alkoxy, or haloalkoxy, and those compounds carried through the subsequent sequence. Coupling of (76) with (64) using peptide coupling procedures described above to give an amide that can be heated in acetic acid at 100 °C to give (77). Compound (77) can be reacted with SEM-C1 and diisopropylethylamine in dichloromethane to give (78). For convenient illustration, the SEM protecting groups on the benzimidazoles are shown attached to particular nitrogens of the benzimidazole. The actual substitution positions of the SEM groups may be at either nitrogen (i.e., (78) may be a mixture of regioisomers). In subsequent compounds (79) through (80), the positional isomerism of the SEM group results in mixtures of SEM regioisomers that may or may not be

178

2016238925 07 Oct 2016 separable. In practice the SEM regioisomers can be carried through as mixtures. Compound (78) can be reacted with (71) as described above to give (79). Compound (79) can be converted to (80) using Selectfluor in a mixture of THF and water, followed by hydrogenation with Pt on carbon in ethylacetate and reduction with sodium borohydride in methanol or chiral reduction conditions with (5) or (R) a,a-diphenyl-2-pyrrolidinemethanol, diethylaniline borane and trimethylborane.

Compound (80) can be converted to compounds (81) by mesylation with methanesulfonyl chloride and triethylamine at temperatures less than 0 °C, followed by reaction with primary amine H₂N-D and deprotection using 4 N HC1 in 1,4-dioxane. Similarly, the functionality of T-R_D, wherein T and R_Dare as defined above, can be introduced to compounds of Formula (77) to give compounds of Formula 0 (XXIV-1) at the end of the synthetic sequence.

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Scheme XXIV

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Certain amines, D-NH₂, in the foregoing Schemes are represented by formula (84), and may be prepared according to the general method shown in Scheme XXV, wherein R_N is as defined above (e.g., halogen, alkyl, haloalkyl) and R_M is -N(RsRs ) (e.g., -NEt₂), heterocyclyl (e.g., pyrrolidin-l-yl,

G₃

,etc., wherein G₃ is defined above, is a nitrogen containing

heterocycle substituted with G₃, and 'I'*'¹· is a nitrogen containing bridged, bicyclic heterocycle), or -ORs (e.g., -O-t-butyl, -O-isopropyl, etc.). Fluoronitrobenzenes (82) can be reacted with an appropriate amine in the presence of dibasic potassium phosphate in a solvent such as DMSO optionally with heating to give intermediates (83), wherein R_M is -N(RsRs ) (e.g., -NEt₂) or g₃

heterocyclyl (e.g., pyrrolidin-l-yl, piperidin-l-yl, , etc.). Fluoronitrobenzenes (82) can also be reacted with alkali metal alkoxides (e.g., potassium tert-butoxide) to give intermediates (83), wherein R_M is -OR_S (e.g., -O-t-butyl, -O-isopropyl, etc.). Intermediates (83) may be converted to (84) using well-known nitro reduction conditions. For example, (83) can be converted to (84) by catalytic hydrogenation using palladium on carbon. Alternatively, (83) can be converted to (84) by reaction with iron/ammonium chloride in THF/methanol/water as solvent. Other conditions for .5 effecting nitro reduction include those described in the foregoing schemes and those generally known to one skilled in the art.

NO₂ (82)

Scheme XXV

(84)

Certain compounds of the present invention (XXVI-10) can be prepared as shown generally in Scheme XXVI, where D, T, and R_D are as described above. Reaction of compounds (1) with compounds (III), using the conditions described generally in Scheme II for the preparation of compounds (IV), can provide diketone compounds (XXVI-1). Compounds (XXVI-1) can be converted to compounds (XXVI-2) using the general conditions of Scheme II for the conversion of (IV) to (V). Compounds (XXVI-2) can be converted to compounds (XXVI-3) using the general

181

2016238925 07 Oct 2016 conditions of Scheme II for the conversion of (V) to (VI). Compounds (XXVI-3) can be converted to compounds (XXVI-4) using the general conditions of Scheme II for the conversion of (VI) to (VII).

Compounds of formula (XXVI-4) can be converted to compounds (XXVI-5) using the general conditions of Scheme VII for the conversion of (II) to (III). Compounds (XXVI-5) can be converted to compounds (XXVI-6) using the general conditions of Scheme VII for the conversion of (III) to (IV). Compounds (XXVI-6) can be converted to compounds (XXVI-7) using the general conditions of Scheme II for the conversion of (VII) to (VIII). For example, compounds (XXVI-6) (1 equivalent) can be reduced with hydrogen gas (1 atm) in the presence of PtO₂ (about 0.2 equivalents) in a solvent such as ethanol:THF (1:1). Compounds (XXVI-7) can be converted to compounds (XXVI-8) using 0 the methods described generally in Scheme II for conversion of (VIII) to (IX). For example, reaction of (XXVI-7) (1 equivalent) with l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.5 to 3 equivalents) and HATU (about 1.6 equivalents) in the presence of diisopropylethylamine (3 equivalents) in DMSO at about room temperature can provide the compounds (XXVI-8). Compounds (XXVI-8) can be converted to compounds (XXVI-9) using the methods described generally in 5 Scheme II for conversion of (DC) to (X). For example, reaction of (XXVI-8) (1 equivalent) with HC1 in dioxane at about room temperature can provide the compounds (XXVI-9). Compounds (XXVI-9) can be converted to compounds (XXVI-10) by reaction with an appropriate acid using the methods described generally in Scheme II for the conversion of (X) to (XI). For example, reaction of (XXVI9) (1 equivalent) with 2-(methoxycarbonylamino)-3-methylbutanoic acid (about 2 to 3 equivalents), !0 HATU (about 2.5 to 3.5 equivalents), and diisopropylethylamine (about 10 equivalents) in a solvent such as DMSO can provide the products (XXVI-10).

182

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(1) (ΠΙ)

(XXVI-4)

(XXVI-7)

(XXVI-8)

(XXVI-1)

(XXVI-2)

(XXVI-5)

(XXVI-6)

(XXVI-9)

Scheme XXVI

Certain compounds of the present invention (XXVII-7) can be prepared as shown generally in

Scheme XXVII, where D, T, and R_D are as described above. Compounds (XXVI-1) can be converted to compounds (XXVII-1) using the general conditions of Scheme XII for the conversion of (3) to (11). Compounds (XXVII-1) can be converted to compounds (XXVII-2) by reduction using conditions described generally above in Scheme II. For example (XXVII-1) (1 equivalent) can be reduced with iron powder (about 6 equivalents) and ammonium chloride (about 3 equivalents) in 10 ethanol:THF:water (1:1:0.25) with heating up to the reflux temperature to provide (XXVII-2).

Compounds (XXVII-2) can be converted to compounds (XXVII-3) using the conditions described above for conversion of VIII to IX in Scheme II, (12) to (13) in Scheme XII, or (XXVI-7) to (XXVI8) in Scheme XXVI. Compounds (XXVII-3) can be converted sequentially to compounds (XXVII-4) and (XXVII-5) using the methods and conditions described generally in Scheme VII for the

183 conversion of (II) to (III) to (V). Compounds (XXVII-5) can be converted sequentially to compounds (XXVII-6) and (XXVII-7) using the methods and conditions described generally above, for example

2016238925 07 Oct 2016

(XXV11-7)

Scheme XXVII using the methods to convert (IX) to (X) to (XI) in Scheme II.

(XXVII-5)

Certain compounds of the invention of general formula (XXVIII-7), where D, T, and R_D are as described above, can be prepared according to the sequence of Scheme XXVIII. Compounds (XXVIII-1) can be prepared from 2-bromo-l-(4-nitrophenyl)ethanone, l-(4-chloro-310 nitrophenyl)ethanone, and an amine D-NH₂ according to the methods described above to prepare compounds (VII) in Scheme II, (XXVI-4) in Scheme XXVI,, and (VII) in Scheme IV. Compounds (XXVIII-1) (1 equivalent) can be converted to compounds (XXVIII-2) by reaction with neat 4methoxybenzylamine (about 4-6 equivalents) with heating to around 140-150 °C. Compounds (XXVIII-2) can be converted to compounds (XXVIII-3) by reduction according to the conditions described generally in Scheme II to prepare compounds (VIII). For example, reaction of (XXVIII-2) (1 equivalent) with PtO₂ (about 0.4-0.5 equivalents) in a solvent such as ethanol:THF (1:1) under a hydrogen atmosphere (1-4 atm) can provide compounds (XXVIII-3). Compounds (XXVIII-3) can be converted to compounds (XXVIII-4) according to the conditions described generally in Scheme II to

184

2016238925 07 Oct 2016 prepare compounds (IX). For example, reaction of (XXVIII-3) (1 equivalent) with \-(tertbutoxycarbonyl)pyrrolidine-2-carboxylic acid (about 2-3 equivalents), HATU (about 2-3 equivalents), and diisopropylethylamine (about 3 equivalents) in a solvent such as DMSO at room temperature can provide compounds (XXVIII-4). Compounds (XXVIII-4) (1 equivalent) can be converted to compounds (XXVIII-5) by reaction with DDQ (about 1.2 equivalents) in a solvent mixture of CH₂Cl₂:water (20:1) at room temperature. Compounds (XXVIII-5) can be converted to compounds (XXVIII-6) according to the general methods described in Scheme IV to prepare compounds (XI) (e.g., heating in acetic acid to around 60-70 °C). Compounds (XXVIII-6) can further be converted to compounds (XXVIII-7) by using the standard deprotection and coupling methods referred to in

Scheme IV to prepare compounds (XIII) or (XIV).

Scheme XXVIII

Certain compounds of the invention (XXIX-9) where D, T, and R_D are as described above, can be prepared according to the sequence of Scheme XXIX. Compounds (XXIX-1) can be prepared from 2-bromo-l-(4-bromophenyl)ethanone, l-(4-chloro-3-nitrophenyl)ethanone, and an amine DNH₂ according to the methods described above to prepare compounds (VII) in Scheme II, (XXVI-4) in Scheme XXVI, and (VII) in Scheme IV. Compounds (XXIX-1) (1 equivalent) can be converted to compounds (XXIX-2) by reaction with neat 3,4-dimethoxybenzylamine (about 10 equivalents) with heating up to around 140-150 °C. Compounds (XXIX-2) can be converted to compounds (XXIX-3)

185

2016238925 07 Oct 2016 by reduction according to the conditions described generally in Scheme II to prepare compounds (VIII). For example, reaction of (XXIX-2) (1 equivalent) with PtO₂ (about 0.1 equivalent) in a solvent such as ethanol:THF:EtOAc (1:1) under a hydrogen atmosphere (e.g., 1 atm) can provide compounds (XXIX-3). Compounds (XXIX-3) can be converted to compounds (XXIX-4) according to the conditions described generally in Scheme II to prepare compounds (IX). For example, reaction of (XXIX-3) (1 equivalent) with a substituted proline like (5)-1 -((.5)-2-(mcthoxycarbonylamino)-3methylbutanoyl)pyrrolidine-2-carboxylic acid (about 1.2-1.5 equivalents), HOBt (about 1.2-1.5 equivalents), EDAC (about 1.2-1.5 equivalents), and A'-mcthylmorpholinc (about 5-6 equivalents) in a solvent such as DMF at room temperature can provide compounds (XXIX-4). Compounds (XXIX-4) can be deprotected to compounds (XXIX-5) by reaction with excess TFA in solvents such as methylene chloride at about room temperature. Compounds (XXIX-5) can be converted to compounds (XXIX-6) according to the general methods described in Scheme IV to prepare compounds (XI) (e.g., heating in acetic acid to around 60-80 °C). Compounds (XXIX-6) can be converted to compounds (XXIX-7) according to the general conditions of Scheme VII to prepare compounds (III). For example, reaction of (XXIX-6) (1 equivalent) with PdCl₂(dppf) (about 0.1 equivalent), potassium acetate (about 3-5 equivalents), and bis(pinacolato)diboron (about 3 equivalents) in a solvent such as toluene with heating to 80-100 °C can provide compounds (XXIX7). Compounds (XXIX-7) can be converted to compounds (XXIX-8) according to the general conditions of Scheme VII to prepare compounds (V). For example, reaction of compounds (XXIX-7) !0 (1 equivalent) with Intermediate ID (about 2 equivalents), IM sodium carbonate (about 3 equivalents), and PdCl₂(dppf) (about 0.1 equivalent) in a solvent such as toluene at around 80-100 °C can provide compounds (XXIX-8). Compounds (XXIX-8) can further be converted to compounds (XXIX-9) by using the standard deprotection (e.g., HCl/dioxane) and coupling methods (e.g., carboxylic acid, HOBt, EDAC, and A'-mcthylmorpholinc) referred to in Scheme IV to prepare compounds (XIV).

186

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Certain compounds of the present invention (XXX-8) can be prepared as shown in Scheme

XXX. An ester (XXX-1) can be reacted with a suitable reducing agent such as DIBAL-H, in a solvent such as THF, dichloromethane, or diethyl ether, to the corresponding alcohol then oxidized to the aldehyde (XXX-2) by employing a suitable oxidizing agent such as PDC in a solvent such as dichloromethane, THF or diethyl ether. A pyrrole of formula (XXX-4) can be prepared by reacting (XXX-3) (available from an aniline, an aldehyde and KCN using the Strecker reaction) together with 10 aldehyde (XXX-2) with a base such as potassium hydroxide in a solvent such as ethanol (Synlett, 2003, ppi427-1430). The bromine atoms in the pyrrole compounds (XXX-4) can be converted to a bis-borane compound (XXX-5) by utilization of palladium catalysis as described above in Scheme VII. The pyrrole compounds (XXX-5) can be reacted with bromoimidazoles like Intermediate ID using Suzuki reaction conditions to give the phenylimidazole (XXX-6). A variety of reaction 15 conditions are well known to those of skill in the art to be effective in mediating the Suzuki reaction.

187

In particular, the reaction to produce (XXX-6) can be performed with Pd(dppf)Cl₂ catalyst and

2016238925 07 Oct 2016 potassium carbonate in a mixture of toluene and water and with heating to about 100 °C. Removal of the Boe protecting groups to give (XXX-7) can be accomplished by treatment with an acid, such as

TFA, HC1, or formic acid. Certain compounds of the present invention (XXX-8), wherein T, R_D, and

D are as described above, may be prepared by coupling of (XXX-7) with an acid of choice using the standard peptide coupling reagents and conditions described above.

(XXX-4)

(XXX-6)

(XXX-7)

(XXX-8)

Scheme XXX

The present invention also contemplate Schemes XXXI-XXXIII to make a compound of the invention. For instance, compounds of the invention (XXXI-5) may be prepared using the sequence of steps outlined generally in Scheme XXXI. This sequence parallels that of Scheme XXX. A compound (XXXI-1) may be converted to a compound (XXXI-2) by sequential Heck reaction with ethylacrylate followed by reduction to an aldehyde (XXXI-2). An aldehyde like (XXXI-2) may be reacted with a compound (XXX-3) analogously to the conditions of Scheme XXX to provide compounds (XXXI-3). Compounds (XXXI-3) in turn may be converted to boronate compounds (XXXI-4) using the condition described above generally in Scheme VII. Compounds (XXXI-4) may be converted to compounds (XXXI-5) over several steps including Suzuki reaction, deprotection and coupling as described generally in the foregoing Schemes.

188

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SEM ^SEK)

(XXXI-1) (ΧΧΧΙ-2)

SEM /

(XXXI-3)

(XXXI-4)

H

(XXXI-5) ^rd

Scheme XXXI

As described in Meyer et al. Synthesis, 2005, pp. 945-956 and Meyer et al Synlett, 2003, ppi427-1430, substituted α-aminonitriles can be reacted with α,β-unsaturated carbonyl compounds to provide substituted hydroxy-cyano pyrrolidines. In analogous fashion, a compound (XXXII-1) may be reacted with an α,β-unsaturated aldehyde (XXXII-2) to give a pyrrolidine (XXXII-3). The hydroxy and cyano groups of compounds such as (XXXII-3) may be reduced off using reagents such as NaBH₃CN or NaBH₃CN with FeSO₄ as described in Synthesis, 2005, pp. 945-956. The nitro group 0 of compounds such as (XXXII-3) may be reduced using standard conditions such as catalytic hydrogenation or reduction with iron powder and ammonium chloride. Typical nitro reduction conditions are described elsewhere herein. The Boe group of compounds such as (XXXII-3) may be removed using standard conditions such as with TFA/CH₂C1₂ or HC1 in dioxane. Compounds such as (XXXII-4) may be reacted with an appropriate A'-protcctcd proline acid under standard conditions as .5 described elsewhere herein to give compounds (XXXII-5). Compounds such as (XXXII-5) may be deprotected and coupled with an acid of choice as described herein to give compounds (XXXII-6) wherein T, R_D, and D are as described herein.

189

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(XXXII-6)

Scheme XXXII

Further compounds of the invention may be prepared as generally outlined in Scheme

XXXIII. Compounds such as (XXXIII-1) may be prepared from 4-nitro-o-phenylenediamine by acylation with a protected proline acid (see Tetrahedron 2003, pp 2701-2712), cyclization (see Tet. Lett. 2003, 5807-5810), SEM protection, and nitro reduction. Compounds such as (XXXIII-1) may be converted to the Strecker product (XXXIII-2) by reaction with an aldehyde D-CHO and KCN in analogy with the process referred to in Scheme XXX. Compounds such as (XXXIII-2) may be condensed with compounds such as (XXXI-2) followed by reduction to give compounds such as (XXXIII-3) (see for example Meyer et al. Synthesis, 2005, pp. 945-956 and Meyer et al Synlett, 2003, ppl427-1430). Compounds such as (XXXIII-3) may be deprotected using standard conditions for removal of Boe and SEM groups (see General Procedure 23) and the resultant amino compound reacted with an appropriate acid under conventional amide bond forming conditions to give compounds (XXXIII-4) wherein T, R_D, and D are as described herein.

SEM

Pi (XXXIII-1)

SEM ,^SEM

(XXXIII-3)

Scheme XXXIII

190

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Certains compounds of the invention may also be prepared using the methods shown generally in Scheme XXXIV. The ketone XXXIV-1 (Reference: US20090076076; pl9, [0146]) can be homologated in two steps to the aldehyde XXXIV-3. In the first step, the ketone can be reacted with dimethylsulfonium methylide in dimethylsulfoxide to produce the epoxide XXXIV-2. The 5 epoxide can be rearranged to the aldehyde by treatment with an acid such p-toluenesulfonic acid with heating in toluene at temperatures between around 80-110 °C (References: J. Am. Chem. Soc. (1965) 1353, 1358; J. Org. Chem. (1972) 4075, 4076, 4077; Bioorg. Med. Chem. Lett. (2009) 5684, 5686). The aldehyde XXXIV-3 can be converted to the diol XXXIV-4 with potassium carbonate and formaldehyde in ethanol as described generally in J. Am. Chem. Soc, 1951, 73, p5171 and 0 US5095153, Example 3a. The diol can be converted to the bismesylate XXXIV-5 by reaction with excess methanesulfonyl chloride and triethylamine in dichloromethane at 0 °C to room temperature. The bismesylate can be converted to the azide XXXIV-6 by reaction with sodium azide (about 1 equivalent) in DMPU and heating up to around 110 °C. The azide can be converted to the phosphorimidate XXXIV-7 by reaction with freshly distilled triethylphosphite (about 1 equivalent) in 5 anhydrous toluene/tetrahydrofuran at room temperature. The phosphorimidate can be converted to the azetidine-phosphonate XXXIV-8 by heating in o-xylene up to around 150 °C. The azetidinephosphonate can be converted to the azetidine XXXIV-9 by reaction with trifluoroacetic acid in dichloromethane at room temperature. The azetidine can be reacted with an appropriate aryl halide (e.g., iodide) using the Buchwald reaction to generate an N-arylazetidine XXXIV-10. Appropriate !0 conditions include reaction with an aryliodide (about 2 equivalent), Pd₂(dba)₃ (about 0.025 equivalent), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; about 0.1 equivalents) and sodium tert-butoxide (about 1.2 equivalent) with heating in a solvent such as dioxane to 80-100 °C, optionally with microwave irradiation. The bisbromide may be converted to the bisboronate XXXIV11 by reaction with bis(pinacolato)diborane, potassium acetate, and PdCl₂(dppf) in a solvent such as 25 DME, dioxane, or DMSO with heating up to around 85 °C. The bisboronate can be converted to compounds of the invention XXXIV-12 by reaction with an appropriate halide (i.e. Suzuki reaction) such as methyl (S)-l-((S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan2ylcarbamate.

191

OH OH

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NaN₃, DMPU

I

XXX V-7

XXXIV-9

XXXIV-8

XXXIV-10

XXX V-11

XXXIV-12

MeO₂CHN

NHCO₂Me

XXXIV-1

K₂CO₃aq CH₂O EtOH

XXXIV-4

OMs

XXXIV-6

Scheme XXXIV

Certain compounds of the invention may also be prepared using the methods shown generally in Scheme XXXV. Compounds such as XXXV-1 can be prepared using known methods by alkylation of a malonate ester with a benzyl halide. Compound XXXV-1 can be converted to compound XXXV-2 by reduction with lithium aluminum hydride. Compound XXXV-2 can be converted to compound XXXV-3 by reaction with Ms₂O and a base such as diisopropylethylamine.

Compound XXXV-3 may be converted to compound XXXV-4 using methods analogs to those to convert XXXIV-5 to XXXIV-9 (see Scheme XXXIV). Similarly compound XXXV-4 may be converted to compound XXXV-5 using a Buchwald reaction analogous to that of Scheme XXXIV.

192

Compounds XXXV-5, in turn, may be converted to XXXV-6 by demethylation (e.g. with BBr₃) and triflate formation with Tf₂O. Compounds XXXV-6 may be converted to compounds XXXV-7 by analogy with the conversion of XXXIV-10 to XXXIV-11. Finally, compounds XXXV-7 may be converted to compounds XXXV-8 using the Suzuki coupling of Scheme XXXIV.

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In the foregoing Schemes (Schemes I-XXXV), compounds are shown wherein an aromatic ring (e.g., phenyl) is substituted with groups in a particular regiochemistry (e.g., para). A starting material or intermediate with para-substitution provides a final product with para-substitution in the foregoing Schemes. It is understood by one of skill in the art that substitution in the foregoing Schemes of a starting material or intermediate with a different regiochemsitry (e.g., meta) would provide a final product with a different regiochemistry. For example, replacement of a para193

2016238925 07 Oct 2016 substituted starting material or intermediate in the foregoing Schemes with a meta substituted starting material or intermediate would lead to a meta-substituted product.

If a moiety described herein (e.g., -NH₂ or -OH) is not compatible with the synthetic methods, the moiety may be protected with a suitable protecting group that is stable to the reaction conditions used in the methods. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and methods for protecting or deprotecting moieties are well know in the art, examples of which can be found in Greene and Wuts, supra. Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in 0 the reactants used. Solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art based on the present invention.

Other compounds of the invention can be similarly prepared according to the above-described schemes as well as the procedures described in following Intermediates, General Procedures, and Examples, as appreciated by those skilled in the art. It should be understood that the above-described 5 embodiments and schemes and the following Intermediates, General Procedures, and Examples are given by way of illustration, not limitation. Various changes and modifications within the scope of the present invention will become apparent to those skilled in the art from the present description.

Example compounds below were named using ACD Name version 12 (ACD Name vl2). Other compounds were named using ChemDraw version 9.0 (v9), unless otherwise indicated as being !0 named using ACD Name vl2. Both naming programs may provide a chemical name that depends on the tautomeric structure chosen for naming. Structures may be shown or named as any chemically distinct tautomer.

For example, the tautomeric structure:

(.S')-6.6'-((2//.5//)-l-phcnylpyrrolidinc-2.5-diyl)bis(2-((.S')-pyrrolidin-2-yl)-l//-bcnzo|0/|imidazolc) (Chemdraw v9);

6.6'-| (2//.5//)-1-phcnylpyrrolidinc-2.5-diyl|bisi2-|(2.S')-pyrrolidin-2-yl|-1//-benzimidazole J (ACD

Name vl2).

The tautomeric structure:

194 is given the following names:

(.S')-5.5'-((2//.5//)-l-phcnylpyrrolidinc-2.5-diyl)bis(2-((.S')-pyrrolidin-2-yl)-l//-bcnzo|0/|imidazolc) (Chemdraw v9);

5,5'-[(2R,5R)-1 -phenylpyrrolidine-2,5-diyl]bis{2-[(2S)-pyrrolidin-2-yl]-1 //-benzimidazole} (ACD

Name vl2).

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is given the following names:

(.S')-5.5'-((2/?.5/?)-l-phcnylpyrrolidinc-2.5-diyl)bis(2-((.S')-pyrrolidin-2-yl)-l//-bcnzo|0/|imidazolc) (Chemdraw v9);

5-| (2//.5//)-1-phcnyl-5-{2-| (2.S')-pyrrolidin-2-yl |-1//-bcnzimidazol-6-yl [pyrrolidin-2-yl |-2-| (2.8)pyrrolidin-2-yl |-1//-benzimidazole (ACD Name vl2).

Certain compounds in the Examples below can be purified using reverse-phase HPLC.

Purification can be conducted using either a C18 or C8 reverse-phase column. Compounds can be eluted using a gradient of about 10-100% acetonitrile in 0.1% aqueous TFA; about 60-100% methanol in 10 mM aqueous ammonium acetate; or about 10-95% methanol in 10 mM aqueous ammonium acetate. For purifications conducted with TFA, the product thus obtained may be in the form of a

TFA salt. Compounds may be characterized as the TFA salt or as the free base following neutralization, extraction and isolation.

Certain compounds in the Examples below can be purified using normal phase silica gel chromatography including traditional flash chromatography or an automated purification system (e.g., Isco Combi-Flash, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 pm silica gel, 25 Isco gold columns). Compounds can also be purified by prep-TEC.

Typical solvents for silica gel chromatography include: Ethyl acetate in hexanes, Diethyl ether in hexanes, THF in hexanes, Ethyl acetate in methylene chloride, Methanol in methylene chloride, Methanol in methylene chloride with NH₄OH, Acetone in hexanes, and Methylene chloride in hexanes.

Synthesis of Intermediates

195

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Η

Intermediate 1

(.S')-/i77-butyl 2-(4-bromo-1 f/-i midazol-2-yl (pyrrolidine-1 -carboxylate

Intermediate 1A

(.S')-Zi77-butyl 2-formylpyrrolidine-l-carboxylate

To an oven-dried 500-mL 3-neck flask purged with nitrogen was added oxalyl chloride (5.32 mL, 60.8 mmol) and anhydrous dichloromethane (125 mL), and the solution was cooled to -78 °C. A 0 solution of anhydrous DMSO (7.30 mL, 103 mmol) in anhydrous dichloromethane (25 mL) was added dropwise from a constant-pressure addition funnel over a 20-minute period. A solution of (5)iert-butyl 2-(hydroxymethyl)pyrrolidine-l-carboxylate (9.41 g, 46.8 mmol) in anhydrous dichloromethane (50 mL) was added dropwise from a constant-pressure addition funnel over a 20minute period, and then the reaction mixture was stirred at -78 °C for 30 minutes. Triethylamine 5 (32.6 mL, 234 mmol) was added dropwise via syringe over a 5-minute period and the thick white mixture was stirred in an ice-water bath for 30 minutes. The reaction was quenched with 10% (w/v) aq. citric acid (30 mL). The mixture was partitioned in a separatory funnel between Et₂O (550 mL) and 10% (w/v) aq citric acid. The layers were separated, and the organic phase was washed with water and brine. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated to !0 afford a yellow oil (9.4 g), which was used directly in the next reaction.

Intermediate IB

(.S)-/i77-biityl 2-( lf/-imidazol-2-yl)pyrrolidinc-l -carboxylate

The product from Intermediate 1A (20 g, 100 mmol) was dissolved in methanol (50.2 mL) 25 and ammonium hydroxide (50.2 mL) was added. To this solution glyoxal (40% in water; 24.08 mL, 211 mmol) was added, dropwise, over 10 minutes. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, diluted with 50 mL of water, and then extracted with ethyl acetate. The organic layer was washed with brine, dried (Na₂SO₄) and concentrated to a tan solid. The solid was treated with ether and concentrated. The solid was then 30 triturated with 2:1 diethyl ether:hexanes (150 mL) to afford 17 g of solid, which was used directly in the next reaction. 'HNMR (400 MHz, DMSO-d₆) δ ppm 1.14/1.40 (s, 9H), 1.81-2.12 (m, 4H), 3.323.33 (m, 1H), 3.35-3.50 (m, 1H), 4.72-4.81 (m, 1H), 6.84 (s, 1 H), 11.68 (s, 1 H).

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Intermediate 1C

(.S')-/i77-butyl 2-(4,5-dibromo-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate

A'-Bromosuccinimidc (108 mmol) was added to a cold (0 °C) solution of the product from

Intermediate IB (12.05 g, 50.8 mmol) in dichloromethane (200 mL). The mixture was stirred in ice bath for 2 hours and then concentrated, dissolved in ethyl acetate (250 mL), washed with water (3x150 mL) and brine (1x100 mL), dried (MgSO₄), and concentrated to very dark residue. The residue was mixed with and concentrated from dichloromethane/hexanes (1:1) to get brown solid (~I9 g). The solid was triturated with ether (-100 mL) and filtered to isolate a tan solid (13.23 g, 65% yield). Ή NMR (400 MHz, CDC1₃) δ ppm 1.49 (s, 9 H), 1.86 - 2.17 (m, 3 H), 2.80 - 2.95 (m, 1 H),

3.30 - 3.44 (m, 2 H), 4.85 (dd, 7=7.54, 2.55 Hz, 1 H), 10.82 (s, 1 H); MS (DCI+) m/z 394/396/398 (M+H)⁺.

Intermediate ID

(.S')-/i77-butyl 2-(4-bromo-17/-imidazol-2-yl(pyrrolidine-1 -carboxylate .5 The product from Intermediate 1C (6.25 g, 15.82 mmol) was dissolved in dioxane (200 mL) and water (200 mL) in a 1 L round bottom flask equipped with a condenser and glass stopper. A solution of sodium sulfite (22.38 g, 174 mmol) in water (200 mL) was added, and the mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature, and dioxane and some water were removed by rotary evaporation. The residue was extracted with dichloromethane.

!0 The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation, co-evaporating with 2:1 hexane s/dichloromethane (100 mL) to give a beige foam (4.38 g). The foam was dissolved in dichloromethane (2 mL), hexanes (2 mL) were added, and the resultant solution was applied to a column, and purified by silica gel flash chromatography eluting with 30% to 80% ethyl acetate/hexanes to afford the title compound as a white solid (3.48 g). 'H NMR (400 MHz, CDC1₃) δ ppm 1.48 (s, 9 H), 1.83 - 2.33 (m, 3 H), 2.79 3.02 (m, 1 H), 3.37 (dd, 7=7.10, 5.37 Hz, 2 H), 4.88 (dd, 7=7.59, 2.49 Hz, 1 H), 6.92 (s, 1 H), 10.70 (br s, 1 H); MS (ESI+) m/z 316/318 (M+H)⁺.

O

Intermediate 2 (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid

To (5)-2-amino-3-methylbutanoic acid (57 g, 487 mmol) dissolved in dioxane (277 mL) was added a 2 N aqueous sodium hydroxide solution (803 mL, 1606 mmol) followed by the dropwise addition of methyl chloroformate (75 mL, 973 mmol) over 1 hour which caused warming of the

197 solution to occur. After the addition, the mixture was heated at 60 °C for 22 hours, then cooled and extracted with dichloromethane (400 mL). The resultant aqueous layer was cooled in an ice bath, and then 12 N hydrochloric acid was added dropwise until the pH was 2. The resultant mixture was stirred at 0 °C for 2 hours, and then the resultant solid was collected by vacuum filtration, and dried in a vacuum oven to provide 80g (94%) of the title compound as a colorless solid. 'H NMR (400 MHz,

DMSO-4,) δ ppm 12.50 (bs, 1H), 7.34 (d, J = 8.6 Hz, 1H), 3.84 (dd, J = 8.6, 6.0 Hz, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.86 (t, J = 7.0 Hz, 6H).

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O

Intermediate 3 methyl (5)-1 -((5)-2-carbamoylpyrrolidin-1 -yl)-3-methyl-1 -oxobutan-2-ylcarbamate

Intermediate 3A (5)-pyrrolidine-2-carboxamide hydrochloride salt

To (5)-/i77-biityl 2-carbamoylpyrrolidine-l-carboxylate (29.8 g, 139 mmol) was added a solution of 4 N HC1 in dioxane (209 mL, 836 mmol), and the resultant mixture was stirred at room temperature for 18 hours. The mixture was then concentrated and triturated with diethyl ether then vacuum filtered and dried under vacuum to provide 21.6 g (104%) of the title product as a colorless solid.

!0

Intermediate 3B methyl (5)-1 -((5)-2-carbamoylpyrrolidin-1 -yl)-3-methyl-1 -oxobutan-2-ylcarbamate

Intermediate 3A (21.6 g, 144 mmol), Intermediate 2 (29.1 g, 166 mmol), IHbenzo[<7][l,2,3]triazol-l-ol hydrate (27.6 g, 180 mmol), A'L((cthylmimo)mcthylcnc)-A'%V'25 dimethylpropane-1,3-diamine hydrochloride (34.6 g, 180 mmol) and 4-methylmorpholine (63.5 mL,

578 mmol) were dissolved in dichloromethane (960 mL) and stirred at room temperature for 18 hours. The resultant solution was then concentrated to a residue, water was then added and the solution extracted with a 25% isopropanol in chloroform solution (2x2000 mL). The organic layer was washed with brine, and then the organic extract was dried over MgSO₄, then concentrated to a yellow 30 oil which was purified by column chromatography eluting with a gradient of 0-10% methanol in dichloromethane to provide 25 g (64%) of the title compound as a colorless solid. 'H NMR (400 MHz, DMSO-J₆) δ ppm 7.28 (m, 2H), 6.81 (s, 1H), 4.24 (dd, J = 8.1, 4.4 Hz, 1H), 4.00 (t, J = 8.4 Hz,

198

1H), 3.75 (m, 1H), 3.55 (m, 1H), 3.50 (s, 3H), 2.02 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H), 0.92 (d, J =

6.7 Hz, 3H), 0.86 (d, J = 8.6 Hz, 3H).

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Intermediate 4 methyl (5)-1 -((5)-2-(5-bromo-17/-imidazol-2-yl )pyrrolidin-1 -yl)-3-methyl-1 -oxobutan-2-ylcarbamate

Intermediate 4A (5')-5-bromo-2-(pyrrolidin-2-yl)-l//-imidazolc hydrochloride

A mixture of Intermediate ID (5.0g, 15.8 mmol) in 4 M HCl/Dioxane (40 mL) was allowed to stir for one hour. The mixture was concentrated to afford 3.99 g (100%) of the title compound. MS (ESI) m/z 217 (M+H)⁺.

Intermediate 4B methyl (5)-1 -((5)-2-(5-bromo-1E/-imidazol-2-yl)pyrrolidin-1 -yl)-3-methyl-1 -oxobutan-2-ylcarbamate

A mixture of Intermediate 4A (3.99g, 15.8 mmol), Intermediate 2 (2.77 g, 15.8 mmol), N-(3dimethylaminopropyl) -N -ethylcarbodiimide hydrochloride (3.63 g, 19.0 mmol), 1-hydroxybenzotriazole hydrate (2.90 g, 19.0 mmol) and Λ'-mcthylmorpholinc (12.2 mL, 111.0 mmol) in DMF (150 mL) were allowed to stir overnight. The mixture was diluted with H₂O and extracted with !0 EtOAc (3x300 mL). The organic was washed with H₂O and brine. The organic phase was then dried (MgSO₄), filtered and concentrated. Purification by chromatography (silica gel, 75% EtOAc in hexanes) afforded 5.2 g (88%) of the title compound. 'H NMR (400 MHz, DMSO-7₆) δ ppm 0.79 (dd, 7=6.67, 3.63 Hz, 6 H), 1.84 - 1.96 (m, 3 H), 2.02 - 2.14 (m, 2 H), 3.51 (s, 3 H), 3.66 - 3.80 (m, 2 H), 3.96 - 4.03 (m, 1 H), 4.91 - 4.99 (m, 1 H), 7.06 (d, 7=1.52 Hz, 1 H), 7.26 (d, 7=8.46 Hz, 1 H), 25 12.01 (s. I H): MS (ESI) mz 373 (M+H) .

Intermediate 5 (IS,45)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diyl dimethanesulfonate

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Intermediate 5A

2-bromo-1 -(4-chloro-3 -nitrophenyl)ethanone

Method A:

To a flask equipped with a magnetic stir bar and under an atmosphere of N2 was added 4’5 chloro-3’-nitroacetophenone (10.0 g, 50.1 mmol) and THF (100 mF). To this stirring mixture was added portion-wise phenyltrimethylammonium tribromide (19.78 g, 52.6 mmol) over a 15 minutes time period. The resultant mixture was then stirred with monitoring every hour via ECMS. After 3 hours, the mixture was then filtered and resulting solids washed with EtOAc. The organic solution was then concentrated, FQO and 10% aq. NaHCC^ were added, and the mixture was washed with

EtOAc (2x300 mF). The combined organic layers were then washed with brine, dried (MgSOq). filtered and concentrated. The residue material was then subjected to purification via crystallization. The residue was dissolved in EtOAc (100 mF) and hexanes were slowly added until the mixture was cloudy. After standing for a few hours, 2-bromo-l-(4-chloro-3-nitrophenyl)ethanone (9.81 g, 70%) was collected as an off white colored solid product. 'H NMR (500 MHz, DMSOvf) δ ppm 5.00 (s, 2

H) 7.98 (d, J=8.54Hz, 1 H) 8.24 (dd, J=8.54, 2.14 Hz, 1 H) 8.61 (d, J=1.98 Hz, 1 H).

Method B:

In a 500 mF round-bottomed flask was added l-(4-chloro-3-nitrophenyl)ethanone (11.98 g, 60 mmol) in benzene (75 mF) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was added !0 dropwise over 5 minutes to give a deep red solution. The mixture was stirred for 1 hour to give a yellow solution that was concentrated in vacuo to a yellow solid. Recrystallized from 9:1 hexane/ethyl acetate gave 2-bromo-l-(4-chloro-3-nitrophenyl)ethanone as yellow needles.

Intermediate 5B l,4-bis(4-chloro-3-nitrophenyl)butane-l,4-dione

Zinc (II) chloride (14.68 g, 108 mmol) was added to toluene (81 mF) followed by diethylamine (8.35 mF, 81 mmol) and tert-butanol (7.73 mF, 81 mmol). The resultant heterogeneous solution was stirred at room temperature for approximately 2 hours. Afterwards Intermediate 5A (15.0 g, 53.9 mmol) and 4’-chloro-3’-nitroacetophenone (16.13 g, 81 mmol) were added to the 30 solution in one portion, and the resultant mixture was stirred at room temperature for 42 hours. The reaction was then quenched with 5% aqueous sulfuric acid (500 mF) and stirred vigorously to induce solid formation. The resultant solid was collected by vacuum filtration, then washed with toluene, water, and methanol successively. Then the solid was added to a solution of hot ethyl acetate and resulting heterogeneous solution was stirred for 30 minutes. The solid was then collected and dried 35 overnight in a vacuum oven to provide 16.6 g (78%) of the title compound. 'H NMR (400 MHz,

200

DMS0-J₆) δ 8.61 (d, J = 1.9 Hz, 2H), 8.27 (dd, J = 8.4, 1.9 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 3.48 (s,

4H).

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Intermediate 5C (IS,45)-1,4-bis(4-chloro-3-nitrophenyl)butane-l,4-diol (R)-(+)-a,a-Diphenyl-2-pyrrolidinemethanol (1.08g, 4.28mmol) was dissolved in 70 mL of THF at ambient temperature in a dry flask under nitrogen and trimethyl borate (650 uL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hour. The solution was cooled in a cold bath to ~ 10 °C and the A'.A'-dicthylanilinc borane (9.18 mL, 51.6 mmol) was added dropwise with some bubbling. After 15 minutes, this solution was transferred to an addition funnel and added dropwise to l,4-bis(4-chloro-3-nitrophenyl)butane-l,4-dione (Intermediate 5B) (10.Og, 25.2 mmol) suspended in 200 mL of THF and cooled to ~ 10 °C. Bubbling was observed. After the addition, the mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30 mL or methanol was added dropwise until bubbling stopped, then the mixture was allowed to stir at ambient temperature for 30 minutes. The mixture was filtered to get rid of a trace of insoluble unreacted starting material. The filtrate was concentrated, poured into 1 M HC1 and extracted into ethyl acetate, dried over sodium sulfate, and concentrated to give the title compound (9.9 g, 99%) as a yellow waxy solid. Chiral HPLC e.e. >99.9% (RR diol was undetectable). 'H NMR (400 MHz, DMSO-J₆) δ ppm 7.94 (d, J = 1.9 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.60 (dd, J = 8.4, 1.9 Hz, 2H), !0 4.65 (m,2H), 1.62 (m,4H).

Intermediate 5D (IS,45)-1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-diyl dimethanesulfonate

In a 1 L round-bottomed flask containing Intermediate 5C (20.0 g, 49.9 mmol) was added 310 mL of dichloromethane with stirring and cooling in an ice bath. To the slurry was added 25 triethylamine (20.84 mL, 150 mmol) and after 10 minutes stirring in the ice bath, a solution of methanesulfonyl chloride (8.5 mL, 110 mmol) in dichloromethane (10 mL) was added dropwise to the reaction. After complete addition, the flask was removed from the ice bath and stirred at room temperature for 3 hours. To the reaction was added water (400 mL) with vigorous stirring for 20 minutes. The solid was collected by filtration and washed thoroughly with water di chloromethane and diethyl ether. The solid was dried overnight in a vacuum drying oven at 60 °C to provide a white solid (20.49 g, 73.7% yield). Ή NMR (400 MHz, DMSO-J₆) δ ppm 1.81-1.91 (m, 2 H) 2.06 (m, 2

H) 3.18 (s, 6 H) 5.73 - 5.84 (m, 2 H) 7.71 - 7.77 (m, 2 H) 7.80 - 7.85 (m, 2 H) 8.13 (d, 7=1.74 Hz, 2 H).

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(l//.4//)-l.4-bis(4-chloro-3-nitrophcnyl)butanc-l.4-diol (l//.4//)-l.4-bis(4-chloro-3-nitrophcnyl)butanc-l.4-diol can be prepared using (5)-(-)-α,α5 diphenyl-2-pyrrolidinemethanol and the method of Intermediate 5C.

(17/,47/)-1,4-bis(4-chloro-3 -nitrophenyl)butane-1,4-diyl dimethanesulfonate (17/,47/)-1,4-bis(4-chloro-3-nitrophenyl)butane-l,4-diol can be transformed to (17/,47/)-1,4bis(4-chloro-3-nitrophenyl)butane-l,4-diyl dimethane sulfonate as described under Intermediate 5D.

Intermediate 6

(17/,47/)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate

Intermediate 6A

1,4-Bis(4-nitrophenyl)butane-1,4-dione

Anhydrous zinc(II)chloride (2.73 g, 20.00 mmol) was stirred in dry benzene (15 mL) while diethylamine (1.558 mL, 15.00 mmol) and /-butanol (1.435 mL, 15.00 mmol) were added, and the resulting mixture was stirred at room temperature for 90 minutes to give a cloudy solution. To this mixture was added 2-bromo-l-(4-nitrophenyl)ethanone (2.44 g, 10.00 mmol) and 1-(4nitrophenyl)ethanone (2.477 g, 15.00 mmol), and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The resulting residue was triturated with dichloromethane to give an orange solid that was collected by filtration and dried to give the title compound (2.0 g, 61% yield).

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Intermediate 6B (I//.4//)-1 ,4-bis(4-nitrophenyl)butane-1,4-diol

To (5)-(-)-a,a-diphenyl-2-pyrrolidinemethanol (2.71 g, 10.70 mmol) was added THF (80 mF) at 23 °C. The very thin suspension was treated with trimethyl borate (1.44 g, 13.86 mmol) over 30 seconds, and the resulting solution was mixed at 23 °C for 1 hour. The solution was cooled to 16-19 °C, and ΜΛ'-dicthylanilinc borane (21.45 g, 132 mmol) was added dropwise via syringe over 3-5 minutes (caution: vigorous H₂ evolution), while the internal temperature was maintained at 16-19 °C. After 15 minutes, the H₂ evolution had ceased. To a separate vessel was added the product from Example 6A (22.04 g, 95 wt%, 63.8 mmol), followed by THF (80 mF), to form an orange slurry.

After cooling the slurry to 11 °C, the borane solution was transferred via cannula into the dione slurry over 3-5 minutes. During this period, the internal temperature of the slurry rose to 16 °C. After the addition was complete, the reaction was maintained at 20-27 °C for an additional 2.5 hours. After reaction completion, the mixture was cooled to 5 °C and methanol (16.7 g, 521 mmol) was added dropwise over 5-10 minutes, maintaining an internal temperature <20 °C (note: vigorous H₂ evolution). After the exotherm had ceased (ca. 10 minutes), the temperature was adjusted to 23 °C, and the reaction was mixed until complete dissolution of the solids had occurred. Ethyl acetate (300 mF) and 1 M HC1 (120 mF) were added, and the phases were separated. The organic phase was then washed successively with 1 M HC1 (2x120 mF), H₂O (65 mF), and 10% aq. NaCl (65 mF). The organics were dried over MgSO₄, filtered, and concentrated in vacuo. Crystallization of the product !0 occurred during the concentration. The slurry was warmed to 50 °C, and heptane (250 mF) was added over 15 minutes. The slurry was then allowed to mix at 23 °C for 30 minutes and filtered. The wet cake was washed with 3:1 heptane:ethyl acetate (75 mF), and the orange, crystalline solids were dried at 45 °C for 24 hours to provide the title compound (15.35 g, 99.3% ee, 61% yield), which was contaminated with 11% of the meso isomer (vs. dl isomer).

Intermediate 6C (17/,47/)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate

The product from Intermediate 6B (5.01 g, 13.39 mmol) was combined with 2methyltetrahydrofuran (70 mF) and cooled to -5 °C, and Λ'.Λ'-diisopropylcthylaminc (6.81 g, 52.7 30 mmol) was added over 30 seconds. Separately, a solution of methane sulfonic anhydride (6.01 g, 34.5 mmol) in 2-methyltetrahydrofuran (30 mF) was prepared and added to the diol slurry over 3 minutes, maintaining the internal temperature between -15 °C and -25 °C. After mixing for 5 minutes at -15 °C, the cooling bath was removed and the reaction was allowed to warm slowly to 23 °C and mixed for 30 minutes. After reaction completion, the crude slurry is used directly without purification or 35 isolation.

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Intermediate 7 ((I 1,4-bis(4-bromophenyl)butane-1,4-diyl dimethanesulfonate

Intermediate 7A

1,4-bis(4-bromophenyl)butane-1,4-dione

To a solution of zinc(II) chloride (19.62 g, 144 mmol) in benzene (108 mL) were added diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and the mixture was stirred at room temperature for 2 hours. 2-Bromo-l-(4-bromophenyl)ethanone (20.0 g, (72 0 mmol) and 1 -(4-bromophenyl)ethanone (21.48 g, 108 mmol) were added in one portion, and the mixture was stirred overnight (18 hours). The reaction mixture was quenched with 5% H₂SO₄ (500 mL) and stirred vigorously to induce precipitation of the product, which was collected by vacuum filtration and washed with benzene, water, methanol, and then dichloromethane, successively. The product was dried under vacuum to give the title compound as a white solid (11.15 g, 39.1% yield).

.5

Intermediate 7B (I 1,4-bis(4-bromophenyl)butane-1,4-diol

To (S)-(-)-a,a-diphenyl-2-pyrrolidinemethanol (3.81 g, 15.04 mmol) was added THF (140 mF) at 23 °C. The thin slurry was treated with trimethyl borate (2.189 mF, 19.63 mmol) to form a !0 clear solution. After stirring for 1.5 hours, the solution was cooled to 10-15 °C, and N,Ndiethylaniline borane (33.1 mF, 186 mmol) was added over 5-10 minutes via a syringe. A slight exotherm and H₂ evolution were observed. To a separate vessel was charged Intermediate 7A (35.045 g, 88 mmol), followed by THF (140 mF), to form a slurry. The slurry was cooled to 10 °C. The cooled borane solution was transferred via cannula into the dione slurry over approximately 5 25 minutes, maintaining the internal temperature <25 °C. After the transfer was complete, the slurry was held at 15 °C for 5 minutes and then the temperature was maintained at 23 °C for 3 hours. After reaction completion, the solution was cooled to 5 °C, and methanol (31.6 mF, 780 mmol) was added slowly to maintain a temperature <20 °C (note: vigorous evolution of hydrogen). The hazy solution was mixed for an additional 1 hour in order to ensure complete quenching. The hazy solution was 30 diluted with EtOAc (500 mF) and 1 M HC1 (220 mF). The phases were separated, and the organic phase was washed successively with 1 MHC1 (2x220 mF), H2O (110 mF), and 25% aq. NaCl (110 mF). The organic layer was concentrated in vacuo; then the residue was dissolved in EtOAc, filtered,

204 concentrated and crystallized from EtOAc/hexane to provide the title compound (16.92 g; 100% ee;

47% isolated yield).

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Intermediate 7C (I /?.4/?)-1,4-bis(4-bromophenyl)butane-l ,4-diyl dimethane sulfonate

To Intermediate 7B (0.60 g, 1.500 mmol) in anhydrous CH₂C1₂ (15 mL) at 0 °C was added Et₃N (0.627 mL, 4.50 mmol), and the resulting mixture was stirred at 0 °C for 10 minutes until a homogenous solution was obtained. To the cooled solution was added methanesulfonyl chloride (0.292 mL, 3.75 mmol) dropwise, and the resulting mixture was stirred at 0 °C for 1.5 hours until the 0 reaction was complete as determined by TLC (1:1 EtOAc:hexanes). Solvent was removed in vacuo to give a solid, which was dried in vacuo.

,CO₂H

Intermediate 8 .5 (25,45)-1 -(ter/-biitoxycarbonyl )-4-(/i77-biityldimcthylsilyloxy)pyrrolidinc-2-carboxylic acid (25,45)-l-(/i77-Butoxycarbonyl)-4-hydroxypyrrolidinc-2 -carboxylic acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined in dichloromethane (106 mL) and dimethylformamide (22 mL) at ambient temperature and treated with portionwise addition of tertbutylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted !0 with water and extracted into ethyl acetate and concentrated to provide the title compound.

O

O

Intermediate 9 (5)-1 -((5) -2 -(methoxycarbonylamino) -3 -methylbutanoyl)pyrrolidine -2-carboxylic acid

Intermediate 2 (150 g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF (1500 mL) were charged to a flask. The mixture was stirred for 15 minutes to give a clear solution. EDC hydrochloride (172 g, 899 mmol) was charged and mixed for 20 minutes. The mixture was cooled to °C and (f)-prolinc benzyl ester hydrochloride (207 g, 856 mmol) charged. Triethylamine (109 g, 1079 mmol) was then charged in 30 minutes. The resulting suspension was mixed at room 30 temperature for 1.5 hours. The reaction mixture was cooled to 15 °C and 1500 mL of 6.7% NaHCO₃

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2016238925 07 Oct 2016 charged in 1.5 hours, followed by the addition of 1200 mL of water over 60 minutes. The mixture was stirred at room temperature for 30 minutes, an then it was filtered and washed with water/DMF mixture (1:2, 250 mL) and then with water (1500 mL). The wet cake was dried at 55 °C for 24 hours to give 282 g of product (5)-benzyl 1-((5)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine5 2-carboxylate as a white solid (90%).

(5)-Bcnzyl I-((.S)-2-(mcthoxycarbonylamino)-3-mcthylbutanoyl)pyrrolidinc-2-carboxylate (40 g) and 5% Pd/Alumina were charged to a Parr reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6x20 psig) followed by a hydrogen purge (6x30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 0 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately

135 g solution. Heptane (120 mL) was added, and the solution was stirred until solids formed. After an addition 2-3 hours, additional heptane (240 mL) was added drop-wise, the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound (5)-1-((5)-2(methoxycarbonylamino) -3 -methylbutanoyl)pyrrolidine -2-carboxylic acid.

.5

Intermediate 10

4-Cyclohexyl-3 -fluoroaniline hydrochloride

Intermediate 10A !0 3-Fluoro-4-iodoaniline

To a suspension of 3-fluoroaniline (1.0 mL, 1.16 g, 10.39 mmol) and solid sodium bicarbonate (1.75 g, 20.79 mmol) in 1:1 methanol-dichloromethane (20 mL) at 0 °C was added a solution of benzyl trimethylammonium dichloroiodate (3.62 g, 10.39 mmol) in dichloromethane (15 mL) over 30 minutes. The mixture was then allowed to warm to room temperature for 1 hour. The 25 mixture was quenched by addition of water and the organic layer was extracted with water (2x). Drying (Na₂SO₄) and concentration in vacuo afforded an oil, which was chromatographed over a 100 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (2.20 g, 89%) as a pink solid. 'H NMR (400 MHz, CDC1₃) δ ppm 7.41 (dd, J = 8.3,

7.3 Hz, 1 H), 6.42 (dd, J= 9.9, 2.5 Hz, 1 H), 6.27 (dd, J= 8.5, 2.5 Hz, 1 H), 3.81 (s, 2 H); MS +ESI 30 m/z (rel abundance) 238 (100, M+H).

Intermediate 10B

4-(Cyclohexen-1 -yl)-3-fluoroaniline

The procedure to prepare the title compound is described in General Procedure 1.2A.

Intermediate 10C

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4-Cyclohexyl-3 -fluoroaniline hydrochloride

A solution of 4-(cyclohexen-l-yl)-3-fluoroaniline (General Procedure 1.2A) (1.16 g, 6.07 mmol) in ethanol (30 mL) was treated with 10% palladium on carbon (300 mg) followed by hydrogenation at one atmosphere for 18 hours. The mixture was filtered through diatomaceous earth 5 and concentrated to about one quarter volume and treated with a solution of hydrogen chloride in dioxane (4 TV, 10 mL). The mixture was then partially concentrated in vacuo to about one quarter volume and diluted with ether (ca. 100 mL) and the solids were collected by filtration. After drying in a vacuum oven at 50 °C for 3 hours, these procedures afforded the title compound (1.13 g, 81%) as a light grey solid. Ή NMR (400 MHz, DMSO-J₆) δ ppm 7.35 (t, J= 8.1 Hz, 1 H), 7.03 (d, J= 9.4 0 Hz, 2H), 2.76 (dd, J= 15.6, 6.9 Hz, 1 H), 1.74 (m, 5 H), 1.40 (m, 4 H), 1.21 (m, 1 H). MS (DCI+) m/z (rel abundance) 194 (100, M+H), 211 (67, M+NH₄).

Intermediate 11A A'-(4-bromo-5-fliioro-2-nitrophcnyl)-2.2.2-trifliioroacctamidc

To a flask containing trifluoroacetic anhydride (10.0 mL, 70.5 mmol) at 0 °C was added 4bromo-3-fluoroaniline (2.0,g, 10.5 mmol) and stirring was continued for 30 minutes (Charifson, P.S.; et al. J. Med. Chem. 2008, 51, 5243-5263). Potassium nitrate (1.3 g, 12.6 mmol) was added and the solution was allowed to warm to 25 °C. The solution was concentrated, the residue dissolved in EtOAc and washed with 10% NaHCO₃, brine, dried (Na₂SO₄), and filtered. The filtrate was !0 concentrated to give the title compound (3.5 g, 10.5 mmol, 100%).

Intermediate 11B

4-bromo-5 -fluoro-2-nitroaniline

To 7V-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.5 g, 10.5 mmol) was 25 added CH₃OH (30mL) followed by l.OAf K₂CO₃ (10.5mL, 10.5 mmol), and the solution was stirred for 30 minutes (Charifson, P.S.; et al. J. Med. Chem. 2008, 51, 5243-5263). The solution was diluted with H₂O and stirred for 1 hour. The resulting orange solid was collected by filtration and dried in a vacuum oven to give the title compound (2.l,g, 8.8 mmol, 84%).

Intermediate 11C

4-bromo-5 -fluorobenzene-1,2-diamine

To a solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in THF (9.0mL), EtOH (9.0 mL) and H₂O (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g,

6.4 mmol), and the mixture was heated at 95 °C for 4 hours. The cooled mixture was diluted with 35 EtOH, filtered through diatomaceous earth until no further color came through the filter, and concentrated. The residue was dissolved in EtOAc, washed with H₂O, brine, dried (Na₂SO₄), filtered

207 and concentrated. Hexane was added and the resulting solid collected by filtration to give the title compound (710 mg, 3.5 mmol, 81%).

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Intermediate 12

4-bromo-3 -chlorobenzene-1,2-diamine

Intermediate 12A

4-bromo-3-chloro-2 -nitroaniline

3- Chloro-2-nitroaniline (5.00 g, 29.0 mmol) was dissolved in glacial acetic Acid (258 mL). 0 A'-Bromosuccinimidc (5.06 g, 28.4 mmol) was added and the resulting mixture was refluxed for 1 hour. The reaction was cooled to room temperature and poured into water to give a precipitate that was filtered, rinsed with water and dried to constant weight to give the title compound (4.78 g, 67%). 'H NMR (400 MHz, CDCL₃) δ ppm 7.46 (d, J= 9.0, 1H), 6.64 (d, J= 9.0, 1H), 4.74 (s, 2H).

Intermediate 12B

4-bromo-3 -chlorobenzene-1,2-diamine

4- Bromo-3-chloro-2-nitroaniline (4.78 g, 19.01 mmol) was dissolved in ethanol (112 mL). Tin (II) chloride (14.42 g, 76 mmol) was added, and the resulting mixture was stirred at reflux for 12 hours. The mixture was cooled to room temperature, poured into water, and adjusted to pH 5 with !0 saturated sodium bicarbonate solution. The resulting solid was filtered and rinsed well with ethyl acetate. The filtrate was washed with water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% EtOAc in hexane to give the title compound (3.32 g, 79%). 'H NMR (400 MHz, CDC1₃) δ ppm 6.94 (d, 1H), 6.51 (d, J= 7.0, 1H), 3.87 (br s, 2H), 3.46 (br s, 2H).

Intermediate 13

4-bromo-3 -methylbenzene-1,2-diamine

Intermediate 13A

A'-(3-bromo-2-mcthyl-6-nitrophcnyl)-2.2.2-trifluoroacctamidc

To a solution of 3-bromo-2-methylaniline (1.0 g, 5.37 mmol) in CH₂C1₂ (4.0 mL) at 0 °C was added trifluoroacetic anhydride (2.0 mL, 14.2 mmol). The mixture was stirred at 0 °C for 30 minutes, and solid potassium nitrate (0.679 g, 6.72 mmol) was added. The cooling bath was removed, and the mixture was stirred at room temperature overnight. LCMS showed a single product formed. The 35 mixture was concentrated in vacuo, and the residue was partitioned between water and CH₂C1₂ (2*).

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The organic layers were combined and dried over Na₂SO₄. The drying agent was filtered off and the crude product was purified by crystallization from aq EtOH to give the title compound (1.3 g, 74%).

Intermediate 13B

3-bromo-2-methyl-6-nitroaniline

A solution of 7V-(3-bromo-2-methyl-6-nitrophenyl)-2,2,2-trifluoroacetamide (1.3 g, 3.97 mmol) in CH₃OH (30 mL) was treated with potassium carbonate (1.099 g, 7.95 mmol), and the mixture was stirred at 50 °C overnight. The mixture was cooled to room temperature and poured into water, 1/V aq HCI was added to adjust to pH 6, and the mixture was extracted with CH₂C1₂ (3x). The 0 combined extracts were dried over Na₂SO₄, and the drying agent was filtered off and solvent was removed in vacuo to give the title compound as a yellow solid (0.57 g, 62%).

Intermediate 13C

4-bromo-3 -methylbenzene-1,2-diamine

To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70 °C for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH₂C1₂ (2χ), and the combined extracts were dried over Na₂SO₄. The drying agent was filtered off and solvent was removed in vacuo to give !0 the title compound as an oil (0.34 g, 88%).

Intermediate 14

-bromo-3 -fluorobenzene-1,2-diamine

To a solution of 4-bromo-2-fluoro-6-nitroaniline (0.5 g, 2.1 mmol) in THF (4.6 mL), EtOH 25 (4.6 mL) and H₂O (1.5 mL) was added iron powder (0.6 g, 10.6 mmol) and ammonium chloride (0.17 g, 3.2 mmol). The resulting mixture was stirred at 95 °C for 22 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was washed with EtOH until no further color came through the filter. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated to give the title 30 compound (0.43 g, 99%) as a brown, waxy solid.

Intermediate 15

4-bromo-3 -fluorobenzene-1,2-diamine

Intermediate 15A

-fluoro-2 -nitroaniline

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To a pressure tube was added 1,3-difluoro-2-nitrobenzene (2.8 mL, 26.4 mmol) and 7 NNH₃in CH₃OH (10 mL, 70 mmol). The tube was sealed and the mixture was stirred at room temperature for 5 days. The solution was diluted with H₂O, extracted with CH₂C1₂, and the combined extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated to give an oil. The oil was 5 triturated with hexane and the resulting orange solid was collected by filtration to give the title compound (2.1 g, 51%).

Intermediate 15B

4-bromo-3 -fluoro-2 -nitroaniline

To a solution of 3-fluoro-2-nitroaniline (2.1 g, 13.4 mmol) in DMF (30 mL) at 0 °C was added a solution of A'-bromosuccinimidc (2.4 g, 13.4 mmol) in DMF (20 mL). The resulting solution was stirred at 0 °C for 30 minutes and then warmed to room temperature over 1 hour. The solution was diluted with EtOAc, washed with H₂O and brine, dried over MgSO₄, filtered and concentrated to give the title compound (3.1 g, 97%).

.5

Intermediate 15C

4-bromo-3 -fluorobenzene-1,2-diamine

To a solution of 4-bromo-3-fluoro-2-nitroaniline (3.0 g, 12.8 mmol) in THF (30 mL) was added EtOH (30 mL) and H₂O (10 mL) followed by iron powder (3.6 g, 63.8 mmol) and ammonium !0 chloride (1.0 g, 19.2 mmol). The resulting mixture was stirred at 80 °C for 16 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was washed with EtOH until no further color came through the filter. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% EtOAc in hexane to give the title compound (2.2 g, 84%).

Intermediate 16

4-cyclopropyl-2-fluoroaniline

4-Cyclopropyl-2-fluoro-1 -nitrobenzene (prepared as described in General Procedure 1.2C) (2.2 g, 12.14mmol) was dissolved in 7 mL of an ethanol:THF:water 3:3:1 (v/v) mixture. To this was 30 added ammonium chloride (1.02 g, 19.07 mmol) followed by iron powder (3.50 g, 62.7mmol). The resulting mixture was heated in a 90 °C oil bath under a nitrogen atmosphere with rapid stirring for one hour. The reaction mixture was vacuum filtered through a sand and diatomaceous earth plug. The filtrate was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was washed with brine, dried (MgSO₄) and concentrated in vacuo to 35 provide an orange oil (1.90 g).

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Intermediate 17

2-(methoxycarbonylamino)-3-methylbut-2-enoic acid

Η O

Intermediate 17A ethyl 2-(methoxycarbonylamino)-3-methylbut-2-enoate

A benzene solution (90 mL) of ethyl-3-methyl-2-oxobutanoate (4.03 g, 28.0 mmol), methyl carbamate (2.098g, 28.0 mmol) and pyridine 4-methylbenzenesulfonate (0.70 g, 2.80 mmol) was heated to reflux in a round bottom flask equipped with a Dean-Stark trap and reflux condenser. After

44hours of heating the mixture was cooled and then partitioned between ethyl acetate (50mL) and brine (50 mL). The organic phase was washed with brine (2x50 mL) then dried (MgSO₄) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate-hexanes) to provide the title compound as an off white crystalline solid (1.487 g, 26%).

Intermediate 17B

2-(methoxycarbonylamino)-3-methylbut-2-enoic acid

The product from Intermediate 17A (0.373 g, 1.85 mmol) was dissolved in 2 mL of a 1: l(v/v) ethanokwater mixture at room temperature. To this was added lithium hydroxide (0.095 g, 3.99 !0 mmol) in one portion. After stirring overnight, the reaction mixture was partitioned between ethyl acetate (25 mL) and 1 N HCI (5 mL) to which was added solid NaCl. The aqueous phase was extracted with ethyl acetate one time and the combined organics washed with brine (3x5 mL) then dried (MgSO₄) and concentrated to give the title compound (0.289 g, 90%) as an off white solid sufficiently pure for use as isolated.

Intermediate 18 (2.S'.3aS'.6aS')-Zi77-butyl 2-carbamoylhexahydrocyclopenta[b]pyrrole-l(2H)-carboxylate

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Intermediate 18A (2S,3aS,6baS)-2-benzyl 1 -tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

To a suspension of (2.S'.3aS'.6a.S')-bcnzyl octahydrocyclopenta[6]pyrrole-2-carboxylate 5 hydrochloride (2.0 g, 7.10 mmol) in dichloromethane (36 mL) at room temperature was added di-tertbutyl dicarbonate (1.7 Og, 7.81 mmol) followed by triethylamine (2.18 mL, 15.62 mmol). The solution rapidly becomes homogeneous along with vigorous gas evolution which quickly subsides. After two hours, the mixture was diluted with dichloromethane, washed with brine (3x60 mL), dried (MgSO₄) and concentrated. The crude product was purified by chromatography on silica gel (ethyl 0 acetate-hexanes) to give the title compound (2.58 g, quantitative) as a clear oil.

Intermediate 18B (2.S'.3aS'.6aS)-1 -(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid

The product from Intermediate 18A (2.45 g, 7.1mmol) was dissolved in methanol (35 mL) at room temperature. To this was added Pearlman’s catalyst (0.153 g ) followed by vacuum degassing (3x) and hydrogen addition (balloon). After one hour, the reaction mixture was vacuum filtered through diatomaceous earth and the filtrate concentrated to give a clear thick oil (1.89 g, quantitative) which was sufficiently pure for use as isolated.

Intermediate 18C (2.S'.3aS'.6aS')-/i77-butyl 2-carbamoylhexahydrocyclopenta[b]pyrrole-l(2H)-carboxylate

The product from Intermediate 18B (1.81 g, 7.1 mmol) was dissolved in THF (40 mL) at room temperature under nitrogen. To this was added Λ'-mcthyl morpholine (1.0 mL, 9.09 mmol) and the resulting solution was cooled to -15 °C. To the cold solution was added isobutylchloroformate

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2016238925 07 Oct 2016 (1.03 mL, 7.81 mmol) dropwise via syringe. A white precipitate forms at once. On completion of the addition, the mixture was allowed to stir in the cold for twenty minutes. Ammonia gas was then introduced by bubbling through the mixture for two minutes with additional cooling. On completion of the addition, the reaction was allowed to warm to ice bath temperature and stir for one half hour 5 and then warmed to room temperature. After fifteen minutes at room temperature, the mixture was poured into brine (450 mL) and extracted with dichloromethane (6x50 mL). The combined extracts were dried (MgSO₄) and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate-hexanes) to give the title compound (1.68 g, 93%) as a sticky white foam.

Intermediate 19

(.S'./'.)-/i77-butyl 2-(5-(3-oxoprop-l-enyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-127-benzo[ri]imidazol2-yl)pyrrolidine-1 -carboxylate

Intermediate 19A

(.S'./'.)-/i77-biityl 2-(5-(3-ethoxy-3-oxoprop-1 -enyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-IHbenzo \d\ imidazol-2 -yl)pyrrolidine -1 -carboxylate

To (5)-ter ί-butyl 2 -(5 -bromo -1-((2 -(trimethylsilyl)ethoxy)methyl) - 127-benzo \d\ imidazol-2 yl)pyrrolidine-l-carboxylate (2.973 g, 5.99 mmol), ethyl acrylate (0.714 mL, 6.59 mmol), tn-tertbutylphosphonium tetrafluoroborate (0.104 g, 0.359 mmol), A'.A'-dicyclohcxylmcthylaminc (1.461 !0 mL, 6.89 mmol), and tris(dibenzylideneaoetone)dipalladium(0) (0.164 g, 0.18 mmol) dissolved in

THF (18 mL) had nitrogen bubbled through the solution for 15 minutes to remove the oxygen, and then the mixture heated at 60 °C for 2 hours. After cooling to room temperature the solution was filtered through diatomaceous earth and washed with EtOAc. The filtrated was then concentrated to a residue, and then the residue was dissolved in dichloromethane and extracted with water. The organic 25 layer was then dried and concentrated. The residue was purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 2.56 g, (83%) of the title compound. MS (ESI) m/z 516 (M+H)⁺.

Intermediate 19B

(.S'./'.)-/i77-biityl 2-(5-(3-hydroxyprop-l-enyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lHbenzo [d\ imidazol-2 -yl)pyrrolidine -1 -carboxylate

Intermediate 19A (2.56 g, 4.97 mmol) was dissolved in THF (17 mL), and the mixture was cooled to -78 °C in a dry ice acetone bath. Then a solution of diisobutylaluminium hydride (1.0 N in THF, 22.75 mL, 24.75 mmol) was added dropwise. The resultant mixture was allowed to slowly 35 warm to room temperature overnight, and then was quenched with a 1 TV aqueous sodium hydroxide solution. The mixture was then added to ethyl acetate and extracted with an aqueous solution of

213

Rochelle’s salt (sodium, potassium tartrate). The organic layers were combined and dried, and then concentrated. The residue was purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 0.93 g, (40%) of the title compound. MS (ESI) m/z 474 (M+H)⁺.

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Intermediate 19C (S,E)-tert-buty\ 2-(5-(3-oxoprop-l-enyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[ri]imidazol2-yl)pyrrolidine-1 -carboxylate

The product of Intermediate 19B (0.93 g, 1.96 mmol) was dissolved in dichloromethane (7.5 mL) and pyridinium dichromate (1.11 g, 2.95 mmol) was added, and the resultant mixture was stirred 0 at room temperature overnight. The solution had hexanes added to it, and then it was filtered through diatomaceous earth. The filtrate was then concentrated to a residue which was then dissolved in dichloromethane and extracted with water. The organic layer was then dried, concentrated and the residue purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 0.3 g, (32%) of the title compound. Ή NMR (400 MHz, DMSO-d₆) δ ppm 9.65 (d, J=7.8 Hz, 1H), 8.05 (m, 1H),

7.82 (d, J=15.8 Hz, 1H), 7.70 (m, 2H), 6.87 (dd, J=15.8, 7.8 Hz, 1H), 5.70 (s, 2H), 5.14 (m, 1H), 3.57 (m, 2H), 3.42 (m, 1H), 2.40 (m, 5H), 1.30 (s, 4H), 0.95 (s, 5H), 0.80 (m, 2H), -0.10 (s, 9H); MS (ESI) m/z 472 (M+H)⁺.

!0

Intermediate 20A l-(4-chloro-2-fluoro-5-nitrophenyl)ethanone

To a solution of 4-chloro-2-fluoro-5-nitrobenzoic acid (16.0 g, 72.9 mmol) in anhydrous CH₂C1₂ (400 mL) was added oxalyl chloride (9.57 mL, 109 mmol) and DMF (2 drops), and the resulting mixture was stirred at room temperature until gas evolution ceased. The mixture was 25 concentrated and dried in vacuo. In a separate, heat-dried reaction flask a mixture of ZnBr₂ (24.6 g , 109 mmol) in anhydrous THF (300 mL) at -78°C was added a solution of CH₃MgBr (29.1 mL, 3.0 M in Et₂O, 87 mmol) dropwise. The resulting mixture was stirred at -78 °C for 15 minutes, and then the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was cooled to -78 °C and a solution of the acid chloride in anhydrous THF (100 mL) was added 30 dropwise, followed by Pd(PPh₃)₄ (1.68 g, 1.46 mmol). The resulting mixture was allowed to stir at 78 °C for 10 minutes, and was then allowed to warm to ambient temperature and stirred for an additional 16 hours. The mixture was quenched by adding aq. 1 M HC1, diluted with H₂O (100 mL), and extracted with CH₂C1₂ (3x300 mL). The combined organic extracts were dried (MgSO₄), filtered

214 and concentrated. The crude product was purified by column chromatography (silica gel, 5% EtOAc in hexanes) to afford the title compound (11.79 g, 74%).

Intermediate 20A may also be prepared by reacting the intermediate acid chloride with dimethylmalonate, MgCl₂, and triethylamine in methylene chloride, followed by acidic hydrolysis and decarboxylation.

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Intermediate 20B

2-bromo-1 -(4-chloro-2-fluoro-5 -nitrophenyl)ethanone

The product of Intermediate 20A (3.0 g, 13.79 mmol) dissolved in THF (100 mF) was treated with pyridinium bromide perbromide (4.63 g, 14.48 mmol) portionwise over several minutes. The resulting mixture was stirred at ambient temperature for 2 hours and then filtered. The filtered solids were rinsed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 20% EtOAc in hexanes) to afford the title compound (3.8 g, .5 93%).

Intermediate 20C

1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-dione

Intermediate 20A (4.92 g, 22.62 mmol) and Intermediate 20B (4.47 g, 15.08 mmol) were processed using the method described in Intermediate 5B to afford the title compound (4.74 g, 73%).

Intermediate 20D (lS,4S)-l,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-l,4-diol

The product of Intermediate 20C (1.0 g, 2.309 mmol) was processed using the method described in Intermediate 5C to afford the title compound (0.96 g, 95%). In the chiral reduction to form Intermediate 20D, the reaction proceeds with lower stereoselectivity than in the case of Intermediate 5C.

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Intermediate 20E (1 S,4S)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diyl dimethanesulfonate

To a solution of Intermediate 20D (0.95 g, 2.17 mmol) in anhydrous CH₂C1₂ (20 mL) at 0 °C was added methanesulfonyl chloride (0.42 mL, 5.43 mmol), followed by the dropwise addition of triethylamine (0.91 mL, 6.52 mmol). The resulting mixture was stirred at room temperature for 90 minutes, and was then concentrated in vacuo. Hexanes were added, and the resulting solids were collected by filtration, washed with H₂O, and dried in vacuo to provide the title compound (1.29 g, 0 100%).

Intermediate 21 (lS,4S)-l-(4-chloro-2-fluoro-5-nitrophenyl)-4-(4-chloro-3-nitrophenyl)butane-l,4-diyl dimethane sulfonate

Intermediate 21 can be made from Intermediate 20B and l-(4-chloro-3-nitrophenyl)ethanone (commercially available from Aldrich) following the general methods to prepare Intermediate 20E.

Intermediate 22A l-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (4-Methoxyphenyl)magnesium bromide (0.5 M in THF, 90 mL, 45.0 mmol) was added slowly (~25 minutes) via cannula to a cold (0 °C) solution of 1-benzylpiperidin-4-one (5.4 mL, 30.2

216 mmol) in THF (60 mL). The reaction was stirred at 0 °C under nitrogen for 2 hours. The reaction was quenched with saturated aqueous NH₄C1 then diluted with ether. The organic fraction was washed with saturated aqueous NH₄C1 (2x) brine (lx) and concentrated. Purification using flash chromatography (5 - 100% EtOAc/hexane) provided 4.02 g (44%) of the titled compound. MS (DCI) m/z 298 (M+H)⁺.

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Intermediate 22B l-benzyl-4-(4-methoxyphenyl)-l,2,3,6-tetrahydropyridine

6 M HC1 (100 mL, aqueous) was added to a solution of 1-benzyl-4-(4methoxyphenyl)piperidin-4-ol (12.31 g, 41.36 mmol) in dioxane (50 mL), and the reaction was heated to strong reflux (110 °C). After 2 hours, the reaction was not complete. The heat was turned off and the reaction was left to stir at ambient temperature for 2 days. The reaction had progressed but was not complete so it was heated to 110 °C. After 1 hour, the reaction was cooled and the volume was reduced by approximately one third. The solution was then cooled in an ice bath and neutralized with NaOH pellets. The thick suspension was filtered. The precipitate was rinsed with water and then dried under vacuum at 70°C to afford 6.2 g (47%) of the titled compound. ^H NMR (400 MHz, CDC1₃) δ ppm 2.74 - 2.62 (m, 1H), 3.30 - 3.06 (m, 2H), 3.50 (d, J = 18.5, 1H), 3.67 - 3.56 (m, 1H), 3.82 (s, 3H), 4.03 - 3.90 (m, 1H), 4.21 (dd, J = 5.7, 13.0, 1H), 4.34 (dd, J = 5.1, 13.0, 1H), 5.88 (s, 20 1H), 6.88 (d, J = 8.7, 2H), 7.32 (d, J = 8.7, 2H), 7.51 - 7.43 (m, 3H), 7.71 (dd, J = 2.7, 6.3, 2H), 12.85 (s, 1H); MS (ESI) m/z 280 (M+H)⁺; MS (DCI) m/z 280 (M+H)⁺

Intermediate 22C

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4-(4-methoxyphenyl)piperidine

The product from Intermediate 22B (6.2 g) in trifluoroethanol (60 mL) was added to 20% Pd(OH)2-C, wet (1.240 g, 8.83 mmol) in a 250 mL stainless steel pressure bottle. The mixture was shaken under 30 psi of hydrogen at 50 °C for 23 hours. The mixture was filtered through a PTFE 5 membrane, concentrated and dried under vacuum to afford 4.33 g of the desired product as the HC1 salt. (HC1 salt)¹H NMR (400 MHz, CDC1₃) δ ppm 2.03 (d, J = 13.1, 2H), 2.28 - 2.11 (m, 2H), 2.72 (t, J = 10.2, 1H), 3.08 - 2.91 (m, 2H), 3.62 (d, J = 8.3, 2H), 3.79 (s, 3H), 6.86 (d, J = 8.3, 2H), 7.16 (d, J =

8.5, 2H), 9.65 (d, J = 83.1, 2H); MS (DCI) m/z 192 (M+H)⁺

Intermediates 23, 24, and 25 can be prepared using the methodology used to prepare Intermediate 22C

H

Intermediate 23

4-(4-fluorophenyl)piperidine

F

H

Intermediate 24

4-(2,4-difluorophenyl)piperidine

Intermediate 25

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4-(3,5 -difluorophenyl)piperidine

Intermediate 26A tert-butyl 4-fluoro-4-phenylpiperidine-l-carboxylate

A solution of diethylaminosulfur trifluoride (4 mL, 32.7 mmol) in dichloromethane (tO mL) was added to a cold (-78 °C; dry ice/acetone bath) solution of tert-butyl 4-hydroxy-4phenylpiperidine-1-carboxylate (8.05 g, 29.0 mmol) in dichloromethane (100 mL) under nitrogen. The reaction was stirred at -78 °C for ~ 1 hour. The reaction was removed from the bath and warmed 0 to ambient temperature then stirred another 30 minutes. The reaction was quenched with saturated aqueous NaHCO₃ (100 mL). The organic fraction was washed with brine (~50 mL). Then 3chloroperoxybenzoic acid (1.0995 g, 6.37 mmol) was added to the reaction and stirred at ambient temperature for 30 minutes. This step was quenched with saturated aqueous NaHCO₃ (100 mL). The organic fraction was washed with saturated aqueous NaHCO₃ (1x100 mL), water (1x100 mL), and .5 brine (1x100 mL), dried (MgSO₄), tested for peroxide (3-10 ppm) and concentrated to light yellow oil. The oil was dried under vacuum to afford 8.27 g (100%) of the titled compound. NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (d, J = 5.7, 9H), 1.96 - 1.85 (m, 3.5H), 2.03 (ddd, J = 5.2, 13.3, 17.8, 1.5H), 3.06 (s, 2H), 3.98 (d, J = 12.0, 2H), 7.33 (d, J = 7.1, 1H), 7.46 - 7.36 (m, 4H); MS (DCI) m/z 280 (M+H⁺, 60%), 297 (M+NH₄ ⁺, 100%).

4-fluoro-4-phenylpiperidine

Hydrochloric acid (4 AT in dioxane, 20 mL, 80 mmol) was added to a solution of tert-butyl 425 fluoro-4-phenylpiperidine-1-carboxylate (8.27 g, 29.6 mmol) in dioxane (10 mL). The reaction was stirred at ambient temperature for 4 hours. The reaction was concentrated to an oil. Ether was added, and the resulting solid was sonicated and then stirred vigorously overnight to provide a tan solid. The

219 solid was filtered, rinsed with ether and dried under vacuum at 60 °C for 3 hours to provide 5.56 g (87%) of the titled product. MS (DCI) m/z 180 (M+H)⁺.

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Intermediate 27A tert-butyl 4-(hydroxydiphenylmethyl)piperidine-1 -carboxylate

A solution of di-tert-butyl dicarbonate (8.43 mL, 36.7 mmol) in dichloromethane (15 mL) was added to a solution of diphenyl(piperidin-4-yl)methanol (8.0721 g, 30.2 mmol) in dichloromethane (100 mL); triethylamine (5.1 mL, 36.6 mmol) was added and the reaction was stirred 0 at ambient temperature for 2 hours. The reaction was diluted with dichloromethane and then washed with saturated aqueous NaHCO3 (2χ), water (lx), and brine (lx), dried (MgSO4) and concentrated to afford 11.63 g (105%) of the titled compound. MS (ESI) m/z 367 (M+H)⁺, 366 (M-H)⁺.

H

Intermediate 27B

4-(fluorodiphenylmethyl)piperidine

The title compound was prepared from tert-butyl 4-(hydroxydiphenylmethyl)piperidine-lcarboxylate using the general methods of Intermediates 26A and 26B. 3.37 g (100%) as HCI salt, MS (DCI) m/z 270 (M+H)⁺

General Procedures

General Procedure 1. Synthesis of 4-aminosuhstituted anilines

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Step 1

Step 2

Intermediate anilines having an amino group para to the aniline can be made using a two-step

procedure.

Fluoronitrobenzenes, fluoronitropyridines, or fluoronitropyrimidines can be reacted in N V

Step 1 with an appropriate amine H , where represents any amine group that can be present in R_M and attached through nitrogen, in the presence of dibasic potassium phosphate (equivalents ) or potassium carbonate in a solvent such as DMSO optionally with heating and optional microwave irradiation. Step 2 can be accomplished by standard nitro reduction conditions such as catalytic hydrogenation using palladium on carbon or Raney-nickel. Alternatively, the reduction can be effected with iron/ammonium chloride in THF/methanol/water as solvent. Where the group

H is an optionally substituted cyclic amine (e.g., piperidine, pyrrolidine), the optionally substituted cyclic amines can be accessed as described herein or using generally known methodologies. See for example the methods shown in Patel et al. J Medicinal Chemistry 49(25) 7450 (2006).

.5 Illustration of General Procedure 1: General Procedure 1A

Step 1

-(2,6 -difluoro-4 -nitrophenyl) -4 -phenylpiperidine

In a 100 mL round-bottom flask was mixed 3,4,5-trifluoronitrobenzene (1.751 mL, 15 mmol) and potassium phosphate, dibasic (5.23 g, 30.0 mmol) in DMSO (15.00 mL) to give a yellow 20 suspension. 4-Phenylpiperidine (2.419 g, 15.00 mmol) was added portion-wise as a solid over 10 minutes to produce a deeper yellow suspension and a mild exotherm. The mixture was stirred for 1 hour and partitioned between EtOAc and water. The EtOAc layer was washed 2* by 50 mL each with water and brine, dried (Na₂SO₄), filtered and concentrated to give the title compound as a yellow solid (4.53 g, 95% yield).

Step 2

3,5 -difluoro-4 -(4-phenylpiperidin-1 -yl)aniline

In a 500 mL round-bottom flask was added 1-(2,6-difluoro-4-nitrophenyl)-4-phenylpiperidine (4.53 g, 14.23 mmol), iron (3.97 g, 71.2 mmol), and ammonium chloride (1.142 g, 21.35 mmol) in a

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2016238925 07 Oct 2016 solvent mixture of EtOH (60 mL)/THF (60 mL)/water (20 mL). The mixture was refluxed for 3 hours with vigorous stirring, cooled, filtered through diatomaceous earth and the filtrate was concentrated.

The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na₂SO₄), filtered and evaporated to give the title compound as yellow solid (3.93 g, 96% yield). Ή NMR (400 MHz, DMSO-4,) δ ppm 1.63-1.81 (m, 4 H) 2.54 - 2.64 (m, 1 H) 2.95 - 3.03 (m, 2 H) 3.09 (t, 7=10.57 Hz, 2 H) 5.42 (s, 2 H) 6.10 - 6.21 (m, 2 H) 7.15 - 7.22 (m, 1 H) 7.25 - 7.34 (m, 4 H); MS (ESI+) m/z 289 (M+H)⁺.

Illustration of General Procedure 1: General Procedure IB

Step 1

5- nitro-2-(pyrrolidin-1 -yl)pyridine

To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100 mL) at room temperature was added pyrrolidine (15.72 mL, 189 mmol) and the mixture was heated at 70 °C for 18 hours. The cooled solution was concentrated in vacuo and the residue partitioned between CH₂C1₂.5 and 1MNaOH. The organic layer was dried (Na₂SO₄), filtered and solvent removed in vacuo to give title compound (9.52 g, 78%). MS (ESI) m/z 194 (M+H)⁺.

Step 2

6- (pyrrolidin-1 -yl)pyridin-3 -amine

5-Nitro-2-(pyrrolidin-l-yl)pyridine (9.52 g, 49.3 mmol) was dissolved in THF (50 mL) and !0 DMF (40 mL) and added to a pressure bottle containing Raney-nickel 2800, water slurry (45%) (9.52 g, 162 mmol). The mixture was stirred for 2 hours at 30 psi under H₂ gas. The solution was filtered through a nylon membrane, washed with CH₃OH and the filtrate concentrated in vacuo to give the title compound (7.78 g, 97%). Ή NMR (400 MHz, DMSO-7₆) δ ppm 1.81-1.91 (m, 4H) 3.17-3.29 (m, 4H) 4.30 (s, 2H) 6.25 (d, J=8.7, 1H), 6.90 (dd, J=2.8, 8.7, 1H), 7.55 (d, J=2.6, 1H); MS (ESI) m/z 25 164 (M+H)⁺.

Illustration of General Procedure 1, step 2: General Procedure 1C

4-(3,5 -dimethylpiperidin-1 -y 1)-3,5 -difluoroaniline

1-(2,6-Difluoro-4-nitrophenyl)-3,5-dimethylpiperidine (14.01 g, 51.8 mmol) and THF (240 30 mL) were added to Raney-nickel 2800, water slurry (14.01 g, 239 mmol) in a 500 mL stainless steel pressure bottle. The mixture was stirred for 8 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane and concentrated to give the title compound.

Illustration of General Procedure 1, step 2: General Procedure ID

-methyl-4-(piperidin-1 -yl)aniline

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To a solution of l-(2-methyl-4-nitrophenyl)piperidine (6.75 g, 30.6 mmol) in ethyl acetate (50 mL) was added 10% palladium on carbon (0.033 g, 0.306 mmol) and the mixture hydrogenated (hydrogen balloon) at room temperature for 20 hours. The mixture was then filtered through diatomaceous earth and washed with ethyl acetate; the filtrate was then concentrated to afford 5.5 g (94%) of the title compound. MS (ESI) m/z 191 (M+H)⁺.

Illustration of General Procedure 1, step 1: General Procedure IE

1-(4 -nitrophenyl) -4 -phenylpiperidine

An oven-dried 20 mL microwave tube was charged with 4-fluoronitrobenzene (0.752 mL, 0 7.02 mmol), 4-phenylpiperidine (1.166 g, 7.02 mmol), and potassium carbonate (0.970 g, 7.02 mmol) under nitrogen, anhydrous DMSO (7 mL) was added, the tube was sealed with an aluminum crimp cap, and heated in a microwave reactor (Personal Chemistry, 300 W, 2.4 bar) at 190 °C for 10 minutes. TLC (SiO₂, 5% EtOAc/hexanes) showed complete reaction. The reaction was poured into water (50 mL), stirred for 5 minutes, and vacuum filtered in a Buchner funnel. The collected yellow 5 solids were washed with water (2x10 mL) and Et₂O (5 mL), and the bright yellow solid was dried in vacuo to provide the title compound (1.712 g, 6.06 mmol, 86%). 'H NMR (400 MHz, CDCfi) δ ppm 1.73 - 1.90 (m, 2 H), 2.00 (d, 7=13.34 Hz, 2 H), 2.73 - 2.86 (m, 1 H), 3.02 - 3.17 (m, 2 H), 4.10 (d, 7=13.23 Hz, 2 H), 6.87 (d, 7=9.43 Hz, 2 H), 7.23 (t, 7=7.75 Hz, 3 H), 7.33 (t, 7=7.43 Hz, 2 H), 8.14 (d, 7=9.33 Hz, 2 H); MS (ESI+) m/z 283 (M+H)⁺.

!0

The following amines can be made using methods shown in the foregoing General Procedure 1:

4-(4,4-dimethylpiperidin-1 -y 1)-3,5 -difluoroaniline;

4-(2 -azabicyclo [2.2.2] octan-2-yl) -3,5 -difluoroaniline;

3.5- difluoro-4-(4-isopropylpiperidin-l-yl)aniline;

3,5-difluoro-4-(4-(trifluoromethyl)piperidin-l -yl)aniline;

4-(4-/i77-biitylpipcridin-1 -yl)-3,5 -difluoroaniline;

3,5 -difluoro -4 -(6-azaspiro [2.5] octan-6 -yl)aniline;

4-(3,3 -dimethylazetidin-1 -y 1)-3,5 -difluoroaniline;

4-(4,4-difluoropiperidin-1 -yl)-3,5 -difluoroaniline;

3,5 -difluoro -4 -(4-fluoropiperidin-1 -yl)aniline;

3,5 -difluoro -4 -(piperidin-1 -yl)aniline;

2,3,5,6-tetrafluoro-4-(piperidin-l-yl)aniline;

-methyl -4-(piperidin-1 -yl)aniline;

3.5- difluoro-4-((3aR,7aS)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7a70-yl)aniline;

A''^l-/t'/7-butyl-2-fliiorobcnzcnc-l.4-diaminc:

3,5 -difluoro -4 -(4-methylpiperidin-1 -yl)aniline;

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3.5 -dichloro-4-(piperidin-1 -yl)aniline;

2.5 -difluoro -4 -(piperidin-1 -yl)aniline;

4-((2Λ,65)-2,6-dimethylpiperidin-1-yl)-3,5-difluoroaniline;

2.3.5 -trifluoro-4-(piperidin-1 -yl)aniline;

4-((lR,55)-3-azabicyclo[3.2.0]heptan-3-yl)-3,5-difluoroaniline;

-fluoro -4 -(piperidin-1 -yl)aniline;

3.5 -difluoro -4 -(3 -azaspiro [5.5] undecan-3 -yl)aniline;

3,5 -difluoro -4 -(isoindolin-2-yl)aniline;

3,5 -difluoro -4 -(1,4 -dioxa-8 -azaspiro [4.5] decan-8 -yl)aniline;

4-(4-phenyl-5,6-dihydropyridin-1 (26/)-yl [aniline:

3- fluoro-4-(4-phenylpiperidin-l-yl)aniline;

4- (4,4-diphenylpiperidin-1 -yl)-3,5 -difluoroaniline;

4-(4-phenylpiperidin-l-yl)aniline;

l-(l-(4-amino-2,6-difluorophenyl)-4-phenylpiperidin-4-yl)ethanone;

3,5-difluoro-4-(4-(3-phenylpropyl)piperidin-l-yl)aniline;

3,5 -difluoro -4 -(8 -azaspiro [4.5 ] decan-8 -yl)aniline;

3,5 -difluoro -4 -(3 -phenylpiperidin-1 -yl)aniline;

3,5 -difluoro -4 -(3 -phenylpyrrolidin-1 -yl) aniline;

3,5 -difluoro -4 -(4-(4 -(trifluoromethyl)phenyl)piperazin-1 -yl)aniline;

!0 3,5 -difluoro -4 -(4-phenylpiperazin-1 -yl)aniline;

4-(4 -(2,6 -difluorophenyl)piperazin-1 -yl) -3,5 -difluoroaniline;

3,5 -difluoro -4 -(4-(pyrimidin-2 -yl)piperazin-1 -yl)aniline;

3,5 -difluoro -4 -(2-phenylmorpholino)aniline;

(S) -3,5 -difluoro-4-(2 -phenylmorpholino)aniline

3,5 -difluoro -4 -(2-phenylpiperidin-1 -yl)aniline;

4-((2 S, 6R) -2,6-dimethylmorpholino) -3,5 -difluoroaniline;

4-(4 -cyclohexylpiperidin-1 -yl) -3,5 -difluoroaniline;

4-(4 -benzylpiperidin-1 -yl) -3,5 -difluoroaniline;

3,5 -difluoro -4 -(4-(4 -methoxyphenyl)piperidin-1 -yl) aniline;

3,5 -difluoro -4 -(4-(4 -fluorophenyl)piperidin-1 -yl) aniline;

4-(4-(3,4 -difluorophenyl)piperidin-1 -yl) -3,5 -difluoroaniline;

4-(4-(3,5 -difluorophenyl)piperidin-1 -yl) -3,5 -difluoroaniline;

3,5 -difluoro -4 -(4-fluoro -4 -phenylpiperidin-1 -yl)aniline;

3,5-difluoro-4-(4-(fluorodiphenylmethyl)piperidin-l-yl)aniline;

4-(4-fluoro-4-phenylpiperidin-l -yl)aniline;

3,5 -difluoro -4 -(4-(pyridin-2-yl)piperidin-1 -yl)aniline;

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3,5 -difluoro -4 -(4-(naphthalen-2 -yl)piperidin-1 -yl)aniline;

3.5- difluoro-4-(4-(naphthalen-l-yl)piperidin-l-yl)aniline; and

3.5- difluoro-4-(4-(4-(trimethylsilyl)phenyl)piperidin-l-yl)aniline.

General Procedure 1.1. 4-Alkoxy-substituted aniline

Intermediate anilines having an alkoxy substituent para to the aniline may be prepared through a two-step procedure wherein Gi₀ is -OR_S (e.g., -O-t-butyl, -O-isopropyl, -O-CH₂-(3ethyloxetan-3-yl), -O-CH₂-(l,3-dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -0-(1,3-dioxan-50 yl)). In Step 1, fluoronitrobenzenes can be reacted with an appropriate alcohol and base (e.g.,

Cs₂CO₃, potassium tert-butoxide) in DMSO or like solvent with heating to between 50-100 °C. Step 2 can be accomplished by standard nitro reduction conditions such as catalytic hydrogenation using palladium on carbon or Raney nickel as described elsewhere herein. Alternatively, the reduction can be effected with iron/ammonium chloride in THF/methanol/water as solvent.

.5

Illustration of General Procedure 1.1: General Procedure 1.1 A Step 1

-ethyl-3 -((4-nitrophenoxy)methyl)oxetane

To a solution of 4-fluoronitrobenzene (3.76 mL, 35.4 mmol) in DMSO (35 mL) at room !0 temperature was added cesium carbonate (7.09 mL, 89.0 mmol) followed by 3-ethyl-3oxetanemethanol (4.48 mL, 42.5 mmol). The mixture was heated to 70 °C for 2 hours. After cooling water was added and the resulting precipitate was filtered, washed with water, and dried in a vacuum oven to provide the title compound (8.28 g, 98% yield).

Step 2

4-((3 -ethyloxetan-3 -yl)methoxy)aniline

To a solution of 3-ethyl-3-((4-nitrophenoxy)methyl)oxetane (8.28 g, 34.9 mmol) in a 3:3:1 mixture of THF:EtOH:water (140 mL) at room temperature was added ammonium chloride (2.80 g, 52.3 mmol) followed by iron powder (9.74 g, 174 mmol). The mixture was heated to 90 °C for 1 hour, then it was filtered hot through diatomaceous earth with a THF wash to complete the transfer.

The filtrate was concentrated under reduced pressure, and the residue was taken up in ethyl acetate then washed with brine, dried (Na₂SO₄), and concentrated to provide the title compound (7.12 g, 98% yield) without further purification.

225

4-((3-ethyloxetan-3-yl)methoxy)-3,5-difluoroaniline;

4-(( 1,3 -dioxolan-4-yl)methoxy)aniline;

4-(1,3 -dioxan-5 -yloxy)aniline.

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General Procedure 1.2. Aniline formation through Suzuki-type reaction

Certain intermediate anilines can be made from a bromide, iodide, or triflate (i.e., Xi ₂ = Br, I, 0 or OTf) through a Suzuki, Stille, or other similar transition metal-mediated carbon-carbon bond forming reaction to form products where R_{Mi 2} is cycloalkyl, aryl, heteroaryl, or cycloalkenyl. Above is an illustration of the process conducted on an aniline, however the process can be done also using other functionality which can be converted to an aniline (e.g., a nitro group).

.5 Illustration of General Procedure 1.2. General Procedure 1.2A.

4-(cyclohexen-1 -yl) -3 -fluoroaniline

In a pressure tube, a solution of 3-fluoro-4-iodoaniline (2.29 g, 9.66 mmol) and potassium carbonate (1.74 g, 12.58 mmol) in 4:1 dimethoxyethane-water (33 mL) was degassed by nitrogen sparge for 40 minutes, followed by addition of 1-cyclohexenyl boronic acid pinacol ester (2.7 mL, !0 2.61 g, 12.56 mmol). Then l,l'-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added followed by degassing for another 5 minutes. The pressure tube was sealed and warmed at 100 °C for 18 hours. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and saturated sodium chloride solution. The solution was dried (Na₂SO₄) and stirred with 3-(mercaptopropyl) silica gel for 1 hour. 25 Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (1.16 g, 63%) as a light brown oil. 'H NMR (400 MHz, CDC1₃) δ ppm 7.00 (m, 1 H), 6.37 (m, 2 H), 5.84 (s, 1 H), 3.71 (br s, 2 H), 2.32 (m, 2 H), 2.17 (m, 2 H), 1.73 (m, 2 H), 1.65 (m, 2 H); MS (+DCI) m/z (rel abundance) 192 (100, M+H).

Illustration of General Procedure 1.2. General Procedure 1.2B.

4-cyclopropyl-3,5 -difluoroaniline

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To a pressure tube was added 4-bromo-3,5-difluoroaniline (l.Og, 4.8 mmol), cesium carbonate (4.7g, 14.4 mmol), toluene (lOmL) and water (ImL). The solution was de-gassed with N₂ gas for 30 minutes, followed by the addition of cyclopropyltrifluoro-borate, potassium salt (0.8g, 5.3 mmol), di(l-adamantyl)-w-butylphosphine hydroiodide (0.07g, 0.14 mmol) and palladium(II) acetate (0.02g, 0.096 mmol). De-gassing was continued for 5 minutes, the tube was sealed and heated at 100 °C for 18hours. The cooled solution was diluted with EtOAc, washed with H₂O and brine, dried (Na₂SO₄), and filtered. The filtrate was treated with 3-mercaptopropyl silica gel for 1 hour. The mixture was filtered and concentrated to give crude product which was purified by flash chromatography (0-30% EtOAc/hexane) to give the title compound (0.67 g, 4.0 mmol, 82%).

Illustration of General Procedure 1.2. General Procedure 1.2C.

4-cyclopropyl-2-fluoro-1 -nitrobenzene

A solution of 4-bromo-2-fluoronitrobenzene (0.5g, 2.27mmol), cyclopropylboronic acid (0.293g, 3.41mmol), tribasic potassium phosphate (0.965g, 4.55mmol), tricyclohexylphosphonium 5 tetrafluoroborate (0.021g, 0.057mmol) and palladium (II) acetate ( 6.12mg 0.027mmol) in 11 mL of a toluene-water mixture 10:1 (v/v) was nitrogen purged-vacuum degassed three times. The reaction mixture was then heated in an oil bath at 85°C for four hours. The reaction mixture was partitioned with ethyl acetate and the organic phase water washed then dried (Na₂SO₄) and concentrated. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed !0 with water, dried (Na₂SO₄) and concentrated. The crude product was purified by chromatography on silica gel (ethyl acetate-hexane) to provide the title compound (0.382g, 88%) as a yellow oil.

General Procedure 1.3

Certain intermediate anilines can be made using the general sequence outlined above and illustrated below. The sequence consists of reaction of a fluoronitrobenzene with a cyclic amine moiety (Step 1); conversion to a vinylic coupling partner (Steps 2 and 3); coupling of the vinylic coupling partner with another suitable partner (Step 4); and reduction of the nitro group and olefin 30 (Step 5). Alternatively, this route may be adapted to prepare anilines wherein the olefin remains

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2016238925 07 Oct 2016 intact through selective reduction of the nitro group. Carbon-carbon bond forming reactions that may be suitable for Step 4 include, for example, the Suzuki reaction, the Stille reaction, or the Negishi reaction.

Illustration of General Procedure 1.3: General Procedure 1.3A

Step 1

8-(2,6-difluoro-4-nitrophenyl)-l,4-dioxa-8-azaspiro[4.5]decane

A mixture of l,2,3-trifluoro-5-nitrobenzene (4.0 mL, 34.3 mmol), l,4-dioxa-8azaspiro[4.5]decane (6.59 mL, 51.4 mmol) and potassium carbonate (5.68 g, 41.1 mmol) in DMSO (35 mL) was heated at 100 °C for 3 hours and then cooled to room temperature. The mixture was 0 partitioned between water and EtOAc, and the organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes to give a yellow oil.

Step 2

F

.5 F

1-(2,6-difluoro-4-nitrophenyl)piperidin-4-one

The crude 8-(2,6-difluoro-4-nitrophenyl)-l,4-dioxa-8-azaspiro[4.5]decane from the preceding procedure was dissolved in 4:1 acetone:water (100 mL). Concentrated HC1 (5 mL) was added, and the resulting mixture was stirred at 50 °C for 8 hours and then cooled to room temperature. The !0 mixture was concentrated in vacuo to approximately 20 mL, which was carefully added to concentrated aq. NaHCO₃ (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was triturated with Et₂O and hexanes to give a bright-yellow solid that was collected and dried to provide the title compound (7.13 g, 81%).

Step 3

F

O₂N —— l·/ — OSO₂CF₃

F l-(2,6-difluoro-4-nitrophenyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethane sulfonate

To a solution of 1-(2,6-difluoro-4-nitrophenyl)piperidin-4-one (5.0 g, 19.52 mmol) in anhydrous THF (50 mL) at -78 °C under a dry N₂ atmosphere was added a 1 M THF solution of lithium bis(triethylsilyl)amide (29.3 ml, 29.3 mmol) in THF dropwise over 10 minutes. The resulting deep red solution was stirred at -78 °C for 5 minutes and l,l,l-trifluoro-2V-phenyl-JV228

2016238925 07 Oct 2016 (trifluoromethylsulfonyl)methanesulfonamide (7.67 g, 21.47 mmol) was added. The resulting mixture was stirred at - 78 °C for 1 hour, and then the mixture was allowed to warm to room temperature. The mixture was diluted with EtOAc (100 mL) and washed with 1 N aq. NaOH (50 mL) and water (50 mL), and dried over Na₂SO₄. The drying agent was filtered off, and the solvent was removed in vacuo 5 to give a crude product that was purified by column chromatography on silica gel using a solvent gradient of 0-40% EtOAc in hexanes. The title compound was obtained as a yellow oil that crystallized in vacuo (6.12 g, 81%).

Step 4 (Suzuki reaction)

F

F F l-(2,6-difluoro-4-nitrophenyl)-4-(3,4-difluorophenyl)-l,2,3,6-tetrahydropyridine

A mixture of l-(2,6-difluoro-4-nitrophenyl)-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.18 g, 3.04 mmol), 2-(3,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (1.02 g, 4.25 mmol), lithium chloride (0.387 g, 9.12 mmol) and a 2.0 ATaq. solution of 5 sodium carbonate (4.56 mL, 9.12 mmol) in anhydrous DME (15 mL) was vigorously stirred while bubbling with N₂ gas for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.176 g, 0.152 mmol) was added, and the resulting mixture was degassed for 5 minutes more. The reaction flask was equipped with a condenser and placed in 100 °C oil bath. The dark mixture was stirred at 100 °C under a dry N₂ atmosphere for 16 hours, and was then cooled to room temperature and partitioned !0 between water (50 mL) and EtOAc (2x50 mL). The combined organic layers were dried over

Na₂SO₄, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% EtOAc in hexanes to provide a yellow oil that solidified on standing. The solid was triturated with Et₂O and hexanes, filtered and dried to

(4-(4-(3,4-difluorophenyl)piperidin-1 -yl) -3,5 -difluoroaniline

To a solution of 1-(2,6-difluoro-4-nitrophenyl)-4-(3,4-difluorophenyl)-l,2,3,630 tetrahydropyridine (0.67 g, 1.90 mmol) in THF (20 mL) was added 10% Pd on carbon (50 mg). The reaction flask was flushed with N₂ gas, and the resulting mixture was vigorously stirred under 1 atm

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H₂ gas for 24 hours. The mixture was filtered through diatomaceous earth and concentrated in vacuo to give the title compound as a solid (0.62 g, 100%).

The following amines can be made using methods shown in the foregoing General Procedure 1.3:

3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-f -yl)aniline;

3,5-difluoro-4-(4-(3-(trimethylsilyl)phenyl)piperidin-l-yl)aniline; and

3,5 -difluoro -4-(4-(5 -methylthiophen-2-yl)piperidin-1 -yl)aniline.

General Procedure 2. Pyrrolidine formation from amine and dimesylate (5)

A dimesylate (5) (1 equivalent), as a single stereoisomer or mixture of isomers, may be reacted with between 1 to 20 equivalents of an amine,.D-NH₂, either neat, or in solvents such as tetrahydrofuran or 2-methyltetrahydrofuran with or without a co-solvent such as DMF, at about room temperature to about 100 °C, to give the pyrrolidines such as Formula (6). Where fewer equivalents 5 of amine, D-NH₂, are employed (i.e., 1-2 equivalents), a base such as diisopropylethylamine can be added to promote the reaction. For example, the reaction of a dimesylate (1 equivalent) with excess of an aniline, D-NH₂, (about 5-10 equivalents) can be conducted by heating from 50 to 65 °C in 2methyltetrahydrofuran or DMF until completion of the reaction. Or the dimesylate (1 equivalent) can be reacted neat with excess of an aniline, D-NH₂, (about 15-20 equivalents) at room temperature or !0 with heating to around 65 °C. The reaction can be partitioned between an organic solvent (e.g., ethyl acetate) and dilute aqueous HC1, followed by separation of the organic layer, optional washing of the organic with water, drying the organic layer with a drying agent (e.g., MgSO₄, Na₂SO₄), filtration and evaporation of solvent. The product can be purified by column chromatography over silica gel, eluting with standard solvents such as mixtures of ethyl acetate and hexane; or alternatively the 25 product can be purified by trituration or recrystallization.

Illustration of General Procedure 2: General Procedure 2A (25,55)-1 -(4-tert-butylphenyl )-2,5 -bis(4-nitrophenyl)pyrrolidine

To the crude product solution of Intermediate 6C (7.35 g, 13.39 mmol) was added d-tert30 butylaniline (13.4 g, 90 mmol) at 23 °C over 1 minute. The reaction was heated to 65 °C for 2 hours.

After completion, the reaction mixture was cooled to 23 °C and diluted with 2-methyltetrahydrofuran (fOO mL) and f MHC1 (150 mL). After partitioning the phases, the organic phase was treated with f Λ7 HCI (f40 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt% aq. NaCl (fOO mL), and the phases

230

2016238925 07 Oct 2016 were partitioned. The organic phase was washed with 25 wt% aq. NaCl (50 mL), dried over MgSO₄, filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 25 methyltetrahydrofuramheptane (1:4, 20 mL). The solids were suspended in CH₃0H (46 mL) for 3 hours, filtered, and the wet solid was washed with additional CH₃0H (18 mL). The solid was dried at 45 °C in a vacuum oven for 16 hours to provide the title compound (3.08 g).

General Procedure 3. Pyrrolidine formation from amine and bisbromophenyldimesylate

OMs	r T rii ?
	d-nh₂
Br·^	OMs ------------'

General Procedure 3 can be conducted using conditions substantially similar to the conditions of General Procedure 2.

Illustration of General Procedure 3: General Procedure 3A (2.S'.5.S')-2.5-bis(4-bromophcnyl)-1 -(4-tert-butylphenyl)pyrrolidine

Intermediate 7C was dissolved in anhydrous DMF (5 mL), and 4-tert-butylaniline (2.39 mL, mmol) was added. The resulting mixture was stirred at 40 °C for 4 hours, and then it was partitioned between 1 N aq. HCI (30 mL) and EtOAc (30 mL). The organic layer was washed with H₂O and dried over Na₂SO₄. The drying agent was filtered off, the solvent was removed in vacuo, !0 and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes. The title compound was obtained as a colorless solid (0.71 g, 92%). 'H NMR indicated this material was a 87:13 mixture of trans:cis pyrrolidine isomers.

General Procedure 4.

Pyrrolidine formation from amine and dimesylate (52)

General Procedure 4 can be conducted using conditions substantially similar to the conditions of General Procedure 2. For example, a dimesylate (52) (1 equivalent), as a single stereoisomer or mixture of isomers, may be reacted with between 1 to 20 equivalents of an amine D-NH₂ either neat, or in solvents or mixtures of solvents including ethanol, acetonitrile, methylene chloride,

231

2016238925 07 Oct 2016 tetrahydrofuran , 2-methyltetrahydrofuran, DMF, or DMA, at about room temperature to about 100 °C, to give the pyrrolidines such as Formula (53). Alternatively, a dimesylate (52) (1 equivalent) can be reacted with an amine D-NH₂ (1-4 equivalents) in the presence of a base like diisopropylethylamine (3-10 equivalents) in solvents or mixtures of solvents including methylene 5 chloride, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, or DMA at temperatures from around room temperature to about 70 °C. Where fewer equivalents of amine D-NH₂ are employed (i.e., 1-2 equivalents), greater amounts of a base (about 8-10 equivalents) such as diisopropylethylamine may be added to promote the reaction. For less reactive amines (e.g., 2,5-difluoro-4(trifluoromethyl)aniline, 2-fluoropyridin-4-amine), a reaction time of several days may be required. 0 The reaction can be partitioned between an organic solvent (e.g., ethyl acetate) and water or dilute aqueous HC1, followed by separation of the organic layer, optional washing of the organic with water and/or brine, drying the organic layer with a drying agent (e.g., MgSO₄, Na₂SO₄), filtration and evaporation of solvent. The product (53) can be purified by column chromatography over silica gel, eluting with standard solvents such as mixtures of ethyl acetate and hexane or methylene chloride in 5 hexane. The methylene chloride/hexane system can be used to remove residual amine in cases where the reaction is quenched in water instead of aqueous HC1. In such cases a second chromatography using an ethyl acetate/hexane system may be necessary to separate cis from trans pyrrolidine products. Or alternatively, the product can be purified by trituration or recrystallization.

!0 Illustration of General Procedure 4: General Procedure 4A (2/?.5/?)-2.5-bis(4-chloro-3-nitrophcnyl)-l -(4-cyclohcxylphcnyl)pyrrolidinc

To Intermediate 5D (4.99 mmol) in dimethylformamide (8 mL) was added 4cyclohexylaniline (5.24 g, 29.9 mmol), and the solution was heated at 65 °C for 2 hours. The reaction mixture was then poured into 1 M HC1 and extracted into dichloromethane. The organic phase was 25 concentrated and purified with a CombiFlash® 80g silica column eluting with 0-20% ethyl acetate in hexanes to give 1.38 g (51%) of the title compound.

Illustration of General Procedure 4: General Procedure 4B l-(4-((27?,57?)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-phenylpiperidine 30 A 250 mL flask was charged with 3,5-difluoro-4-(4-phenylpiperidin-l-yl)aniline (3.1 g, 10.76 mmol), Intermediate 5D (5.0 g, 8.97 mmol), DMF (15 mL) and diisopropylethylamine (15.7 mL, 90 mmol). The resulting slurry was placed in a 60 °C oil bath and heated under N₂ for 18 hours. The amber solution was cooled, diluted with 300 mL of ethyl acetate, washed 2* 100 mL water, 2* 100 mL with 1 N HC1, brine, dried (Na₂SO₄), filtered and concentrated. The crude material was flash 35 chromatographed on a 330 g silica cartridge eluting with 50-80% dichloromethane in hexane to remove unreacted aniline. The column fractions containing the product were combined and

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2016238925 07 Oct 2016 concentrated to give an orange solid that was dissolved in 20 mL of hot ethyl acetate, treated with 15 mL hexane, and allowed to stir at ambient temperature overnight producing a precipitate (cis pyrrolidine) that was removed by filtration. The filtrate was concentrated and chromatographed again on a 330 g silica cartridge eluting with 40-70% methylene chloride in hexane to give 1 -(4-((2R.5R)5 2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-phenylpiperidine as an orange foam (2.26 g, 36%). MS (ESI+) m/z 653 (M+H)⁺.

Illustration of General Procedure 4: General Procedure 4C l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2-fluorophenyl)-4-phenylpiperidine

Intermediate 5D (6.0 g, 10.76 mmol), 3-fluoro-4-(4-phenylpiperidin-l-yl)aniline (4.37 g,

16.15 mmol), and diisopropylethylamine (15.04 mL, 86 mmol) were combined in N,Ndimethylacetamide (15 mL) and heated at 60 °C for 3 hours. The solution was diluted with water, extracted into dichloromethane and washed with brine. The organics were concentrated and purified by chromatography, eluting with 30-100% dichloromethane in hexanes to give 5.05 g (74%) of a 5 yellow solid.

Illustration of General Procedure 4: General Procedure 4D (2/?.5/?)-2.5-bis(4-chloro-3-nitrophcnyl)-l-(4-cthoxyphcnyl)pyrrolidinc

Intermediate 5D (2.5805 g, 4.63 mmol) and 4-ethoxyaniline (2.4 mL, 18.60 mmol) were !0 combined in DMF (30 mL) and stirred at room temperature overnight. The reaction was diluted with

EtOAc/ether and washed with water (2x), brine (lx) and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc) to provide 1.8 g of the title compound (77%).

Illustration of General Procedure 4: General Procedure 4E

I-(4-((2//.5//)-2.5-bis(4-chloro-2-fluoro-5-nitrophcnyl)pyrrolidin-1 -yl)-2.6-difluorophcnyl)pipcridinc

To a solution of (IS,45)-1,4-bis(4-chloro-2-fluoro-5-nitrophenyl)butane-l,4-diyl dimethanesulfonate (500 mg, 0.843 mmol) in CH₃CN (4.5 ml) was added 3,5-difluoro-4-(piperidin-l-yl)aniline (358 mg, 1.685 mmol) and Hunig's base (0.736 mL, 4.21 mmol). The suspension was heated at 75 °C for 24 hours. Solvent was removed by rotary evaporation and the residue was dissolved in EtOAc, washed with 1 N HC1, FQO, brine, dried (MgSO^). filtered and concentrated. The crude product was chromatographed on an ISCO 24g silica gel cartridge eluting with 20-70% CFQCQ/hexane to provide the title compound with some of the corresponding cis-pyrrolidine isomer.

The following substituted pyrrolidines can be made using the foregoing general methods:

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2016238925 07 Oct 2016

1- (4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4,4dimethylpiperidine;

2- (4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-2azabicyclo[2.2.2]octane;

1-(4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4isopropylpiperidine;

l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4(trifluoromethyl)piperidine;

l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-tert0 butylpiperidine;

6-(4-( (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-6azaspiro [2.5] octane;

l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4,4dimethylpiperidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-(3,3-dimethylazetidin-l-yl)-3,5difluorophenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-phenoxyphenyl)pyrrolidine;

-(4-((27/,57/)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin-1 -yl)phenyl)pyridin-2( 1 77)-one; (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(2,5-difluoro-4-(trifluoromethyl)phenyl)pyrrolidine;

!0 2-(4-((2//.5//)-2.5-bis(4-chloro-3-nitrophcnyl)pyrrolidin-1-yl)phcnyl (oxazole:

4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2-fluoropyridine;

(27/,57/)-1-(4-chloro-3-fluorophenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine; l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4,4difluoropiperidine;

l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-fluoropiperidine;

1-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine; (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-fluorophenyl)pyrrolidine;

(27/,57/)-1-(4-ter/-butylphenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine; (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-cyclopropyl-3,5-difluorophenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-cyclohexyl-3-fluorophenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(3,4-difluorophenyl)pyrrolidine; (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-(2,2-difluoroethoxy)phenyl)pyrrolidine;

1-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-1-yl)-2,6-difluorophenyl)-3,5dimethylpiperidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-[4-(pentafluoro-X⁶-sulfanyl)phenyl]pyrrolidine (ACD

Name vl2);

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2016238925 07 Oct 2016

2- (4-((2//.5//)-2.5-bis(4-chloro-3-nitrophcnyl)pyrrolidin-1-yl)phcnyl)pyridinc:

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-(2-methoxyethoxy)-3-methylphenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-chlorophenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-((3-ethyloxetan-3-yl)methoxy)phenyl)pyrrolidine;

(27/,57/)-1-(biphenyl-4-yl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;

(27/,57/)-1-(4-(1,3-dioxan-5-yloxy)phenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;

(27/,57/)-1-(4-((1,3-dioxolan-4-yl)methoxy)phenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-((3-ethyloxetan-3-yl)methoxy)-3,50 difluorophenyl)pyrrolidine;

1-(4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,3,5,6-tetrafluorophenyl)piperidine;

-(4-((27/,57/)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin-1 -yl)-2-methylphenyl)piperidine;

(3a//, 7a.S')-2-(4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6difluorophenyl)octahydro -1 H-i soi ndol e;

4-((2//.5//)-2.5-bis(4-chloro-3-nitrophcnyl)pyrrolidin-1-yl)-A''-/i77-butyl-2-fliioroanilinc:

-(4-((27/,57/)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin-1 -yl)-2,6-difluorophenyl)-4methylpiperidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-(cyclopentyloxy)-3-fluorophenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(3-fluoro-4-(methylthio)phenyl)pyrrolidine !0 l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-dichlorophenyl)piperidine; l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,5-difluorophenyl)piperidine;

(27/, 65)-1-(4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-2,6dimethylpiperidine;

1- (4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,3,6-trifluorophenyl)piperidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-cyclopropylphenyl)pyrrolidine;

(17/,55)-3-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-3azabicyclo [3.2.0]heptane;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-cyclopropyl-2-fluorophenyl)pyrrolidine;

-(4-((27/,57/)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin-1 -yl)-2-fluorophenyl)piperidine;

l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)phenyl)-4-phenylpiperidine;

3- (4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-3- azaspiro [5.5]undecane;

2- (4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)isoindoline;

8-(4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-l,4-dioxa-835 azaspiro [4.5] decane;

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2016238925 07 Oct 2016 l-(4-((2J?,5J?)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-phenyl-l,2,3,6tetrahydropyridine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4,4diphenylpiperidine;

l-(l-(4-((2J?,5J?)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4phenylpiperidin-4 -yl)ethanone;

l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)piperidine; l-(4-(2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(30 phenylpropyl)piperidine;

8-(4-( (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-8azaspiro [4.5] decane;

-(4-((2R,5R)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin-1 -yl)-2,6-difluorophenyl)-4-(naphthalen-2yl)piperidine;

2-(l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)piperidin-4yl)pyridine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(4(trimethylsilyl)phenyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(naphthalen-l!0 yl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(3phenylpropyl)piperidine;

6-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-6azaspiro [2.5] octane;

l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-tertbutylpiperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4(naphthalen-2-yl)piperidine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-3,530 dimethylpiperidine;

r-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-2,3dihydrospiro [indene -1,4'-piperidine];

1-(4-( (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-3phenylpiperidine;

(2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)-l-(3,5-difluoro-4-(3-phenylpyrrolidin-lyl)phenyl)pyrrolidine;

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2016238925 07 Oct 2016 l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(4methoxyphenyl)piperidine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-fluoro-4phenylpiperidine;

1 -(4-((2R,5R)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin-1 -yl)phenyl)-4-fluoro-4-phenylpiperidine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4(fluorodiphenylmethyl)piperidine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4phenylpiperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(4fluorophenyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(3,4difluorophenyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(3,55 difluorophenyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(3(trimethylsilyl)phenyl)piperidine;

(2R, 5 R) -1 -(4-(benzyloxy)phenyl) -2,5 -bis(4-chloro -3 -nitrophenyl)pyrrolidine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(4!0 (trifluoromethyl)phenyl)piperazine;

-(4-( (2R,5R)-2-(4-chloro-2-fluoro-5 -nitrophenyl)-5 -(4-chloro-3 -nitrophenyl)pyrrolidin-1 -yl)-2,6difluorophenyl)piperidine;

4-benzyl-l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6- difluorophenyl)piperidine;

4-(4-( (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-2phenylmorpholine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-2phenylpiperidine;

(2S,6R)-4-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)30 2,6-dimethylmorpholine;

3-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-3azaspiro [5.5]undecane;

-(4-( (2R,5R)-2,5 -bis(4-chloro-2-fluoro-5 -nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4cyclohexylpiperidine;

(S)-4-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-2phenylmorpholine;

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2016238925 07 Oct 2016 l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(2,4difluorophenyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(4fluorophenyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4phenylpiperazine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(4(trifluoromethyl)phenyl)piperazine;

1- (4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(2,6- difluorophenyl)piperazine;

2- (4-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6difluorophenyl)piperazin-1 -yl)pyrimidine;

5-((2S,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2-(4-phenylpiperidin-lyl)pyrimidine;

.5 5-((2S,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2-(piperidin-l-yl)pyrimidine; l-(4-((2S,5S)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(2,6difluorophenyl)piperazine;

l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(5methylthiophen-2-yl)piperidine; and !0 l-(4-((2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-fluoro-

4-phenylpiperidine.

General Procedure 5. Nitro reduction

(6) (7)

Compounds (6) (1 equivalent) can be reduced to (7) by reaction with iron powder (about 6 equivalents) and ammonium chloride (about 3 equivalents) in a solvent of THF:ethanol:water (1:1:0.2) with heating to about 60-80 °C. The reaction can be worked up by cooling, filtering through diatomaceous earth, washing with ethanol and concentrating in vacuo. Alternatively, (6) (1 equivalent) can be reduced to (7) by hydrogenation (30 psi H₂) in the presence of PtO₂ (about 0.4 equivalents) in a solvent of ethanol:THF (about 1:1). The reaction can be worked up by filtration and evaporation of solvent. Alternatively, the reduction of (6) (1 equivalent) to (7) can be effected by exposure to 30 psig hydrogen gas in the presence of Raney-nickel Grace 2800 (50% by weight of reactant) in a solvent such as tetrahydrofuran with shaking. The reaction can be worked up by

238 filtration and evaporation of solvent. The product (7) can be purified by chromatography over silica gel using typical organic solvents including mixtures of ethyl acetate and hexane.

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General Procedure 5.1. Nitro reduction for pyrrole

(11) (12)

Compounds (11) can be converted to (12) using the conditions described generally for General Procedure 5, particularly through the iron reduction method.

Illustration of General Procedure 5.1: General Procedure 5.1A

F F

4,4'-(l-(4-Fluorophenyl)-127-pyrrole-2,5-diyl)dianiline

To a solution of l-(4-fluorophenyl)-2,5-bis(4-nitrophenyl)-127-pyrrole (1.017 g, 2.496 mmol) in ethanol (15 mL) and THF (15 mL) was added iron powder (0.836 g, 14.98 mmol) followed by ammonium chloride (0.401 g, 7.49 mmol) and water (3.75 mL). The reaction mixture was refluxed 5 for 45 minutes. The reaction mixture was slurry filtered through diatomaceous earth and washed with ethanol. The combined filtrates were concentrated, and the residue purified by column chromatography (gradient elution from 30% to 50% EtOAc:hexanes) to provide 1.09 g (77%) of the title compound.

Compounds (7) (1 equivalent) can be converted to compounds (8) by reaction with \-(tertbutoxycarbonyl)pyrrolidine-2-carboxylic acid (about 2.5 equivalents) and HATU (about 2 to 3 25 equivalents) in the presence of diisopropylethylamine (3-4 equivalents) in DMSO at about room

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2016238925 07 Oct 2016 temperature. Alternatively to using HATU, this reaction can be promoted using T3P or l-ethyl-3-(3dimethylaminopropyl) carbodiimide/1-hydroxybenzotriazole. The reaction can also be conducted in solvents such as tetrahydrofuran, ethyl acetate, or DMF. The reaction can be worked up by partitioning between an organic solvent (e.g., ethyl acetate) and water or dilute aqueous HC1, followed 5 by separation of the organic layer, optional washing of the organic with water and/or brine, drying the organic layer with a drying agent (e.g., MgSO₄, Na₂SO₄), filtration and evaporation of solvent. The product (8) can be purified by column chromatography over silica gel, eluting with standard organic solvents including mixtures of ethyl acetate and hexane.

.0

Aniline compounds (12) can be converted to amides (13) using the conditions described generally above in General Procedure 6.

Illustration of General Procedure 6.1: General Procedure 6.1A

(2S,2'S)-/er/-butyl 2,2'-(4,4'-(l-(4-/ert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,l20 phenylene )bis(azanediyl)bis(oxomethylene))dipyrrolidine-1 -carboxylate

To a solution of 4,4'-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)dianiline (0.310 g, 0.813 mmol) in DMF (5 mL) was added (.8)-1-(/m-biitoxycarbonyl)pyrrolidinc-2-carboxylic acid (0.385 g, 1.79 mmol) 1-hydroxybenzotriazole hydrate (0.274 g; 1.79 mmol) and N-(3-dimethylaminopropyl)/V-cthylcarbodiimidc hydrochloride (0.343 g, 1.79 mmol), and the mixture stirred overnight. The 25 mixture was poured into water and extracted CH₂C1₂. The organic extract was dried (Na₂SO₄), filtered and concentrated to give a crude product that was purified by trituration with ether to give 325 mg (51%) of the title compound. 'H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (s, 24 H) 1.83 (s, 6 H)

2.15 (s, 2 H) 3.45 (m, 4 H) 4.18 (s, 2 H) 6.40 (s, 2 H) 6.98 (s, 6 H) 7.37 (s, 6 H) 9.98 (s, 2 H).

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General Procedure 7. Suzuki coupling

(34.1) (35.1)

(36.1)

Dibromo compounds (34.1) (1 equivalent) can be converted to diboronate compounds (35.1) by mixing with bis(pinacolato)diborane (about 2 to 4 equivalents), potassium acetate (about 4-8 equivalents), and l,l’-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloromethane complex (PdCl₂(dppf)) (about 0.1 to 0.2 equivalents) in a solvent such as DME, dioxane, or DMSO, degassing the mixture and heating to about 85 °C. The reaction can be worked up by cooling to room temperature, diluting with methylene chloride, optionally washing the organics with water and/or brine, drying the organics with a drying agent (e.g., MgSO₄, Na₂SO₄), filtration and evaporation of 0 solvent. Compounds (35.1) can be converted to compounds (36.1) by mixing with Intermediate ID (about 1 to 2 equivalents), aqueous sodium carbonate solution (about 1 to 3.5 equivalents), and PdCl₂(dppf) (about 0.03 to 0.2 equivalents) in a solvent like dimethoxyethane or toluene:ethanol (1:1), degassing, and heating the reaction to around 80-100 °C. The reaction can be worked up by cooling to room temperature, partitioning between an organic solvent (e.g., ethyl acetate) and water, .5 optionally washing the organics with water and/or brine, drying the organics with a drying agent (e.g.,

MgSO₄, Na₂SO₄), filtration and evaporation of solvent. Alternatively, the reaction can be worked up by concentration in vacuo, partitioning between 25% isopropylalcohol/chloroform, drying the organics (e.g., Na₂SO₄), filtration, and evaporation of the solvent. Compounds (35.1) and (36.1) can be purified by column chromatography over silica gel, eluting with standard organic solvents !0 including mixtures of ethyl acetate and hexane; or purified by trituration or recrystallization.

Illustration of General Procedure 7: General Procedure 7A

racemic trans-1 -(4-ter/-butylphenyl)-2.5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-225 yl)phenyl)pyrrolidine

Racemic trans-2,5-bis(4-bromophenyl)-l-(4-tert-butylphenyl)pyrrolidine (3.88 g, 7.56 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (6.72 g, 26.5 mmol), [1,1’bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.617 g, 0.756 mmol), and potassium acetate (3.34 g, 34.0 mmol) were combined in dimethoxyethane (70 mL) and nitrogen gas was sparged

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2016238925 07 Oct 2016 through the solution for 10 minutes. The reaction mixture was then heated at 85 °C for 1 hour. The reaction solution was cooled to room temperature, filtered through diatomaceous earth and washed with ethyl acetate (20 mL). The filtrate was dried and concentrated, and the residue was purified by column chromatography on silica gel, eluting with a solvent gradient of 0-10% ethyl acetate in hexane 5 followed by trituration of the resultant solid with diethyl ether to give the title compound (1.14 g, 25%) as a 1/1 mixture of trans stereoisomers.

(2.S'.2'.S)-/i77-biityl 2,2'-(5,5'-(4,4'-(l-(4-/ert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,lphenylene))bis( 1 f/-imidazolc-5.2-diyl))dipyrrolidinc-1 -carboxylate

Racemic trans-1 -(4-iert-butyl phenyl )-2,5 -bis(4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)pyrrolidine (0.915 g, 1.506 mmol), Intermediate ID (1.429 g, 4.52 mmol), and [1,1’bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.123 g, 0.151 mmol) were dissolved in a mixture of toluene (7 mL), ethanol (7 mL) and a 2 N aq. sodium bicarbonate solution (2.64 mL, 5.28 mmol). Nitrogen gas was bubbled through the solution for 10 minutes, and then the reaction mixture was heated at 100 °C for 3 hours. The reaction solution was cooled to room temperature and water (20 mL) was added. Then the reaction mixture was extracted with dichloromethane (50 mL), dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of 0-80% ethyl acetate in hexane to give the title compound (0.93 g, 75%) as a 1/1 mixture of trans stereoisomers.

!0

General Procedure 7.1. Suzuki coupling for pyrroles

Dibromo compounds (46) can be converted sequentially to compounds (47) and (43) using the conditions described generally above in General Procedure 7.

Illustration of General Procedure 7.1: General Procedure 7. IB

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l-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-pyrrole

To a solution of 2,5-bis(4-bromophenyl)-l-(4-tert-butylphenyl)-lH-pyrrole (2.32 g, 4.56 mmol) in DMSO (26 mL) at room temperature were added bis(pinacolato)diborane (2.54 g, 10.02 5 mmol), potassium acetate (5.00 g, 36.4 mmol) and PdCl₂(dppf) (744 mg, 0.91 mmol). The mixture was degassed and heated to 85 °C. After 4 hours, the mixture was cooled to room temperature, diluted with dichloromethane and washed with water followed by brine. The organic phase was dried (Na₂SO₄) and concentrated. The residue was taken up in 20% ethyl acetate/hexanes and filtered through a short plug of silica gel (elution with 20% ethyl acetate :hexanes) and concentrated to afford the title compound as a light yellow solid (1.62 g; 59% yield).

(25,2’.S')-/i77-biityl 2,2'-(4,4'-(4,4'-(l-(4-tert-butylphenyl)-lH-pyrrole-2,5-diyl)bis(4,lphenylene))bis( 1 H-imidazole-4,2-diyl))dipyrrolidine-1 -carboxylate

A mixture of Intermediate ID (664 mg, 2.10 mmol), l-(4-tert-butylphenyl)-2,5-bis(4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-pyrrole (1.48 g, 2.45 mmol), 2 M sodium carbonate (1400 pL, 2.80 mmol), and Pd(dppf)Cl₂ (51.2 mg, 0.070 mmol) in DME (2800 pL) was subjected to microwave irradiation at 140 °C for 20 minutes. The mixture was diluted with ethyl acetate, then washed with water and brine, and dried over Na₂SO₄. The product was purified on silica gel eluting 20 with 30 to 70% ethyl acetate:hexanes to provide the title compound (140 mg; 24% yield).

General Procedure 8. Buchwald reaction

Compounds (64) (1 equivalent) can be converted to compounds (65) by mixing with tert25 butyl 2-carbamoylpyrrolidine-l-carboxylate (about 3 equivalents), cesium carbonate (about 3

243

2016238925 07 Oct 2016 equivalents), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (about 0.05 to 0.3 equivalents), and tris(dibenzylideneaeetone)dipalladium(0) (about 0.05 to 0.2 equivalents) in dioxane, degassing the mixture, and heating to around 100 °C for between about 1 to 8 hours. Alternatively, the reaction can be conducted using potassium carbonate (about 3 equivalents), Pd(OAc)₂ (about 0.02 equivalents), 5 and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (about 0.04 equivalents). The reaction can be conducted in a flask with a reflux condenser under inert atmosphere or in a sealed tube. The products (65) can be purified by silica gel chromatography eluting with standard solvents including ethyl acetate and methylene chloride.

Illustration of General Procedure 8: General Procedure 8A

(2S,2'S)-tert-butyI 2.2'-(4.4'-((2/?.5/?)-l-(4-cyclohcxylphcnyl)pyrrolidinc-2.5-diyl)bis(2-nitro-4.1phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate (2/?.5/?)-2.5-Bis(4-chloro-3-nitrophcnyl)-l-(4-cyclohcxylphcnyl)pyrrolidinc (General

Procedure 4A) (1.29 g, 2.39 mmol), (S)-tert-butyl 2-carbamoylpyrrolidine-l-carboxylate (1.53 g, 7.16 mmol), cesium carbonate (2.33g, 7.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.33 g, 0.573 mmol), and tris(dibenzylideneaoetone)dipalladium(0) (0.328 g, 0.358 mmol) were combined in dioxane (18 mL) and nitrogen was bubbled through the solution for 15 minutes. Then the flask was capped with a reflux condenser and the solution was heated at 100 °C for 8 hours. After !0 filtering through diatomaceous earth and concentrating, the residue was purified with a CombiFlash® 80g silica column, eluting with 0-20% ethyl acetate in dichloromethane to give 1.71 g (80%) of the title compound.

Illustration of General Procedure 8: General Procedure 8B, Example 1A

(2.S'.2'.S')-Zi77-butyl 2.2'-(4.4'-((2/?.5/?)-l-(3.5-difluoro-4-(4-phcnylpipcridin-l-yl)phcnyl)pyrrolidinc-

2,5-diyl)bis(2-nitro-4,l-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate

244

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To a 100 mL round-bottomed flask was added l-(4-((27?,57?)-2,5-bis(4-chloro-3nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-phenylpiperidine (2.26 g, 3.46 mmol), (S)-tertbutyl 2-carbamoylpyrrolidine-l-carboxylate (2.223 g, 10.37 mmol), cesium carbonate (3.38 g, 10.37 mmol), tris(dibenzyideneaoetone)dipalladium(0) (0.190 g, 0.207 mmol) and (9,9-dimethyl-9H5 xanthene-4,5-diyl)bis(diphenylphosphine) (0.300 g, 0.519 mmol) in dioxane (34.6 mL) to give a purple suspension. The mixture was sparged with N₂ for 20 minutes, heated under N₂ at 100 °C for 3 hours, cooled and poured into EtOAc. The EtOAc layer was washed 2x50 mL with H₂O and then with saturated NaCI. The EtOAc layer was treated simultaneously for 1 hour with 3-mercaptopropyl silica and Na₂SO₄, filtered and concentrated. Purification using chromatography on a 120 g silica 0 cartridge eluting with 1-3 % methanol in methylene chloride gave material that was 90% pure by HPLC. A second column on a 120 g silica cartridge eluting with 15-50% EtOAc in hexane provided the title compound as an orange foam (2.6 g, 72%, 97% purity by HPLC). MS (ESI+) m/z 1009 (M+H)⁺.

Illustration of General Procedure 8: General Procedure 8B, Example IB (mono-displacement) methyl (5)-l-((5)-2-(4-((27?,57?)-5-(4-chloro-3-nitrophenyl)-l-(3,5-difluoro-4-(4-phenylpiperidin-lyl)phenyl)pyrrolidin-2-yl)-2-nitrophenylcarbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2ylcarbamate l-(4-((27?,57?)-2,5-Bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4phenylpiperidine (0.745 g, 1.14 mmol) was dissolved in dioxane (12 mL) in a tube and treated with methyl (5)-1-((5)-2-carbamoylpyrrolidin-l-yl)-3-methyl-l-oxobutan-2-ylcarbamate (0.309 g, 1.14 mmol), cesium carbonate (0.409 g, 1.25 mmol), Xantphos (0.066 g, 0.11 mmol), and tris(dibenzylideneaoetone)dipalladium(0) (0.052 g, 0.057mmol). Nitrogen was bubbled through this mixture for 15 minutes, then the tube was sealed and heated at 100 °C for 2 hours. The mixture was diluted with water, extracted into dichloromethane, concentrated, and purified by chromatography, eluting with 0-5% methanol in dichloromethane to give 0.44 g (43%) of a dark yellow solid.

Illustration of General Procedure 8: General Procedure 8B, Example 2

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/ert-butyl 2.2'-(4.4'-((2//.5//)-l-(3.5-difluoro-4-(pipcridin-l-yl)phcnyl)pyrrolidinc-2.5-diyl)bis(5fluoro-2-nitro-4,1 -phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate

To a round bottom flask was combined I-(4-((2//.5//)-2.5-bis(4-chloro-2-fluoro-55 nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)piperidine (4.1 g, 6.68 mmol), (.S')-/i77-butyl 2carbamoylpyrrolidine-l-carboxylate (4.30 g, 20.05 mmol), cesium carbonate (6.1 g, 18.72 mmol), and XantPhos (0.696 g, 1.203 mmol) followed by dioxane (30 ml) and the solution was de-gassed with N₂gas for 30 minutes. The solution was stirred vigorously to keep the solids mixing and kept the flow rate of N₂ gas at a high rate to ensure complete de-gassing of the mixture. 0 Tris(dibenzylideneacetone)dipalladium (0.367 g, 0.401 mmol) was added and the solution heated at 100 °C for 2 hours under N₂ gas. The solution was cooled and diluted with EtOAc, filtered through diatomaceous earth, washed with H₂O and brine, dried (Na₂SO₄), filtered, treated for 30 minutes with 3-mercaptopropyl-functionalized silica gel, filtered and concentrated to give crude product. Purification was run on an ISCO 120g silica gel cartridge eluting with 0-40% EtOAc/hexane over 30 5 minutes to give the title compound (4.52 g, 4.66 mmol, 69.8%).

General Procedure 8.1. Buchwald with dipeptide

dimethyl (2R, 2’R)-\,V-((2S,2’S)-29(4,4’-((2 R. 57/)-1 -(3-fluoro-4-morpholinophenyl)pyrrolidin-2,520 diyl)bis(2-nitro-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3methyl-1 -oxobutane-2,1 -diyl)dicarbamate

In a microwave tube, a suspension of 4-(4-((27/,57/)-2,5-bis(4-chloro-3nitrophenyl)pyrrolidin-l-yl)-2-fluorophenyl)morpholine (1.39 g, 2.48 mmoL), Intermediate 3B (2.02 g, 7.43 mmol), XantPhos (129 mg, 0.22 mmol) and cesium carbonate (2.42 g, 7.43 mmoL) in dioxane 25 (14 mL) was degassed by nitrogen sparge for 30 minutes. The mixture was treated with tris(dibenzylideneacetone)dipalladium (0) (68 mg, 0.074 mmol) followed by degassing for another 5

246 minutes. The microwave tube was sealed and the mixture was warmed at 100 °C for 2 hours. The mixture was cooled and diluted with ethyl acetate and extracted with water (3x) and saturated sodium chloride solution. The solution was dried (Na₂SO₄) and stirred overnight with 3-(mercaptopropyl) silica gel. Filtration and concentration in vacuo afforded a solid which was chromatographed over a

340 g silica gel cartridge, eluting with 0-10% methanol in dichloromethane. These procedures afforded the title compound as an orange solid. 'H NMR (400 MHz, DMSO-J₆) δ ppm 0.80-0.90 (m, 12H) 1.74 (br s, 2H) 1.82-2.03 (m, 10H) 2.08-2.20 (m, 2H) 2.71-2.81 (m, 4H) 3.52 (s, 6H) 3.62 (m, 4H) 3.76 (s, 2H) 4.02 (m, 2H) 4.50 (d, J=4.4 Hz, 2H) 5.39 (s, 2H) 6.04-6.19 (m, 2H) 6.74f6.81 (m,

1H) 7.32 (d, J=8.4 Hz, 2H) 7.47-7.60 (m, 4H) 7.80 (d, J=1.5 Hz, 2H) 10.41 (s, 2H); MS (ESI) m/z 0 1031 (M+H)⁺.

General Procedure 9. Nitro reduction

2016238925 07 Oct 2016

Boc Boc Boc Boc ' \ ' \

N O	D	C\ HJ V-NH	r-N Ό	D	C) N V-NH ^v
			--)^/
o₂n'		no₂	h₂n		nh₂
	(65)			(66)

Compounds (65) (1 equivalent) can be converted to compounds (66) by hydrogenation with 5 hydrogen gas (1-4 atm) over a catalyst such as PtO₂ (about 0.2 to 0.3 equivalents) or Raney-nickel (e.g., 50% aqueous; 1 equivalent by weight) in solvents such as tetrahydrofuran, ethanol, or mixtures thereof. The reaction can be worked up by filtration through diatomaceous earth or silica gel, and the filtrate concentrated to give compounds (66). Reduction of (65) (1 equivalent) can also be effected by reaction with iron powder (about 6 equivalents) and ammonium chloride (about 3 equivalents) in a !0 solvent of THF:ethanol:water (1:1:0.2) with heating to about 60-100 °C.

Illustration of General Procedure 9: General Procedure 9A, Example 1

(2.S'.2'.S')-/i77-biityl 2,2'-(4,4'-((2R,5R)-l-(4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2amino-4,1 -phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate

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A solution of (2.S'.2'.S')-Zi'/7-butyl 2.2'-(4.4'-((2/?.5/?)-l-(4-(4-phcnylpipcridin-lyl)phenyl)pyrrolidine-2,5 -diyl)bis(2-nitro-4,1 phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate (2.287 g, 2.350 mmol) in THF (60 mL) was added to PtO₂ (0.457 g, 2.014 mmol) in a 250 mL stainless steel pressure bottle and 5 stirred for 4 hours at room temperature under 30 psi hydrogen pressure. The mixture was then filtered through a nylon membrane and the filtrate concentrated by rotary evaporation and dried in vacuo to give the title compound as a brown solid (2.02 g, 94%). 'H NMR (400 MHz, DMSO-0/,) δ ppm 1.30 1.44 (m, 18 H), 1.53 - 1.98 (m, 11 H), 2.08 -2.29 (m, 1 H), 2.43 - 2.60 (m, 3 H), 3.35 - 3.50 (m, 4 H), 4.16 - 4.29 (m, 2 H), 4.79 (d, 7=35.46 Hz, 4 H), 4.97 (s, 2 H), 6.21 (d, 7=8.89 Hz, 2 H), 6.41 (dd, 0 7=20.66, 7.86 Hz, 2 H), 6.53 - 6.61 (m, 2 H), 6.66 (d, 7=8.89 Hz, 2 H), 6.93 - 7.06 (m, 2 H), 7.17 (t,

7=6.89 Hz, 1 H), 7.21 - 7.32 (m, 4 H), 9.18 (d, 7=39.25 Hz, 2 H); MS (ESI+) m/z 913 (M+H)⁺; MS (ESI-) zw/z 911 (M-H)’.

Illustration of General Procedure 9: General Procedure 9A, Example 2 tert-butyl 2.2'-(4.4'-((2/?.5/?)-l-(3.5-difluoro-4-(pipcridin-l-yl)phcnyl)pyrrolidinc-2.5-diyl)bis(2amino-5-fluoro-4,l-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate tert-Butyl 2.2'-(4.4'-((2/?.5/?)-l-(3.5-difluoro-4-(pipcridin-l-yl)phcnyl)pyrrolidinc-2.5diyl)bis(5 -fluoro-2-nitro-4,1 -phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1 -carboxylate (4.5 g, 4.64 mmol) and THF (100 ml) were added to PtO₂ (0.900 g, 3.96 mmol) in a 250 ml stainless !0 steel pressure bottle and stirred for 22 hours under a hydrogen atmosphere (30 psi) at room temperature. The mixture was filtered through a nylon membrane and concentrated to a yelloworange foam.

Illustration of General Procedure 9: General Procedure 9B

(2S,2'S)-tert-butyl 2.2'-(4.4'-((2/?.5/?)-l-(3.5-difluoro-4-(4-phcnylpipcridin-l-yl)phcnyl)pyrrolidinc-

2,5-diyl)bis(2-amino-4,l-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate

In a 250 mL pressure bottle were combined (2S,2'S)-tert-butyl 2,2'-(4,4'-((2Λ,5Λ)-1-(3,5difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,l30 phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate (General Procedure 8B) (2.6 g, 2.58 mmol) and Raney-nickel 2800 (45% w/w in water, 2.6 g, 44 mmol) in THF (40 mL). The

248 vessel was sealed and stirred under 30 psi H₂ for 5 hours. The solution was filtered through a nylon membrane and the filtrate was concentrated to afford the title compound as a tan foam (2.44 g, quantitative yield) that was used without purification. MS (ESI+) m/z 949 (M+H)⁺.

Illustration of General Procedure 9: General Procedure 9C

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dimethyl (|(2/?.5/?)-l-(4.5.6.7-tctrahydro-l.3-bcnzothiazol-2-yl)pyrrolidinc-2.5-diyl|bisi(2aminobenzene-4,1 -diyl )carbamoyl(2.S')pyrrolidinc-2.1 -di y 11 (2,S) -3 -methyl-1 -oxobutane-1,2diyl]})biscarbamate (ACD Name vl2))

Dimethyl (|(2/?.5/?)-l-(4.5.6.7-tctrahydro-l.3-bcnzothiazol-2-yl)pyrrolidinc-2.5-diyl|bisi(2nitrobcnzcnc-4. l-diyl)carbamoyl(2.S')pyrrolidinc-2. l-diyl|(2.S')-3-mcthyl-l -oxobutane-1,2diyl]})biscarbamate (ACD Name vl2)) (0.59 g, 0.596 mmol) was dissolved in tetrahydrofuran (15 mL) and treated with Raney-nickel slurry in water (0.25 mL). The flask was evacuated and opened to a hydrogen balloon and stirred at ambient temperature for 1 hour. The solution was filtered through a silica plug and concentrated to dryness to give the title compound.

Illustration of General Procedure 9: General Procedure 9D

dimethyl (2S,2'S)-l,T-((2<S',2'S)-2,2'-(4,4'-((27?,57?)-l-(4-chloro-3-fluorophenyl)pyrrolidine-2,520 diyl)bis(2-amino-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3methyl-1 -oxobutane-2,1 -diyl)dicarbamate

Dimethyl (2S,2'S)-l,l'-((2<S',2'S)-2,2'-(4,4'-((27?,57?)-l-(4-chloro-3-fluorophenyl)pyrrolidine-

2,5-diyl)bis(2-nitro-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3methyl-l-oxobutane-2,l-diyl)dicarbamate (l.Og, 1.02 mmol) and tetrahydrofuran (25 mL) were added 25 to platinum oxide (0.20 g, 0.88 mmol) in a pressure bottle and stirred at ambient temperature under hydrogen at 30 psi for 1.5 hours. The solution was filtered through a nylon membrane and concentrated to dryness to give 100% yield of a brown residue that was used without purification.

Illustration of General Procedure 9: General Procedure 9E

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ο

Ck dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((27/,57/)-1-(3,5-difluoro-4-(4-phenyl-5,6-dihydropyridinl(2H)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,lphenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3 -methyl-1 -oxobutane-2,1 5 diyl)dicarbamate

Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((27/,57/)-l-(3,5-difluoro-4-(4-phenyl-5,6dihydropyridin-l(277)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-nitro-4,lphenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3 -methyl-1 -oxobutane-2,1 diyl)dicarbamate (150 mg, 0.134 mmol) was dissolved in a mixture of THF (1 mL) and absolute 0 EtOH (1 mL) under nitrogen. A solution of ammonium chloride (10.73 mg, 0.201 mmol) in water (0.333 mL), followed by iron powder (37.4 mg, 0.669 mmol) was added, and the mixture was heated under a reflux condenser in an oil bath at 90 °C. After 1 hour, the reaction mixture was cooled to room temperature, vacuum filtered through a bed of Celite 545, and washed thoroughly with EtOAc. The filtrate was concentrated by rotary evaporation to remove the organic solvents. The residue was 5 dissolved in EtOAc (50 mL), washed with water (2x25 mL) and brine (25 mL), dried over anhydrous

MgSO₄, filtered, and concentrated by rotary evaporation. The residue was purified by SiO₂ flash chromatography (Alltech Extract-Clean column, 10 g bed) eluting with a step gradient of 3% to 4% methanol/CH₂Cl₂ to afford the product as a yellow solid (77 mg, 0.073 mmol, 54%). 'H NMR (400 MHz, DMSO-A) δ ppm 0.92 (dd, 7=13.07, 6.56 Hz, 12 H), 1.58 - 1.75 (m, 2 H), 1.83 -2.09 (m, 8 H), 20 2.13 - 2.28 (m, 1 H), 3.17 (s, 2 H), 3.38 - 3.68 (m, 8 H), 3.55 (s, 6 H), 3.84 (s, 2 H), 4.05 (t, 7=8.35

Hz, 2 H), 4.37 - 4.47 (m, 2 H), 4.93 (s, 4 H), 5.01 (d, 7=5.10 Hz, 2 H), 5.85 - 6.00 (m, 2 H), 6.14 (s, 1 H), 6.44 (d, 7=8.02 Hz, 2 H), 6.55 - 6.66 (m, 2 H), 7.02 (d, 7=7.81 Hz, 2 H), 7.21 - 7.49 (m, 8 H), 9.28 (s, 2 H); MS (ESI+) m/z 1061 (M+H)⁺; MS (ESI-) m/z 1059 (M-H)’.

General Procedure 10. Benzimidazole formation

(66) (57)

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Compounds (66) can be converted to compounds (57) by heating neat in acetic acid or with acetic acid in toluene or dioxane at 50-80 °C. The reaction can be worked up by concentrating the solution, neutralizing with aqueous sodium bicarbonate solution, extracting with an organic solvent (e.g., dichloromethane), drying the organic solvent mixture (e.g., MgSO₄, Na₂SO₄), filtering and 5 concentrating in vacuo. The reaction can also be conducted in toluene as solvent with added acetic acid (about 3 to 5 equivalents) also with heating to 50-80 °C. Workup can consist of simple solvent evaporation and the removal of residual acetic acid by the addition and evaporation of toluene. Compounds (57) can be purified by chromatography over silica gel eluting with ethyl acetate/dichloromethane or methanol/dichloromethane. Although the cyclization depicted above is 0 shown with a t-butoxycarbonyl (Boe) group attached, the reaction can also be conducted with the groups -T-R_d attached, wherein T and R_D are as defined herein.

Illustration of General Procedure 10: General Procedure 10A; Example 1

(2.S'.2'.S')-/i77-biityl 2,2'-(5,5'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(lHbcnzo|0/|imidazolc-5.2-diyl))dipyrrolidinc-1-carboxylate

As a mixture of trans diastereomers, (2.S'.2'.S')-/i77-biityl 2,2'-(5,5'-(l-(4-tertbutylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,1 phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-l-carboxylate (0.355 g) was dissolved in !0 neat acetic acid (3 mL) and heated at 72 °C for 2 hours. The solution was concentrated and then poured into water where the pH was adjusted to ~7-8 with sodium bicarbonate. The product was extracted into dichloromethane, concentrated and purified by chromatography on silica gel with a 40 g column, eluting with 0-5%methanol/dichloromethane to give 0.185 g (55%) of the title compound as a light yellow solid.

Illustration of General Procedure 10: General Procedure 10A; Example 2

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2016238925 07 Oct 2016 (2.S'.2'.S')-/i77-biityl 2.2'-(6.6'-((2/?.5/?)-l-(3.5-difluoro-4-(4-phcnylpipcridin-l-yl)phcnyl)pyrrolidinc2.5-diyl)bis( I A/-bcnzo|0/|imidazolc-6.2-diyl))dipyrrolidinc-1-carboxylate

A solution of (2.S'.2'.S')-/i77-biityl 2,2'-(4,4'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-lyl)phenyl)pyrrolidine-2,5-diyl)bis(2-amino-4,l5 phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate (2.4 g, 2.57 mmol) and acetic acid (1.54 g, 25.7 mmol) in toluene (50 mL) was heated at 70 °C for 2 hours, cooled and concentrated. The residue was azeotroped 3x15 mL with toluene and dried under vacuum to give a yellow foam (2.34 g, quantitative yield) that was used without purification. MS (ESI+) m/z 913 (M+H)⁺.

.0 Illustration of General Procedure 10: General Procedure 10A; Example 3 (25,2'5)-tert-butyl 2.2'-(6.6'-((2/?.5/?)-l-(3.5-difluoro-4-(pipcridin-l-yl)phcnyl)pyrrolidinc-2.5diyl)bis(5-fluoro-1 f/-bcnzo|d|imidazolc-6.2-diyl))dipyrrolidinc-1-carboxylate

To crude tert-butyl 2.2'-(4.4'-((2/?.5/?)-l-(3.5-difluoro-4-(pipcridin-l-yl)phcnyl)pyrrolidinc5 2,5-diyl)bis(2-amino-5-fluoro-4,l-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-lcarboxylate (from General Procedure 9A, Example 2) was added toluene (45 ml) followed by acetic acid (2.66 ml, 46.4 mmol) and the solution was stirred at 50 °C for 16 hours. The cooled solution was concentrated , azeotroped twice with toluene, and the crude residue was purified on an ISCO 40 g silica gel cartridge eluting with 0-5% CH3OH/CH2CI2 to give the title compound (2.85 g).

!0

Illustration of General Procedure 10: General Procedure 10B, Example 1 ci

methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(4-chloro-3-fluorophenyl)-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-127-benzimidazol-5-yl}pyrrolidin-225 yl]-127-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate (ACD Name vl2) Dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(4-chloro-3-fluorophenyl)pyrrolidine-

2,5-diyl)bis(2-amino-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3methyl-l-oxobutane-2,l-diyl)dicarbamate (General Procedure 9D) (0.98 g, 1.01 mmol) was dissolved in toluene (12 mL) and treated with glacial acetic acid (1.16 mL, 20.2 mmol) and heated at 65 °C for

1.5 hours. The mixture was concentrated, dissolved in dichloromethane, and washed with sodium bicarbonate solution. The organic reaction mixture was concentrated and purified by chromatography, eluting with 0-6% methanol in dichloromethane to give 0.17 g (19%) of the title

252 compound as a dark yellow solid. 'H NMR (400 MHz, DMSO-r/₆) δ ppm 0.77 - 0.90 (m, 12 H) 1.66 1.78 (m, 2 H) 1.88 - 1.95 (m, 2 H) 1.96 - 2.06 (m, 4 H) 2.15 - 2.24 (m, 4 H) 2.54 - 2.60 (m, 2 H) 3.54 (s, 6 H) 3.79 - 3.86 (m, 4 H) 4.06 (t, J=8.46 Hz, 2 H) 5.10 - 5.18 (m, 2 H) 5.37 - 5.45 (m, 2 H) 6.16 (dd, J=9.49, 2.01 Hz, 1 H) 6.22 (dd, J=13.55, 2.06 Hz, 1 H) 7.00 - 7.11 (m, 3 H) 7.22 (s, 1 H) 7.28 (d,

J=8.57 Hz, 2 H) 7.32 (s, 1 H) 7.40 (d, J=8.24 Hz, 1 H) 7.47 (d, J=8.13 Hz, 1 H) 12.07 (d, J=2.93 Hz, 2

H); MS (APCI+) m/z 884 (M+H)⁺.

2016238925 07 Oct 2016

Illustration of General Procedure 10: General Procedure 10B; Example 2

methyl {(2S)-l-[(2S)-2-{6-[(2R,5R)-l-[3-fluoro-4-(methylsulfonyl)phenyl]-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-127-benzimidazol-6-yl}pyrrolidin-2yl]-127-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate (ACD Name vl2)

To a suspension of dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(3-fluoro-4(methylsulfonyl)phenyl)pyrrolidine-2,5 -diyl)bis(2-amino-4,1 5 phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3 -methyl-1 -oxobutane-2,1 diyl)dicarbamate (0.190 g, 0.197 mmol) in toluene (2 mL) was added acetic acid (1 mL, 17.48 mmol), and the reaction mixture was stirred at 60 °C overnight. LCMS shows completion of reaction. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCO₃. The organic extract was separated, dried over anhydrous sodium sulfate, filtered, concentrated on a 20 rotovap and purified by reverse phase HPLC using 5-100% acetonitrile/ water(TFA). Pure fractions were combined, neutralized with saturated solution of NaHCO₃, and concentrated. The residue was extracted with CH₂C1₂. The organic extract was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to supply the title compound (30 mg) as a white solid.

General Procedure 11. Procedure to Remove t-Butoxy carbonyl Protecting Groups

253

Removal of a t-butoxycarbonyl (Boe) protecting group, according to the above depiction can be effected using standard conditions such as by treatment with an acid, such as TFA, HC1, or formic acid. For example, reaction with TFA/CH₂C1₂ or HC1 in dioxane at room temperature can remove the

Boe protecting group. Compounds may be used or isolated as the salt or free base.

After removal of the Boc-protecting groups and in cases where compounds have been / processed through as mixtures of cis, and trans diastereomers may be subject to separation using standard chromatographic methods (e.g., normal phase silica gel or reverse phase). For example, compounds of general type 11-1 and 11-2 can

2016238925 07 Oct 2016

JWV

I

A. ' , and trans,

:, the cis

11-2

Illustration of General Procedure 11. General Procedure HA (HCl-Dioxane), Example 1

(.S)-5.5'-(l-(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl)bis(2-((.S)-pyrrolidin-2-yl)-l//benzo [d\ imidazole) (2.S'.2'.S')-/i77-Butyl 2,2'-(5,5'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(lHbenzo[ri]imidazole-5,2-diyl))dipyrrolidine-l-carboxylate (0.204 g, 0.264 mmol) was dissolved in THF 20 (2 mL) at room temperature and treated with 4 M HC1 in dioxane (2 mL). After completion of the reaction, the mixture was concentrated to dryness to provide the crude title compound.

Illustration of General Procedure 11. General Procedure HA (HCl-Dioxane), Example 2 (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidm-l-yl)phenyl)pyrrolidme-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) - ΙΗ-benzo \d\ imidazole)

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A solution of (2S,2'5)-/ert-butyl 2,2'-(6,6'-((27?,57?)-l-(3,5-difluoro-4-(4-phenylpiperidin-lyl)phenyl)pyrrolidine-2,5-diyl)bis(127-benzo[ri]imidazole-6,2-diyl))dipyrrolidine-1 -carboxylate (2.34 g, 2.57 mmol) in dioxane (25 mL) was treated with 4 Mhydrogen chloride in dioxane (16.06 mL, 64.3 mmol) to give a tan suspension. The mixture was sonicated for 10 minutes to break up solids into a 5 fine suspension, stirred for 2 hours and concentrated. The residue was azeotroped 3x30 mL with toluene and dried to give the HCI salt of the title compound as a tan powder that was used without purification (assume quantitative yield, 2.57 mmol). MS (ESI+) m/z 713 (M+H)⁺.

Illustration of General Procedure 11. General Procedure HA (HCl-Dioxane), Example 3

6,6'-{(27?,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(25)pyrrolidin-2-yl]-1 //-benzimidazole} (ACDName vl2)

To a solution of (25'.2'5')-/i77-biityl 2,2'-(6,6'-((27?,57?)-l-(3,5-difluoro-4-(piperidin-lyl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-127-benzo[ri]imidazole-6,2-diyl))dipyrrolidine-lcarboxylate (2.85 g, 3.26 mmol) in dioxane (10 ml) was added 4 M HCl/dioxane (10.0 mL, 40.0 .5 mmol) and the solution was vigorously stirred at room temperature for 1 hour. The solution was concentrated, dissolved in minimal H₂O and applied to an ISCO 130 g C18 cartridge and eluted with 0-100% CH₃CN/(0.1% TEA/H₂O). Desired fractions were combined, made basic with 10% NaHCO₃ solution, and extracted with EtOAc. The combined extracts were dried (MgSO₄), filtered and concentrated to give the title compound (932.5 mg, 1.386 mmol, 42.5%).

Illustration of General Procedure 11. General Procedure 11B (TFA-CH2CI2)

(5)-5,5'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-127-benzo[ri]imidazole) (2S,2'5)-/ert-Butyl 2,2'-(5,5'-( 1 -(4-fluorophenyl)pyrrolidine-2,5-diyl)bis( 1Hbenzo[ri]imidazole-5,2-diyl))dipyrrolidine-l-carboxylate (0.120 g, 0.163 mmol) was dissolved in dichloromethane (2 mL) at room temperature and treated with TEA (1 mL). The mixture was concentrated to dryness, dissolved in 25% isopropanol/dichloromethane and washed with sodium bicarbonate solution. The resulting solids were filtered off and dried. The organic filtrate was concentrated and dried to give the more title compound. The batches of off-white solid were combined to give the titled compound (0.062 g 72% yield).

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The following compounds as free base or salt can be made using General Procedure 8, General

Procedure 9A (PtO₂), General Procedure 10/10A, and General Procedure 11/11A:

(5)-6.6'-((2/?.5/?)-l-(4-(pyridin-2-yl)phcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-l//benzo \d\ imidazole);

(5)-6,6'-((2J?,5J?)-l-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2yl)- 127-benzo \d\ imidazole);

(5)-6,6'-((2/?.5/?)-l-(4-(2-mcthoxycthoxy)phcnyl)pyrrolidinc-2.5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-l//benzo \d\ imidazole);

(5)-6,6'-((2Λ, 5/?)-l-(4-chlorophcnyl)pyrrolidinc-2.5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-l//0 benzo[r/]imidazole);

(5)-6,6'-((2R,5R)-l-(3-methyl-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2yl)- 127-benzo \d\ imidazole);

(5)-6,6'-((2S,55)-l-(4-cyclopropyl-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)1 //-benzo [d\ imidazole);

(5)-6.6'-((25'.55)-l-(4-cyclopropyl-2-fluorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-l//benzo [d\ imidazole);

(5)-6,6'-((2/?.5/?)-l -(3 -fluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5 -diyl)bis(2-((5)-pyrrolidin-2-yl)I //-benzo \d\ imidazole);

(5)-6.6'-((2/?.5/?)-l-(3.5-difluoro-4-(4-(trifluoromcthyl)pipcridin-l-yl)phcnyl)pyrrolidinc-2.5!0 diyl)bis(2-((5)-pyrrolidin-2-yl)-127-benzo[i/]imidazole);

(5)-6,6'-((2/?.5/?)-l-(4-(4-/i77-biitylpipcridin-l-yl)-3.5-difliiorophcnyl)pyrrolidinc-2.5-diyl)bis(2 -((5)pyrrolidin-2-yl) - 127-benzo [d\ imidazole);

(5)-6,6'-((2J?,5J?)-l-(4-(4,4-dimethylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - 127-benzo [d\ imidazole);

(5)-6,6'-((2J?,5J?)-l-(3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - 127-benzo [d\ imidazole);

(5)-6,6'-( (2R. 5/?)-1 -(3.5-difluoro-4-(isoindolin-2-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin2-yl)-1 //-benzo [d]imidazole);

2-(4-((2J?,5J?)-2,5-bis(2-((5)-pyrrolidin-2-yl)-127-benzo[i/]imidazol-6-yl)pyrrolidin-l-yl)-2,63 0 difluorophenyl)-2-azabicyclo [2.2.2] octane;

(5)-6,6'-((2R,5J?)-l-(3,5-difluoro-4-(4-isopropylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - 127-benzo [d] imidazole);

(5)-6,6'-((2/?.5/?)-l-(4-(3.3-dimcthylazctidin-l-yl)-3.5-difluorophcnyl)pyrrolidinc-2.5-diyl)bis(2-( (5)pyrrolidin-2-yl) - 127-benzo [d] imidazole);

(5)-6,6'-((2/?.5/?)-l-(4-(4-phcnylpipcridin-l-yl)phcnyl)pyrrolidinc-2.5-diyl)bis(2 -((5)-pyrrolidin-2-yl)I //-benzo \d\ imidazole);

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6,6'-{(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)pyrrolidin-2-yl]-lH-benzimidazole} (ACDName vl2);

(S)-6,6'-((2S,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole) (S,S,S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-lH-benzo[d]imidazole);

(S,S,S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(2,3-dihydrospiro[indene-l,4'-piperidine]-r-yl)-3,50 difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole); (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-methoxyphenyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-fluoro-4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(fluorodiphenylmethyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro!0 2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(3-(trimethylsilyl)phenyl)piperidin-l-yl)phenyl)pyrrolidine2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-(3,4-difluorophenyl)piperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-(3,5-difluorophenyl)piperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-l-yl)phenyl)pyrrolidine30 2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

6-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)-5-(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol6-yl)pyrrolidin-2-yl)-5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole;

(S)-6,6'-((2R,5R)-l-(4-(4-benzylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-benzylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

257

2016238925 07 Oct 2016 (S)-6,6'-((2S,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

4-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol-6-yl)pyrrolidin-l-yl)-2,6difluorophenyl)-2-phenylmorpholine;

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(2-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(2S,6R)-4-(4-((2R,5R)-2,5-bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol-6-yl)pyrrolidin1 -yl) -2,6-difluorophenyl) -2,6-dimethylmorpholine;

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(50 fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-cyclohexylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-4-(4-((2R,5R)-2,5-bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol-6-yl)pyrrolidin-l-yl)2,6-difluorophenyl)-2 -phenylmorpholine;

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperazin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S,R)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,4R)-4fluoropyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-(2,6-difluorophenyl)piperazin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5!0 diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-(2,4-difluorophenyl)piperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2S,5S)-l -(4-(4-(2,6-difluorophenyl)piperazin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(5-methylthiophen-2-yl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole); and (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,530 diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole).

Procedure 9B (Raney-nickel), General Procedure 10/10A, and General Procedure 11/11A:

(5)-6,6'-((2R,5R)-l -(biphenyl -4-yl)pyrrolidine-2,5 -diyl)bis(2 -((5)-pyrrolidin-2-yl)-17735 benzo[ri]imidazole);

258

2016238925 07 Oct 2016 (5)-6,6'-((27?,57?)-l-(4-(cyclopentyloxy)-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2yl)-1 H-be nzo [d\ imidazole);

(5)-6,6'-((2/?.5/?)-l-(3.5-difluoro-4-((3a/?.7aS)-l//-isoindol-2(3//.3a//.4//.5//.6//.7//.7a//)yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-l//-bcnzo|0/| imidazole);

(5)-6,6'-((2/?. 5/?)-1 -(3.5-dichloro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin2-yl)-1 //-benzo [d\imidazole);

(5)-6,6'-((2/?. 5/?)-1 -(2.5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin2-yl)-I //-benzo [d\imidazole);

(5)-6,6'-((2Λ,5Λ)-1-(4-( (2Λ,65)-2,6-dimethylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,50 diyl)bis(2-((5)-pyrrolidin-2-yl)-l//-bcnzo|0/|imidazolc):

(5)-6,6'-((2/?. 5/?)-1 -(2.3,5-trifluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)pyrrolidin-2-yl) - I //-be nzo [d\ imidazole);

(5)-6,6'-((2/?.5/?)-l-(4-cyclohcxyl-3-fliiorophcnyl)pyrrolidinc-2.5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-l//benzo [d\ imidazole);

(5)-6.6'-((2/?.5/?)-l-(3.4-difliiorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-l//benzo [d\ imidazole);

(5)-6,6'-((27?,57?)-l-(4-ethoxyphenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-127benzo [d\ imidazole);

(5)-6,6'-((2/?. 5/?)-1 -(4-(2.2-difluoroethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-l//!0 benzo[ri]imidazole);

(5)-6,6'-((2/?.5/?)-l-(4-(3.5-dimcthylpipcridin-l-yl)-3.5-difluorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)pyrrolidin-2-yl) - I //-be nzo [d\ imidazole);

6,6'-{(27?,57?)-l-[4-(pentafluoro-X⁶-sulfanyl)phenyl]pyrrolidine-2,5-diyl}bis{2-[(25)-pyrrolidin-2-yl]I//-benzimidazole [ (ACD Name vl2);

(5)-6,6'-((2S,55)-l-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-l//benzo [d\ imidazole);

(5)-6.6%(2/?.5/?)-l-(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-l//benzo [d\ imidazole);

(S,5)-6,6'-((27?,57?)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,45)-4-

0 methoxypyrrolidin-2-yl) -I //-benzo [d\imidazole);

(S,5)-6,6'-((27?,57?)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((2S,45)-4fluoropyrrolidin-2-yl)-1 //-benzo [d\imidazole);

(S, 5)-6,6'-((2/?.5/?)-l-(4-fluorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((25.45) -4-fluoropyrrolidin-2-yl)-l//benzo [d\ imidazole);

(S, 5)-6,6'-((2/?.5/?)-l-(4-fluorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((25'.45)-4-mcthoxypyrrolidin-2-yl)I //-benzo \d\ imidazole);

259

2016238925 07 Oct 2016 (5)-6.6'-((2/(.5/()-l-(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-5.5-dimcthylpyrrolidin-2-yl)I //-benzo [dj imidazole);

(5.5) -6.6'-((2/(.5/()-l-(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl)bis(2-((25'.45)-4-fliioropyrrolidin-2-yl)-

I //-benzo [d\ imidazole);

(5)-6,6'-( (27(,57()-1-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((35)-2azabicyclo [2.2.1 ]heptan-3 -yl)-1 H-be nzo \d\ imidazole);

(5)-6,6'-( (27(, 5/?)-1 -(3.5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-indolin-2yl)-1 H-be nzo [d] imidazole);

(5./()-6.6'-((2/(.5/()-1-(3.5-difliioro-4-(pipcridin-1-yl)phcnyl)pyrrolidinc-2.5-diyl)bis(2-((25.4/()-40 methoxypyrrolidin-2-yl) -1 //-benzo [d] imidazole);

(5)-6.6'-((2/?.5/?)-1-(4-/i77-biitylphcnyl)pyrrolidmc-2.5-diyl)bis(2-((5)-4-mcthylcncpyrrolidin-2-yl)I //-benzo \d\ imidazole);

(5)-6,6'-((2R,5R)-1 -(4-(4,4-diphenylpiperidin-1 -yl)-3,5 -difluorophenyl)pyrrolidine-2,5 -diyl)bis(2-((5)pyrrolidin-2-yl) -1 H-be nzo [d] imidazole);

1-( I -(4-((2/(.5/()-2.5-bis(2-((5)-pyrrolidin-2-yl)-1//-bcnzo|0/|imidazol-6-yl)pyrrolidin-1 -yl)-2.6difluorophenyl)-4-phenylpiperidin-4-yl)ethanone;

(5)-6,6'-( (2R. 57()-1-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin2-yl)-I //-benzo [d]imidazole);

(5.5.5) -6,6'-((27(,57()-1-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2- !0 ((25'.3a5'.6aS)-octahydrocyclopcnta|b|pyrrol-2-yl)-l//-bcnzo|0/|imidazolc):

(5.5.5) -6,6'-((2/(.57()-1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2 -((2S,3aS,6aS)octahydrocyclopenta[b]pyrrol-2-yl)-1 //-benzo [d]imidazole);

(5)-6,6'-( (27(,57()-1-(3,5-difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(2((5)-pyrrolidin-2-yl)-1 //-benzo [d] imidazole);

(5)-6,6'-( (27(,57()-1-(3-fluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - 177-benzo [d] imidazole);

(5.5.5) -6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2- ((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(3-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)3 0 pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(3-phenylpyrrolidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2S,5R)-l-(2-(4-phenylpiperidin-l-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole); and

260 (S)-6,6'-((2S,5R)-l-(2-(piperidin-l-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole).

2016238925 07 Oct 2016

Procedure 9E (Fe/NH₄C1), General Procedure 10/10A, and General Procedure 11/11A: (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(3-phenylpropyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)phenyl)pyrrolidine-2,5-diyl)bis(50 fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-tert-butylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(naphthalen-2-yl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole); and (S)-6,6'-((2R,5R)-l-(4-(benzyloxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-lHbenzo [d] imidazole).

Illustration of General Procedure 11. General Procedure 11C (monodeprotection)

(2S,3aS,6aS)-tert-butyl 2-(5-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)-5-(2-((2S,3aS,6aS)octahydrocyclopenta[b] pyrrol -2 -yl) -1 H-benzo [d] imidazol -5 -yl)pyrrolidin-2 -yl) -1 H-benzo [d] imidazol 2-yl)hexahydrocyclopenta[b]pyrrole-l(2H)-carboxylate

The starting di-Boe-protected amine (1.24 g, 1.36 mmol) was dissolved in dichloromethane (12 mF) at ambient temperature and treated with aliquots of trifluoroacetic acid (0.10 mF, 1.35 mmol) 25 every thirty minutes for 1.5 hours. The solution was concentrated to dryness then re-dissolved into dichloromethane and washed with sodium bicarbonate solution. After concentration, the residue was purified by chromatography, eluting with 0-20% methanol in dichloromethane to give 425 mg (38%) of the title mono-deprotected amine as a yellow powder.

General Procedure 12. Endcap addition.

261

2016238925 07 Oct 2016 .5

MeO₂CHN—L^z _s

Reaction of an amine with an acid to form an amide as depicted above can be effected as described generally in Scheme 1 and other foregoing Schemes. The reaction can be promoted by a peptide coupling reagent, such as EDAC/HOBT, PyBOP, HATU, T3P or DEPBT, in a solvent such as THF, DMF, dichloromethane, ethyl acetate, or DMSO, with or without the addition of an amine base such as Hunig’s base, A'-mcthylmorpholinc. pyridine, 2,6-lutidine, or triethylamine, to give amide products. For example, an amine (1 equivalent) can be reacted with acids (2 equivalents) such as, but not limited to, 2-(methoxycarbonylamino)-3-methylbutanoic acid, 2-(methoxycarbonylamino)-3,3dimethylbutanoic acid, 2-cyclohexyl-2-(methoxycarbonylamino)acetic acid, 2(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid, or those listed below under General Procedure 19. Final coupling products may contain varying amounts of stereoisomers with respect to the pyrrolidine ring. In the case of fluoro-substituted benzimidazole-containing products (e.g. Example 6.1, Example 6.12, Example 6.16), final purification to remove residual amounts of another stereoisomer may require chiral chromatography as described below in General Procedure 12C.

Illustration of General Procedure 12. General Procedure 12A

dimethyl (2.S'.2'.S')-I.l'-((2.S'.2'.S')-2.2'-(5.5'-((2/?.5/?)-l-(4-Zi77-butylphcnyl)pyrrolidinc-2.5-diyl)bis(l//benzo[ri]imidazole-5,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3 -methyl-1 -oxobutane-2,1 -diyl)dicarbamate and dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(5,5'-((2S,5S)-l-(4-/ert-butylphenyl)pyrrolidine-2,5diyl)bis(lH-benzo[ri]imidazole-5,2-diyl))bis(pyrrolidine-2, l-diyl))bis(3-methyl-l -oxobutane-2,1diyl)dicarbamate (5)-5,5'-( l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-lHbenzo[ri]imidazole) (0.150 g, 0.261 mmol) and diisopropylethylamine (0.365 mL, 2.09 mmol) were dissolved in DMSO (3 mL) at room temperature and treated with (5)-2-(methoxycarbonylamino)-3methylbutanoic acid (0.105 g, 0.601 mmol) followed by HATU (0.204 g, 0.536 mmol). The solution

262 was stirred for 1 hour at room temperature then diluted with water. The solid product was filtered off and purified by chromatography on silica gel with a 12 g column, eluting with 0-8% methanol in dichloromethane to give 0.143 g (60%) of a yellow solid as a mixture of trans diastereomers. 'H

NMR (400 MHz, DMSO-%) δ ppm 0.75 - 0.92 (m, 12 H) 1.07 (s, 9 H) 1.64 - 1.76 (m, 2 H) 1.85 5 2.04 (m, 6 H) 2.12 - 2.26 (m, 4 H) 2.43 (dd, J=7.75, 4.07 Hz, 2 H) 3.53 (s, 6 H) 3.76 - 3.87 (m, 4 H)

4.04 (dd, J=11.49, 6.51 Hz, 2 H) 5.12 (t, J=7.59 Hz, 2 H) 5.35 (d, J=3.25 Hz, 2 H) 6.25 (d, J=8.46 Hz, 2 H) 6.85 - 6.96 (m, 2 H) 7.07 (t, J=7.97 Hz, 2 H) 7.19 (s, 1 H) 7.28 (d, J=8.35 Hz, 3 H) 7.38 (dd, J=8.19, 1.90 Hz, 1 H) 7.46 (d, J=8.13Hz, 1 H) 11.97 - 12.09 (m, 2H).

2016238925 07 Oct 2016

Illustration of General Procedure 12. General Procedure 12B

NHCO₂Me

.5 dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2S,55)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,lphenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3 -methyl-1 -oxobutane-2,1 diyl)dicarbamate and dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'-((2R,5R)-l-(4-tertbutylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine2,1 -diyl))bis(3 -methyl-1 -oxobutane-2,1 -diyl)dicarbamate (2.S'.2'.S')-A''jV'-(4.4'-((2.S'.5.S')-l-(4-/i77-Biitylphcnyl)pyrrolidinc-2.5-diyl)bis(4.1phenylene))dipyrrolidine-2-carboxamide and (2.S'.2'.S')-A'.A'''-(4.4'-((2/?.5/?)-1 -(4-tertbutylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-carboxamide (29.0 mg, 0.050 mmol), (.S')-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg, 0.110 mmol) and Λ'-mcthylmorpholinc (0.027 mL, 0.250 mmol) were combined in DMF (2 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (50% to 80%) to give a solid. The solid was triturated with ethyl acetate/hexane to give the title compound (13 mg, 29%) as a mixture of trans diastereomers. Ή NMR (400 MHz, DM SOY) δ ppm 0.85 - 0.95 (m, 12 H) 1.11 (s, 9 H) 1.59 - 1.65 (m, 2 H) 1.79 - 2.04 (m, 8 H) 2.10 - 2.18 (m, 2 H) 2.41-2.46 (m, 2H) 3.52 (s, 6 H) 3.57 - 3.67

263 (m, 2 H) 3.76 - 3.86 (m, 2 H) 4.00 (t, J=7.56 Hz, 2 H) 4.39 - 4.46 (m, 2 H) 5.15 (d, J=7.00 Hz, 2 H)

6.17 (d, J=7.70 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=7.37 Hz, 4 H) 7.30 (d, J=8.20 Hz, 2 H)

7.50 (d, J=8.24 Hz, 4 H) 9.98 (s, 2 H); MS (ESI+) m/z 895 (M+H)⁺.

Illustration of General Procedure 12. General Procedure 12C

2016238925 07 Oct 2016

methyl {(25)-1 -[(25)-2-{5-[(27/,57/)-1 -[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{6-fluoro-2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-177-benzimidazol-5yl}pyrrolidin-2-yl] -6-fluoro- 177-benzimidazol-2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-20 yl} carbamate

To a solution of (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (116 mg, 0.660 mmol) in CH₂C1₂ (1.0 mL) was added EDC (127 mg, 0.660 mmol) and the solution was stirred at room temperature for 20 minutes. This solution was then cannulated into a solution of 6,6'-{(27/,57/)-l-[3,5difluoro-4-(piperidin-1 -yl)phenyl]pyrrolidine-2,5 -diyl} bis { 5 -fluoro-2-[(25)-pyrrolidin-2-yl] -1775 benzimidazole} (ACD Name vl2) (148 mg, 0.220 mmol) and Hunig's base (0.231 ml, 1.320 mmol) in CH₂C1₂ (1.000 mL) followed by the addition of HOBT (101 mg, 0.660 mmol), and the solution was then stirred at room temperature for 1 hour. The solution was diluted with CH₂C1₂, washed with H₂O, dried (Na₂SO₄), filtered and concentrated. The product may be subject to further purification.

From a separate experiment using the above coupling procedure, crude product (about 4 20 mmol) was purified on a Teledyne/ISCO Combiflash® Rf System using a Cl8 cartridge eluting with 0-30% CH₃CN/(0.1%TFA/H₂O) over 30 minutes. The desired fractions were made basic with 10% NaHCO₃ solution and extracted with EtOAc. The combined extracts were dried (Na₂SO₄), filtered and concentrated to give a white solid (545 mg). This material was then re-purified on a Waters preparative HPLC system using a C18 column eluting with 0-95% CH₃CN/(0.1% TFA/H₂O) over 40 25 minutes to give material (195 mg) containing mostly the title compound and a residual amount of a diastereomeric product. To remove remaining amounts of the diastereomer, chiral chromatography was mn on this sample using a Chiralpak® IA column (5 cm* 15 cm, 20 mL/minute) and eluting with 55/30/15 hexane/THF/[CH₃OH/EtOH 8:2] to give the title compound (116 mg, 0.118 mmol). 'H NMR (400 MHz, CDC1₃) δ ppm 10.51-10.60 (m, 1H) 10.33-10.41 (m, 1H) 7.43-7.50 (m, 1H) 7.32 (t,

264

1H) 7.13 (d, 1H) 6.93 (t, 1H) 5.82 (d, 2H) 5.28-5.48 (m, 6H) 4.26-4.39 (m, 2H) 3.78-3.90 (m, 2H)

3.70-3.71 (d, 6H) 3.57-3.67 (m, 2H) 3.44-3.57 (m, 1H) 2.99-3.12 (m, 2H) 2.79-2.98 (m, 4H) 1.782.58 (m, 12H) 1.41-1.51 (m, 2H) 0.80-0.95 (m, 12H); MS (ESI) m/z 987 (M+H)⁺.

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dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(5,5'-((2S,55)-1-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(127benzo[ri]imidazole-5,2-diyl))bis(pyrrolidine-2,1 -diyl))bis(3 -methyl-1 -oxobutane-2,1 -diyl)dicarbamate

The mixture of trans diastereomers was chromatographed by chiral chromatography on a 0 Chiralpak IA column eluting with a mixture of hexane/EtOH/CH₃OH/l,2dichloroethane/diethylamine (25/25/25/25/0.1) to give two separate isomers. 'H NMR (400 MHz, DMSO-A) δ ppm 0.75 - 0.89 (m, 12 H) 1.64 - 1.73 (m, 2 H) 1.85 - 2.03 (m, 6 H) 2.12 - 2.24 (m, 4 H) 2.81 - 2.90 (m, 2 H) 3.52 (s, 6 H) 3.76 - 3.87 (m, 4 H) 4.01 - 4.09 (m, 2 H) 5.08 - 5.16 (m, 2 H) 5.34 (q, J=6.65 Hz, 2 H) 6.26 (dd, J=9.05, 4.50 Hz, 2 H) 6.67 - 6.78 (m, 2 H) 7.03 (t, J=8.02 Hz, 2 H) 7.20 5 (s, 1 H) 7.24 - 7.32 (m, 3 H) 7.36 (d, J=8.13 Hz, 1 H) 7.44 (d, J=7.92 Hz, 1 H) 12.01 - 12.07 (m, 2 H).

and

dimethyl (2S,2'_lS)-l,l'-((2S,2'S)-2,2'-(5,5'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5diyl)bis( l//-bcnzo|i/|imidazolc-5.2-diyl))bis(pyrrolidinc-2. l-diyl))bis(3-methyl-l -oxobutane-2,120 diyl)dicarbamate

Ή NMR (400 MHz, DMSO-A) δ ppm 0.74 - 0.93 (m, 12 H) 1.69 (t, J=9.65 Hz, 2 H) 1.82 - 2.06 (m, 6 H) 2.09 - 2.26 (m, 4 H) 3.04 - 3.23 (m, 2 H) 3.52 (s, 6 H) 3.73 - 3.90 (m, 4 H) 4.06 (t, J=8.46 Hz, 2 H) 5.05 - 5.21 (m, 2 H) 5.29 - 5.44 (m, 2 H) 6.21 - 6.32 (m, 2 H) 6.67 - 6.86 (m, 2 H) 7.05 (t, J=8.78 Hz, 2 H) 7.18 (s, 1 H) 7.23 - 7.33 (m, 3 H) 7.37 (d, J=8.13 Hz, 1 H) 7.45 (d, J=8.02 Hz, 1 H) 12.04 (d, 25 J=14.96Hz, 2 H).

265

General Procedure 15. Benzimidazole synthesis through methoxybenzylamine displacement route I

Shown generally in Scheme VIII, is a method of preparing certain compounds (57) and (59).

Illustrated below in General Procedure 15A is a representative synthesis of (57) where D is 4-tertbutylphenyl.

Illustration of General Procedure 15. General Procedure 15A

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The five steps illustrated above are described by the following experimental procedures:

4.4'-( I -(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl)bisC'V-(4-mcthoxybcnzyl)-2 -nitroaniline) l-(4-/i77-Biitylphcnyl)-2.5-bis(4-chloro-3-nitrophcnyl)pyrrolidinc (4.41 g, 8.57 mmol) was combined, neat, with p-mcthoxy benzylamine (8.93 mL, 68.6 mmol) and heated at 145 °C for 1 hour.

The mixture was diluted with dichloromethane and filtered. The filtrate was washed with 0.5 MHC1, NaHCO₃ solution, and then brine. The organic phase was concentrated and purified by 15 chromatography on silica gel with an 80 g column, eluting with 0-50% ethyl acetate/hexanes to give 4.13g (67%) of an orange foamy solid.

4.4'-( I -(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl)bisC'VI-(4-mcthoxybcnzyl)bcnzcnc-l.2-diaminc) 4,4'-(l-(4 -/i77-Biitylphcnyl)pyrrolidinc-2.5-diyl)bisC'V-(4-mcthoxybcnzyl)-2-nitroaniline) (2 g,

2.79 mmol) was dissolved in a mixture of THF (15 mL), ethanol (15 mL), and ethyl acetate (5 mL).

Then platinum oxide (0.254 g, 1.12 mmol) was added as a THF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to a hydrogen balloon. The mixture was stirred at room temperature for 20 hours, then filtered through diatomaceous earth, concentrated, and

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(2.S'.2'.S')-/i77-biityl 2,2'-(5,5'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-(45 methoxybenzylamino)-5,l-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-l-carboxylate

4,4'-(l-(4 -ter/-B utyl phc nyl (pyrrol idi nc -2,5 -di yl )bi s( ΑΊ -(4 -methoxybenzyl)benzene -1,2diamine) (0.422 g, 0.643 mmol) and diisopropylethylamine (0.674 mL, 3.86 mmol) were dissolved in DMSO (6 mL) at room temperature and treated with .S'-Boc-prolinc (0.319 g, 1.48 mmol) followed by HATU (0.514 g, 1.35 mmol). The solution was stirred for 1 hour at room temperature and then 0 diluted with water. The solid product was filtered off and purified by chromatography on silica gel with a 40 g column, eluting with 0-50% ethyl acetate in dichloromethane to give the title compound (0.565 g, 84%) as a yellow solid.

(2.S'.2'.S')-/i77-butyl 2,2'-(5,5'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,15 phenylene )bis(azanediyl)bis(oxomethylene))dipyrrolidine-1 -carboxylate (2.S'.2'.S')-/i77-Butyl 2,2'-(5,5'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-(4methoxybenzylamino)-5,l-phenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-l-carboxylate (0.565 g, 0.538 mmol) was dissolved in dichloromethane (5 mL) and water (0.25 mL) at room temperature and treated with DDQ (0.244 g, 1.076 mmol) portionwise over 2 minutes. The mixture !0 was diluted with sodium bicarbonate solution, extracted into dichloromethane, concentrated and purified by chromatography on silica gel with a 40 g column, eluting with 0-15% methanol/dichloromethane to give the title compound (0.355 g, 81%) as a yellow solid.

(2.S'.2'.S')-/i77-biityl 2,2'-(5,5'-( 1 -(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(\H25 benzo[7]imidazole-5,2-diyl))dipyrrolidine-1 -carboxylate (2.S'.2'.S')-/i77-Butyl 2,2'-(5,5'-(l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,lphenylene)bis(azanediyl)bis(oxomethylene))dipyrrolidine-l-carboxylate was dissolved in neat acetic acid (3 mL) and heated at 72 °C for 2 hours. The solution was concentrated and then poured into water. The pH was adjusted to ~7-8 with sodium bicarbonate. The product was extracted into 30 dichloromethane, concentrated and purified by chromatography on silica gel with a 40 g column, eluting with 0-5%methanol/dichloromethane to give the title compound (0.185 g, 55%) as a light yellow solid.

General Procedure 16. Benzimidazole synthesis through methoxybenzylamine displacement route II

267

Illustrated below in General Procedure 16A is a representative synthesis of (57) where D is 4fluorophenyl.

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Illustration of General Procedure 16. General Procedure 16A

4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(7V-(4-methoxybenzyl)-2-nitroaniline)

2,5-Bis(4-chloro-3-nitrophenyl)-l-(4-fluorophenyl)pyrrolidine (0.88 g, 1.86 mmol) was combined with 4-methoxy benzylamine (3.64 mL, 28.0 mmol) and heated at 145 °C for 1 hour in a microwave reactor. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated and purified by chromatography on silica gel with a 330 g column, eluting with 0-60% ethyl acetate/hexanes to give 0.79g (62%) of an orange foam solid.

4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitroaniline)

4,4'-(l-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(A'-(4-mcthoxybcnzyl)-2-nitroaniline) (0.78 g, 1.15 mmol) was dissolved in dichloromethane (10 mL) at room temperature and treated with TFA (1.8 mL, 23.0 mmol) for 3 hours. The residue was concentrated and partitioned between 20 dichloromethane and sodium bicarbonate solution. The organics were concentrated and purified by chromatography on silica gel with a 40 g column, eluting with dichloromethane to give 0.218 g (43%) of the trans isomer.

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4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)dibenzene-l,2-diamine

4,4'-(l-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitroaniline) (0.218 g, 0.50 mmol) was dissolved in DMF (5 mL) then platinum oxide (0.226 g, 0.99 mmol) was added as a THF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to hydrogen balloon.

The mixture was stirred at room temperature for 20 hours. The solution was taken on to the next step without purification.

(2.S'.2'.S')-/i77-butyl 2,2'-(5,5'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,lphenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate

The crude DMF solution of 4,4'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)dibenzene-l,2diamine was treated with diisopropylethylamine (0.296 mL, 1.70 mmol) and .S'-Boc-prolinc (0.192 g, 0.89 mmol) followed by HATU (0.322 g, 0.85 mmol). The solution was stirred for 1.5 hours at room temperature, and then the reaction mixture was diluted with water. The solid product was filtered off and purified by chromatography on silica gel with a 12 g column, eluting with 0-3% methanol in dichloromethane to give 0.235 g (72%) of a yellow solid, for which the regiochemistry of acylation was arbitrarily assigned as reacting at the meta-amino group.

(2.S'.2'.S')-/i77-biityl 2,2'-(5,5'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(lH-benzo[ri]imidazole-5,2diyl))dipyrrolidine-l-carboxylate !0 (2.S'.2'.S')-/i77-Butyl 2,2'-(5,5'-(l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-amino-5,lphenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l-carboxylate was dissolved in neat acetic acid (2 mL) and heated at 60 °C for 1 hour. The solution was concentrated then poured into water and adjusted pH to ~7-8 with sodium bicarbonate. The product was extracted into dichloromethane, concentrated and purified by chromatography on silica gel with a 12 g column, eluting with 0-20% 25 ethyl acetate in dichloromethane to give the title compound (0.124 g, 55%) as a light yellow solid.

General Procedure 17. Suzuki Couplings offN-Aryl group

Fsuz

Intermediate compounds such as 2,5-bis(4-chloro-3-nitrophenyl)-l-(4-iodophenyl)pyrrolidine (or the corresponding triflate, nonaflate, or bromide) can be further elaborated through a Suzuki reaction as shown with an appropriate boronic acid or ester where Rs_uz represents a suitable

269 cycloalkyl, aryl, cycloalkenyl, or heteroaryl group. Suitable conditions for effecting this Suzuki reaction include those described in Scheme V for the synthesis of compounds (37).

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Illustration of General Procedure 17: General Procedure 17A

4-(5-(4-((2/?.5/?)-2.5-bis(4-chloro-3-nitrophcnyl)pyrrolidin-l -yl)phcnyl)pyridin-2-yl)morpholinc (27?,57?)-2,5-Bis(4-chloro-3-nitrophenyl)-l-(4-iodophenyl)pyrrolidine (1.869 g, 3.2 mmol), 4(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.929 g, 3.20 mmol), potassium phosphate (1.359 g, 6.40 mmol), tris(dibenzylideneaoetone)dipalladium(0) (0.029 g, 0.032 0 mmol) and l,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.028 g, 0.096 mmol) were combined in THF (18 mL)/water (6 mL). The mixture was purged with nitrogen for 15 minutes and stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting 5 with ethyl acetate/hexane (20% to 40%) to give the title compound (1.01 g, 51%) as a solid.

General Procedure 18. Proline amide synthesis

Particular substituted proline amides can be made using methods such as those shown in

General Procedures 18A-18C.

Illustration of General Procedure 18. General Procedure 18A

methyl (2.S')-l-((3.S')-3-carbamoyl-2-azabicyclo|2.2J |hcptan-2-yl)-3-mcthyl-l-oxobutan-2ylcarbamate (3.S')-2-((.S')-2-(Mcthoxycarbonylamino)-3-mcthylbiitanoyl)-2-azabicyclo|2.2 J |hcptanc-3carboxylic acid (1.78 g, 5.97 mmol), 2-(3H-[l,2,3]triazolo[4,5-6]pyridin-3-yl)-l,l,3,3tetramethylisouronium hexafluorophosphate (2.49 g, 5.56 mmol), and diisopropylethylamine (2.61

270 mL, 14.92 mmol) were dissolved in acetonitrile (30 mL) at ambient temperature and treated by dropwise addition with 28% ammonium hydroxide solution (2.49 g, 17.98 mmol). The resulting mixture was stirred for 1 hour and then diluted with water and extracted into dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give methyl (2.8')-l-((3.8')-3-carbamoyl-2-azabicyclo|2.2.1 |hcptan-2-yl)-3-mcthyl-l-oxobutan-2ylcarbamate as a white waxy solid.

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Illustration of General Procedure 18. General Procedure 18B

EDC/HOBT

------►

NH₄OH

(2.8,4.8)-/(//7-butyl 2-carbamoyl-4-methoxypyrrolidine-1 -carboxylate (25,45)-l-(tert-Butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (2.9 g, 11.82 mmol) was dissolved in acetonitrile (150 mL) and cooled in an ice bath. TV¹ -((Ethylimino)mcthylcnc)-A''.A''dimethylpropane-1,3-diamine hydrochloride (2.72 g, 14.19 mmol) and 127-benzo[ri][l,2,3]triazol-l-ol hydrate (2.17 g, 14.19 mmol) were added, and the mixture was stirred at ambient temperature for 15 hours, becoming clear. 28% Ammonium hydroxide (4.93 mL, 35.5 mmol) was added dropwise resulting in a precipitate. After stirring for 2 hours, then mixture was concentrated, diluted with water and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 100% yield of (25,45)-tert-butyl 2-carbamoyl-4methoxypyrrolidine-1-carboxylate as a white waxy solid.

!0

Other amides that can be prepared using General Procedure 18B include: (25.4/?)-/i77-butyl 2-carbamoyl-4-methoxypyrrolidine-1 -carboxylate;

(25.45)-/i77-butyl 2-carbamoyl-4-fluoropyrrolidine-1 -carboxylate; and (5)-/i77-butyl 5-carbamoyl-2,2-dimethylpyrrolidine-l-carboxylate.

Illustration of General Procedure 18. General Procedure 18C

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(.S')-/i77-butyl 2-carbamoyl-4-methylenepyrrolidine-1 -carboxylate

(.S')-l-(/i77-Biitoxycarbonyl)-4-mcthylcncpyrrolidinc-2-carboxylic acid (1.05 g, 4.48 mmol) and A'-mcthylmorpholinc (0.64 mL, 5.83 mmol) were dissolved in tetrahydrofuran (25 mL) and cooled to -15 °C in a dry ice/acetone bath. Isobutyl chloroformate (0.65 mL, 4.93 mmol) was added 5 dropwise and the solution was stirred for 15 minutes. The internal temperature was lowered to -25 °C and ammonia (g) was bubbled through the solution for 2 minutes, then the flask was transferred to an ice bath and stirred for another 20 minutes. The solution was poured into brine and extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated. This residue was triturated with ether/hexanes, filtered, and dried to give 0.97 g (81%) of (5')-/<?r/-bntyl 2-carbamoyl-40 methylenepyrrolidine -1 -carboxylate as a white solid.

General Procedure 19

O

Amino acid carbamate intermediates can be made using the method and general illustration 5 shown above to prepare Intermediate 2.

The following compounds can be made following General Procedure 19 starting from the appropriate amino acid:

(5)-2-(methoxycarbonylamino)-2-(tetrahydro-227-pyran-4-yl)acetic acid;

!0 (.S')-2-cyclohcxyl-2-(mcthoxycarbonylamino)acctic acid;

(5)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid;

(5)-2-cyclobutyl-2-(methoxycarbonylamino)acetic acid;

(5)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid;

(5)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid;

(25.3//)-3-mcthoxy-2-(mcthoxycarbonyl ami no)butanoic acid;

(2S,35)-3-methoxy-2-(methoxycarbonylamino)butanoic acid; (5')-2-(mcthoxycarbonylamino)-2-((//)-tctrahydrofiiran-3-yl)acctic acid;

(5)-2-(methoxycarbonylamino)-2-((5)-tetrahydrofuran-3-yl)acetic acid;

(5)-2-(2,3-dihydro-177-inden-2-yl)-2-(methoxycarbonylamino)acetic acid.

(S) -3 -ethyl -2 -(methoxycarbonylamino)pentanoic acid; and (S) -2 -(ethoxycarbonylamino) -3 -methylbutanoic acid.

General Procedure 20

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As described above generally in Scheme XIII, diamines (79) can be converted to benzimidazoles (81) in two steps.

Illustration of General Procedure 20. General Procedure 20A (S)-tert-butyl 2-(6-bromo-5-fluoro-127-benzo[i/]imidazol-2-yl)pyrrolidine-1 -carboxylate

To a solution of 4-bromo-5-fluorobenzene-l,2-diamine (1.7 g, 8.4 mmol) in DMSO (42 mL) was added (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.8 g, 8.4 mmol) followed by HATU (3.5 g, 9.3 mmol) and A'.A'-diisopropyl-A'-cthylaminc (3.7 mL, 21.1 mmol), and the solution 0 was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with H₂O and brine, dried (Na₂SO₄), filtered and concentrated. Acetic acid (40 mL) was added, and the mixture was stirred at 60 °C for 4 hours. Then, the reaction mixture was cooled and concentrated. The residue was azeotroped 2 times with toluene to give crude product which was purified by flash chromatography (0-50% EtOAc/hexane) to give the title compound (2.5g, 6.4 mmol, 77%).

.5 (S)-tert-butyl 2-(5-bromo-6-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-127-benzo[<7]imidazol-2yl)pyrrolidine-l -carboxylate

To a solution of (S)-tert-butyl 2-(6-bromo-5-fluoro-127-benzo[<7]imidazol-2-yl)pyrrolidine-lcarboxylate (2.5 g, 6.4 mmol) in THF (32 mL) was added sodium hydride (0.27 g, 6.8 mmol) and !0 stirring was continued for 30 minutes. 2-(Trimethylsilyl)-ethoxymethyl chloride (1.2 mL, 6.8 mmol) was added and stirring was continued for 30 minutes. Water was added to quench the reaction. The mixture was diluted with EtOAc, washed with I A' HC1, H₂O, and brine, dried (Na₂SO₄), filtered and concentrated to an oil. The oil was purified by flash chromatography (0-30% EtOAc/hexane) to give the title compound (2.9 g, 5.7 mmol, 89%).

The following compounds of general formula (81) can be made following General Procedure 20 starting from the appropriate diamine:

(S)-tert-butyl 2-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-127-benzo[i/]imidazol-2-yl)pyrrolidine1-carboxylate;

(S)-tert-butyl 2-(5-bromo-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-127-benzo[i/]imidazol-2yl)pyrrolidine -1 -carboxylate;

(S)-tert-butyl 2-(5 -bromo-4-chloro-1 -((2-(trimethylsilyl)ethoxy)methyl)- 17/-bcnzo| 0/|imidazol-2yl)pyrrolidine -1 -carboxylate;

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(.S')-/i77-butyl 2-(5 -bromo-4-fluoro-1 -((2-(trimcthylsilyl )cthoxy)mcthyl)-1 H-bcnzo| 0/|imidazol-2yl)pyrrolidine -1 -carboxylate;

(.S')-/i77-butyl 2-(6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-6]pyridin-2yl)pyrrolidine -1 -carboxylate;

(.S')-/i77-butyl 2-(5-bromo-7-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[fr]imidazol-2yl)pyrrolidine -1 -carboxylate;

(.S')-/i77-butyl 2-(5-bromo-6-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[fr]imidazol-2yl)pyrrolidine -1 -carboxylate;

(.S')-/i77-butyl 2-(5-bromo-6-(trifluoromethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH0 benzo [d] imidazol -2 -yl)pyrrolidine -1 -carboxylate;

(.S')-/i77-butyl 2-(5-bromo-7 -(trifluoromethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)- 1Hbenzo [d] imidazol -2 -yl)pyrrolidine -1 -carboxylate;

(.S')-/i77-butyl 2-(5-bromo-6-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[fr]imidazol-2yl)pyrrolidine -1 -carboxylate;

(.S')-/i77-butyl 2-(5-bromo-7-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[fr]imidazol-2yl)pyrrolidine-l-carboxylate; and

(.S')-mcthyl 5 -bromo-2-( 1 -(/m-butoxycarbonyl )pyrrolidin-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)1 H-benzo [d] imidazole -7 -carboxylate.

!0 General Procedure 21

As described above generally in Scheme XIII, compounds (81) can be converted to compounds (82.2). Illustrated below in General Procedure 21A is a representative synthesis of compounds (82.2) where X_i3 is fluoro at the 6-position of the benzimidazole moiety. For convenient illustration, the SEM protecting groups on the benzimidazoles are shown attached to particular 25 nitrogens of the benzimidazole. In General Procedures 21A and 22A, the actual substitution positions of the SEM groups were not determined and may be at either nitrogen.

Illustration of General Procedure 21. General Procedure 21 A.

(2.S'.2'.S')-/i77-butyl 2.2'-(5.5'-(fiiran-2.5-diyl)bis(6-fluoro-l-((2-(trimcthylsilyl)cthoxy)mcthyl)-IHbcnzo|0/|imidazolc-5.2-diyl))dipyrrolidinc-1-carboxylate

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In a pressure tube were combined (.S')-/i77-butyl 2-(5-bromo-6-fluoro-1-((2(trimethylsilyl)ethoxy)methyl)-lH-benzo[</]imidazol-2-yl)pyrrolidine-l-carboxylate (600 mg, 1.2 mmol), 2,5-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furan (186 mg, 0.6 mmol), cesium fluoride (353 mg, 2.3 mmol) and DMF (4 mL), and the mixture was de-gassed with N₂ gas for 30 5 minutes. To this mixture was added [(/-Bu)₂PCl]₂PdCl₂ (PXPd) (15.7 mg, 0.03 mmol) and the tube was sealed and heated at 100 °C for 18 hours. The cooled solution was diluted with EtOAc, filtered through diatomaceous earth. The filtrate was washed with H₂O and brine, dried (Na₂SO₄), filtered and treated with 3-mercaptopropyl silica gel for 30 minutes. The mixture was filtered, and the filtrate concentrated to give crude product which was purified by flash chromatography (0-50% 0 EtOAc/hexane) to give the title compound (269mg, 0.29 mmol, 50%).

di-tert-butyl (2S,2'S)-2,2'-{[(2£)-l,4-dioxobut-2-ene-l,4-diyl]bis(6-fluoro-l-{[2(trimcthylsilyl)cthoxy |mcthyl [ -1f/-bcnzimidazolc-5.2-diyl) Jdipyrrolidinc-1 -carboxylate (ACD Name vl2)

To a solution of (2.S'.2'.S')-/i77-butyl 2,2’-(5,5’-(furan-2,5-diyl)bis(6-fluoro-l-((2(trimethylsilyl)ethoxy)methyl)-lH-benzo[</]imidazole-5,2-diyl)dipyrrolidine-l-carboxylate (340 mg, .36 mmol) in THF (8 mL) was added Selectfluor® (1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) (258 mg, 0.73 mmol) followed by H₂O (1 mL). The solution was stirred for 1 hour, diluted with EtOAc, washed with H₂O and brine, dried (Na₂SO₄), 20 filtered and concentrated to give the title compound.

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/\ di-tert-butyl (2S,2'S)-2,2'-[(l,4-dioxobutane-l,4-diyl)bis(6-fluoro-l-{[2(trimethylsilyl)ethoxy]methyl}-127-benzimidazole-5,2-diyl)]dipyrrolidine-l-carboxylate (ACD Name vl2)

To a solution of di-tert-butyl (2.S'.2'.S')-2.2'-{|(2A')-l.4-dioxobut-2-cnc-l.4-diyl|bis(6-fliioro-l{[2-(trimethylsilyl)ethoxy]methyl}-127-benzimidazole-5,2-diyl)}dipyrrolidine-l-carboxylate (346 mg, 0.36 mmol) in EtOAc (7 mL) was added platinum (3% on carbon) (71 mg, 0.36 mmol) and the solution was stirred under H₂ gas at 1 atm for 2 hours. The solution was filtered, washed with EtOAc and the filtrate concentrated to give a residue which was purified by flash chromatography (0-50% 0 EtOAc/hexane) to give the title compound (269 mg, 0.28 mmol, 78%).

General Procedure 22

As described above generally in Scheme XIII, compounds (82.2) can be converted to compounds (84). Illustrated below in General Procedure 22A is a representative synthesis of 5 compounds (84) where D is 4-tert-butylphenyl, the stereochemistries of the alcohols on the butane1,4-diyl group are both (.S'), and X_i3 is 6-fluoro. The cyclization to form the pyrrolidine can form the trans-pyrrolidine along with varying amounts of the cis-pyrrolidine. The cis-pyrrolidine may be separated after deprotection (see General Procedure 23) or after any step following the deprotection.

Illustration of General Procedure 22. General Procedure 22A

F o=

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2016238925 07 Oct 2016 di-/c77-butyl (2.8.2)8)-2.2'-{|( 1.8.4.8)-1.4-dihydroxybutanc-1.4-diyl|bis(6-fluoro-l-{|2(trimcthylsilyl)cthoxy |mcthyl [ -17/-bcnzimidazolc-5.2-diyl) [dipyrrolidinc-1 -carboxylate (ACD Name vl2)

To a solution of (//)-(+)-a.a-diphcnyl-2-pyrrolidinemethanol (59.9 mg, 0.24 mmol) in THF (2.8 mL) was added trimethylborate (0.034 mL, 0.31 mmol), and the resultant solution was stirred for minutes. The solution was cooled to 0 °C and A'.A'-dicthylanilinc borane (0.4 mL, 2.2 mmol) was added in portions over 30 minutes with stirring continued at 0 °C. This solution was added via cannula to a 0°C solution of di-tert-butyl (2.8'.2)8)-2.2'-|(l.4-dioxobutanc-l.4-diyl)bis(6-fliioro-l-{|2(trimethylsilyl)ethoxy]methyl}-l//-benzimidazole-5,2-diyl)]dipyrrolidine-1 -carboxylate (265 mg, .28 0 mmol) in THF (2.8 mL) and then warmed to room temperature and stirred for 16 hours. The solution was cooled to 0 °C and CH₃OH (0.09 mL, 2.2 mmol) was added, and the solution was warmed to room temperature and stirred for 2 hours. I A'HC’I was added, and the aqueous solution was extracted with EtOAc. The combined extracts were washed with brine, dried (Na₂SO₄), filtered and concentrated. Purification was run by flash chromatography (0-3% CH₃OH/CH₂C1₂) to give the title .5 compound (248 mg, 0.26 mmol, 93%).

di-/c77-butyl (2.8)2)8)-2.2'- {| (2//.5//)-1 -(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl |bis(6-fluoro-1 -{[2(trimcthylsilyl)cthoxy |mcthyl}-1//-bcnzimidazolc-5.2-diyl) Jdipyrrolidinc-1 -carboxylate (ACD Name vl2)

To a solution of di-tert-butyl (2.8.2)8)-2.2'-{|( 1.8.4.8)-1.4-dihydroxybutanc-1.4-diyl|bis(6fluoro -1 - {[2 -(trimethylsilyl)ethoxy]methyl} -1//-benzimidazole -5,2 -diyl)} dipyrrolidine -1 -carboxylate (100 mg, .10 mmol) in CH₂C1₂ (1 mL) at -20 °C was added triethylamine (0.044 mL, 0.31 mmol) followed by mesyl chloride (0.018 mL, 0.23 mmol) and the solution stirred at -20 °C for 1 hour. 4tert-Butyl aniline (0.083 mL, 0.52 mmol) was added in one portion, and the solution was allowed to warm to room temperature overnight, with stirring. The solution was diluted with EtOAc, washed with 17V HC1, H₂O, and brine, dried (Na₂SO₄), filtered and concentrated. Purification by flash chromatography (0-50% EtOAc/hexane) gave the title compound (46 mg, 0.04 mmol, 41%).

General Procedure 23. De-boc/de-SEMProcedure

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Simultaneous removal of Boe and SEM protecting groups, according to the above depiction can be effected using standard conditions such as by treatment with an acid, such as HC1 in solvents such as dioxane or methanol or mixtures thereof at temperature from about room temperature to about 5 60 °C. The compounds obtained on deprotection may consist of a mixture of stereoisomers that may be separated by reverse-phase HPLC. The de-protected compounds obtained may be isolated as either the salt directly from the reaction or reverse-phase HPLC or as the free base following neutralization, extraction into organic solvent and standard isolation.

Illustration of General Procedure 23. General Procedure 23A

6,6'-[(2R,5R)-1 -(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl|bisi5-fliioro-2-|(2.S')-pyrrolidin-2-yl|-1Hbenzimidazole} (ACD Name vl2)

To a solution of di-tert-butyl (2S,2'R)-2,2'-{[(2R,5R)-1 -(4-tert-butylphenyl)pyrrolidine-2,55 diyl]bis(6-fluoro-1 -{[2-(trimethylsilyl)ethoxy]methyl} -1 H-bcnzimidazolc-5,2-diyl)}dipyrrolidine-1 carboxylate (44 mg, 0.04 mmol) in dioxane (1 mL) was added 4 M HCl/dioxane (1 mL, 4.0 mmol) and the solution was stirred at 50 °C for 2 hours. The cooled solution was concentrated and placed under vacuum for 1 hour to provide the crude title compound that was used without purification.

The following list of diamines

4-bromo-3-methylbenzene-1,2-diamine;

-bromo -3 -fluorobenzene -1,2-diamine;

4-bromo -3 -fluorobenzene -1,2-diamine;

4-bromo-3-chlorobenzene-l,2-diamine; and

4-bromo-5 -fluorobenzene-1,2-diamine.

can be subjected to a sequence of General Procedures 20/20A, 21/21 A, 22/22A, 23/23A to give the following compounds: 6,6'-[l-(4-terAbutylphenyl)pyrrolidine-2,5-diyl]bis{4-fluoro-2-[(2S)-pyrrolidin-2-yl]-lHbenzimidazole} (ACD Name vl2);

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6,6'-[(27/,57/)-l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl]bis{7-fluoro-2-[(2S)-pyrrolidin-2-yl]-177benzimidazole} (ACD Name vl2);

6,6'-[(27/,5S)-l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl]bis{7-fluoro-2-[(2S)-pyrrolidin-2-yl]-177benzimidazole} (ACD Name vl2);

6,6'-[(27/,57/)-l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl]bis{7-chloro-2-[(2S)-pyrrolidin-2-yl]-177benzimidazole} (ACD Name vl2);

6,6'-[(27/,5S)-l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl]bis{7-chloro-2-[(2S)-pyrrolidin-2-yl]-177benzimidazole} (ACD Name vl2);

6,6'-[(27/,57/)-l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl]bis{7-methyl-2-[(2S)-pyrrolidin-2-yl]-1770 benzimidazole} (ACD Name v 12);

6,6'-[(27/,5S)-l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl]bis{7-methyl-2-[(2S)-pyrrolidin-2-yl]-177benzimidazole} (ACD Name vl2);

6,6'-{(27/,57/)-l-[3-fluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)pyrrolidin-2-yl]-177-benzimidazole} (ACD Name vl2);

6,6'-{(27/,57/)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)pyrrolidin-2-yl]-177-benzimidazole} (ACD Name vl2); and

6,6'-{(27/,57/)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2|(2.S')-pyrrolidin-2-yl|-l//-bcnzimidazolc} (ACD Name vl2).

!0 Examples

The following example compounds 1.1-1.8 can be made from the appropriate listed substituted pyrrolidine following the methods of General Procedure 8.1, General Procedure 9C (Raney-nickel), and General Procedure 10B.

Pyrrolidines:

(2//.5//)-2.5-bis(4-chloro-3-nitrophcnyl)-1-(4-phcnoxyphcnyl)pyrrolidinc:

-(4-((27/,57/)-2,5 -bis(4-chloro-3-nitrophenyl)pyrrolidin-1 -yl)phenyl)pyridin-2( lH)-one; (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(2,5-difluoro-4-(trifluoromethyl)phenyl)pyrrolidine;

0 4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2-fluoropyridine;

l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4,4difluoropiperidine;

l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-fluoropiperidine; (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-((3-ethyloxetan-3-yl)methoxy)phenyl)pyrrolidine; and (17/,5S)-3-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-3azabicyclo[3.2.0]heptane.

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?BS

Example 1.1 methyl {(25)-1-[(25)-2-{5-[(27/,57/)-5-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-35 methylbutanoyl }pyrrolidin-2-yl ]-12/-benzimidazol-5-yl }-l -(4-phenoxyphenyl)pyrrolidin-2-yl ]-127benzimidazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate ‘HNMR (400 MHz, DMSO-c/,) δ ppm 0.78 - 0.91 (m, 12 H) 1.70 (d, J=6.83 Hz, 2 H) 1.86 - 1.96 (m,

H) 1.99 (d, J=2.17 Hz, 4 H) 2.15 - 2.25 (m, 4 H) 2.55 - 2.61 (m, 2 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.06 (t, J=8.40 Hz, 2 H) 5.13 (t, J=7.26 Hz, 2 H) 5.35 - 5.43 (m, 2 H) 6.35 (d, J=9.11 Hz, 2 H) 6.62 - 6.69 0 (m, 2 H) 6.71 (d, J=8.02 Hz, 2 H) 6.93 (t, J=7.43 Hz, 1 H) 7.08 (t, J=9.43 Hz, 2 H) 7.18 - 7.25 (m, 3

H) 7.27 - 7.34 (m, 3 H) 7.39 (d, J=8.13 Hz, 1 H) 7.47 (d, J=8.02 Hz, 1 H) 12.05 (d, J=12.04 Hz, 2 H); MS (ESI+) m/z 924.4 (M+H)⁺.

methyl {(25)-1 -| (25)-2-(5-] (2//.5//)-5-{2-| (25)-1 -{(25)-2-[(methoxycarbonyl)amino]-3methylbutanoyl} pyrrolidin-2-yl] -127-benzi midazol-5 -yl} -1 -[4-(2-oxopiperidin-1 -yl)phenyl]pyrrolidin2-yl} -1 //-bcnzimidazol -2-yl )pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, DMSO-r/₆) δ ppm 0.76 - 0.92 (m, 12 H) 1.66 - 1.76 (m, 6 H) 1.91 (dd, J=13.61,

7.54 Hz, 2 H) 1.95 - 2.04 (m, 4 H) 2.20 (dd, J=16.26, 3.80 Hz, 6 H) 2.58 - 2.64 (m, 2 H) 3.39 - 3.45 (m, 2 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.02 - 4.09 (m, 2 H) 5.09 - 5.19 (m, 2 H) 5.35 - 5.43 (m, 2 H) 6.29 (d, J=8.89 Hz, 2 H) 6.70 - 6.78 (m, 2 H) 7.07 (d, J=8.13 Hz, 2 H) 7.22 (s, 1 H) 7.29 (d, J=8.35 Hz, 2 H) 7.33 (s, 1 H) 7.38 (d, J=8.35 Hz, 1 H) 7.47 (d, J=8.13 Hz, 1 H) 12.04 (s, 2 H); MS (ESI+) m/z

929.5 (M+H)⁺.

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Example 1.3 methyl {(25)-1-[(25)-2-{5-[(25,5R)-l-[2,5-difluoro-4-(trifluoromethyl)phenyl]-5-{2-[(25)-l-{(25)-25 [(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-2yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, DMSO-4,) δ ppm 0.76 - 0.94 (m, 12 H) 1.83 - 2.07 (m, 8 H) 2.14 - 2.28 (m, 4 H) 2.35 - 2.45 (m, 2 H) 3.54 (s, 6 H) 3.75 - 3.94 (m, 4 H) 4.07 (dd, J=8.19, 4.93 Hz, 2 H) 5.19 (dd, J=31.50, 3.74 Hz, 4 H) 6.48 - 6.61 (m, 1 H) 7.20 - 7.35 (m, 5 H) 7.40 - 7.46 (m, 1 H) 7.49 - 7.56 (m, 2 0 H) 7.58 - 7.65 (m, 1 H) 12.12 (d, J=4.66 Hz, 2 H); MS (APCI+) m/z 936.24 (M+H)⁺.

methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-(2-fluoropyridin-4-yl)-5-{2-[(25)-l-{(25)-215 [(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-2yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, DMSO-4,) δ ppm 0.77 - 0.91 (m, 12 H) 1.32 (td, J=14.99, 7.43 Hz, 1 H) 1.53 (dt, J=21.23, 6.63 Hz, 1 H) 1.74 (dd, J=11.93, 6.07 Hz, 2 H) 1.86 - 2.05 (m, 6 H) 2.14 - 2.23 (m, 4 H) 3.54 (s, 6 H) 3.77 - 3.86 (m, 4 H) 4.05 - 4.10 (m, 2 H) 5.11 - 5.18 (m, 2 H) 5.45 - 5.59 (m, 2 H) 5.79 (s, 1

H) 6.18 - 6.23 (m, 1 H) 7.03 - 7.13 (m, 2 H) 7.23 (s, 1 H) 7.29 (d, J=8.35 Hz, 2 H) 7.34 (d, J=1.52 Hz,

H) 7.42 (d, J=8.35 Hz, 1 H) 7.47 - 7.56 (m, 2 H) 12.11 (s, 2 H); MS (ESI+) m/z 851.3 (M+H)⁺.

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Example 1.5 methyl {(25)-1-[(25)-2-{5-[(27?,57?)-l-[4-(4,4-difluoropiperidin-l-yl)-3,5-difluorophenyl]-5-{2-[(25)l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-55 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.74 - 0.93 (m, 12 H) 1.63 - 1.74 (m, 2 H) 1.85 - 2.06 (m, 12

H) 2.19 (dd, J=9.49, 5.37 Hz, 4 H) 2.86 - 2.96 (m, 4 H) 3.54 (s, 6 H) 3.76 - 3.86 (m, 4 H) 4.07 (t,

J=8.24 Hz, 2 H) 5.09 - 5.20 (m, 2 H) 5.33 - 5.42 (m, 2 H) 5.92 (d, J=12.90 Hz, 2 H) 7.07 (t, 1=7.37

Hz, 2 H) 7.21 (s, 1 H) 7.26 - 7.33 (m, 3 H) 7.41 (d, J=8.13 Hz, 1 H) 7.49 (d, J=8.13 Hz, 1 H) 12.08 (d, 0 J=12.90 Hz, 2 H); MS (ESI+) m/z 987.5 (M+H)⁺.

methyl {l-[(25)-2-{5-[(27?,57?)-l-[3,5-difluoro-4-(4-fluoropiperidin-l-yl)phenyl]-5-{2-[(25)-l-{215 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2yl]-17/-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, DMSO-4,) δ ppm 0.74 - 0.91 (m, 12 H) 1.63-1.71 (m, 6 H) 1.76 - 1.97 (m, 4 H)

1.98 - 2.07 (m, 4 H) 2.14 - 2.23 (m, 4 H) 2.71 - 2.78 (m, 2 H) 2.90 - 3.00 (m, 2 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.06 (t, J=8.73 Hz, 2 H) 4.58 - 4.78 (m, 1 H) 5.11 -5.18 (m, 2 H) 5.33 -5.43 (m, 2 H) 5.90 (d,

J=12.69 Hz, 2 H) 7.07 (t, 1=7.37 Hz, 2 H) 7.20 (s, 1 H) 7.26 - 7.32 (m, 3 H) 7.41 (d, J=8.24 Hz, 1 H)

7.49 (d, J=8.24 Hz, 1 H) 12.07 (d, J= 16.48 Hz, 2 H); MS (ESI+) m/z 969.5 (M+H)⁺.

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methyl {(25)-l-[(25)-2-{5-[(27/,57/)-l-{4-[(3-ethyloxetan-3-yl)methoxy]phenyl}-5-{2-[(25)-l-{(25)2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-177-benzimidazol-5-yl }pyrrolidin-25 yl]-I /7-bcnzi midazol -2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'H NMR (400 MHz, DMSOY) δ 12.26 - 11.98 (m, 2H), 7.44 (d, J= 8.2, 1H), 7.37 (d, J= 8.2, 1H),

7.33 - 7.18 (m, 4H), 7.05 (t, J= 8.1, 2H), 6.62 - 6.53 (m, 2H), 6.26 (d, J= 8.8, 2H), 5.40 - 5.30 (m, 2H), 5.17 - 5.08 (m, 2H), 4.29 (d, J= 5.7, 2H), 4.22 (d, J= 5.8, 2H), 4.06 (t, J= 8.3, 2H), 3.86 - 3.75 (m, 6H), 3.53 (s, 6H), 2.54 (s, 2H), 2.24 - 2.12 (m, 4H), 2.06 - 1.83 (m, 6H), 1.75 - 1.62 (m, 4H), 0 0.91 - 0.74 (m, 15H); MS (ESI+) m/z 946.5 (M+H)⁺.

ABS o

Example 1.8 methyl {(25)-1-[(25)-2-{5-[(27/,57/)-1-{4-[(17/,55)-3-azabicyclo[3.2.0]hept-3-yl]-3,5-difluorophenyl}15 5 - { 2- [(25) -1 - {(25)-2- [(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] -177benzimidazol-5-yl [pyrrolidin-2-yl |-177-bcnzimidazol-2-yl [pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2yl} carbamate *HNMR (400 MHz, DMSOY) δ ppm 0.82 (s, 12 H) 1.61 (s, 3 H) 1.71 (d, 2 H) 1.97 (m, 9 H) 2.20 (s,

H) 2.74 - 2.78 (m, 2 H) 2.85 (s, 5 H) 3.53 (s, 6 H) 3.82 (s, 3 H) 4.06 (s, 2 H) 5.14 (s, 2 H) 5.38 (s, 2

H) 5.91 (s, 2 H) 7.09 (s, 1 H) 7.37 (m, 6 H) 7.63 (s, 1 H) 7.88 (s, 1 H) 12.05 (s, 2 H); MS (ESI+) m/z

963.5 (M+H)⁺, (ESI-) m/z 961.4 (M-H)’.

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The following example compounds 2.1-2.17 can be made from the appropriate listed substituted pyrrolidine following the methods of General Procedure 8.1, General Procedure 9D (PtO2), and

General Procedure 10B.

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Pyrrolidines:

2-(4-((2//.5//)-2.54ns(4-chloro-3-nitrophcnyl)pyrrolidin-1-yl)phcnyl)oxazolc: (27/,57/)-1-(4-chloro-3-fluorophenyl)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidine;

(27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(4-((3-ethyloxetan-3-yl)methoxy)-3,5difluorophenyl)pyrrolidine;

1-(4-( (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,3,5,6-tetrafluorophenyl)piperidine; (27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)-l-(3-fluoro-4-(methylsulfonyl)phenyl)pyrrolidine (obtained .5 by mCPBA oxidation of (27/,57/)-2,5 -bis(4-chloro-3 -nitrophenyl)-1-(3 -fluoro-4(methylthio)phenyl)pyrrolidine);

4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-7V-tert-butyl-2-fluoroaniline;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(3!0 phenylpropyl)piperidine;

l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(naphthalen-l30 yl)piperidine;

1-(4-( (2R,5R)-2,5-bis(4-chloro-2-fluoro-5-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-3,5dimethylpiperidine; and l-(4-((2R,5R)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-(4(trifluoromethyl)phenyl)piperazine.

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ABS

Example 2.1 methyl {(25)-1-[(25)-2-(5-{(2J?,5J?)-5-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }-l-[4-( l,3-oxazol-2-yl)phenyl ]pyrrolidin-25 yl} -I H-bcnzimidazol -2-yl )pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl}carbamate ‘HNMR (400 MHz, DMSO-d₆) δ ppm 0.74 - 0.91 (m, 12 H) 1.70 - 1.79 (m, 2 H) 1.89 (ddd, J=14.20, 7.05, 6.94 Hz, 2 H) 1.95 - 2.04 (m, 4 H) 2.13 - 2.23 (m, 4 H) 2.55 - 2.61 (m, 2 H) 3.53 (s, 6 H) 3.77 3.84 (m, 4 H) 4.05 (t, J=8.67 Hz, 2 H) 5.09 - 5.18 (m, 2 H) 5.46 - 5.54 (m, 2 H) 6.45 (d, J=8.89 Hz, 2 H) 7.08 (t, J=7.75 Hz, 2 H) 7.13 (s, 1 H) 7.23 (s, 1 H) 7.28 (d, J=8.24 Hz, 2 H) 7.33 (s, 1 H) 7.39 (d, 0 J=8.13 Hz, 1 H) 7.45 - 7.56 (m, 3 H) 7.94 (s, 1 H) 12.06 (s, 2 H); MS (ESI+) m/z 899.4 (M+H)⁺.

methyl {(25)-1-[(25)-2-{5-[(2J?,5J?)-l-(4-chloro-3-fluorophenyl)-5-{2-[(25)-l-{(25)-215 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, DMSO-4,) δ ppm 0.77 - 0.90 (m, 12 H) 1.66 - 1.78 (m, 2 H) 1.88 - 1.95 (m, 2 H)

1.96 - 2.06 (m, 4 H) 2.15 - 2.24 (m, 4 H) 2.54 - 2.60 (m, 2 H) 3.54 (s, 6 H) 3.79 - 3.86 (m, 4 H) 4.06 (t, J=8.46 Hz, 2 H) 5.10 - 5.18 (m, 2 H) 5.37 - 5.45 (m, 2 H) 6.16 (dd, J=9.49, 2.01 Hz, 1 H) 6.22 (dd, 20 J=13.55, 2.06 Hz, 1 H) 7.00 - 7.11 (m, 3 H) 7.22 (s, 1 H) 7.28 (d, J=8.57 Hz, 2 H) 7.32 (s, 1 H) 7.40 (d, J=8.24 Hz, 1 H) 7.47 (d, J=8.13 Hz, 1 H) 12.07 (d, J=2.93 Hz, 2 H); MS (APCI+) m/z 884 (M+H)⁺.

285

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Example 2.3 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-[4-(l,3-dioxan-5-yloxy)phenyl]-5-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-25 yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO-fo) δ ppm 12.28 - 11.98 (m, 2H), 7.45 (d, J= 8.1, 1H), 7.37 (d, J= 8.2,

1H), 7.32 - 7.23 (m, 3H), 7.21 (s, 1H), 7.12 - 7.01 (m, 2H), 6.62 - 6.51 (m, 2H), 6.24 (d, J= 8.9, 2H),

5.40 - 5.27 (m, 2H), 5.18 - 5.09 (m, 2H), 4.72 (d, 7= 6.1, 1H), 4.67 (d, 7= 6.2, 1H), 4.06 (t, 7= 8.4, 2H), 4.01 - 3.75 (m, 7H), 3.68 - 3.58 (m, 2H), 3.52 (d, 7= 15.9, 6H), 2.28 - 1.83 (m, 12H), 1.74 0 1.62 (m, 2H), 0.93 - 0.73 (m, 12H); MS (ESI+) m/z 934.5 (M+H)⁺.

ABS

Example 2.4 methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-[4-(l,3-dioxolan-4-ylmethoxy)phenyl]-5-{2-[(25)-l-{(25)-215 [(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-2yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO-fo) δ ppm 12.27- 11.95 (m, 2H), 7.43 (d,7= 8.1, 1H), 7.35 (d,7= 8.2,

1H), 7.32 - 7.22 (m, 3H), 7.19 (s, 1H), 7.03 (t,7= 7.4, 2H), 6.59 - 6.47 (m, 2H), 6.23 (d,7= 8.8, 2H),

5.39 - 5.27 (m, 2H), 5.16 - 5.04 (m, 2H), 4.83 (d, 7= 2.6, 1H), 4.74 (s, 1H), 4.22 - 4.12 (m, 1H), 4.04 (t, 7= 8.3, 2H), 3.88 (t, 7= 7.5, 1H), 3.83 - 3.67 (m, 6H), 3.57 - 3.47 (m, 7H), 2.29 - 1.80 (m, 12H),

1.74 - 1.60 (m, 2H), 0.93 - 0.71 (m, 12H); MS (ESI+) m/z 934.4 (M+H)⁺.

286

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Example 2.5 methyl {(25)-1 -| (25)-2-{6-| (2//.57/)-1 -{4-[(3-ethyloxetan-3-yl)methoxy]-3,5-difluorophenyl}-5-{2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-bcnzi midazol -65 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-t/₆) δ 12.30 - 12.02 (m, 2H), 7.47 (d, J= 8.3, 1H), 7.40 (d, J= 8.3, 1H),

7.34 - 7.16 (m, 4H), 7.06 (t, J= Ίβ, 2H), 5.98 (d, J= 12.3, 2H), 5.46 - 5.30 (m, 2H), 5.24 - 5.05 (m, 2H), 4.29 (d, J= 5.5, 2H), 4.21 (d, J= 5.8, 2H), 4.05 (t, J= 8.2, 2H), 3.90 - 3.72 (m, 6H), 3.52 (s,

6H), 2.27 - 1.81 (m, 12H), 1.73 - 1.60 (m, 4H), 0.91 - 0.69 (m, 15H); MS (ESI+) m/z 982.4 (M+H)⁺.

Example 2.6 methyl {(25)-l-[(25)-2-(6-{(27/,57/)-5-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3methylbutanoyl}pyrrolidin-2-yl]-127-benzimidazol-6-yl}-l-[2,3,5,6-tetrafluoro-4-(piperidin-lyl)phenyl]pyrrolidin-2-yl} -177-benzi midazol-2-yl )pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-215 yl} carbamate 'HNMR (400 MHz, DMSO-4,) δ 12.10 (dd, J= 58.0, 37.7, 2H), 7.52 - 7.21 (m, 6H), 7.07 (t, J= 8.1, 2H), 5.52 - 5.29 (m, 2H), 5.17 - 5.03 (m, 2H), 4.12 - 3.93 (m, 2H), 3.88 - 3.66 (m, 4H), 3.53 (s, 6H), 2.87 - 2.71 (m, 4H), 2.27 - 1.76 (m, 14H), 1.50 - 1.32 (m, 6H), 0.93 - 0.70 (m, 12H); MS (ESI+) m/z 987.3 (M+H)⁺.

287

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Example 2.7 methyl {(25)-l-[(25)-2-{6-[(27/,57/)-l-[3-fluoro-4-(methylsulfonyl)phenyl]-5-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-177-benzimidazol-6-yl }pyrrolidin-25 yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 0.81 - 0.97 (m, 12 H), 1.30 (s, 2 H), 1.82 (d, J=4.2 Hz, 2 H),

1.90 - 2.35 (m, 12 H), 3.60 (s, 6 H), 3.88 (s, 3 H), 4.13 (t, J=8.3 Hz, 2 H), 5.20 (t, J=7.3 Hz, 2 H), 5.62 (s, 2 H), 6.26 - 6.40 (m, J=9.5 Hz, 2 H), 7.15 (d, J=7.0 Hz, 2 H), 7.30 (s, 1 H), 7.32 - 7.45 (m, 4 H),

7.49 (d, J=8.2 Hz, 1 H), 7.56 (d, J=8.1 Hz, 1 H), 12.16 (s, 2 H); MS (ESI+) m/z 928.4 (M+H)⁺, (ESI-) .0 m/z 926.3 (M-H)’.

Example 2.8 methyl {(25)-1-[(25)-2-{6-[(27/,57/)-1-{4-[acetyl(tert-butyl)amino]-3-fluorophenyl}-5-{2-[(25)-l15 {(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-177-benzimidazol-6yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Starting from 4-((2//.5//)-2.5-bis(4-chloro-3-nitrophcnyl)pyrrolidin-1-yl)-A'-/i’/7-biityl-2fluoroaniline, the initial product of the sequence outlined above was methyl {(25)-l-[(25)-2-{6[(27/,57/)-1-[4-(tert-butylamino)-3-fluorophenyl]-5-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-320 methylbutanoyl}pyrrolidin-2-yl] -1 //-benzi midazol -6-yl}pyrrolidin-2-yl] -1 //-benzimidazol-2yl}pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate (ACD Name vl2). The A'-acctyl group was added by reaction with acetic anhydride/pyridine to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73 - 0.90 (m, 12 H), 1.13 (d, 7=5.20 Hz, 9 H), 1.37 - 1.44 (m, 4 H), 1.62 - 1.72 (m, 2H), 1.92 -2.02 (m, 9 H), 2.10 - 2.26 (m, 5 H), 2.51 -2.58 (m, 2 H), 3.52 (s, 6 H), 3.73 - 3.85 (m,

4 H), 3.98 - 4.12 (m, 2 H), 5.09 - 5.17 (m, 2 H), 5.36 - 5.48 (m, 3 H), 6.08 - 6.18 (m, 3 H), 6.74 - 6.87

288 (m, 1 H), 7.08 (dd, 7=13.72, 8.29 Hz, 3 H), 7.20 (s, 1 H), 7.24 - 7.31 (m, 4 H), 7.40 (d, 7=8.24 Hz, 1

H), 7.48 (d, 7=8.13 Hz, 1 H), 12.01 (s, 1 H), 12.17 (s, 1 H); MS (ESI+) m/z 964 (M+H)⁺.

2016238925 07 Oct 2016

methyl {(25)-1-[(2S)-2-{6-[(27/,57/)-1-[3,5-difluoro-4-(4-methylpiperidin-l-yl)phenyl]-5-{2-[(2S)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-177-benzimidazol-6yl} pyrrolidin-2-yl] - 177-benzimidazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO-7₆) δ ppm 0.75 - 0.90 (m, 12 H), 1.05 - 1.18 (m, 2 H), 1.24 - 1.37 (m, 2

H), 1.45 - 1.54 (m, 2 H), 1.62 - 1.73 (m, 2 H), 1.84 - 2.05 (m, 7 H), 2.12 - 2.25 (m, 5 H), 2.69 - 2.81 (m, 4 H), 3.52 (s, 6 H), 3.77 - 3.86 (m, 4 H), 4.05 (t, J=8.35 Hz, 2 H), 5.10 - 5.18 (m, 2 H), 5.35 (q, J=7.34 Hz, 2 H), 5.87 (d, J=12.69 Hz, 2 H), 7.02 - 7.10 (m, 2 H), 7.19 (s, 1 H), 7.24 - 7.32 (m, 3 H), 7.39 (d, J=8.24 Hz, 1 H), 7.47 (d, J=8.13 Hz, 1 H), 12.06 (d, J=20.93 Hz, 2 H); MS (ESI+) m/z 966 (M+H)⁺.

ABS

Example 2.10

289 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-{3,5-difluoro-4-[4-(3-phenylpropyl)piperidin-l-yl]phenyl}-5{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol5-yl}pyrrolidin-2-yl] -I H-bcnzi midazol-2-yl [ pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-2-yl}carbamate 'H NMR (400 MHz, DMSO-d₆) δ ppm 0.72 - 0.95 (m, 12 H), 1.00-1.31 (m, 9 H), 1.46 - 1.59 (m, 4

H), 1.61 - 1.79 (m, 2 H), 1.83 - 2.08 (m, 6 H), 2.11 - 2.27 (m, 4 H), 2.77 (s, 4 H), 3.54 (s, 6 H), 3.82 (s, 4 H), 4.06 (t, 7=8.46 Hz, 2 H), 5.08 - 5.19 (m, 2 H), 5.28 - 5.46 (m, 2 H), 5.88 (d, 7=12.79 Hz, 2 H), 7.01 - 7.10 (m, 2 H), 7.10 - 7.33 (m, 9 H), 7.40 (d, 7=8.13 Hz, 1 H), 7.48 (d, 7=8.13 Hz, 1 H), 11.71 - 12.51 (m, 2 H); MS (ESI+) m/z 1069 (M+H)⁺; MS (ESI-) m/z 1067 (M-H)’.

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Example 2.11 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-[4-(8-azaspiro[4.5]dec-8-yl)-3,5-difluorophenyl]-5-{2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5yl}pyrrolidin-2-yl] -I H-bc nzi m i dazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-7₆) δ ppm 0.73 - 0.93 (m, 12 H), 1.29 - 1.43 (m, 9 H), 1.52 (t, 7=6.83 Hz,

5 H), 1.68 (s, 2 H), 1.81 - 2.08 (m, 6 H), 2.10 - 2.26 (m, 4 H), 2.75 (s, 4 H), 3.54 (s, 6 H), 3.82 (s, 4

H), 4.06 (t, 7=8.40 Hz, 2 H), 5.09 - 5.19 (m, 2 H), 5.29 - 5.46 (m, 2 H), 5.88 (d, 7=12.58 Hz, 2 H), 7.03 - 7.11 (m, 2 H), 7.20 (s, 1 H), 7.25 - 7.33 (m, 3 H), 7.40 (d, 7=8.24 Hz, 1 H), 7.49 (d, 7=8.24 Hz, 1 H), 11.63 - 12.57 (m, 2 H); MS (ESI+) m/z 1005 (M+H)⁺; MS (ESI-) m/z 1003 (M-H)’.

290

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Example 2.12 methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-{3,5-difluoro-4-[4-(2-naphthyl)piperidin-l-yl]phenyl}-5-{2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-bcnzi midazol-5 5 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO-J₆) δ ppm 0.76 - 0.91 (m, 12 H), 1.24 (d, J=2.28 Hz, 2 H), 1.63 - 2.08 (m,

H), 2.20 (s, 4 H), 2.86 - 3.19 (m, 5 H), 3.53 (s, 6 H), 3.82 (s, 4 H), 4.06 (t, 7=8.29 Hz, 2 H), 5.10 5.22 (m, 2 H), 5.32 - 5.48 (m, 2 H), 5.93 (d, 7=12.90 Hz, 2 H), 7.03 - 7.16 (m, 2 H), 7.19 - 7.36 (m, 4

H), 7.39 - 7.55 (m, 5 H), 7.69 - 7.89 (m, 4 H), 11.71 - 12.63 (m, 2 H); MS (ESI+) m/z 1077 (M+H)⁺; 0 MS (ESI-) m/z 1075 (M-H)’.

Example 2.13 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-{3,5-difluoro-4-[4-(pyridin-2-yl)piperidin-l-yl]phenyl}-5-{2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-bcnzi midazol-5 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

291 'H NMR (400 MHz, DMSO-A) δ ppm 0.71 - 1.02 (m, 12 H), 1.62 - 1.83 (m, 6 H), 1.81 - 2.08 (m, 7

H), 2.10 - 2.29 (m, 4 H), 2.47 - 2.63 (m, 2 H), 2.81 - 3.07 (m, 4 H), 3.53 (s, 6 H), 3.82 (s, 4 H), 4.06 (t,

7=8.89 Hz, 2 H), 5.10-5.21 (m, 2 H), 5.31 -5.47 (m, 2 H), 5.91 (d, 7=12.69 Hz, 2 H), 7.04-7.13 (m,

H), 7.14 - 7.20 (m, 1 H), 7.20 - 7.34 (m, 5 H), 7.41 (d, 7=8.24 Hz, 1 H), 7.49 (d, 7=8.35 Hz, 1 H),

7.62 - 7.72 (m, 1 H), 8.45 (d, 7=4.55 Hz, 1 H), 11.74 - 12.57 (m, 2 H); MS (ESI+) m/z 1028 (M+H)⁺;

MS (ESI-) m/z 1026 (M-H)’.

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ABS

Example 2.14 methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(3,5-difluoro-4-{4-[4-(trimethylsilyl)phenyl]piperidin-lyl}phenyl)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-127benzimidazol-5 -yl [ pyrrolidin-2-yl | -1 //-bcnzimidazol-2-yl [ pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate ‘HNMR (400 MHz, DMSO-A) δ ppm 0.20 (s, 9 H), 0.74 - 0.94 (m, 12 H), 1.59 - 1.75 (m, 6 H), 1.83 15 - 2.09 (m, 7 H), 2.13 - 2.29 (m, 4 H), 2.44 - 2.59 (m, 2 H), 2.84 - 3.15 (m, 4 H), 3.53 (s, 6 H), 3.82 (s,

H), 4.06 (t, 7=8.46 Hz, 2 H), 5.15 (d, 7=3.04 Hz, 2 H), 5.31 - 5.47 (m, 2 H), 5.92 (d, 7=12.79 Hz, 2 H), 7.04 - 7.14 (m, 2 H), 7.21 (d, 7=7.92 Hz, 3 H), 7.27 - 7.37 (m, 3 H), 7.37 - 7.45 (m, 3 H), 7.50 (d, 7=8.02 Hz, 1 H), 12.10 (d, 7=17.57 Hz, 2 H); MS (ESI+) m/z 1099 (M+H)⁺; MS (ESI-) m/z 1097 (ΜΗ)’.

292

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Example 2.15 methyl {(25)-1-[(25)-2-{5-[(27/,57/)-l-{3,5-difluoro-4-[4-(l-naphthyl)piperidin-l-yl]phenyl}-5-{2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 27-benzi midazol-5 - yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate ‘HNMR (400 MHz, DMSO-7,) δ ppm 0.74 - 0.94 (m, 12 H), 1.64 - 2.05 (m, 12 H), 2.13 - 2.29 (m, 3 H), 2.45 - 2.62 (m, 2 H), 2.90 - 3.01 (m, 7=11.06 Hz, 2 H), 3.08 - 3.25 (m, 2 H), 3.53 (s, 6 H), 3.82 (s, 4 H), 4.06 (t, 7=8.29 Hz, 2 H), 5.08 - 5.23 (m, 2 H), 5.32 - 5.52 (m, 2 H), 5.94 (d, 7=12.69 Hz, 2 H), 7.04 - 7.17 (m, 2 H), 7.20 - 7.37 (m, 4 H), 7.38 - 7.59 (m, 6 H), 7.75 (d, 7=8.35 Hz, 1 H), 7.86 - 7.95 (m, 1 H), 8.14 (d, 7=8.24 Hz, 1 H), 11.61 - 12.69 (m, 2 H); MS (ESI+) m/z 1077 (M+H)⁺; (ESI-) m/z

1075 (M-H)’.

ABS

Example 2.16 methyl {(25)-1 -| (25)-2-{5-| (5//)-1-|4-(3.5-dimcthylpipcridin-1-yl)-3.5-difluorophcnyl |-5-{6-fluoro-2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 //-bcnzi midazol-5 yl}pyrrolidin-2-yl] -6-fluoro-17/-bcnzimidazol-2-yl [pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate ‘HNMR (400 MHz, DMSO-7₆) δ ppm 0.64 - 0.94 (m, 18 H) 1.56 - 1.73 (m, 4 H) 1.75 - 1.93 (m, 6 H)

1.95 - 2.06 (m, 6 H) 2.12 - 2.26 (m, 4 H) 2.69 - 2.79 (m, 1 H) 3.20 - 3.29 (m, 1 H) 3.53 (s, 6 H) 3.74 293

3.89 (m, 4 H) 3.97 - 4.10 (m, 2 H) 5.05 - 5.19 (m, 2 H) 5.48 - 5.62 (m, 2 H) 5.87 (dd, J=11.49, 7.92

Hz, 2 H) 7.02 (dd, J=3.90, 1.95 Hz, 1 H) 7.12 (d, J=6.83 Hz, 1 H) 7.26 - 7.37 (m, 3 H) 7.40 (dd,

J=11.11, 6.02 Hz, 1 H) 12.08 - 12.16 (m, 1 H) 12.23 - 12.31 (m, 1 H); MS (APCI+) m/z 1016 (M+H)⁺.

2016238925 07 Oct 2016

ABS

F

Example 2.17 methyl {(25)-l-[(25)-2-{5-[(27?,57?)-l-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-lyl}phenyl)-5-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lHbenzimidazol-5-yl [ pyrrolidin-2-yl |-17/-bcnzimidazol-2-yl [ pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-20 yl} carbamate

Ή NMR (400 MHz, DMS0-d₆) δ ppm 0.69 - 0.96 (m, 14 H) 1.10 - 1.29 (m, 2 H) 1.69 (m, 2 H) 1.99 (m, 4 H) 2.20 (m, 2 H) 2.99 (m, 6 H) 3.22 - 3.26 (m, 6 H) 3.54 (s, 6 H) 3.82 (m, 6 H) 5.15 (m, 2 H) 5.39 (m, 2 H) 5.95 (m, 2 H) 7.03 (d, J=8.78 Hz, 2 H) 7.22 (m, 2 H) 7.24 - 7.36 (m, 2 H) 7.40 - 7.56 (m, 4 H) 12.06 (s, 2 H); MS (ESI+) m/z 1096.4, (ESI-) m/z 1094.3.

.5

The following Example compounds 3.1-3.51 can be made from the appropriate listed intermediates following the methods of General Procedures 12/12A.

Intermediate amines:

(5)-6.6'-((2/?.5/?)-l-(4-(pyridin-2-yl)phcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-IT/20 benzo[ri]imidazole);

(5)-6,6'-((27?,57?)-l-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2yl)- ΙΗ-benzo \d\ imidazole);

(5)-6,6'-((2/?.5/?)-l-(4-(2-mcthoxycthoxy)phcnyl)pyrrolidinc-2.5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-IT/benzo [d] imidazole);

(5)-6.6'-((2/?.5/?)-l-(4-chlorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-IT/benzo [d] imidazole);

(5)-6,6'-((2/?. 5R)-1 -(biphenyl -4-yl)pyrrolidine-2,5 -diyl)bis(2 -((5)-pyrrolidin-2-yl)-IT/benzo [d] imidazole);

294

2016238925 07 Oct 2016 (5)-6.6'-((2/?.5/?)-l-(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-l//benzo [d] imidazole);

(5.5) -6,6'-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((25,45)-4methoxypyrrolidin-2-yl) - ΙΗ-benzo [d] imidazole);

(5,5)-6,6'-((2R,5R)-l -(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((25,45)-4fluoropyrrolidin-2-yl) -1 H-be nzo [d] imidazole);

(5.5) -6.6'-((2/?.5/?)-l-(4-fluorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((25.45)-4-fliioropyrrolidin-2-yl)-l//benzo [d] imidazole);

(5.5) -6,6'-((2R,5R)-l-(4-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((25,45)-4-methoxypyrrolidin-2-yl)-

I//-benzo| ό/| imidazole):

(5)-6,6'-((2R,5R)-l-(4-ieri-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((5)-5,5-dimethylpyrrolidin-2-yl)I //-benzo [dj imidazole);

(5.5) -6,6'-((2R,5R)-l-(4-iert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((25,45)-4-fluoropyrrolidin-2-yl)127-benzo [dj imidazole);

(5)-6,6'-((25,55)-l-(4-cyclopropyl-2-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-12/benzo [d] imidazole);

(5)-6,6'-((2/?.5/?)-l -(3 -fluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5 -diyl)bis(2-((5)-pyrrolidin-2-yl)127-benzo [dj imidazole);

(5)-6,6'-( (2R. 5/?)-1 -(3.5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin!0 2-yl)-12/-benzo[ri]imidazole);

(5)-6,6'-((2/?.5/?)-l -(3 -fluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5 -diyl)bis(2-((5)pyrrolidin-2-yl) - I //-be nzo [d] imidazole);

(5)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - I //-be nzo [d] imidazole);

(5)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((35)-2azabicyclo [2.2.1 ]heptan-3 -yl)- I //-benzo [d] imidazole);

(5)-6,6'-( (2R. 5/?)-1 -(3.5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-indolin-2yl)- I //-be nzo [d] imidazole);

(5)-6.6'-((2/?.5/?)-1-(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-4-mcthylcncpyrrolidin-2-yl)30 I//-benzo|ό/| imidazole):

(5.5.5) -6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-lH-benzo[d]imidazole);

(5.5.5) -6,6'-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-lH-benzo[d]imidazole);

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6,6'-{(27/,57/)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(25)pyrrolidin-2-yl]-127-benzimidazole} (ACDName vl2);

(S,S,S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-(3,4-difluorophenyl)piperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,50 diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2S,5R)-l-(2-(4-phenylpiperidin-l-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2((S)-pyrrolidin-2-yl) - ΙΗ-benzo [d]imidazole);

.5 (S)-6,6'-((2S,5R)-l-(2-(piperidin-l-yl)pyrimidin-5-yl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-(2,6-difluorophenyl)piperazin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2S,5S)-l-(4-(4-(2,6-difluorophenyl)piperazin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5!0 diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole); and (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole).

Intermediate acids:

(5)-2-(methoxycarbonylamino)-3-methylbutanoic acid;

(5)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid;

(5)-2-cyclohexyl-2-(methoxycarbonylamino)acetic acid;

(5)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid;

(5)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid;

(25.3//)-3-mcthoxy-2-(mcthoxycarbonyl ami no)butanoic acid;

(2S,35)-3-methoxy-2-(methoxycarbonylamino)butanoic acid;

(5)-2-(methoxycarbonylamino)-2-((7/)-tetrahydrofuran-3-yl)acetic acid;

(5)-2-(methoxycarbonylamino)-2-((5)-tetrahydrofuran-3-yl)acetic acid;

(5)-2-(2,3-dihydro-127-inden-2-yl)-2-(methoxycarbonylamino)acetic acid;

2-(/i'r/-biitoxycarbonylamino)acctic acid;

2-(methoxycarbonylamino)-3-methylbut-2-enoic acid;

296

2016238925 07 Oct 2016 (S) -tetrahydrofuran-2-carboxylic acid (S)-3-ethyl-2-(methoxycarbonylamino)pentanoic acid; and (S) -2 -(ethoxycarbonylamino) -3 -methylbutanoic acid.

ABS

Example 3.1 methyl {(25)-1-[(25)-2-(5-{(2J?,5J?)-5-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }-l-[4-(pyridin-2-yl)phenyl ]pyrrolidin-2-yl }I H-bcnzi m i dazol -2 -yl)pyrrolidin-1 -yl] -3 -methyl -1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-d₆) δ ppm 12.28 - 11.98 (m, 2H), 8.42 (d, J = 4.4, 1H), 7.70 - 7.56 (m, 4H), 7.46 (d, J= 8.2, 1H), 7.38 (d, J= 8.2, 1H), 7.34 (s, 1H), 7.30 - 7.20 (m, 3H), 7.16 - 7.02 (m, 3H), 6.42 (d, J= 8.7, 2H), 5.56 - 5.42 (m, 2H), 5.18 - 5.06 (m, 2H), 4.03 (t, J= 9.3, 2H), 3.88 - 3.73 (m, 4H), 3.52 (s, 6H), 2.25 - 1.62 (m, 14H), 0.92 - 0.67 (m, 12H); MS (ESI+) m/z 909.5 (M+H)⁺.

ABS

Example 3.2 methyl {(25)-1 -| (2.8)-2-{5-| (2/?.5/?)-1 -|3-chloro-4-(trifluoromcthoxy)phcnyl |-5-{2-| (2.8)-1 -((2.8)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-2yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO-fo) δ ppm 12.31 - 12.01 (m, 2H), 7.48 (d, J= 7.9, 1H), 7.40 (d, J= 8.2,

1H), 7.34 - 7.17 (m, 4H), 7.15 - 6.99 (m, 3H), 6.44 (s, 1H), 6.30 (d, J= 8.9, 1H), 5.55 - 5.37 (m, 2H),

5.19 - 5.04 (m, 2H), 4.04 (t, J= 7.8, 2H), 3.89 - 3.73 (m, 4H), 3.52 (s, 6H), 2.28 - 1.79 (m, 12H),

1.77 - 1.59 (m, 2H), 0.92 - 0.64 (m, 12H); MS (ESI+) m/z 950.4 (M+H)⁺.

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2016238925 07 Oct 2016

ABS

N

Example 3.3 methyl {(25)-1 -| (25)-2-(5-( (2//.5//)-5-{2-| (25)-1-{(25)-2-|(mcthoxycarbonyl (amino |-3methylbutanoyl} pyrrolidin-2-yl] -1//-benzi midazol-5 -yl} -1 -[4-(2-methoxyethoxy)phenyl]pyrrolidin-25 yl}-I H-bcnzi midazol -2-yl (pyrrol idi n -1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO-J₆) δ ppm 12.27 - 11.97 (m, 2H), 7.44 (d, J= 8.4, 1H), 7.36 (d, J= 7.7,

1H), 7.33 - 7.25 (m, 3H), 7.20 (s, 1H), 7.12 - 7.00 (m, 2H), 6.58 - 6.47 (m, 2H), 6.24 (d, J= 9.0, 2H),

5.40 - 5.27 (m, 2H), 5.19 - 5.08 (m, 2H), 4.06 (t, J= 8.3, 2H), 3.88 - 3.76 (m, 6H), 3.54 (s, 6H), 3.51

- 3.45 (m, 2H), 3.21 (s, 3H), 2.26 - 1.83 (m, 12H), 1.75 - 1.64 (m, 2H), 0.93 - 0.74 (m, 12H); MS 0 (ESI+) m/z 906.4 (M+H)⁺.

Example 3.4 methyl {(25)-l-[(25)-2-{5-[(2//,5//)-l-(4-chlorophenyl)-5-{2-[(25)-l-{(25)-215 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-l//-benzimidazol-5-yl}pyrrolidin-2yl]-I H-bcnzi midazol -2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate ‘HNMR (400 MHz, DM SO® δ ppm 12.05 (s, 2H), 7.44 (d, J= 8.2, 1H), 7.36 (d, J= 8.1, 1H), 7.31 - 7.22 (m, 3H), 7.19 (s, 1H), 7.03 (t, J= 8.2, 2H), 6.94 - 6.83 (m, 2H), 6.29 (d, J= 9.1, 2H), 5.42 5.32 (m, 2H), 5.16 - 5.04 (m, 2H), 4.04 (t, J= 8.4, 2H), 3.85 - 3.75 (m, 4H), 3.51 (s, 6H), 2.25 - 1.58 (m, 14H), 0.90 - 0.73 (m, 12H); MS (ESI+) m/z 866.4 (M+H)⁺.

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2016238925 07 Oct 2016

4BS

Example 3.5 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-(biphenyl-4-yl)-5-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-127-benzimidazol-5-yl }pyrrolidin-25 yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, DMSO-4,) δ 12.11 - 11.66 (m, 2H), 7.47 (d, J= 8.3, 1H), 7.43 - 7.33 (m, 4H), 7.32 - 7.19 (m, 7H), 7.17 - 7.06 (m, 3H), 6.43 (d, J= 8.8, 2H), 5.52 - 5.41 (m, 2H), 5.18 - 5.09 (m, 2H), 4.05 (t, J= 8.2, 2H), 3.87 - 3.76 (m, 4H), 3.53 (s, 6H), 2.25 - 2.11 (m, 4H), 2.05 - 1.62 (m, 10H), 0.91 - 0.74 (m, 12H); MS (ESI+) m/z 908.5 (M+H)⁺.

ABS

Example 3.6 dimethyl ([(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{127-benzimidazole-5,2diyl(25)pyrrolidine-2,1 -diyl [(15)-2-oxo-1 -(tetrahydro-2H-pyran-4-yl)ethane-2,1 -diyl] })biscarbamate 15 'HNMR (400 MHz, DM SO-®,) δ ppm 1.07 (s, 9 H) 1.22 - 1.32 (m, 2 H) 1.42 - 1.57 (m, 4 H) 1.64 -

1.72 (m, 2 H) 1.82 (dd, J=21.90, 10.63 Hz, 4 H) 1.92 - 2.02 (m, 4 H) 2.10 - 2.25 (m, 4 H) 2.90 - 2.99 (m, 1 H) 3.04 - 3.19 (m, 4 H) 3.53 (s, 6 H) 3.56 - 3.63 (m, 1 H) 3.66 - 3.79 (m, 4 H) 3.83 (d, J=3.04 Hz, 4 H) 4.14 (q, J=8.10 Hz, 2 H) 5.07 - 5.15 (m, 2 H) 5.33 - 5.40 (m, 2 H) 6.24 (d, J=8.89 Hz, 2 H)

6.85 - 6.94 (m, 2 H) 7.09 (dd, J=14.10, 8.46 Hz, 2 H) 7.16 - 7.22 (m, 2 H) 7.30 - 7.41 (m, 3 H) 7.44 (d, J=9.43 Hz, 1 Η) 11.99 - 12.12 (m, 2 H); MS (ESI+) m/z 972.5 (M+H)⁺.

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ABS

Example 3.7 methyl {(25)-l-[(2S,45)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2-[(2S,45)-4methoxy-1 -{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-I H-bcnzi midazol 5 5-yl}pyrrolidin-2-yl] -1 H-bcnzimidazol-2-yl} -4-methoxypyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate ‘HNMR (500 MHz, DMSO-r/₆) δ ppm 0.76 - 0.87 (m, 12 H) 1.35 - 1.40 (m, 2 H) 1.45 (s, 4 H) 1.66 -

1.72 (m, 2 H) 1.95 (dd, J=13.28, 7.17 Hz, 2 H) 2.14 (td, J=12.32, 5.87 Hz, 2 H) 2.41 - 2.46 (m, 2 H)

2.76 (s, 4 H) 3.03 - 3.18 (m, 2 H) 3.25 (d, J=3.66 Hz, 6 H) 3.54 (s, 6 H) 3.64 (td, J=11.14, 5.65 Hz, 2

H) 4.05 - 4.13 (m, 4 H) 4.19 - 4.27 (m, 2 H) 5.10 - 5.16 (m, 2 H) 5.31 - 5.39 (m, 2 H) 5.88 (d, J=12.66 Hz, 2 H) 7.06 (t, J=8.47 Hz, 2 H) 7.21 - 7.31 (m, 4 H) 7.41 (d, J=8.09 Hz, 1 H) 7.48 (dd, J=8.39, 1.83 Hz, 1 H) 11.81 - 11.91 (m, 2 H); MS (ESI+) m/z 1011.6 (M+H)⁺.

ABS

methyl {(25)-l-[(2S,45)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2-[(2S,45)-4fluoro-1 -{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5yl[pyrrolidin-2-yl] -1 H-bcnzimidazol-2-yl} -4-fluoropyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2yl} carbamate

Ή NMR (500 MHz, DMSO-t/₆) δ ppm 0.80 - 0.99 (m, 12 H) 1.38 (d, J=4.73 Hz, 2 H) 1.45 (s, 4 H) 1.64 - 1.74 (m, 2 H) 2.00 - 2.08 (m, 2 H) 2.37 - 2.45 (m, 2 H) 2.76 (s, 4 H) 3.08 - 3.19 (m, 2 H) 3.55 (s, 6 H) 3.99 - 4.26 (m, 6 H) 5.30 - 5.39 (m, 4 H) 5.47 (d, J=53.41 Hz, 4 H) 5.89 (d, J=12.66 Hz, 2 H)

300

7.02 - 7.11 (m, 2 H) 7.27 (d, J=25.02 Hz, 2 H) 7.41 (d, J=8.09 Hz, 3 H) 7.47 (d, J=7.93 Hz, 1 H) 11.85 (d, J=31.74 Hz, 2 H); MS (ESI+) m/z 987.5 (M+H)⁺.

ABS

2016238925 07 Oct 2016

Example 3.9 methyl {(2S)-l-[(2S,4S)-4-fluoro-2-{5-[(2R,5R)-5-{2-[(2S,4S)-4-fluoro-l-{(2S)-2[(methoxycarbonyl)amino] -3 -methylbutanoyl }pyrrolidin-2-yl] -1 H-bcnzi midazol-5 -yl} -1 -(4fluorophenyl)pyrrolidin-2-yl] -I H-bcnzi m i dazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 0.82 -0.98 (m, 12 H) 1.68 - 1.77 (m, 2 H) 1.91 -2.09(m, 4 H)

2.36 - 2.44 (m, 2 H) 2.59 - 2.66 (m, 2 H) 3.52 - 3.57 (m, 6 H) 3.72 - 3.98 (m, 2 H) 4.07 - 4.18 (m, 4 H)

5.19 (t, J=8.08 Hz, 1 H) 5.31 - 5.44 (m, 4 H) 5.48 - 5.57 (m, 1 H) 6.24 - 6.31 (m, 2 H) 6.70 - 6.78 (m,

H) 7.02 - 7.12 (m, 2 H) 7.17 (s, 1 H) 7.24 - 7.34 (m, 2 H) 7.39 (t, J=7.92 Hz, 2 H) 7.47 (dd, J=20.38, 8.35 Hz, 1 H) 11.78 - 12.06 (m, 2 H); MS (ESI+) m/z 886.4 (M+H)⁺.

.5

methyl {(2S)-l-[(2S,4S)-2-{5-[(2R,5R)-l-(4-fluorophenyl)-5-{2-[(2S,4S)-4-methoxy-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-220 yl]-1 H-bcnzimidazol-2-yl} -4-methoxypyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, DMSO-4,) δ ppm 0.77 - 0.90 (m, 12 H) 1.66 - 1.76 (m, 2 H) 1.88 - 2.01 (m, 2 H) 2.06 - 2.19 (m, 2 H) 2.54 - 2.62 (m, 2 H) 3.25 (d, J=5.86 Hz, 6 H) 3.54 (s, 6 H) 3.59 - 3.72 (m, 2 H) 3.97 - 4.14 (m, 6 H) 4.16 - 4.30 (m, 2 H) 5.05 - 5.19 (m, 2 H) 5.36 (d, J=3.25 Hz, 2 H) 6.28 (dd, J=7.26, 4.34 Hz, 2 H) 6.69 - 6.79 (m, 2 H) 7.04 (d, J=8.57 Hz, 2 H) 7.22 - 7.33 (m, 4 H) 7.38 (d,

J=8.02Hz, 1 H) 7.45 (d, J=8.24Hz, 1 Η) 11.81 (s, 2 H); MS (ESI+) m/z 910.4 (M+H)⁺.

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ABS

Example 3.11 methyl {(2S)-l-[(5S)-5-{5-[(2R,5R)-l-(4-/ert-butylphenyl)-5-{2-[(2S)-l-{(2S)-25 [(methoxy carbonyl)amino] -3 -methylbutanoyl} -5,5 -dimethylpyrrolidin-2-yl] -1 H-benzi midazol -5 yl }pyrrolidin-2-yl] -1 H-benzi midazol-2-yl} -2,2-dimethylpyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate

Ή NMR (400 MHz, DMSO-ty) δ ppm 0.81 (d, J=6.61 Hz, 6 H) 0.89 (d, J=6.72 Hz, 6 H) 1.07 (s, 9 H)

1.38 (s, 6 H) 1.62 (s, 6 H) 1.68 - 1.77 (m, 4 H) 1.82 (s, 2 H) 1.94 (dd, J=13.61, 6.78 Hz, 2 H) 2.10 0 2.18 (m, 2 H) 2.27 (dd, J=4.12, 2.60 Hz, 2 H) 3.15 (d, J=3.36 Hz, 6 H) 3.96 - 4.03 (m, 2 H) 5.30 - 5.43 (m, 6 H) 6.24 - 6.31 (m, 2 H) 6.70 (t, J=6.67 Hz, 2 H) 6.84 - 6.91 (m, 2 H) 7.05 - 7.13 (m, 2 H) 7.24 (s, 1 H) 7.36 (d, J=1.08 Hz, 1 H) 7.40 (d, J=7.59 Hz, 1 H) 7.49 (d, J=8.78 Hz, 1 H) 12.16 (d, J=29.28 Hz, 2 H); MS (ESI+) m/z 944.5 (M+H)⁺.

ABS

Example 3.12 methyl {(2S)-l-[(2S,4S)-2-{5-[(2R,5R)-l-(4-/ert-butylphenyl)-5-{2-[(2S,4S)-4-fluoro-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2yl] -I H-bc nzi m i dazol -2-yl} -4-fluoropyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.79 -0.97 (m, 12 Η) 1.07 (s, 9 Η) 1.66 - 1.75 (m, 2 Η) 1.99 2.08 (m, 2 H) 2.40 (dd, J=17.02, 3.04 Hz, 2 H) 3.09 - 3.21 (m, 4 H) 3.55 (s, 6 H) 4.05 - 4.13 (m, 4 H)

4.16 - 4.27 (m, 2 H) 5.35 (dd, J=8.51, 3.09 Hz, 4 H) 5.46 (d, J=53.24 Hz, 2 H) 6.23 - 6.29 (m, 2 H)

6.91 (d, J=8.89 Hz, 2 H) 7.03 - 7.11 (m, 2 H) 7.23 (d, J=3.47 Hz, 1 H) 7.28 (s, 1 H) 7.39 (dd, J=8.08,

4.72 Hz, 3 H) 7.44 (d, J=8.57 Hz, 1 Η) 11.80 (d, J=20.06 Hz, 2 H); MS (ESI+) m/z 924.4 (M+H)⁺.

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methyl {(2.8.3//)-1 -| (2.8)-2-{5-| (2.8,5.8)-1-(4-cyclopropyl-2-fliiorophcnyl)-5-(2-{ (2.8)-1 -[7V5 (methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-lH-benzimidazol-5-yl)pyrrolidin-2-yl]-lHbenzimidazol-2-yl }pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2-yl} carbamate

Ή NMR (500 MHz, DMSO-7₆) δ ppm 0.35 - 0.57 (m, 2 H) 0.66 - 0.85 (m, 2 H) 1.07 - 1.17 (m, 7 H)

1.59 - 1.69 (m, 1 H) 1.82 (s, 2 H) 1.95 -2.12 (m, 5 H) 2.13 -2.33 (m, 5 H) 3.17-3.35 (m, 6 H) 3.48 3.65 (m, 6 H) 3.85 - 3.95 (m, 4 H) 4.29 - 4.38 (m, 2 H) 5.11 - 5.25 (m, 2 H) 5.58 (s, 2 H) 6.44 - 6.57 0 (m, 2 H) 6.59 - 6.70 (m, 1 H) 7.07 - 7.19 (m, 2 H) 7.25 - 7.32 (m, 2 H) 7.35 - 7.41 (m, 2 H) 7.45 (d,

7=8.24 Hz, 2 H) 12.05 (d, 7=16.63 Hz, 2 H); MS (ESI+) m/z 922A (M+H)⁺, (ESI-) m/z 920.3 (M-H)’.

Example 3.14 tert-butyl {2-| (2.8)-2-(5-{(2.8',5.8')-5-{2-| (2.8')-1 -{[(tert-butoxycarbonyl)amino]acetyl}pyrrolidin-2-yl]lH-benzimidazol-5-yl}-l-[3-fluoro-4-(piperidin-l-yl)phenyl]pyrrolidin-2-yl}-lH-benzimidazol-2yl)pyrrolidin-1 -yl] -2-oxoethyl} carbamate

Ή NMR (400 MHz, DMSO-7₆) δ ppm 1.16-1.43 (m, 18 H) 1.42 - 2.27 (m, 14 H) 2.58 - 2.70 (m, 5

H) 3.38 - 4.02 (m, 9 H) 5.14 (s, 2 H) 5.33 (s, 3 H) 6.04 (s, 2 H) 6.74 (s, 3 H) 7.04 - 7.60 (m, 7 H) 20 11.83 - 12.43 (m, 2 H); MS (ESI+) m/z 933.4 (M+H)⁺, (ESI-) m/z 931.4 (M-H)’.

303

2016238925 07 Oct 2016

Example 3.15 methyl {(25)-1-[(25)-2-{5-[(2S,55)-l-[3-fluoro-4-(piperidin-l-yl)phenyl]-5-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-25 yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO-7₆) δ ppm 0.73 - 0.93 (m, 12 H) 1.32 - 1.57 (m, 6 H) 1.58 - 2.06 (m, 14 H) 2.18 (s, 4 H) 2.67 (dd, 7=3.69, 1.95 Hz, 4 H) 3.75 - 3.87 (m, 6 H) 4.07 (t, 2 H) 5.13 (s, 2 H) 5.37 (dd, 7=6.02, 2.11 Hz, 2 H) 6.04 (s, 2 H) 6.65 (s, 1 H) 7.09 (s, 2 H) 7.16 - 7.23 (m, 1 H) 7.23 - 7.48 (m, 5 H) 12.01 (s, 2 H); MS (ESI+) m/z 933.5 (M+H)⁺, (ESI-) m/z 931.4 (M-H)’.

ABS o

Example 3.16 methyl {(2S,3R)-l-[(25)-2-{5-[(2S,55)-l-[3-fluoro-4-(piperidin-l-yl)phenyl]-5-(2-{(25)-l-[7V(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-lH-benzimidazol-5-yl)pyrrolidin-2-yl]-lHbenzimidazol-2-yl {pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO-fo) δ ppm 1.00-1.14 (m, 6 H) 1.33 - 1.55 (m, 6 H) 1.59 - 2.28 (m, 14 H) 2.58 - 2.71 (m, 4 H) 3.10 - 3.27 (m, 6 H) 3.54 (d, 7=1.41 Hz, 6 H) 3.71 - 3.90 (m, 6 H) 4.21 - 4.33 (m, 2 H) 5.02 - 5.22 (m, 2 H) 5.37 (dd, 7=6.02, 2.01 Hz, 2 H) 6.04 (s, 2 H) 6.58 - 6.84 (m, 1 H) 7.06 (d, 7=22.88 Hz, 2 H) 7.16 - 7.32 (m, 2 H) 7.39 (d, 7=8.13 Hz, 2 H) 11.90 - 12.34 (m, 2 H); MS (ESI+) m/z 965.5 (M+H)⁺, (ESI-) m/z 963.3 (M-H)’.

304

2016238925 07 Oct 2016

ABS

Example 3.17 dimethyl {[(2S,5S)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[lH-benzimidazole-5,2di y I (2.S')py rrol i di nc -2,1 -diyl (3 -methyl -1 -oxobut-2 -ene -1,2-diyl)]} biscarbamate

Ή NMR (400 MHz, DMS0-J₆) δ ppm 0.87 - 1.20 (m, 9 H) 1.60 - 1.77 (m, 14 H) 1.80 - 2.35 (m, 10 H) 3.16 - 3.79 (m, 10 H) 5.14 (s, 2 H) 5.37 (s, 2 H) 6.24 (d, 2=3.04 Hz, 2 H) 6.92 (dd, 2=8.57, 6.29 Hz, 2 H) 7.11 (s, 3 H) 7.31 (s, 1 H) 7.39 (d, 2=8.13 Hz, 1 H) 7.50 (d, 2=8.24 Hz, 1 H) 8.89 (d, 2 H) 11.64 - 12.14 (m, 2 H); MS (ESI+) m/z 884.5 (M+H)⁺, 918.4 (M+NH₃+NH₄)⁺.

ABS

Example 3.18 dimethyl ({(2R,5R)-1 -[3,5-difluoro-4-(piperidin-1 -yl)phenyl]pyrrolidine-2,5-diyl}bis{ 1Hbenzimidazole-5.2-diyl(2.S')pyrrolidinc-2.1-diyl | (1.5)-2 -oxo-1 -(tetrahydro-2H-pyran-4-yl)ethane-2,ldiyl] })biscarbamate

Ή NMR (400 MHz, DMS0-J₆) δ ppm 1.13 - 1.33 (m, 4 H) 1.36 - 1.57 (m, 10 H) 1.65 - 1.71 (m, 2 H) 1.79 - 1.90 (m, 2 H) 1.96 - 2.03 (m, 4 H) 2.13 - 2.26 (m, 4 H) 2.76 (s, 4 H) 2.93 - 3.15 (m, 4 H) 3.53 (s, 6 H) 3.62 (dd, J=10.03, 2.01 Hz, 2 H) 3.68 - 3.80 (m, 4 H) 3.81 - 3.88 (m, 4 H) 4.11 - 4.18 (m, 2 H) 5.10 - 5.18 (m, 2 H) 5.33 - 5.40 (m, 2 H) 5.82 - 5.92 (m, 2 H) 7.09 (dd, J=12.52, 8.29 Hz, 2 H) 7.17 7.24 (m, 2 H) 7.35 (t, J=8.35 Hz, 2 H) 7.41 (d, J=7.92 Hz, 1 H) 7.47 (d, J=6.94 Hz, 1 H) 12.05 (d,

J=1.73Hz, 1 H) 12.15 (d, J=2.17Hz, 1 H); MS (ESI+) m/z 1035.5 (M+H)⁺.

305

2016238925 07 Oct 2016

methyl {(25)-1 -[(35)-3-{5-[(2R,5R)-l -[3,5-difluoro-4-(pipcridin-l-yl)phcnyl|-5-{2-|(3.S)-2-{(2.S)-2[(methoxycarbonyl)amino] -3 -methylbutanoyl} -2-azabicyclo [2.2.1 ]hept-3 -yl] -1 27-benzi midazol-5 5 yl}pyrrolidin-2-yl] -1 H-bcnzimidazol-2-yl} -2-azabicyclo[2.2.1 ]hept-2-yl] -3-methyl-1 -oxobutan-2yl} carbamate

Ή NMR (400 MHz, DMSO-A) δ ppm 0.80 - 0.87 (m, 6 H) 0.93 (t, J=7.05 Hz, 6 H) 1.36 - 1.48 (m, 10 H) 1.49 - 1.57 (m, 2 H) 1.64 - 1.70 (m, 4 H) 1.72 - 1.79 (m, 4 H) 1.84 - 1.90 (m, 2 H) 1.92 - 1.98 (m, 2 H) 2.61 (s, 2 H) 2.72 - 2.78 (m, 4 H) 3.54 (s, 6 H) 4.10 - 4.17 (m, 2 H) 4.50 (s, 2 H) 4.59 (d, 0 J=7.48 Hz, 2 H) 5.32 - 5.41 (m, 2 H) 5.89 (d, J=12.58 Hz, 2 H) 7.07 (d, J=7.70 Hz, 2 H) 7.18 (d,

J=9.65 Hz, 2 H) 7.21 (s, 1 H) 7.32 (s, 1 H) 7.40 (d, J=8.13 Hz, 1 H) 7.49 (d, J=8.02 Hz, 1 H) 12.01 (dd, J=12.58, 1.08 Hz, 2 H); MS (ESI+) m/z 1003.4 (M+H)⁺.

ABS

Example 3.20 methyl {(2_lS)-l-[(2_lS)-2-{5-[(2R,5R)-l-[3-fluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(2S)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-127-benzimidazol-5yl} pyrrolidin-2-yl] -1

H-benzimidazol-2-yl [pyrrol idi n -1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-A) δ ppm 0.77 - 0.90 (m, 12 Η) 1.66 - 1.75 (m, 8 Η) 1.86 - 1.95 (m, 2 H)

1.96 - 2.05 (m, 4 H) 2.14 - 2.24 (m, 4 H) 3.04 - 3.14 (m, 4 H) 3.53 (s, 6 H) 3.77 - 3.86 (m, 4 H) 4.06 (t, J=8.40 Hz, 2 H) 5.11 - 5.17 (m, 2 H) 5.35 (q, J=6.83 Hz, 2 H) 6.05 - 6.12 (m, 2 H) 6.71 (ddd, J=13.99, 9.22, 4.34 Hz, 1 H) 7.07 (t, J=7.05 Hz, 2 H) 7.16 (t, J=6.94 Hz, 2 H) 7.20 - 7.32 (m, 8 H)

306

7.39 (d, J=8.13 Hz, 1 H) 7.47 (d, J=8.46 Hz, 1 H) 12.05 (d, J=5.64 Hz, 2 H); MS (ESI+) m/z 1009.4 (M+H)⁺.

2016238925 07 Oct 2016

Example 3.21 methyl [(lS)-2-[(2S)-2-{5-[(27?,57?)-l-[3-fluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(2S)-l-{(2S)2-|(mcthoxycarbonyl)amino|-3-mcthylbutanoyl [pyrrolidin-2-yl |-l7/-bcnzimidazol-5-yl [pyrrolidin-2yl] - I H-bc nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -2 -oxo -1 -(tetrahydro-2H-pyran-4 -yl) ethyl] carbamate

Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.76 - 0.92 (m, 6 H) 1.47 - 1.57 (m, 2 H) 1.65 - 1.76 (m, 8 H) 0 1.81 - 1.94 (m, 2 H) 1.94 - 2.04 (m, 4 H) 2.15 - 2.23 (m, 4 H) 3.03 - 3.15 (m, 4 H) 3.53 (s, 6 H) 3.57 3.67 (m, 2 H) 3.70 - 3.79 (m, 2 H) 3.79 - 3.89 (m, 4 H) 4.07 - 4.20 (m, 2 H) 5.10 - 5.19 (m, 2 H) 5.32 5.41 (m, 2 H) 6.04 - 6.11 (m, 2 H) 6.66 - 6.75 (m, 1 H) 7.03 - 7.36 (m, 12 H) 7.39 (dd, J=8.78, 1.63 Hz, 1 H) 7.46 (t, J=8.78 Hz, 1 H) 12.02 - 12.14 (m, 2 H); MS (APCI+) m/z 1051 (M+H)⁺.

Example 3.22 dimethyl ({(2R,5R)-1 -[3,5-difluoro-4-(4-phenylpiperidin-1 -yl)phenyl]pyrrolidine-2,5-diyl}bis{1Hbcnzimidazolc-5.2-diyl(2.S)pyrrolidinc-2. l-diyl|(I.S)-l-cyclohcxyl-2-oxocthanc-2.1diyl] })biscarbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 0.81-1.14 (m, 11 H) 1.40 - 1.71 (m, 20 H) 1.94 -2.05 (m, 4 H) 2.14 - 2.26 (m, 4 H) 2.83 - 2.91 (m, 2 H) 2.93 - 3.02 (m, 2 H) 3.52 (d, J=3.80 Hz, 6 H) 3.76 - 3.87

307 (m, 4 H) 4.08 (q, J=8.53 Hz, 2 H) 5.14 (d, J=5.86 Hz, 2 H) 5.33 - 5.45 (m, 2 H) 5.85 - 5.98 (m, 2 H)

7.05 - 7.31 (m, 11 H) 7.42 (d, J=9.76 Hz, 1 H) 7.49 (d, J=8.24 Hz, 1 H) 12.00 (s, 1 H) 12.16 (d,

J=3.58 Hz, 1 H); MS (ESI+) m/z 1107.5 (M+H)⁺.

2016238925 07 Oct 2016

Example 3.23 dimethyl ({(27/,57/)-1 -[3,5 -difluoro-4-(4-phenylpiperidin-1 -yl)phenyl]pyrrolidine-2,5 -diyl}bis {177benzimidazole-5.2-diyl(2.S)pyrrolidinc-2. l-diyl|(I.S)-2 -oxo-1 -(tetrahydro-2H-pyran-4-yl)ethane-2,ldiyl] })biscarbamate 'H NMR (400 MHz, DMS0-d₆) δ ppm 1.14 - 1.37 (m, 4 H) 1.43 - 1.57 (m, 4 H) 1.61 - 1.72 (m, 6 H) 1.77-1.91 (m, 2 H) 1.96 - 2.05 (m, 4 H) 2.14 - 2.25 (m, 4 H) 2.87 - 3.02 (m, 6 H) 3.06 - 3.22 (m, 2 H) 3.53 (s, 6 H) 3.58 - 3.67 (m, 2 H) 3.68 - 3.79 (m, 5 H) 3.81 - 3.89 (m, 4 H) 4.11 - 4.19 (m, 2 H) 5.14 (dd, J=7.32, 2.98 Hz, 2 H) 5.34 - 5.42 (m, 2 H) 5.85 - 5.95 (m, 2 H) 7.06 - 7.17 (m, 3 H) 7.19 - 7.29 (m, 6 H) 7.35 (t, J=9.05 Hz, 2 H) 7.42 (d, J=8.57 Hz, 1 H) 7.47 (d, J=8.78 Hz, 1 H) 12.05 (s, 1 H) .5 12.16 (d, J=1.41 Hz, 1 H); MS (ESI+) m/z 1111.5 (M+H)⁺.

Example 3.24 dimethyl ({(27/,57/)-1 -[3,5 -difluoro-4-(4-phenylpiperidin-1 -yl)phenyl]pyrrolidine-2,5 -diyl}bis {177benzimidazole-5,2-diyl(2S)pyrrolidine-2,1 -diyl[(I .S')-1 -cyclopentyl-2-oxoethane-2,1 20 diyl] })biscarbamate

308 'H NMR (400 MHz, DMSO-4,) δ ppm 1.16-1.28 (m, 4 H) 1.31 - 1.54 (m, 10 H) 1.55 - 1.73 (m, 10

H) 1.95 - 2.06 (m, 4 H) 2.09 - 2.24 (m, 7 H) 2.85 - 3.07 (m, 4 H) 3.53 (s, 6 H) 3.82 (s, 4 H) 4.15 (t,

J=8.51 Hz, 2 H) 5.11 - 5.18 (m, 2 H) 5.34 - 5.43 (m, 2 H) 5.92 (d, J=12.69 Hz, 2 H) 7.06 - 7.18 (m, 3

H) 7.19 - 7.31 (m, 6 H) 7.37 - 7.45 (m, 3 H) 7.50 (d, J=8.35 Hz, 1 H) 12.01 (s, 1 H) 12.08 (s, 1 H);

MS (ESI+) m/z 1079.4 (M+H)⁺.

2016238925 07 Oct 2016

Example 3.25 methyl {(27/)-1 -[(2S)-2-{5-[(27/,57/)-1-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2-[(2S)-l-{(27/)-20 [(methoxycarbonyl)amino] -3 -methylbutanoyl} -2,3 -dihydro-1 H-i ndol-2-yl ] -177-benzi midazol -5 yl}pyrrolidin-2-yl]-177-bcnzi midazol -2-yl} -2,3-dihydro-1 H-indol-1 -yl]-3-methyl-1 -oxobutan-2yl} carbamate *HNMR (400 MHz, DMSO-4,) δ ppm 0.90 (dd, J=31.72, 6.23 Hz, 12 H) 1.31 - 1.51 (m, 7 H) 1.52 1.70 (m, 2 H) 2.06 - 2.29 (m, 4 H) 2.74 (s, 6 H) 3.08 (d, J=15.40 Hz, 6 H) 3.69 - 3.89 (m, 2 H) 4.27 (s,

1 H) 5.26 - 5.39 (m, 2 H) 5.77 - 6.01 (m, 4 H) 7.01 - 7.33 (m, 12 H) 7.37 - 7.53 (m, 2 H) 8.12 - 8.25 (m, 2 H) 12.34 (d, J=42.07 Hz, 2 H); MS (ESI+) m/z 1047.4 (M+H)⁺.

methyl {(2S)-l-[(2S)-2-{5-[(27/,57/)-l-(4-tert-butylphenyl)-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino] -3 -methylbutanoyl} -4-methylidenepyrrolidin-2-yl] -177-benzi midazol-5 yl}pyrrolidin-2-yl] -I //-be nzi m i dazol -2-yl} -4-methylidenepyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate

309

1H NMR (400 MHz, DMSO-4,) δ ppm 0.74 - 0.92 (m, 12 H) 1.07 (s, 9 H) 1.68 (s, 2 H) 1.91 (ddd,

J=14.64, 7.64, 7.43 Hz, 2 H) 2.61 - 2.75 (m, 2 H) 2.97 - 3.09 (m, 2 H) 3.13 (s, 1 H) 3.54 (s, 6 H) 3.94

- 4.08 (m, 2 H) 4.46 (d, J=12.36 Hz, 2 H) 4.60 (d, J=14.20 Hz, 2 H) 5.02 (s, 3 H) 5.10 (s, 2 H) 5.31 5.45 (m, 4 H) 6.24 (d, J=8.67 Hz, 2 H) 6.86 - 6.94 (m, 2 H) 7.07 (t, J=8.51 Hz, 2 H) 7.20 (s, 1 H) 7.26 (s, 1 H) 7.34 - 7.50 (m, 4 H) 12.05 (d, J= 15.72 Hz, 2 H); MS (ESI+) m/z 912.4 (M+H)⁺.

2016238925 07 Oct 2016

Example 3.27 dimethyl ({(27/,57/)-1 -[3,5 -difluoro-4-(4-phenylpiperidin-1 -yl)phenyl]pyrrolidine-2,5 -diyl}bis { 1//0 benzimidazole-5,2-diyl(2S)pyrrolidine-2,1 -diyl[( I .S')-1 -(2,3-dihydro-17/-inden-2-yl)-2-oxoethane-2,1 diyl] })biscarbamate 'H NMR (400 MHz, DMSO-7,) δ ppm 1.51-1.76 (m, 6 H) 1.94 - 2.06 (m, 4 H) 2.12 - 2.28 (m, 8 H)

2.69 - 2.89 (m, 12 H) 2.92 - 3.05 (m, 1 H) 3.55 (s, 6 H) 3.77 - 3.86 (m, 4 H) 4.36 - 4.43 (m, 2 H) 5.16 - 5.24 (m, 2 H) 5.35 - 5.48 (m, 2 H) 5.97 (d, J=12.90 Hz, 2 H) 7.01 - 7.30 (m, 17 H) 7.34 (s, 1 H) 7.46 (d, J=8.35 Hz, 1 H) 7.54 - 7.60 (m, 2 H) 12.07 (s, 1 H) 12.18 (s, 1 H); MS (ESI+) m/z 1175.5 (M+H)⁺.

Example 3.28

310

2016238925 07 Oct 2016 methyl {(2S)-l-[(2S,3a5',6aS)-2-{5-[(27?,57?)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2[(2S,3aS,6aS)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[6]pyrrol2-yl ]-l//-benzimidazol-5-yl }pyrrolidin-2-yl ]-l//-benzimidazol-2-yl }hexahydrocyclopenta[6]pyrrol1 (2//) -yl] -3 -methyl-1 -oxobutan-2 -yl} carbamate

Ή NMR (400 MHz, DMSO® δ ppm 0.72 - 0.92 (m, 12 Η) 1.50 - 1.59 (m, 4 Η) 1.62 - 1.72 (m, 8 H)

1.73-1.81 (m, 2 H) 1.83 - 1.92 (m, 4 H) 1.95 - 2.03 (m, 2 H) 2.06 - 2.15 (m, 4 H) 2.38 - 2.46 (m, 2 H)

2.75 - 2.83 (m, 1 H) 2.86 - 3.01 (m, 4 H) 3.54 (s, 6 H) 4.01 (td, J=13.28, 6.83 Hz, 4 H) 4.78 (dd, J=7.70, 4.23 Hz, 2 H) 5.13 (t, J=8.24 Hz, 2 H) 5.33 - 5.45 (m, 2 H) 5.92 (dd, J=12.90, 2.82 Hz, 2 H) 7.07 (d, J=8.67 Hz, 2 H) 7.15 (t, J=6.94 Hz, 1 H) 7.20 - 7.29 (m, 5 H) 7.34 (d, J=4.01 Hz, 1 H) 7.39 0 7.47 (m, 3 H) 7.50 (d, J=8.02 Hz, 1 H) 11.97 (s, 1 H) 12.06 (s, 1 H);MS (ESI+) m/z 1107.4 (M+H)⁺.

ABS

Example 3.29 methyl {l-[(2S)-2-{5-[(2/?,5/?)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(2S)-l-{35 cthyl-2-|(mcthoxycarbonyl)amino|pcntanoyl [pyrrolidin-2-yl |-l//-bcnzimidazol-5-yl [pyrrolidin-2-yl |17/-bcnzi midazol -2-yl }pyrrolidin-1 -yl] -3 -ethyl-1 -oxopentan-2-yl} carbamate

Ή NMR (400 MHz, DMSO® δ ppm 0.16 (t, 7=6.02 Hz, 1 H) 0.34 (t, 7=6.89 Hz, 1 H) 0.56 - 0.99 (m, 10 H) 1.16 - 1.36 (m, 4 H) 1.53 - 1.80 (m, 8 H) 1.93 - 2.09 (m, 4 H) 2.14 - 2.30 (m, 4 H) 2.80 3.13 (m, 11 H) 3.53 (s, 6 H) 3.73 - 3.95 (m, 4 H) 4.24 - 4.41 (m, 2 H) 5.09 -5.20 (m, 2 H) 5.30-5.44 (m, 2 H) 5.83 - 5.96 (m, 2 H) 7.03 - 7.36 (m, 11 H) 7.39 - 7.62 (m, 2 H) 12.00 (s, 1 H) 12.13 - 12.20 (m, 1 H); MS (ESI+) m/z 1083.5 (M+H)⁺.

311

2016238925 07 Oct 2016

ABS

Example 3.30 dimethyl ({(27?,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{ \Hbenzimidazole-5,2-diyl(2S,3aS,6aS)hexahydrocyclopenta[6]pyrrole-2,l(227)-diyl[(lS)-l-cyclopentyl5 2-oxoethane-2,1-diyl] })biscarbamate 'H NMR (400 MHz, DMSO-ty,) δ ppm 1.17- 1.32 (m, 10 H) 1.36 - 1.49 (m, 10 H) 1.51 - 1.79 (m, 10

H) 1.87 (dd, J=15.83, 7.26 Hz, 2 H) 1.98 (dd, J=13.07, 8.40 Hz, 2 H) 2.05 - 2.16 (m, 6 H) 2.36 - 2.46 (m, 4 H) 2.72 - 2.81 (m, 6 H) 3.54 (s, 6 H) 4.11 (q, J=9.40 Hz, 2 H) 4.75 - 4.85 (m, 2 H) 5.08 - 5.18 (m, 2 H) 5.36 (dt, J=13.66, 6.83 Hz, 2 H) 5.88 (ddd, J=12.69, 3.52, 3.42 Hz, 2 H) 7.07 (d, J=8.35 Hz, 0 2 H) 7.21 (s, 1 H) 7.31 (d, J=4.01 Hz, 1 H) 7.41 (d, J=8.24 Hz, 1 H) 7.46 - 7.56 (m, 3 H) 11.88 (d,

J=2.49 Hz, 1 H) 12.01 (d, J=3.36 Hz, 1 H); MS (ESI+) m/z 1083.5 (M+H)⁺.

Example 3.31 ({(27?,57?)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis[ \Hbenzimidazole-5,2-diyl(2S)pyrrolidine-2,l-diyl])bis[(2S)-tetrahydrofuran-2-ylmethanone] 'H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 - 1.49 (m, J=15.83 Hz, 2 H) 1.60 - 1.75 (m, 8 H) 1.77 1.91 (m, 6 H) 1.94 - 2.12 (m, 8 H) 2.16 - 2.27 (m, 2 H) 2.86 - 3.08 (m, 5 H) 3.74 (t, J=6.99 Hz, 6 H)

4.57 - 4.63 (m, 2 H) 5.13 (dd, J=9.00, 1.30 Hz, 2 H) 5.33 - 5.43 (m, 2 H) 5.93 (d, J=13.34 Hz, 2 H)

312

7.06 - 7.16 (m, 3 H) 7.20 - 7.29 (m, 5 H) 7.32 (s, 1 H) 7.42 (d, J=8.57 Hz, 1 H) 7.52 (d, J=8.13 Hz, 1

H) 12.00 (s, 1 H) 12.08 (s, 1 H); MS (ESI+) m/z 909.4 (M+H)⁺.

2016238925 07 Oct 2016

dimethyl ({(27?,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{177benzimidazole-5,2-diyl(25,3a5,6a5)hexahydrocyclopenta[6]pyrrole-2,l(277)-diyl[(15)-2-oxo-l(tetrahydro-277-pyran-4-yl)ethane-2,1-diyl] })biscarbamate 'HNMR (400 MHz, DMSO-4,) δ ppm 1.10 - 1.27 (m, 4 H) 1.33 - 1.51 (m, 12 H) 1.51 - 1.65 (m, 6 H) 0 1.67 - 1.80 (m, 4 H) 1.83 - 2.00 (m, 6 H) 2.08 - 2.17 (m, 4 H) 2.39 - 2.45 (m, 2 H) 2.73 - 2.85 (m, 8 H)

3.03 - 3.12 (m, 2 H) 3.53 (s, 6 H) 3.70 - 3.87 (m, 2 H) 4.04 - 4.17 (m, 2 H) 4.74 - 4.83 (m, 2 H) 5.08 5.17 (m, 2H) 5.31 -5.42 (m, 2 H) 5.83 - 5.93 (m, 2 H) 7.04-7.11 (m, 2 H) 7.21 (d, J=15.83 Hz, 2 H) 7.41 (d, J=8.02Hz, 1 H) 7.46 -7.55 (m, 3 H) 11.96 (d, J=4.12Hz, 1 H) 12.11 (d, J=4.55 Hz, 1 H); MS (ESI+) m/z 1115.4 (M+H)⁺.

ABS

Example 3.33 methyl {(25,37?)-l-[(25,3a5,6a5)-2-{5-[(27?,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-(2{(25,3a5,6a5)-l-[2V-(methoxycarbonyl)-O-methyl-L-threonyl]octahydrocyclopenta[6]pyrrol-2-yl}177-benzimidazol-5-yl)pyrrolidin-2-yl]-177-benzimidazol-2-yl}hexahydrocyclopenta[6]pyrrol-l(277)yl] -3 -methoxy-1 -oxobutan-2-yl} carbamate

313 'H NMR (400 MHz, DMS0-d₆) δ ppm 0.95 (d, J=6.18 Hz, 3 H) 1.03 (d, J=5.75 Hz, 3 H) 1.35 - 1.49 (m, 8 H) 1.50 - 1.64 (m, 4 H) 1.66 - 1.81 (m, 6 H) 1.84 - 2.01 (m, 6 H) 2.07 - 2.16 (m, 4 H) 2.73 - 2.84 (m, 6 H) 3.13 (s, 3 H) 3.17 (s, 3 H) 3.54 (s, 6 H) 4.20 - 4.29 (m, 2 H) 4.76 - 4.84 (m, 2 H) 5.12 (t,

J=8.19 Hz, 2 H) 5.37 (dd, J=6.51, 4.88 Hz, 2 H) 5.88 (d, J=13.45 Hz, 2 H) 7.05 (d, J=8.13 Hz, 2 H)

7.20 (s, 1 H) 7.30 (s, 1 H) 7.40 (d, J=7.81 Hz, 1 H) 7.47 - 7.57 (m, 3 H) 11.98 - 12.15 (m, 2 H); MS (APCI+) m/z 1063.4 (M+H)⁺.

2016238925 07 Oct 2016

ABS

Example 3.34 ethyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-[(ethoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5yl}pyrrolidin-2-yl] -1 H-bcnzi midazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.75 - 0.91 (m, 12 H) 1.15 (t, J=7.43 Hz, 6 H) 1.60 - 1.74 (m, 6 H) 1.85 - 2.07 (m, 8 H) 2.16 - 2.27 (m, 4 H) 2.86 - 3.04 (m, 4 H) 3.40 - 3.48 (m, 1 H) 3.76 - 3.85 (m, 5 4 H) 3.98 (q, J=7.08 Hz, 4 H) 4.05 (t, J=8.29 Hz, 2 H) 5.11 - 5.19 (m, 2 H) 5.34 - 5.44 (m, 2 H) 5.92 (d, J=12.69 Hz, 2 H) 7.05 - 7.11 (m, 2 H) 7.15 (t, J=6.94 Hz, 1 H) 7.20 - 7.27 (m, 7 H) 7.31 (s, 1 H) 7.42 (d, J=8.24 Hz, 1 H) 7.50 (d, J=7.92 Hz, 1 H) 12.07 (s, 1 H) 12.12 (s, 1 H); MS (ESI+) m/z 1055.4 (M+H)⁺.

314

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ABS

Example 3.35 dimethyl ({(27/,57/)-1-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-177bcnzimidazolc-5.2-diyl )(25')pyrrolidinc-2.1 -diyl [(15)-2-oxo-1 -(tetrahydro-277-pyran-4-yl)ethane-2,1 5 diyl]})biscarbamate 'H NMR (400 MHz, DMSO-®,) δ ppm 1.12-1.33 (m, 4 H) 1.38 - 1.55 (m, 10 H) 1.66 - 1.90 (m, 6 H)

1.94-2.04 (m, 4H) 2.11 -2.24 (m, 2 H) 2.75 -2.85 (m, 6 H) 3.01 -3.19(m, 2 H) 3.52 (s, 6 H) 3.63 3.77 (m, 4 H) 3.78 - 3.89 (m, 6 H) 4.08 - 4.18 (m, 2 H) 5.07 - 5.16 (m, 2 H) 5.46 - 5.63 (m, 2 H) 5.81 5.93 (m, 2 H) 6.99 - 7.12 (m, 2 H) 7.31 - 7.44 (m, 4 H) 12.04 - 12.15 (m, 1 H) 12.28 - 12.35 (m, 1 H);

MS (APCI+) m/z 1071.2 (M+H)⁺.

ABS

Example 3.36 methyl {(2S,37/)-l-[(25)-2-{5-[(27/,57/)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-(6-fluoro-2-{(25)15 l-[7V-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-177-benzimidazol-5-yl)pyrrolidin-2yl] -6 -fluoro- 177-benzimidazol -2-yl} pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, DMSO-®,) δ ppm 0.87 - 1.11 (m, 8 H) 1.35 - 1.52 (m, 6 H) 1.71 - 1.84 (m, 2 H) 1.91 - 2.07 (m, 4 H) 2.12 - 2.26 (m, 4 H) 2.79 (s, 4 H) 3.08 (d, J=37.41 Hz, 6 H) 3.41 - 3.48 (m, 2 H) 3.53 (s, 6 H) 3.82 (d, J=4.88 Hz, 4 H) 4.18 - 4.30 (m, 2 H) 5.11 (s, 2 H) 5.47 - 5.63 (m, 2 H) 5.81 20 5.97 (m, 2 H) 6.99 - 7.28 (m, 4 H) 7.37 (dd, J=25.54, 9.60 Hz, 2 H) 12.10 (s, 1 H) 12.22 - 12.35 (m, 1

H); MS (ESI+) m/z 1019.4 (M+H)⁺.

315

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ABS

Example 3.37 methyl {(2_lS)-l-[(2S,3a5,6aS)-2-{5-[(27?,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{6-fluoro-2[(2S,3a5,6aS)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[6]pyrrol5 2-yl] -1 H-benzimidazol -5 -yl}pyrrolidin-2-yl] -6-fluoro- lH-benzimidazol-2yl }hexahydrocyclopenta[b ]pyrrol-1 (227)-yl] -3 -methyl -1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO-d₆) δ ppm 0.80 (dd, J=24.13, 6.45 Hz, 12 H) 1.36 - 1.67 (m, 10 H) 1.69 1.87 (m, 8 H) 1.92 - 2.17 (m, 6 H) 2.37 - 2.47 (m, 2 H) 2.78 (s, 6 H) 3.53 (s, 6 H) 3.92 - 4.07 (m, 2 H)

4.69 - 4.84 (m, 2 H) 5.08 (t, J=8.29 Hz, 2 H) 5.36 - 5.68 (m, 4 H) 5.86 (dd, J=11.71, 8.67 Hz, 2 H)

7.10 (dd, J=31.39, 6.89 Hz, 2 H) 7.28 - 7.51 (m, 4 H) 12.02 (s, 1 H) 12.21 (d, J=7.27 Hz, 1 H); MS (ESI+) m/z 1067.4 (M+H)⁺.

Example 3.38 methyl {(2S,37?)-l-[(2S,3aS',6aS)-2-{5-[(27?,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-(6-fluoro2-{(2S,3a5,6aS)-l-[7V-(methoxycarbonyl)-O-methyl-L-threonyl]octahydrocyclopenta[6]pyrrol-2-yl}1 77-benzimidazol -5 -yl)pyrrolidin-2-yl] -6-fluoro- 177-benzimidazol-2yl} hcxahydrocyclopcntal 61 pyrrol -1 (2/7)-yl | -3 -methoxy-1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO-d₆) δ ppm 0.78 - 1.07 (m, 8 H) 1.36 - 1.51 (m, 8 H) 1.51 - 1.67 (m, 4 H)

1.75 (dd, J=12.20, 6.56 Hz, 4 H) 1.90 (dd, J=20.22, 8.95 Hz, 4 H) 2.00 - 2.14 (m, 4 H) 2.37 - 2.47 (m,

H) 2.79 (s, 6 H) 3.04 - 3.20 (m, 6 H) 3.54 (s, 6 H) 4.14 - 4.29 (m, 2 H) 4.77 (dd, J=18.00, 7.48 Hz, 2

316

Η) 5.07 (t, J=8.24 Hz, 2 H) 5.47 - 5.65 (m, 2 H) 5.80 - 5.94 (m, 2 H) 7.08 (dd, J=27.27, 6.78 Hz, 2 H)

7.28 - 7.57 (m, 4 H) 12.04 (s, 1 H) 12.26 (s, 1 H); MS (ESI+) m/z 1099.4 (M+H)⁺.

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ABS

Example 3.39 dimethyl ({(27/,57/)-1-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-177benzimidazole-5,2-diyl)(25)pyrrolidine-2,1 -diyl [(15)-1 -cyclopentyl-2-oxoethane-2,1diyl] })biscarbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 1.10 - 1.29 (m, 6 H) 1.34 - 1.62 (m, 18 H) 1.71 - 1.86 (m, 2 H) 1.94-2.10 (m, 4H) 2.11 -2.24 (m, 4 H) 2.74 - 2.84 (m, 4 H) 2.94 - 3.12 (m, 2 H) 3.53 (s, 6 H) 3.73 3.87 (m, 4 H) 4.06 - 4.17 (m, 2 H) 5.07 - 5.18 (m, 2 H) 5.47 - 5.63 (m, 2 H) 5.82 - 5.95 (m, 2 H) 7.03 (d, J=6.40 Hz, 1 H) 7.13 (d, J=7.37 Hz, 1 H) 7.30 - 7.46 (m, 4 H) 12.07 (s, 1 H) 12.23 (s, 1 H); MS (APCI+) m/z 1040.3 (M+H)⁺.

ABS

Example 3.40 dimethyl ({(27/,57/)-1-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-17720 benzimidazole-5,2-diyl)(2S,3a5',6a5)hexahydrocyclopenta[A]pyrrole-2,l(277)-diyl[(15)-l-cyclopentyl2-oxoethane-2,1-diyl] })biscarbamate

317

Ή NMR (400 MHz, DMSO-fo) δ ppm 1.12 - 1.25 (m, 8 H) 1.35 - 1.64 (m, 18 H) 1.70 - 1.88 (m, 6 H)

1.92 - 2.15 (m, 8 H) 2.36 - 2.46 (m, 4 H) 2.78 (s, 6 H) 3.53 (s, 6 H) 4.07 (dt, J=18.38, 9.24 Hz, 2 H)

4.72 - 4.83 (m, 2 H) 5.07 (t, J=8.08 Hz, 2 H) 5.46 - 5.65 (m, 2 H) 5.81 - 5.91 (m, 2 H) 7.06 (d, J=6.07

Hz, 1 H) 7.11 - 7.19 (m, 1 H) 7.34 (dd, J=10.63, 4.88 Hz, 1 H) 7.43 (dd, J=11.22, 7.21 Hz, 1 H) 7.51 (dd,J=13.99, 7.92 Hz, 2 H) 11.95 (s, 1 H) 12.20 (s, 1 H); MS (ESI+) m/z 1119.4 (M+H)⁺.

ABS

2016238925 07 Oct 2016

Example 3.41 dimethyl ({(2R,5R)-1 -[3,5-difluoro-4-(piperidin-1 -yl)phenyl]pyrrolidine-2,5-diyl}bis{(6-fluoro-1H0 benzimidazole-5,2-diyl)(2S,3aS,6aS)hexahydrocyclopenta[A]pyrrole-2,l(227)-diyl[(lS)-2-oxo-1(tetrahydro-2H-pyran-4-yl)ethane-2,1-diyl] })biscarbamate 'HNMR (400 MHz, DMSO-J₆) δ ppm 1.30 - 1.65 (m, 18 H) 1.69 - 1.94 (m, 12 H) 2.05 - 2.15 (m, 4

H) 2.37 - 2.45 (m, 4 H) 2.73 - 2.87 (m, 6 H) 2.97 - 3.11 (m, 3 H) 3.53 (s, 6 H) 3.77 (dd, J=27.65,

10.08 Hz, 4 H) 4.06 - 4.14 (m, 2 H) 4.71 - 4.81 (m, 2 H) 5.07 (t, J=8.35 Hz, 2 H) 5.43 - 5.65 (m, 2 H) 5 5.78 - 5.92 (m, 2 H) 6.99 - 7.05 (m, 1 H) 7.09 (t, J=6.94 Hz, 1 H) 7.33 (dd, J=10.03, 6.13 Hz, 1 H)

7.50 (dd, J=18.16, 7.86 Hz, 2 H) 11.99 (s, 1 H) 12.29 (d, J=5.75 Hz, 1 H); MS (ESI+) m/z 1151.4 (M+H)⁺.

Example 3.42

318 methyl {(25)-1 -|(25)-2-{5-| (2/(.5/()-1-{3.5-difluoro-4-|4-(4-fliiorophcnyl)pipcridin-1-yl|phcnyl[-5{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol5-yl}pyrrolidin-2-yl] -1 H-bcnzimidazol-2-yl [pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO-i/,) δ ppm 12.08 (d, J= 18.9, 2H), 7.50 (d, J= 8.0, 1H), 7.41 (d, J= 8.3,

1H), 7.33 - 7.18 (m, 6H), 7.13 - 7.01 (m, 4H), 5.91 (d, J= 13.1, 2H), 5.42 - 5.33 (m,

2H), 5.19 - 5.10 (m, 2H), 4.06 (t, J= 8.6, 2H), 3.86 - 3.77 (m, 4H), 3.53 (s, 6H), 3.03 - 2.83 (m, 5H),

2.28 - 1.54 (m, 18H), 0.91 - 0.73 (m, 12H); MS (ESI+) m/z 1045.4 (M+H)⁺.

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ABS

Example 3.43 methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-(3,5-difluoro-4-{4-[3-(trimethylsilyl)phenyl]piperidin-lyl [phcnyl)-5-{2-| (25)-1-{(25)-2-|(mcthoxycarbonyl)amino|-3-mcthylbiitanoyl[pyrrolidin-2-yl|-1//benzimidazol-5 -yl [ pyrrolidin-2-yl | -1 //-bcnzimidazol-2-yl [ pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate

Ή NMR (400 MHz, DMSO-J₆) δ ppm 12.31 - 12.04 (m, 2H), 7.49 (d, J = 8.4, 1H), 7.40 (d, J = 8.2, 1H), 7.34 - 7.17 (m, 8H), 7.11 - 7.04 (m, 2H), 5.95 - 5.86 (m, 2H), 5.43 - 5.31 (m, 2H), 5.18 - 5.09 (m, 2H), 4.05 (t, J= 8.3, 2H), 3.86 - 3.76 (m, 4H), 3.52 (s, 6H), 3.12 - 2.82 (m, 4H), 2.58 - 2.52 (m, 2H), 2.26 - 1.83 (m, 11H), 1.72 - 1.58 (m, 6H), 0.90 - 0.73 (m, 12H), 0.20 (s, 9H); MS (ESI+) m/z 1099.4 (M+H)⁺.

319

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ABS

Example 3.44 methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-{4-[4-(3,4-difluorophenyl)piperidin-l-yl]-3,5-difluorophenyl}5 - { 2- [(25) -1 - { (25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] -1H5 benzimidazol-5 -yl [ pyrrolidin-2-yl | -1 //-bcnzimidazol-2-yl [ pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate 'H NMR (400 MHz, DMSO-fo) δ ppm 12.32- 12.04 (m, 2H), 7.50 (d, J= 8.5, 1H), 7.41 (d, 2=8.3,

1H), 7.36 - 7.25 (m, 5H), 7.21 (s, 1H), 7.12 - 7.05 (m, 3H), 5.91 (d, J= 12.8, 2H), 5.37 (dd, 2= 6.0,

2.1, 2H), 5.18 - 5.11 (m, 2H), 4.06 (t, 2= 8.3, 2H), 3.86 - 3.79 (m, 4H), 3.53 (s, 6H), 3.12 - 2.83 (m, 0 4H), 2.27 - 2.10 (m, 4H), 2.08 - 1.49 (m, 15H), 0.93 - 0.67 (m, 12H); MS (ESI+) m/z 1063.3 (M+H)⁺.

Example 3.45 methyl {(25)-1 -[(25)-2-{5-[(2R,5R)-l-{4-[4-(3,5-difluorophenyl)piperidin-l-yl]-3,5-difluorophenyl}5 - { 2- [(25) -1 - { (25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] -\H320 benzimidazol-5 -yl [ pyrrolidin-2-yl | -1 //-bcnzimidazol-2-yl [ pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate

Ή NMR (400 MHz, DMSO-r/₆) δ ppm 12.47 - 11.91 (m, 2H), 7.52 - 7.40 (m, 2H), 7.36 - 7.19 (m,

4H), 7.10 (d, J= 7.9, 2H), 7.04 - 6.92 (m, 3H), 5.92 (d, J= 12.7, 2H), 5.46 - 5.32 (m, 2H), 5.20 5 5.10 (m, 2H), 4.06 (t, J= 8.3, 2H), 3.89 - 3.75 (m, 4H), 3.53 (s, 6H), 3.13 - 2.82 (m, 4H), 2.63 - 2.54 (m, 3H), 2.28 - 2.12 (m, 4H), 2.08 - 1.84 (m, 6H), 1.77 - 1.56 (m, 6H), 0.91 - 0.71 (m, 12H); MS (ESI+) m/z 1063.4 (M+H)⁺.

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Example 3.46 methyl {(2S)-l-[(2S)-2-(6-fluoro-5-{(2R,5S)-5-{6-fluoro-2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino] -3 -methylbutanoyl }pyrrolidin-2-yl] -1 H-bcnzi midazol-5 -yl} -1 -[2-(4phenylpiperidin-1 -yl)pyrimidin-5-yl]pyrrolidin-2-yl} -I H-bcnzi midazol-2-yl )py rrolidi η-1 -yl] -3methyl -1 -oxobutan-2 -yl} carbamate

1H NMR (400 MHz, DMSO) δ = 12.42 - 12.16 (m, 2H), 7.81 - 7.55 (m, 4H), 7.45 - 7.12 (m, 9H),

5.23 - 5.06 (m, 2H), 5.02 - 4.86 (m, 2H), 4.57 - 4.45 (m, 2H), 4.13 - 3.96 (m, 2H), 3.92 - 3.70 (m,

4H), 3.53 (s, 6H), 2.75 (t, J=12.8, 2H), 2.62 - 2.54 (m, J=8.1, 2H), 2.28 - 1.59 (m, 15H), 1.53 - 1.36 (m, 2H), 0.98 - 0.66 (m, 12H). MS (ESI; M+H) m/z = 1029.4.

321

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methyl {(2S)-l-[(2S)-2-(6-fluoro-5-{(2R,5S)-5-{6-fluoro-2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino] -3 -methylbutanoyl }pyrrolidin-2-yl] -1 //-bcnzi midazol-5 -yl} -1 -[2(piperidin-1 -yl)pyrimidin-5-yl]pyrrolidin-2-yl} -I //-bcnzimidazol -2-yl (pyrrolidin-1 -yl] -3 -methyl-1 5 oxobutan-2-yl} carbamate

1H NMR (400 MHz, DMSO) δ 12.41 - 12.15 (m, 2H), 7.79 - 7.54 (m, 4H), 7.45 - 7.24 (m, 4H), 5.20

- 5.06 (m, 2H), 5.01 - 4.85 (m, 2H), 4.12 - 4.01 (m, 2H), 3.88 - 3.73 (m, 4H), 3.52 (s, 6H), 3.50 3.42 (m, 4H), 2.55 (s, 2H), 2.27 - 1.77 (m, 12H), 1.51 (s, 2H), 1.38 (s, 4H), 0.93 - 0.73 (m, 12H). MS (ESI; M+H) m/z = 953.4.

ABS

Example 3.48 methyl {(2S,3R)-l-[(2S)-2-{5-[(2R,5R)-l-{4-[4-(2,6-difluorophenyl)piperazin-l-yl]-3,5difluorophenyl}-5-(6-fluoro-2-{(2S)-l-[/V-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrohdin-2-yl}I //-benzi midazol -5 -yl)pyrrolidin-2-yl] -6-fluoro-1 H-benzimidazol-2-yl}pyrrolidin-1 -yl] -3 -methoxy-1 oxobutan-2 -yl} carbamate

322

1H NMR (400 MHz, DMSO) δ 12.37 - 12.08 (m, 2H), 7.41 (dd, J = 11.2, 6.3, 1H), 7.34 (dd, J = 10.4,

4.7, 1H), 7.24 (d, J = 8.3, 1H), 7.18 - 6.97 (m, 6H), 5.90 (dd, J = 22.3, 9.7, 2H), 5.57 (s, 2H), 5.16 5.06 (m, 2H), 4.25 (dd, J = 15.5, 8.2, 2H), 3.87 - 3.76 (m, 3H), 3.53 (s, 6H), 3.50 - 3.40 (m, 2H), 3.25 (d, J = 3.5, 1H), 3.13 (d, J = 1.1, 3H), 3.09 (s, 4H), 3.04 (d, J = 2.6, 3H), 2.96 (s, 4H), 2.55 - 2.47 (m,

2H), 2.26- 1.71 (m, 10H), 1.08 - 0.89 (m, 6H). MS (ESI; M+H) m/z = 1132.4.

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ABS

Example 3.49 methyl {(2S,3R)-l-[(2S)-2-{5-[(2S,5S)-l-{4-[4-(2,6-difluorophenyl)piperazin-l-yl]-3,5difluorophenyl}-5-(6-fluoro-2-{(2S)-l-[7V-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrohdin-2-yl}I //-benzi midazol -5 -yl)pyrrolidin-2-yl] -6-fluoro-I H-bc nzi m i dazol -2-yl}pyrrolidin-1 -yl] -3 -methoxy-1 0 oxobutan-2-yl} carbamate

1H NMR (400 MHz, DMSO) δ 12.33 - 12.04 (m, 2H), 7.41 (dd, J = 11.3, 4.7, 1H), 7.36 (dd, J = 10.5, 3.0, 1H), 7.28 (d, J = 7.9, 1H), 7.21 (d, J = 8.1, 1H), 7.16 (t, J = 7.8, 1H), 7.10 - 6.96 (m, 4H), 5.92 (q, J = 10.7, 2H), 5.69 - 5.49 (m, 2H), 5.12 (dd, J = 7.6, 4.1, 2H), 4.27 (t, J = 7.6, 2H), 3.82 (s, 3H), 3.53 (d, J = 3.1, 6H), 3.47 (d, J = 6.3, 2H), 3.24 (d, J = 2.3, 1H), 3.19 (s, 3H), 3.13 (s, 3H), 3.09 (s, 4H), 15 2.96 (s, 4H), 2.46 (s, 2H), 2.28- 1.71 (m, 10H), 1.09 - 1.00 (m, 6H). MS (ESI; M+H) m/z = 1132.4.

323

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ABS

Example 3.50 methyl {(2S)-l-[(2S)-2-{5-[(2S,55)-1-{4-[4-(2,6-difluorophenyl)piperazin-l-yl]-3,5-difluorophenyl}5-{6-fluoro-2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lHbenzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-benzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 5 oxobutan-2-yl} carbamate

1H NMR (400 MHz, DMSO) δ 12.47 - 11.97 (m, 2H), 7.44 - 7.26 (m, 4H), 7.19 - 6.96 (m, 5H), 5.93 (q, J = 12.0, 2H), 5.67 - 5.48 (m, 2H), 5.18 - 5.07 (m, 2H), 4.05 (dd, J = 14.8, 8.3, 2H), 3.87 - 3.71 (m, 4H), 3.53 (d, J = 3.1, 6H), 3.09 (s, 4H), 2.96 (s, 4H), 2.46 (s, 2H), 2.25 - 1.70 (m, 12H), 0.89 0.76 (m, 12H). MS (ESI; M+H) m/z = 1100.4.

ABS

Example 3.51

324 dimethyl ([(27?,57?)-l-{4-[4-(2,6-difluorophenyl)piperazin-l-yl]-3,5-difluorophenyl}pyrrolidine-2,5diyl]bis{(6-fluoro-lH-benzimidazole-5,2-diyl)(25)pyrrolidine-2, l-diyl[( 15)-2-oxo-l-(tetrahydro-2Hpyran-4-yl)ethane-2,1 -diyl] })biscarbamate

IH NMR (400 MHz, DMSO) δ 12.37 - 12.08 (m, 2H), 7.44 - 7.30 (m, 4H), 7.12 - 6.95 (m, 5H), 5.90 (q, J = 11.6, 2H), 5.66 - 5.47 (m, 2H), 5.16 - 5.05 (m, 2H), 4.17 - 4.04 (m, 2H), 3.88 - 3.61 (m, 7H),

3.52 (d, J = 3.1, 6H), 3.23 - 2.80 (m, 13H), 2.26 - 1.67 (m, 12H), 1.55 - 1.05 (m, 10H). MS (ESI;

M+H) m/z = 1184.4

2016238925 07 Oct 2016

F

Example 3.52 methyl {(25,3R)-l-[(25)-2-{5-[(2R,5R)-l-{3,5-difluoro-4-[4-(40 fluorophenyl)piperidin-1 -yl]phenyl} -5 -(6-fluoro-2- { (25)-1 -[7V-(methoxycarbonyl)-O-methyl-Lthreonyl]pyrrolidin-2-yl}-1 //-bcnzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-lH-benzimidazol-2yl}pyrrolidin-l-yl]-3-methoxy-l-oxobutan-2-yl}carbamatelHNMR (400 MHz, DMSO) δ 12.36 12.06 (m, 2H), 7.41 (dd, J = 11.2, 6.3, IH), 7.34 (dd, J = 10.4, 4.8, IH), 7.30 - 7.20 (m, 3H), 7.17 6.98 (m, 5H), 5.98 - 5.82 (m, 2H), 5.65 - 5.47 (m, 2H), 5.17 - 5.06 (m, 2H), 4.25 (dd, J = 15.6, 8.1,

2H), 3.88 - 3.74 (m, 3H), 3.53 (d, J = 1.3, 6H), 3.49 - 3.38 (m, 2H), 3.31 (d, IH), 3.25 (d, J = 3.7,

IH), 3.13 (d, J = 1.3, 3H), 3.03 (d, J = 2.3, 3H), 3.00 - 2.84 (m, 3H), 2.60 - 2.53 (m, J = 2.5, 2H), 2.26 - 1.55 (m, 14H), 1.28-1.13 (m, IH), 1.10-0.88 (m, 6H). MS (ESI; M+H) m/z = 1113.4.

325

2016238925 07 Oct 2016

Example 3.53 dimethyl (|(2//.5//)-l-{3.5-difluoro-4-|4-(4-fliiorophcnyl)pipcridin-lyl]phenyl}pyrrolidine-2,5-diyl]bis{(6-fluoro-17/-benzimidazole-5,2-diyl)(25)pyrrolidine-2,1diyl|( !5)-2-oxo-l-(tctrahydro-2//-pyran-4-yl)cthanc-2.l-diyl]})biscarbamate 1HNMR (400 MHz,

DMSO) δ 12.36 - 12.07 (m, 2H), 7.44 - 7.22 (m, 6H), 7.12 - 6.99 (m, 4H), 5.88 (dd, J = 23.6, 11.2, 2H), 5.64 - 5.47 (m, 2H), 5.15 - 5.06 (m, 2H), 4.17 - 4.06 (m, 2H), 3.89 - 3.61 (m, 7H), 3.52 (d, J = 3.3, 6H), 3.25 - 2.82 (m, 9H), 2.26 - 2.08 (m, 4H), 2.05 - 1.92 (m, 4H), 1.91-1.57 (m, 9H), 1.54 1.38 (m, 4H), 1.38 - 1.02 (m, 6H). MS (ESI; M+H) m/z = 1165.5.

The following Example compounds 4.1-4.62 can be made from the appropriate listed intermediate following the methods of General Procedures 12/12B.

Intermediate amines:

(5)-6,6'-((27/,57/)-l-(4-(cyclopentyloxy)-3-fluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-215 yl)-17/-benzo[ri]imidazole);

(5)-6.6'-((2//.5//)-l-(3-mcthyl-4-(pipcridin-l-yl)phcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2yl)- 177-benzo \d\ imidazole);

(5)-6,6'-((27/, 57/)-1-(3,5-difliioro-4-((3a//.7aS)-l//-isoindol-2(3//.3a//.4//.5//.6//.7//.7aj^f/)yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-17/-benzo[ri] imidazole);

(5)-6,6'-( (27/,57/)-1-(3,5-dichloro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin2-yl)-I //-benzo [d]imidazole);

(5)-6,6'-( (27/,57/)-1-(2,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin2-yl)-I //-benzo [d]imidazole);

(5)-6,6'-( (27/,57/)-1-(4-( (27/,65)-2,6-dimethylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,525 diyl)bis(2-((5)-pyrrolidin-2-yl)-17/-benzo[ri]imidazole);

326

2016238925 07 Oct 2016 (5)-6,6'-( (27/,57/)-1-(2,3,5-trifluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) -1 H-be nzo [d] imidazole);

(5)-6,6'-((2//.5//)-l-(4-cyclohcxyl-3-fliiorophcnyl)pyrrolidinc-2.5-diyl)bis(2 -((5)-pyrrolidin-2-yl)-177benzo [d] imidazole);

(5')-6.6'-((2/?.5/?)-l-(3.4-difliiorophcnyl)pyrrolidinc-2.5-diyl)bis(2-((5')-pyrrolidin-2-yl)-l//benzo [d] imidazole);

(5)-6,6'-((27/, 5//)-l-(4-cthoxyphcnyl)pyrrolidinc-2.5-diyl)bis(2-((5)-pyrrolidin-2-yl)-177benzo [d] imidazole);

(5)-6.6'-((2/?.5/?)-1-(4-(2.2-difluorocthoxy)phcnyl)pyrrolidinc-2.5-diyl)bis(2-((5')-pyrrolidin-2-yl)-1//0 benzo[ri]imidazole);

(5)-6,6'-((27/, 5/?)-1 -(4-(3.5-dimethylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - I //-be nzo [d\ imidazole);

6,6'-{(27/,57/)-l-[4-(pentafluoro-X⁶-sulfanyl)phenyl]pyrrolidine-2,5-diyl}bis{2-[(25)-pyrrolidin-2-yl]l//-benzimidazole} (ACD Name vl2);

(5)-6,6'-( (25,55)-l-(4-cyclopropylphenyl)pyrrolidine-2,5-diyl)bis(2 -((.S')-py rrolidin-2-yl)-1 //benzo \d\ imidazole);

(5)-6,6'-((25,55)-l-(4-cyclopropyl-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)l//-benzo \d\ imidazole);

(5)-6,6'-((27/,57/)-l-(4-/er/-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-177!0 benzo[ri]imidazole);

1- (l-(4-((27/,57/)-2,5-bis(2-((5)-pyrrolidin-2-yl)-17/-benzo[<7]imidazol-6-yl)pyrrolidin-l-yl)-2,6difluorophenyl)-4-phenylpiperidin-4-yl)ethanone;

(5,5,5)-6,6'-((2Λ,57/)-1-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2((25,3a5',6a5)-octahydrocyclopenta[b]pyrrol-2-yl)-17/-benzo[ri]imidazole);

(5,5,5)-6,6'-((27/,57/)-1-(4-/ert-butylphenyl)pyrrolidine-2,5-diyl)bis(2-((25,3a5,6a5)octahydrocyclopenta[b]pyrrol -2 -yl) -1 H-be nzo [d] imidazole);

2- (4-( (27/,57/)-2,5-bis(2-((5)-pyrrolidin-2-yl)-17/-benzo[<7]imidazol-6-yl)pyrrolidin-l-yl)-2,6difluorophenyl)-2-azabicyclo [2.2.2] octane;

(5)-6,6'-((27/,57/)-l-(3,5-difluoro-4-(4-isopropylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)3 0 pyrrolidin-2-yl) - I //-be nzo [d\ imidazole);

(5)-6,6'-((27/,57/)-l-(4-(4,4-dimethylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - I //-be nzo [d\ imidazole);

(5)-6,6'-( (27/,57/)-1-(4-(3,3-dimethylazetidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl) - I //-be nzo [d\ imidazole);

(5)-6,6'-( (27/,57/)-l-(4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2 -((5)-pyrrolidin-2-yl)I //-benzo \d\ imidazole);

327

2016238925 07 Oct 2016 (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(3-phenylpropyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(naphthalen-2-yl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(2,3-dihydrospiro[indene-l,4'-piperidine]-r-yl)-3,5difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(3-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)0 pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-methoxyphenyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(fluorodiphenylmethyl)piperidin-l-yl)phenyl)pyrrolidine-2,5!0 diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(benzyloxy)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)-pyrrolidin-2-yl)-lHbenzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-l-yl)phenyl)pyrrolidine2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-benzylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro30 2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2S,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

4-(4-((2R,5R)-2,5-bis(2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol-6-yl)pyrrolidin-l-yl)-2,6difluorophenyl)-2 -phenylmorpholine;

328

2016238925 07 Oct 2016 (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(2-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,5-diyl)bis(5fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-4-(4-((2R,5R)-2,5-bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazol-6-yl)pyrrolidin-l-yl)0 2,6-difluorophenyl)-2-phenylmorpholine;

(S)-6,6'-((2S,5R)-l-(3,5-difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)pyrrolidin-2-yl) -1 H-benzo [d] imidazole);

(S)-6,6'-((2R,5R)-l-(4-(4-(2,4-difluorophenyl)piperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5!0 diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole);

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(4-fluorophenyl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole).

(S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-(5-methylthiophen-2-yl)piperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole); and (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole).

Intermediate acids:

(5')-2-(mcthoxycarbonylamino)-3-mcthylbiitanoic acid;

(.S')-2-(mcthoxycarbonylamino)-2-(tctrahydro-2H-pyran-4-yl)acctic acid;

(25.3//)-3 -methoxy-2-(methoxycarbonylamino)butanoic acid;

(5)-2-cyclopropyl-2-(methoxycarbonylamino)acetic acid;

(2S,3R)-3-tert-butoxy-2-(methoxycarbonylamino)butanoic acid;

(5)-2-(methoxycarbonylamino)-2-(tetrahydro-2/7-pyran-4-yl)acetic acid;

(5)-2-cyclopentyl-2-(methoxycarbonylamino)acetic acid; and

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2016238925 07 Oct 2016 (2S,3R)-3 -methoxy-2-(methoxycarbonylamino)butanoic acid.

Example 4.1 methyl {(25)-1-[(25)-2-{6-[(2R,5R)-l-[4-(cyclopentyloxy)-3-fluorophenyl]-5-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-127-benzimidazol-6-yl }pyrrolidin-2yl] -1 27-benzi midazol -2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate ‘HNMR (400 MHz, DMSO-d₆) δ ppm 0.74 - 0.89 (m, 12 H), 1.37 - 1.77 (m, 12 H), 1.81 - 2.06 (m, 6 0 H), 2.11 - 2.29 (m, 4 H), 3.54 (s, 6 H), 3.72 - 3.92 (m, 4 H), 3.95 - 4.16 (m, 2 H), 4.40 - 4.52 (m, 1 H),

5.07 - 5.23 (m, 2 H), 5.26 - 5.44 (m, 2 H), 5.96 - 6.17 (m, 2 H), 6.63 - 6.98 (m, 2 H), 7.00 - 7.16 (m, 2 H), 7.16 - 7.35 (m, 4 H), 7.35 - 7.54 (m, 7=31.23 Hz, 2 H), 11.93 - 12.32 (m, 2 H); MS (ESI) m/z =

934.5 (M+H)⁺.

Example 4.2 methyl {(25)-1 -| (25)-2-(5-{(2/?.5/?)-5-{2-| (25)-1-{(25)-2-|(mcthoxycarbonyl [amino |-3methylbutanoyl }pyrrolidin-2-yl] -1 27-benzi midazol-5 -yl} -1 -[3 -methyl-4-(piperidin-1 yl)phenyl]pyrrolidin-2-yl} -1 27-benzi midazol-2-yl [pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate 'HNMR (400 MHz, DMSO-7,) δ ppm 0.74 - 0.89 (m, 12 H) 1.35-1.41 (m, 2 H) 1.44 - 1.52 (m, 4 H)

1.62 - 1.67 (m, 2 H) 1.86 - 1.93 (m, 5 H) 1.94 - 2.03 (m, 4 H) 2.15 - 2.24 (m, 4 H) 2.48 - 2.54 (m, 6 H)

3.52 (s, 6 H) 3.74 - 3.84 (m, 4 H) 4.00 - 4.09 (m, 2 H) 5.06 - 5.18 (m, 2 H) 5.28 - 5.37 (m, 2 H) 6.07 330

6.12 (m, 1 H) 6.17 - 6.21 (m, 1 H) 6.56 - 6.62 (m, 1 H) 6.99 - 7.30 (m, 6 H) 7.35 (d, J=8.24 Hz, 1 H)

7.44 (d, J=8.24 Hz, 1 Η) 11.94 - 12.04 (m, 2 H); MS (ESI+) m/z 929.5 (M+H)⁺.

2016238925 07 Oct 2016

/

Example 4.3 methyl {(2S)-l-[(2S)-2-{5-[(27?,57?)-l-{3,5-difluoro-4-[(3aR,7aS)-octahydro-2H-isoindol-2yl]phenyl}-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lHbenzimidazol-5 -yl [ pyrrolidin-2-yl | -17/-bcnzimidazol-2-yl [ pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate ‘H NMR (400 MHz, DMSO-r/₆) δ ppm 0.71 -0.94 (m, 12 H) 1.22 - 1.31 (m, 2 H) 1.35 - 1.53 (m, 6 H)

1.66 - 1.74 (m, 2 H) 1.86 - 2.24 (m, 12 H) 2.90 - 2.97 (m, 2 H) 3.05 - 3.15 (m, 2 H) 3.36 - 3.42 (m, 2 H) 3.54 (s, 6 H) 3.77 - 3.86 (m, 4 H) 4.06 (t, J=8.29 Hz, 2 H) 5.09 - 5.20 (m, 2 H) 5.29 - 5.40 (m, 2 H) 5.89 (d, J=12.25 Hz, 2 H) 7.03 - 7.13 (m, 2 H) 7.18 - 7.33 (m, 4 H) 7.40 (d, J=8.13 Hz, 1 H) 7.48 (d, J=8.24 Hz, 1 H) 11.95 - 12.25 (m, 2 H); MS (ESI+) m/z 991.5 (M+H)⁺.

methyl {(2S)-l-[(2S)-2-{5-[(27?,57?)-l-[3,5-dichloro-4-(piperidin-l-yl)phenyl]-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-220 yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'H NMR (400 MHz, DMSO-ri₆) δ ppm 0.68 - 0.94 (m, 12 H) 1.36 - 2.28 (m, 20 H) 2.84 (s, 4 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.04 - 4.09 (m, 2 H) 5.09 - 5.19 (m, 2 H) 5.33 - 5.50 (m, 2 H) 6.30 (t, 7=2.49 Hz,

H) 6.99 - 7.57 (m, 8 H) 12.04 (s, 1 H) 12.09 (s, 1 H); MS (ESI+) m/z 983 (M+H)⁺.

331

2016238925 07 Oct 2016

Example 4.5 methyl {(25)-1 -[(2S)-2-{5-[(27/,57/)-1 -[2,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2-[(2S)-l-{(2S)-25 [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5-yl}pyrrolidin-2yl] - 177-benzimidazol-2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO®,) δ ppm 0.80 (s, 12 H) 1.08 - 2.71 (m, 24 H) 3.53 (s, 6 H) 3.81 (s, 4 H) 3.97-4.11 (m, 2H) 5.13 (s, 2 H) 5.51 (s, 2 H) 6.34 -6.70 (m, 2 H) 7.00 -7.60 (m, 8 H) 11.87 - 12.30 (m, 2 H); MS (ESI+) m/z 952 (M+H)⁺.

methyl {(2.8)-1-| (2.8)-2-{5-| (2//.5//)-1-{4-|(2//.6.8')-2.6-dimcthylpipcridin-1-yl|-3.5-difliiorophcnyl [-5{2-[(2_lS)-l-{(2_lS)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol15 5-yl}pyrrolidin-2-yl] -1 H-bcnzimidazol-2-yl {pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO®) δ ppm 0.58 (s, 6 H) 0.73 - 0.92 (m, 12 H) 1.08 - 2.37 (m, 20 H) 3.53 (s, 6 H) 3.82 (s, 4 H) 4.06 (q, 7=7.92 Hz, 2 H) 5.15 (s, 2 H) 5.39 (s, 2 H) 5.88 (d, 7=13.01 Hz, 2 H)

7.02 - 7.58 (m, 10 H) 12.01 (s, 1 H) 12.18 (s, 1 H); MS (ESI+) m/z 979 (M+H)⁺.

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2016238925 07 Oct 2016

Example 4.7 methyl {(25)-1 -|(2.S')-2-(5-{ (2//.5//)-5-{2-|(2.S')-1 -{(2.S')-2-|(mcthoxycarbonyl (amino |-3methylbutanoyl} pyrrolidin-2-yl] -1 H-benzi m i dazol-5 -yl} -1 - [2,3,5 -trifluoro -4 -(piperidin-1 5 yl)phenyl]pyrrolidin-2-yl} -1 H-benzi midazol-2-yl (pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-2 yl} carbamate

Ή NMR (400 MHz, DMSO-7₆) δ ppm 0.72 - 0.93 (m, 12 H) 1.34 - 2.38 (m, 20 H) 2.77 (s, 4 H) 3.53 (s, 6 H) 3.82 (s, 4 H) 4.00 - 4.13 (m, 2 H) 5.14 (s, 2 H) 5.56 (s, 2 H) 6.27 - 6.47 (m, 1 H) 6.97 - 7.49 (m, 8 H) 12.01 (s, 1 H) 12.08 (d, 7=1.84 Hz, 1 H); MS (ESI+) m/z 970 (M+H)⁺.

ABS

O \

Example 4.8 methyl {(25)-1-[(2S)-2-{5-[(2R,57/)-1-(4-cyclohexyl-3-fluorophenyl)-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl |-IE/-bcnzimidazol-6-yl }pyrrolidin-215 yl] -1 77-benzi midazol -2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate *HNMR (400 MHz, CDC1₃) δ ppm 10.48 (m, 1 H), 10.32 (s, 1 H), 7.70 (d, J= 8.0 Hz, 1 H), 7.53 (s, 1 H), 7.34 (d, J= 8.1 Hz, 1 H), 7.13 (d, J= 5.5 Hz, 3 H), 6.72 (s, 1 H), 6.03 (m, 2 H), 5.40 (m, 5 H), 5.26 (d, J= 1.7 Hz, 3 H), 4.34 (dd, 7= 8.7, 7.0 Hz, 2 H), 3.84 (d, 7= 7.6 Hz, 2 H), 3.70 (s, 6 H), 3.62 (m, 3 H), 3.09 (m, 2 H), 2.57 (m, 4 H), 2.33 (m, 2 H), 2.17 (m, 5 H), 1.97 (m, 3 H), 1.73 (m, 8 H),

1.17 (m, 8 H), 0.89 (t, J = 6.4, 12 H); MS (ESI+) m/z (rel abundance) 933 (100, M+H), 934 (53).

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ABS

Example 4.9 methyl {(2S)-l-[(2S)-2-{5-[(2R57?)-l-(3,4-difluorophenyl)-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-6-yl }pyrrolidin-25 yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate 'HNMR (400 MHz, CDC1₃) δ ppm 10.49 (d, J= 9.0 Hz, 1 H), 10.38 (s, 1 H), 7.70 (d, J= 8.1 Hz, 1 H), 7.51 (s, 1 H), 7.35 (d, J= 8.3 Hz, 1 H), 7.12 (dd, 7= 10.9, 6.3 Hz, 3 H), 6.69 (dd,7=9.4, 5.7 Hz, 1 H), 6.13 (d, 7= 7.2 Hz, 1 H), 6.00 (s, 1 H), 5.41 (m, 4 H), 5.27 (m, 2 H), 4.34 (m, 2 H), 4.06 (d, 7 =

6.6 Hz, 1 H), 3.85 (m, 2 H), 3.73 (s, 6 H), 3.64 (m, 2 H), 3.08 (m, 2 H), 2.61 (m, 2 H), 2.34 (m, 2 H), 0 2.19 (m, 4 H), 1.96 (m, 2 H), 1.79 (m, 2 H), 1.64 (m, 4 H), 0.92 (m, 12 H); MS (ESI+) m/z (rel abundance) 868 (100, M+H), 869 (43).

<0-

Example 4.10 methyl {(2S)-l-[(2S)-2-{6-[(2R57?)-l-(4-ethoxyphenyl)-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2yl]-17/-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate ^XH NMR (400 MHz, DMSO® δ ppm 0.92 - 0.75 (m, 12H), 1.21-1.10 (m, 3H), 1.33 - 1.21 (m, 1H),

1.76 - 1.64 (m, 2H), 2.06 - 1.85 (m, 7H), 2.28 - 2.08 (m, 4H), 3.54 (s, 6H), 3.73 (q, J = 7.0, 2H), 3.81 (s, 4H), 4.11 - 3.99 (m, 2H), 5.18 - 5.06 (m, 2H), 5.33 (s, 2H), 6.24 (d, J = 8.9, 2H), 6.51 (dt, J = 4.9,

9.4, 2H), 7.04 (t, J = 7.7, 2H), 7.34 - 7.18 (m, 4H), 7.36 (d, J = 8.2, 1H), 7.44 (d, J = 8.2, 1H), 12.02 (s, 2H); MS (ESI) m/z 876 (M+H)⁺, 874 (M-H)’.

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methyl {(25)-l-[(25)-2-{6-[(27?,57?)-l-[4-(2,2-difluoroethoxy)phenyl]-5-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-6-yl }pyrrolidin-25 yl]-1 H-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

A NMR (400 MHz, mcthanol-ty) δ ppm 0.85 (dd, J = 6.7, 20.0, 12H), 1.88 - 1.75 (m, 2H), 2.06 -

1.95 (m, 3H), 2.22 - 2.06 (m, 3H), 2.34 - 2.23 (m, 2H), 2.49 - 2.34 (m, 2H), 2.71 - 2.56 (m, 2H), 3.64 (s, 6H), 4.13 - 3.76 (m, 6H), 4.22 (dd, J = 5.4, 10.3, 1H), 5.28 - 5.17 (m, 2H), 5.37 (t, J = 6.4, 2H),

5.96 (tt, J = 3.9, 55.2, 1H), 6.31 (t, J = 9.7, 2H), 6.60 - 6.51 (m, 2H), 6.98 (d, J = 8.4, 1H), 7.23 (d, J =

8.3, 2H), 7.35 (d, J = 17.8, 2H), 7.50 (d, J = 8.3, 2H); MS (ESI) m/z 912 (M+H)⁺, 910 (M-H)’.

Example 4.12 methyl {(25)-1 -| (25)-2-{6-|(2/?.5/?)-1-| 4-(3.5-dimcthylpipcridin-1-yl)-3.5-difliiorophcnyl|-5-{2-| (25)l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-615 yl} pyrrolidin-2-yl] -1 H-bc nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

A NMR (400 MHz, DMSO-d₆) δ ppm 0.50 (q, J = 11.9, 1H), 0.97 - 0.64 (m, 18H), 1.32 - 1.20 (m,

2H), 1.81 - 1.46 (m, 5H), 2.09 - 1.80 (m, 6H), 2.32-2.13 (m, 5H), 2.75 (dd, J = 10.0, 40.2, 2H), 3.18 3.05 (m, 1H), 3.54 (s, 6H), 3.82 (s, 4H), 4.14 - 3.95 (m, 2H), 5.14 (s, 2H), 5.36 (d, J = 7.2, 2H), 5.88 (d, J = 12.8, 2H), 7.14 - 7.02 (m, 2H), 7.19 (s, 1H), 7.33 - 7.23 (m, 3H), 7.41 (d, J = 8.2, 1H), 7.49 (d, 20 J = 8.2, 1H), 12.37 - 11.98 (m, 2H); MS (ESI) m/z 979 (M+H)⁺.

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Example 4.13 methyl {(2S)-l-[(2S)-2-(6-{(2R,5R)-5-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}-l-[4-(pentafluoro-lambda~6— sulfanyl)phenyl]pyrrolidin-2-yl} -I H-bcnzi midazol-2-yl [pyrrol idi η-1 -yl] -3-methyl-1 -oxobutan-2yl} carbamate 'h NMR (400 MHz, DMSO-J₆) δρριη 0.92 - 0.69 (m, 12H), 2.08 - 1.61 (m, 8H), 2.20 (s, 4H), 3.53 (s, 6H), 3.82 (s, 4H), 4.05 (t, J = 8.0, 2H), 5.13 (dt, J = 4.9, 9.8, 2H), 5.49 (dd, J = 10.8, 15.8, 2H), 6.37 (d, J = 8.6, 2H), 7.13 - 6.81 (m, 3H), 7.20 (d, J = 8.8, 1H), 7.28 (dd, J = 4.6, 9.9, 3H), 7.45 - 7.34 (m, 0 4H), 7.48 (d, J = 8.2, 1H), 12.16 (dd, J = 22.6, 68.2, 2H); MS (ESI) m/z 958 (M+H)⁺, 956 (M-H)‘.

ABS

Example 4.14 methyl {(2.8.3/?)-1-| (2.8)-2-{5-| (2.8,5.8)-1-(4-cyclopropylphcnyl)-5-(2-{ (2.8)-1-|A'-(mcthoxycarbonyl)± 5 O-methyl-L-threonyl]pyrrolidin-2-yl} -1 27-benzimidazol-5 -yl)pyrrolidin-2-yl] -I H-bcnzi midazol-2yl} pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, DMSO- d₆) δ ppm 0.37 (m, 2 H) 0.68, (s, 2 H) 1.08 (d, 6 H) 1.54 -1.64 (m, 2 H)

1.69 (s, 2 H) 1.99 (s, 4 H) 2.17 (s, 7 H) 3.18 (s, 6 H) 3.42 - 3.53 (m, 2 H) 3.54 (s, J=1.41 Hz, 6 H) 3.84 (s, 3 H) 4.28 (s, 2 H) 5.12 (s, 2 H) 5.34 (s, 2 H) 6.22 (s, 2 H) 6.61 (s, 2 H) 7.05 (s, 2 H) 7.16 (s, 2 H) 20 7.36 (s, 2 Η) 11.97 (s, 1 H), 12.08 (s, 1H); MS (ESI+) m/z 904.5 (M+H)⁺, (ESI-) m/z 902.3 (M-H)’.

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methyl {(25)-1-[(25)-2-{6-[(2R,57/)-1-(4-cyclopropyl-3,5-difluorophenyl)-5-{2-[(25')-l-{(25')-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-177-benzimidazol-6-yl}pyrrolidin-25 yl] - 177-benzimidazol-2-yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'H NMR (400 MHz, CDC1₃) δ ppm 10.47 (br s, 1H) 10.30-10.41 (br s, 1H) 7.69 (br s, 1H) 7.49 (s,

1H) 7.30-7.43 (br s, 1H) 7.04-7.20 (m, 3H) 5.75-5.89 (m, 2H) 5.37 (m, 4H) 5.23 (s, 2H) 4.34 (t, 2H)

3.83 (m, 2H) 3.71 (s, 6H) 3.56-3.67 (m, 2H) 3.11 (m, 2H) 2.58 (br s, 2H) 2.33 (m, 2H) 2.08-2.27 (m,

4H) 2.01 (m, 2H) 1.78 (br s, 2H) 0.82-0.96 (m, 12H) 0.71 (m, 4H).

ZBS

Example 4.16 dimethyl ([(27/,57/)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{177-benzimidazole-6,2diyl(25)pyrrolidine-2,1 -diyl [(15)-1 -cyclopropyl-2-oxoethane-2,1 -diyl] })biscarbamate

N NMR (500 MHz, DMSO-®,) δ ppm 0.48 -0.24 (m, 7H), 0.89-0.81 (m, 1H), 1.01 (s,3H), 1.07 (s,

6H), 1.14 (dd, J = 8.7, 16.6, 1H), 1.32-1.17 (m, 4H), 1.75 - 1.64 (m, 1H), 2.05 - 1.78 (m, 4H), 2.24 2.09 (m, 3H), 2.45 - 2.39 (m, 2H), 3.21 - 3.12 (m, 1H), 3.53 (s, 6H), 3.72 - 3.63 (m, 2H), 3.76 (s, 2H),

4.03 - 3.85 (m, 2H), 5.17 - 5.04 (m, 1H), 5.44 - 5.26 (m, 2H), 6.26 (d, J = 8.8, 1H), 6.95 - 6.81 (m,

2H), 7.06 - 6.95 (m, 1H), 7.09 (t, J = 8.3, 1H), 7.20 (d, J = 4.3, 1H), 7.35 - 7.25 (m, 1H), 7.55 - 7.36 (m, 4H), 12.28 - 11.84 (m, 2H); MS (ESI+) m/z 884 (M+H)⁺, (ESI-) m/z 882 (M-H).

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Example 4.17 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-[4-(4-acetyl-4-phenylpiperidin-l-yl)-3,5-difluorophenyl]-5-{2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-bcnzi midazol-5 5 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 0.75 - 0.91 (m, 12 H) 1.68 (d, J=4.66 Hz, 2 H) 1.83 (s, 3 H) 1.87 - 2.38 (m, 16 H) 2.78 - 2.90 (m, 4 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.06 (t, J=8.35 Hz, 2 H) 5.09 5.18 (m, 2 H) 5.27 - 5.41 (m, 2 H) 5.88 (d, J=12.90 Hz, 2 H) 7.02 - 7.51 (m, 13 H) 12.07 (d, J=16.91 Hz, 2 H); MS (ESI+) m/z 1070 (M+H)⁺.

Example 4.18 methyl {(25)-l-[(2S,3a5',6a5)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2[(3a5',6a5)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[6]pyrrol-215 yl]-lH-benzimidazol-5-yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}hexahydrocyclopenta[6]pyrrol1 (2H) -yl] -3 -methyl-1 -oxobutan-2 -yl} carbamate *HNMR (400 MHz, DMSO-7₆) δ ppm 0.64 - 0.96 (m, 13 H) 1.31 - 2.18 (m, 21 H) 3.50 - 3.57 (m, 6

H) 3.93 - 4.07 (m, 2 H) 4.72 - 4.85 (m, 1 H) 5.13 (t, 1 H) 5.37 (s, 2 H) 5.90 (dd, 2 H) 7.06 (d, 2 H)

7.21 (s, 1 H) 7.33 (d, 1 H) 7.36 - 7.56 (m, 7=8.13 Hz, 4 H) 11.96 (s, 1 H) 12.03 - 12.08 (m, 1 H) 12.24 20 (none, 1 H); MS (ESI+) m/z 1031.5 (M+H)⁺, (ESI-) m/z 1029.4 (M-H)’.

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Example 4.19 methyl i(2.S')-l-|(2.S'.3aS'.6aS')-2-{5-|(2//.5//)-l-(4-/i77-biitylphcnyl)-5-{2-|(3a.S'.6a.S)-l-{(2.S)-25 [(methoxy carbonyl)amino] -3 -methylbutanoyl} octahydrocyclopenta[b ] pyrrol-2-yl ] - lH-benzimidazol5-yl}pyrrolidin-2-yl] -1 H-benzimidazol -2-yl }hexahydrocyclopenta[b ]pyrrol-1 (277)-y 1 ] -3 -methyl-1 oxobutan-2 -yl} carbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 0.62 - 0.93 (m, 13 H) 1.42 - 2.16 (m, 25 H) 2.78 (s, 1 H) 3.54 (s, 6 H) 4.01 (s, 2 H) 4.77 (s, 1 H) 5.11 (t, 7=8.08 Hz, 2 H) 5.35 (s, 2 H) 6.26 (d, 7=8.67 Hz, 2 H) 6.83 0 - 6.97 (m, 2 H) 7.05 (s, 2 H) 7.21 (s, 1 H) 7.27 - 7.32 (m, 1 H) 7.34 - 7.55 (m, 4 H) 11.92 (s, 1 H)

12.01 (s, 1 H); MS (ESI+) m/z 968.5 (M+H)⁺, (ESI-) m/z 966.4 (M-H)’, 1011.7 (M+COOH-H).

methyl [(25)-1 -(2-{5-| (2//.5//)-1 -(4-/i77-butylphcnyl)-5-{2-|(2.S)-pyrrolidin-2-yl |-1//-bcnzimidazol-5yl}pyrrolidin-2-yl]-lH-benzimidazol-2-yl}pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl]carbamate The title compound can be prepared by reacting the amine with one equivalent of an acid instead of two. Ή NMR (400 MHz, DMSO-7₆) δ ppm 0.67 - 0.90 (m, 6 H) 0.97 - 1.17 (m, 9 H) 1.53 - 2.46 (m, 13 H) 3.26 - 3.42 (m, 7=11.39 Hz, 2 H) 3.54 (s, 3 H) 3.85 (d, 7=4.34 Hz, 2 H) 4.07 - 4.13 (m, 1 H) 20 4.88 - 4.98 (m, 1 H) 5.15 - 5.23 (m, 1 H) 5.45 (d, 7=7.16 Hz, 1 H) 5.50 (d, 7=6.94 Hz, 1 H) 6.26 (d,

7=8.78 Hz, 2 H) 6.92 (d, 7=8.78 Hz, 2 H) 7.19 - 7.77 (m, 7 H) 9.15 (s, 1 H) 9.66 (s, 1 H); MS (ESI+) m/z 731 (M+H)⁺.

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Example 4.21 methyl {(25)-1 -[(25)-2-{5-[(27?,57?)-l-[4-(2-azabicyclo[2.2.2]oct-2-yl)-3,5-difluorophenyl]-5-{25 [(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 27-benzi midazol-5 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'H NMR (400 MHz, DMSO-fo) δ ppm 0.74 - 1.02 (m, 12 H), 1.41 - 2.27 (m, 26 H), 2.65 (s, 1 H),

3.05 - 3.26 (m, 3 H), 3.54 (s, 6 H), 4.06 (t, 7=8.35 Hz, 2 H), 5.07 - 5.20 (m, 2 H), 5.26 - 5.45 (m, 2 H),

5.89 (d, 7=12.36 Hz, 2 H), 7.00 - 7.14 (m, 2 H), 7.16 - 7.33 (m, 4 H), 7.44 (dd, 7=32.42, 8.24 Hz, 2 0 H), 12.06 (two s, 2 H); MS (ESI+) m/z 977 (M+H)⁺, (ESI-) m/z 975 (M-H)’.

methyl {(25)-1-[(25)-2-{5-[(2Λ,5Λ)-1-{3,5-difluoro-4-[4-(propan-2-yl)piperidin-l-yl]phenyl}-5-{215 [(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -127-benzi midazol-5 yl}pyrrolidin-2-yl] -1 H-bcnzi midazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO-7₆) δ ppm 0.74 - 0.91 (m, 18 H), 0.91 - 1.05 (m, 1 H), 1.07-1.21 (m, 3

H), 1.31-1.43 (m, 1 H), 1.51 (d, 7=11.17 Hz, 2 H), 1.63 - 1.77 (m, 2 H), 1.84 -2.26 (m, 11 H), 2.72 2.88 (m, 4 H), 3.54 (s, 6 H) 3.82 (br s, 4 H), 4.06 (t, 7=8.35 Hz, 2 H), 5.07 - 5.23 (m, 2 H), 5.29 - 5.45 (m, 2 H), 5.88 (d, 7=12.79 Hz, 2 H), 7.02 - 7.12 (m, 2 H), 7.16 - 7.32 (m, 4 H), 7.41 (d, 7=8.13 Hz, 1

H), 7.49 (d, 7=8.13 Hz, 1 H), 12.07 (two s, 2 H); MS (ESI+) m/z 994 (M+H)⁺.

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ABS

Example 4.23 dimethyl ({(2R,5R)-1 -[4-(4,4-dimethylpiperidin-1 -yl)-3,5-difluorophenyl]pyrrolidine-2,5diyl}bis{ l//-bcnzimidazolc-5.2-diyl(25)pyrrolidinc-2. l-diyl|( 15)-2-oxo-1 -(tetrahydro-2H-pyran-45 yl)ethane-2,1-diyl] })biscarbamate 'H NMR (400 MHz, DMSO-A) δ ppm 0.87 (s, 6 H), 1.18 - 1.34 (m, 9 H), 1.34 - 1.59 (m, 4 H), 1.61 1.93 (m, 5 H), 1.93 - 2.06 (m, 4 H), 2.09 - 2.27 (m, 4 H), 2.77 (s, 4 H), 2.90 - 3.27 (m, 4 H), 3.53 (s, 6 H), 3.62 (d, 2=11.71 Hz, 1 H), 3.67 - 3.89 (m, 7 H), 4.14 (q, 2=8.10 Hz, 2 H), 5.08 - 5.20 (m, 2 H), 5.30 - 5.43 (m, 2 H), 5.81 - 5.94 (m, 2 H), 7.03 - 7.52 (m, 8 H), 12.10 (two s, 2 H); MS (ESI+) m/z 0 1063 (M+H)⁺, (ESI-) m/z 1061 (M-H)’.

ABS

Example 4.24 methyl {(25)-1-|(25)-2-{5-| (2//.5//)-1-|4-(3.3-dimcthylazctidin-1-yl)-3.5-difluorophcnyl|-5-{2-| (25)15 I-{(25)-2-|(mcthoxycarbonyl)amino|-3-mcthylbutanoyl [pyrrolidin-2-yl |-l4/-bcnzimidazol-5yl} pyrrolidin-2-yl] - 127-benzimidazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-A) δ ppm 0.76-0.94 (m, 12 H), 1.13 (s, 6 H), 1.61-1.74 (m, 2 H), 1.812.28 (m, 9 H), 3.07-3.18 (m, 1 H), 3.49 (s, 4 H), 3.54 (s, 6 H), 3.82 (br s, 4 H), 4.07 (t, 7=8.24 Hz, 2 H), 5.14 (t, 7=7.54 Hz, 2 H), 5.25-5.40 (m, 2 H), 5.79-5.94 (m, 2 H), 7.01-7.07 (m, 2 H), 7.08-7.34 (m, 4 H), 7.39 (d, 7=8.13 Hz, 1 H), 7.47 (d, 7=8.24 Hz, 1 H), 12.05 (two s, 2 H); MS (ESI+) m/z 951 (M+H)⁺.

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Example 4.25 methyl {(25)-1-[(25)-2-(5-{(27?,57?)-5-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3methylbutanoyl }pyrrolidin-2-yl] -1 27-benzi midazol -5 -yl} -1 -[4-(4-phenylpiperidin-1 5 yl)phenyl]pyrrolidin-2-yl} -I H-bcnzi midazol-2-yl (pyrrol idi η-1 -yl]-3-methyl-1 -oxobutan-2yl} carbamate

Ή NMR (400 MHz, DMSO-7₆) δ ppm 0.74 - 0.93 (m, 12 H), 1.61-1.79 (m, 6 H), 1.84 - 2.09 (m, 6

H), 2.11 - 2.27 (m, 4 H), 2.40 - 2.60 (m, 4 H), 3.35 (s, 3 H), 3.53 (s, 6 H), 3.82 (s, 4 H), 4.06 (t, 7=8.29 Hz, 2 H), 5.08 - 5.19 (m, 2 H), 5.28 - 5.46 (m, 2 H), 6.26 (d, 7=8.67 Hz, 2 H), 6.55 - 6.67 (m, 2 H),

7.06 (t, 7=7.32 Hz, 2 H), 7.13 - 7.32 (m, 9 H), 7.37 (d, 7=8.24 Hz, 1 H), 7.45 (d, 7=8.24 Hz, 1 H),

12.02 (s, 2 H); MS (ESI+) m/z 991 (M+H)⁺, (ESI-) m/z 989 (M-H)’.

Example 4.26 methyl {(25)-l-[(25)-2-{5-[(27?,57?)-l-{3,5-difluoro-4-[4-(3-phenylpropyl)piperidin-l-yl]phenyl}-5{6-fluoro-2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lHbenzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-I H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate

342 ^ΧΗ NMR (400 MHz, DMS0-d₆) δ ppm 0.68 - 0.84 (m, 12 H), 0.98 - 1.30 (m, 8 H), 1.47 - 1.60 (m, 5

H), 1.63 - 2.07 (m, 9 H), 2.09 - 2.24 (m, 3 H), 2.78 (s, 4 H), 3.51 (s, 6 H), 3.71 - 3.87 (m, 4 H), 3.97 4.12 (m, 2 H), 5.03 - 5.17 (m, 2 H), 5.43 - 5.63 (m, 2 H), 5.78 - 5.96 (m, 2 H), 7.02 (dd, 7=6.78, 2.33

Hz, 1 H), 7.08 - 7.19 (m, 4 H), 7.19 - 7.35 (m, 5 H), 7.39 (dd, 7=11.28, 6.29 Hz, 1 H), 11.50 - 12.73 (m, 2 H); MS (ESI+) m/z 1105 (M+H)⁺; MS (ESI-) m/z 1103 (M-H)’.

2016238925 07 Oct 2016

Example 4.27 methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-[4-(4-tert-butylpiperidin-l-yl)-3,5-difluorophenyl]-5-{6-fluoro2-[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl }pyrrolidin-2-yl] -1 H-bcnzi midazol-5 yl}pyrrolidin-2-yl] -6-fluoro-1 H-benzimidazol-2-yl {pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl{ carbamate 'HNMR (400 MHz, DMSO-d₆) δ ppm 0.69 - 0.76 (m, 4 H), 0.76 - 0.91 (m, 17 H), 1.13 - 1.27 (m, 3

H), 1.55 (d, 7=11.39 Hz, 2 H), 1.67 - 2.09 (m, 9 H), 2.11 - 2.26 (m, 4 H), 2.72 - 2.94 (m, 4 H), 3.503.57 (m, 6 H), 3.62 - 3.86 (m, 5 H), 3.99 - 4.11 (m, 2 H), 5.03 - 5.17 (m, 2 H), 5.46 - 5.63 (m, 2 H), 5.87 (dd, 7=12.52, 7.21 Hz, 2 H), 7.03 (d, 7=6.40 Hz, 1 H), 7.13 (d, 7=6.94 Hz, 1 H), 7.25 - 7.37 (m, 3 H), 7.40 (dd, 7=11.17, 6.29 Hz, 1 H), 11.67 - 12.63 (m, 2 H); MS (ESI+) m/z 1043 (M+H)⁺; MS (ESI) m/z 1041 (M-H)’.

343

2016238925 07 Oct 2016

Example 4.28 dimethyl ({(2R,5R)-l-[4-(4-tert-butylpiperidin-l-yl)-3,5-difluorophenyl]pyrrolidine-2,5-diyl}bis{(6fluoro-1 H-benzimidazole-5,2-diyl) (2.S) pyrrol idi nc-2.1 -diyl [(IS)-1 -cyclopentyl-2-oxoethane-2,1 5 diyl]} [biscarbamate ‘HNMR (400 MHz, DMSO-d₆) δ ppm 0.80 (s, 9 H), 1.08 - 1.63 (m, 24 H), 1.65 - 1.87 (m, 3 H), 1.92

- 2.25 (m, 10 H), 2.37 - 2.45 (m, 1 H), 2.73 - 2.93 (m, 4 H), 3.60 - 3.91 (m, 4 H), 4.13 (t, 7=8.24 Hz, 2 H), 5.11 (d, 7=6.83 Hz, 2 H), 5.45 - 5.63 (m, 2 H), 5.80 - 5.97 (m, 2 H), 6.95 - 7.08 (m, 1 H), 7.13 (d, 7=6.61 Hz, 1 H), 7.34 (dd, 7=10.25, 3.74 Hz, 1 H), 7.37 - 7.46 (m, 3 H), 11.73 - 12.50 (m, 2 H); MS 0 (ESI+) m/z 1095 (M+H)⁺; MS (ESI-) m/z 1093 (M-H)’.

Example 4.29 methyl {(2S,3R)-3-tert-butoxy-l-[(2S)-2-(5-{(2R,5R)-5-{2-[(2S)-l-{(2S,3R)-3-tert-butoxy-215 [(mcthoxycarbonyl )amino]butanoyl }pyrrolidin-2-yl ]-6-fluoro-1 H-benzimidazol-5-yl }-l-[A-(4-tertbutylpiperidin-1 -yl)-3,5-difluorophenyl ]pyrrolidin-2-yl }-6-fluoro-lH-benzimidazol-2-yl)pyrrolidin-l yl] -1 -oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, DMSO-7,) δ ppm 0.82 (d, 7=14.64 Hz, 13 H), 0.88 - 0.96 (m, 4 H), 1.02 (s, 7 H),

1.12 (d, 7=33.83 Hz, 11 H), 1.49-2.31 (m, 9 H), 2.69 - 2.93 (m, 4H), 3.27 (s, 1 H), 3.50 - 3.57 (m, 6

H), 3.64 - 3.94 (m, 9 H), 4.03 - 4.31 (m, 3 H), 5.06 - 5.23 (m, 1 H), 5.38 - 5.69 (m, 2 H), 5.78 - 5.95

344 (m, 2 H), 6.46 - 6.63 (m, 1 H), 6.70 - 6.87 (m, 1 H), 6.92 - 7.04 (m, 1 H), 7.08 - 7.29 (m, 1 H), 7.34 (dd, 7=10.63, 1.84 Hz, 1 H), 7.38 - 7.55 (m, 1 H), 11.40 - 12.88 (m, 2 H); MS (ESI+) m/z 1159 (M+H)⁺.

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ABS

Example 4.30 methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-{3,5-difluoro-4-[4-(2-naphthyl)piperidin-l-yl]phenyl}-5-{6fluoro -2 -[(25) -1 - {(25)-2- [(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] -\Hbenzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 0 oxobutan-2-yl} carbamate ‘HNMR (400 MHz, DMSO-7₆) δ ppm 0.73 (d, J=6.51 Hz, 4 H), 0.76 - 0.85 (m, 8 H), 1.19 - 1.32 (m,

H), 1.69 - 2.08 (m, 12 H), 2.11 - 2.25 (m, 3 H), 2.67 - 2.78 (m, 1 H), 2.92 - 3.18 (m, 5 H), 3.52 (d,

7=1.19 Hz, 6 H), 3.72 - 3.87 (m, 4 H), 3.99 - 4.11 (m, 2 H), 5.06 - 5.19 (m, 2 H), 5.49 - 5.67 (m, 2 H),

5.83 - 6.00 (m, 2 H), 7.01 - 7.09 (m, 1 H), 7.16 (d, 7=7.05 Hz, 1 H), 7.25 - 7.37 (m, 3 H), 7.38 - 7.53 (m, 4 H), 7.68 - 7.93 (m, 4 H), 11.88 - 12.65 (m, 2 H); MS (ESI+) m/z 1113 (M+H)⁺; MS (ESI-) m/z

1111 (M-H)’.

ABS

Example 4.31

345 methyl {(25)-1-| (25)-2-{5-| (2//.5//)-1-|4-(2.3-dihydro-1'E/-spiro| indene-1.4'-pipcridin|-1'-yl)-3.5difluorophenyl] -5 - { 6 -fluoro-2- [(25) -1 - { (25)-2-[(methoxycarbonyl)amino] -3 methylbutanoyl} pyrrolidin-2-yl] -1 H-be nzi m i dazol-5 -yl} pyrrolidin-2 -yl] -6 -fluoro-1 H-be nzi m i dazol 2-yl [pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, CDC1₃) δ ppm 10.53-10.63 (m, 1H) 10.31-10.41 (m, 1H) 7.43-7.52 (m, 1H) 7.307.40 (m, 1H) 7.10-7.25 (m, 5H) 6.92-7.00 (m, 1H) 5.86 (d, 2H) 5.23-5.51 (m, 6H) 4.26-4.40 (m, 2H) 3.77-3.91 (m, 2H) 3.68-3.72 (m, 6H) 3.56-3.66 (m, 2H) 2.83-3.26 (m, 8H) 1.81-2.61 (m, 16H) 0.711.10 (m, 12H); MS (ESI) m/z 1089 (M+H)⁺.

2016238925 07 Oct 2016

Example 4.32 methyl {(25)-l-[(25)-2-{5-[(2//,5//)-l-[3,5-difluoro-4-(3-phenylpiperidin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-l//-benzimidazol-6yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-7,) δ ppm 12.07 (s, 1 H), 12.01 (s, 1 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.38 (m, 2 H), 7.20 (s, 8 H), 7.09 (m, 2 H), 5.90 (d, J = 12.9 Hz, 2 H), 5.36 (d, J = 7.5 Hz, 2 H), 5.14 (s, 2

H), 4.05 (t, J = 8.1 Hz, 2 H), 3.81 (s, 4 H), 3.54 (s, 6 H), 2.85 (s, 4 H), 2.18 (s, 5 H), 1.94 (m, 7 H),

1.61 (m, 5 H), 0.77 (m, 12 H); MS (ESI+) m/z (rel abundance) 1027 (100, M+H)⁺.

346

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ABS

Example 4.33 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(3-phenylpyrrolidin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-127-benzimidazol-65 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'H NMR (400 MHz, DMSO-®,) δ ppm 12.09 (d, J = 14.8 Hz, 2 H), 7.47 (m, 2 H), 7.45 (m, 2 H), 7.24 (m, 8 H), 7.08 (s, 2 H), 5.93 (d, J = 12.1 Hz, 2 H), 5.38 (s, 2 H), 5.15 (s, 2 H), 4.06 (t, J = 8.4 Hz, 2 H), 3.82 (s, 4 H), 3.53 (s, 6 H), 3.13 (m, 4 H), 2.19 (s, 4 H), 1.90 (m, 6 H), 1.70 (s, 2 H), 0.80 (m, 12 H); MS (ESI+) m/z (rel abundance) 1013 (100, M+H)⁺, 1014 (58).

4BS

Nd

Example 4.34 methyl [(25)-1-|(25')-2-{6-| (2//.5//)-1-{3.5-difluoro-4-|4-(4-mcthoxyphcnyl)pipcridin-1-yl|phcnyl[5 - { 2- [(25) -1 - { (25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] -1/715 benzimidazol-6-yl}pyrrolidin-2-yl]-1 //-bcnzimidazol-2-yl [pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2yl} carbamate 'H NMR (400 MHz, DMSO-®,) δ ppm 0.97 - 0.69 (m, 12H), 1.24 (s, 1H), 1.78 - 1.50 (m, 6H), 2.10 1.85 (m, 7H), 2.19 (s, 4H), 2.47 - 2.38 (m, 1H), 3.03 - 2.80 (m, 4H), 3.53 (s, 6H), 3.69 (s, 3H), 3.82 (s,

4H), 4.17 - 3.93 (m, 2H), 5.22 - 5.08 (m, 2H), 5.45 - 5.29 (m, 2H), 5.91 (d, J = 12.8, 2H), 6.81 (d, J =

347

8.7, 2H), 7.17 - 7.02 (m, 4H), 7.21 (s, 1H), 7.34 - 7.26 (m, 3H), 7.41 (d, J = 8.2, 1H), 7.50 (d, J = 8.2,

1H), 12.17 (dd, J = 19.9, 74.7, 2H); MS (ESI) m/z 1057 (M+H)⁺, 1055 (M-H)⁺.

ABS

2016238925 07 Oct 2016

Example 4.35 methyl {(25)-l-[(25)-2-{6-[(2R,5R)-l-[3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-l-yl)phenyl]-5-{2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-bcnzi midazol -6yl} pyrrolidin-2-yl] -1 H-bc nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO®) δ ppm 0.91 - 0.75 (m, 12H), 2.11 - 1.60 (m, 12H), 2.28 - 2.12 (m, 4H), 2.55 (d, J = 5.5, 2H), 2.84 - 2.71 (m, 2H), 3.28 - 3.06 (m, 2H), 3.53 (s, 6H), 3.83 (s, 4H), 4.11 0 3.99 (m, 2H), 5.19 - 5.09 (m, 2H), 5.45 - 5.30 (m, 2H), 5.94 (d, J = 12.8, 2H), 7.13 - 7.05 (m, 2H),

7.45 - 7.18 (m, 10H), 7.50 (d, J = 8.3, 1H), 12.11 (d, J = 15.2, 2H); MS (ESI) m/z 1045 (M+H)⁺, 1043 (M-H)⁺.

ABS

Example 4.36 methyl {(25)-l-[(25)-2-{6-[(2R,5R)-l-[4-(4-fluoro-4-phenylpiperidin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6yl} pyrrolidin-2-yl] -1 H-bc nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

348

Ή NMR (400 MHz, DMSO® δ ppm 0.92 - 0.74 (m, 12H), 1.23 (d, J = 3.9, 1H), 1.69 (d, J = 3.6,

2H), 2.09 - 1.80 (m, 9H), 2.26 - 2.09 (m, 5H), 2.81 - 2.69 (m, 2H), 3.26 - 3.10 (m, 3H), 3.53 (s, 6H),

3.89 - 3.74 (m, 4H), 4.05 (t, J = 8.4, 2H), 5.18 - 5.06 (m, 2H), 5.34 (d, J = 4.5, 2H), 6.27 (d, J = 8.7,

2H), 6.65 (dt, J = 4.2, 8.6, 2H), 7.06 (t, J = 7.8, 2H), 7.21 (s, 1H), 7.43 - 7.26 (m, 9H), 7.45 (d, J = 8.2,

1H), 12.04 (s, 2H); MS (ESI) m/z 1009 (M+H)⁺, 1007 (M-H)⁺.

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ABS

F F

Example 4.37 methyl {(25)-1 -| (25)-2-( 5-| (2//.57/)-1 -(3,5-difluoro-4-{4-[fluoro(diphenyl)methyl]piperidin-l0 yl}phenyl)-5-{6-fluoro-2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2yl] - 177-benzimidazol -5 -yl} pyrrolidin-2 -yl] -6 -fluoro-17/-bc nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl 1 -oxobutan-2 -yl} carbamate 'HNMR (400 MHz, methanol® δ ppm 0.99 - 0.69 (m, 12H), 1.42 - 1.26 (m, 3H), 1.55 (dd, J = 12.0,

24.4, 2H), 2.42 - 1.85 (m, 12H), 2.62 - 2.43 (m, 3H), 3.01 - 2.74 (m, 4H), 3.63 (s, 6H), 3.90 - 3.77 (m,

2H), 4.05 - 3.90 (m, 2H), 4.20 (d, J = 7.4, 1H), 5.24 - 5.08 (m, 2H), 5.52 (t, J = 5.8, 2H), 5.92 - 5.72 (m, 2H), 7.07 (s, 1H), 7.18 (t, J = 7.3, 2H), 7.29 (t, J = 7.5, 6H), 7.33 (s, 1H), 7.43 (d, J = 7.3, 4H); MS (ESI) m/z 1171 (M+H)⁺.

Example 4.38 methyl {(2S,37/)-l-[(25)-2-{5-[(27/,57/)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-(6fluoro-2-{(25)-l-[3V-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-17/-benzimidazol-520

349 yl)pyrrolidin-2-yl] -6-fluoro-1 H-bcnzi midazol-2-yl [pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2yl} carbamate 'HNMR (400 MHz, DMSO-7₆) δ ppm 0.92 (d, J = 5.5, 2H), 1.04 (dd, J = 5.8, 12.0, 4H), 1.68 (s, 4H),

1.80 (s, 2H), 2.09 - 1.91 (m, 4H), 2.27 - 2.10 (m, 4H), 3.01 - 2.82 (m, 3H), 3.03 (s, 4H), 3.13 (s, 4H),

3.25 (s, 2H), 3.44 (dd, J = 6.5, 12.8, 3H), 3.53 (s, 6H), 3.81 (s, 3H), 4.31 - 4.14 (m, 2H), 5.17 - 5.02 (m, 2H), 5.66 - 5.41 (m, 2H), 5.97 - 5.80 (m, 2H), 7.13 - 6.99 (m, 2H), 7.19 - 7.13 (m, 2H), 7.31 - 7.19 (m, 5H), 7.38 (dd, J = 9.8, 26.3, 2H), 12.39 - 12.01 (m, 2H); MS (ESI) m/z 1095 (M+H)⁺, 1093 (ΜΗ).

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ABS

Example 4.39 dimethyl ({(2R,5R)-1 -[3,5 -difluoro-4-(4-phenylpiperidin-1 -yl)phenyl]pyrrolidine-2,5 -diyl}bis {(6fluoro-IA/-bcnzimidazolc-5.2-diyl)(25)pyrrolidinc-2. l-diyl|( 15)-2 -oxo-1 -(tetrahydro-2H-pyran -4yl)ethane-2,1-diyl] })biscarbamate 'HNMR (400 MHz, DMSO-7₆) δ ppm 1.37 - 1.07 (m, 6H), 1.56 - 1.36 (m, 4H), 1.73 - 1.60 (m, 4H), 1.78 (s, 4H), 2.06 - 1.93 (m, 4H), 2.26 - 2.06 (m, 4H), 3.26 - 2.81 (m, 8H), 3.52 (s, 6H), 3.91 - 3.60 (m, 8H), 4.12 (dd, J = 6.9, 15.8, 2H), 5.11 (s, 2H), 5.54 (d, J = 10.0, 2H), 5.99 - 5.81 (m, 2H), 7.05 (dd, J = 6.3, 23.5, 2H), 7.16 (t, J = 6.9, 1H), 7.31 - 7.20 (m, 5H), 7.45 - 7.30 (m, 4H), 12.23 (d, J = 83.3, 2H); MS (ESI) m/z 1147 (M+H)⁺.

ABS

F F

Example 4.40

350 dimethyl ({(2R,5R)-1 -[3,5-difluoro-4-(4-phenylpiperidin-1 -yl)phenyl]pyrrolidine-2,5-diyl}bis{(6fluoro-1 //-benzimidazole-? ,2-diyl)(2,S')py rrolidinc-2.1 -diyl[(IS)-1 -cyclopentyl-2-oxoethane-2,1 diyl] })biscarbamate 'H NMR (400 MHz, DMSO-fo) δ ppm 1.61 - 1.10 (m, 18H), 1.67 (s, 4H), 1.90 - 1.72 (m, 2H), 2.13 5 1.93 (m, 6H), 2.18 (s, 4H), 3.08 - 2.86 (m, 4H), 3.17 (d, J = 5.1, 1H), 3.52 (s, 6H), 3.89 - 3.70 (m,

4H), 4.20 - 4.01 (m, 2H), 5.11 (s, 2H), 5.56 (d, J = 21.5, 2H), 5.96 - 5.83 (m, 2H), 7.04 (d, J = 6.7, 1H), 7.16 (t, J = 7.0, 2H), 7.31 - 7.20 (m, 4H), 7.39 (dt, J = 8.1, 25.5, 4H), 12.16 (d, J = 61.1, 2H); MS (ESI) m/z 1115 (M+H)⁺, 1113 (M-H)⁺.

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ABS

Example 4.41 methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[4-(benzyloxy)phenyl]-5-{2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl |-l//-bcnzimidazol-5-yl }pyrrolidin-2yl]-1 //-bcnzimidazol-2-yl}pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 12.02 (s, 2H), 7.28 (m, 13H), 6.60 (m, 2H), 6.23 (m, 2H), 5.33 (m, 2H), 5.14 (m, 2H), 4.90 (m, 2H), 3.81 (m, 4H), 3.56 (s, 6H), 2.20 (m, 6H), 1.98 (m, 6H), 1.70 (m, 2H), 0.86 (m, 12H); MS (ESI) m/z 938 (M+H)⁺.

351

Example 4.42 methyl {(25)-l-[(25)-2-{5-[(27/,57/)-1-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-lyl}phenyl)-5-{6-fluoro-2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2yl] -1 H-bcnzi midazol -5 -yl}pyrrolidin-2-yl] -6-fluoro-1 H-benzimidazol-2-yl}pyrrolidin-1 -yl] -3 -methyl 5 l-oxobutan-2-yl} carbamate 'H NMR (400 MHz, DMSO-r/₆) δ ppm 7.55 (m, 2H), 7.48 (d, J=8.8Hz, 2H), 7.34 (m, 2H), 7.18 (m, 2H), 7.04 (d, J=7.8Hz, 2H), 5.99 (m, 2H), 5.63 (m, 2H), 5.13 (m, 2H), 4.06 (m, 2H), 3.80 (m, 2H), 3.53 (s, 6H), 3.25 (m, 8H), 2.99 (m, 4H), 2.05 (m, 12H), 0.81 (m, 12H); MS (ESI) m/z 1132 (M+H)⁺.

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Example 4.43 methyl {(25)-l-[(25)-2-{6-[(27/,57/)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{5-fluoro-2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-17/-benzimidazol-6yl}pyrrolidin-2-yl] -17/-bcnzi midazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate ‘HNMR (400 MHz, DMSO-<7₆) δ ppm 0.68 - 0.89 (m, 12 H) 1.34 - 1.50 (m, 6 H) 1.65 - 2.06 (m, 9 H)

2.12 - 2.24 (m, 4 H) 2.70 - 2.82 (m, 4 H) 3.52 (d, J=2.49 Hz, 6 H) 3.73 - 3.86 (m, 4 H) 3.99 - 4.08 (m,

H) 5.06 - 5.19 (m, 2 H) 5.26 - 5.43 (m, 1 H) 5.46 - 5.56 (m, 1 H) 5.86 (d, 1=12.04 Hz, 2 H) 6.98 (d,

J=6.51 Hz, 1 H) 7.02 - 7.11 (m, 1 H) 7.21 (d, J=6.94 Hz, 1 H) 7.26 - 7.35 (m, 2 H) 7.39 (d, J=8.35 Hz,

H) 7.45 - 7.51 (m, 1 H) 12.01 - 12.26 (m, 2 H); MS (ESI+) m/z 969 (M+H)⁺.

352

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Example 4.44 methyl {(25)-l-[(25)-2-{6-[(2R,5R)-l-[4-(4-benzylpiperidin-l-yl)-3,5-difluorophenyl]-5-{5-fluoro-2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] - I H-bcnzi midazol -65 yl}pyrrolidin-2-yl] -5 -fluoro-1 H-benzimidazol-2-yl [pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl[ carbamate

Ή NMR (400 MHz, DMSO-J₆) δ ppm 0.67 - 0.88 (m, 12 Η) 1.22 (s, 12 Η) 1.42 - 1.51 (m, 5 Η) 1.73 2.04 (m, 12 H) 2.12 - 2.21 (m, 4 H) 2.72 - 2.81 (m, 5 H) 3.48 - 3.54 (m, 6 H) 3.72 - 3.83 (m, 3 H) 3.97

- 4.06 (m, 2 H) 5.05 - 5.13 (m, 2 H) 5.46 - 5.58 (m, 2 H) 5.79 - 5.89 (m, 2 H) 6.99 - 7.04 (m, 1 H) 7.09

- 7.16 (m, 5 H) 7.20 - 7.34 (m, 6 H) 7.35 - 7.42 (m, 1 H) 7.51 - 7.64 (m, 3 H) 12.10 (s, 1 H) 12.23 (s, 1

H); MS (ESI+) m/z 1077 (M+H)⁺.

Example 4.45 dimethyl ([(2R,5R)-1 -(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1 yl[phenyl)pyrrolidine-2,5-diyl]bis{(5-fluoro-lH-benzimidazole-6,2-diyl)(25)pyrrolidine-2,l diyl [(15)-1 -cyclopentyl-2-oxoethane-2,1 -diyl]} [biscarbamate

353 'H NMR (400 MHz, DMSO-7,) δ ppm 1.09 - 1.64 (m, 18 H) 1.71 - 1.86 (m, 2 H) 1.92 - 2.23 (m, 10

H) 2.91 - 3.03 (m, 5 H) 3.22 - 3.30 (m, 4 H) 3.52 (s, 6 H) 3.71 - 3.87 (m, 4 H) 4.12 (t, J=8.40 Hz, 2 H)

5.05 - 5.16 (m, 2 H) 5.48 - 5.65 (m, 2 H) 5.85 - 5.99 (m, 2 H) 7.03 (d, J=8.89 Hz, 3 H) 7.14 (d, J=6.29

2016238925 07 Oct 2016

Hz, 1 H) 7.30 - 7.38 (m, 1 H) 7.40 (d, J=9.54 Hz, 2 H) 7.46 (d, J=8.67 Hz, 2 H) 12.08 (s, 1 H) 12.20 (s, 1 H); MS (ESI+) m/z 1184 (M+H)⁺.

Example 4.46 dimethyl ([(2R,5R)-1 -(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-1 yl}phenyl)pyrrolidine-2,5-diyl]bis{(5-fluoro-lH-benzimidazole-6,2-diyl)(2S)pyrrolidine-2,l0 diyl [(1 .S') -2 -oxo-1 -(tetrahydro-2H-pyran-4-yl)ethane-2,1 -diyl]} )biscarbamate

Ή NMR (400 MHz, DMSO-%) δ ppm 1.09 - 1.33 (m, 4 H) 1.38 - 1.54 (m, 4 H) 1.70 - 1.88 (m, 4 H)

1.92 - 2.05 (m, 4 H) 2.10 - 2.25 (m, 3 H) 2.95 - 3.03 (m, 4 H) 3.03 - 3.20 (m, 3 H) 3.21 - 3.29 (m, 4 H)

3.51 (s, 6 H) 3.62 - 3.89 (m, 6 H) 4.05 - 4.17 (m, 2 H) 5.06 - 5.15 (m, 2 H) 5.48 - 5.64 (m, 2 H) 5.83 5.98 (m, 2 H) 7.03 (d, J=8.67 Hz, 3 H) 7.07 (d, J=6.29 Hz, 1 H) 7.29 - 7.42 (m, 3 H) 7.46 (d, J=8.78 15 Hz, 2H) 12.11 (s, 1 H) 12.32 (s, 1 H); MS (ESI+) m/z 1216 (M+H)⁺.

Example 4.47

354 methyl {(25)-l-[(25)-2-{6-[(2R,5R)-l-[4-(4-benzylpiperidin-l-yl)-3,5-difluorophenyl]-5-{2-[(25)-l{(25)-2-|(mcthoxycarbonyl)amino|-3-mcthylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-6yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate ‘HNMR (400 MHz, DMSO-7₆) δ ppm 12.07 (d, J = 19.1, 2H), 7.48 (d, J = 8.3, 2H), 7.40 (d, J = 8.1,

2H), 7.34 - 7.10 (m, 8H), 7.07 (s, 2H), 5.87 (d, J = 12.3, 2H), 5.35 (s, 2H), 5.14 (s, 1H), 3.78 (d, J =

28.9, 2H), 3.54 (s, 6H), 2.76 (s, 3H), 2.19 (s, 4H), 2.07 - 1.80 (m, 6H), 1.68 (s, 2H), 1.46 (d, J = 10.4, 3H), 1.25 - 1.08 (m, 2H), 0.92 - 0.71 (m, 12H); MS (ESI+) m/z 1041.4 (M+H)⁺, (ESI-) m/z 1039.3 (M-H)’.

2016238925 07 Oct 2016

Example 4.48 methyl {(25)-1-[(25)-2-{5-[(2S,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate ^XH NMR (400 MHz, DMSO-7₆) δ ppm 0.76 - 0.94 (m, 12 H), 1.60 -2.30 (m, 14 H), 2.88 - 3.09 (m, 4 H), 3.54 (s, 6 H), 3.84 (s, 3 H), 4.02 - 4.15 (m, 7=8.1, 8.1 Hz, 2 H), 4.77 - 4.97 (m, 2 H), 5.17 (d, 7=2.9 Hz, 2 H), 5.95 - 6.10 (m, 2 H), 7.08 - 7.70 (m, 13 H), 12.09 - 12.23 (m, 2 H).

355

2016238925 07 Oct 2016

Example 4.49 methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(2-phenylmorpholin-4-yl)phenyl]-5-{2-[(2S)-l{(2.S')-2-|(mcthoxycarbonyl)amino|-3-mcthylbutanoyl }pyrrolidin-2-yl ]-127-benzimidazol-5yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-A) δ ppm 0.69 -0.92 (m, 12 H), 1.69 (d, 7=5.1 Hz, 2 H), 1.82 -2.30 (m, 12 H), 2.70 - 3.16 (m, 7=63.6 Hz, 6 H), 3.54 (s, 6 H), 3.81 (s, 3 H), 3.99 - 4.12 (m, 2 H), 4.47 (dd, 7=9.1, 3.7 Hz, 1 H), 5.08 - 5.19 (m, 2 H), 5.29 - 5.48 (m, 2 H), 5.92 (d, 7=13.4 Hz, 2 H), 7.07 (t, 7=7.9 Hz, 2 H), 7.16 - 7.35 (m, 7=0.8 Hz, 10 H), 7.40 (d, 7=8.1 Hz, 1 H), 7.49 (d, 7=8.3 Hz, 1 H), 12.06 (s, 1 H), 12.11 (s, 1 H); MS (APCI+) m/z 1030.1(M+H).

methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(2-phenylpiperidin-l-yl)phenyl]-5-{2-[(2S)-l{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-127-benzimidazol-55 yl}pyrrolidin-2-yl] -1 H-bcnzi midazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-A) δ ppm 0.81 - 1.01 (m, 12 H), 1.24 - 2.35 (m, 22 H), 3.60 (s, 6 H),

3.89 (s, 4 H), 3.94 - 4.20 (m, 3 H), 5.22 (s, 2 H), 5.30 (d, 7=4.3 Hz, 2 H), 5.73 (dd, 7=13.1, 3.6 Hz, 2 H), 6.92 - 7.44 (m, 13 H), 7.48 (d, 7=8.1 Hz, 1 H), 12.08 (s, 1 H), 12.17 (s, 1 H); MS (APCI+) m/z 1028.2 (M+H)⁺.

ABS

Example 4.51

356

2016238925 07 Oct 2016 methyl [(25)-1-{(25)-2-[5-(1-{4-[(2Λ,65)-2,6-dimethylmorpholin-4-yl]-3,5-difluorophenyl}-5-{6fluoro -2 -[(25) -1 - {(25)-2- [(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] - \Hbenzimidazol -5 -yl} pyrrolidin-2-yl) -6 -fluoro-1 H-benzi m i dazol -2 -yl] pyrrolidin-1 -yl} -3 -methyl-1 oxobutan-2-yl]carbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 0.67 -0.90 (m, 12 H), 0.96 (s, 6 H), 1.01-1.31 (m, 2 H), 1.68 - 2.25 (m, 12 H), 3.51 (s, 6 H), 3.78 (s, 3 H), 4.01 (q, 7=7.2 Hz, 2 H), 5.10 (d, 7=4.8 Hz, 2 H), 5.43 5.65 (m, 2 H), 5.79 - 5.97 (m, 2 H), 7.02 (d, 7=5.3 Hz, 1 H), 7.11 (d, 7=6.8 Hz, 1 H), 7.21 - 7.46 (m, 4 H), 12.11 (s, 1 H), 12.24 (s, 1 H); MS (ESI) m/z 1017.4 (M+H)⁺.

Example 4.52 methyl {(25)-l-[(25)-2-{5-[(2S,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{6-fluoro-2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5yl}pyrrolidin-2-yl] -6-fluoro-1 H-benzimidazol-2-yl (pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-25 yl} carbamate 'HNMR (400 MHz, DMSO-7₆) δ ppm 0.72 - 0.94 (m, 7=10.5, 10.5 Hz, 12 H), 1.36 - 1.58 (m, 6 H),

1.77 - 2.28 (m, 14 H), 2.83 (s, 4 H), 3.53 (s, 6 H), 3.82 (s, 4 H), 3.97 - 4.14 (m, 2 H), 4.92 - 5.07 (m, 2

H), 5.09 - 5.20 (m, 2 H), 5.83 - 6.02 (m, 2 H), 7.21 - 7.79 (m, 6 H), 12.14 - 12.44 (m, 2 H); MS (APCI+) m/z 987.8 (M+H)⁺.

Example 4.53

357

2016238925 07 Oct 2016 methyl {(25)-1 -[(25)-2-{5-[(2R,5R)-l-[4-(3-azaspiro[5.5]undec-3-yl)-3,5-difluorophenyl]-5-{6fluoro -2 -[(25) -1 - {(25)-2- [(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] - \Hbenzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-benzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate 'H NMR (400 MHz, DMSO-7₆) δ ppm 0.64 - 0.94 (m, 12 H), 1.21 - 1.44 (m, 16 H), 1.68 - 2.25 (m, 7=78.0 Hz, 12 H), 2.78 (s, 4 H), 3.53 (s, 6 H), 3.80 (s, 4 H), 4.04 (t, 7=7.1 Hz, 2 H), 5.11 (s, 2 H), 5.55 (dd, 7=19.8, 4.2 Hz, 2 H), 5.79 - 5.99 (m, 2 H), 7.03 (d, 7=6.0 Hz, 1 H), 7.13 (d, 7=6.5 Hz, 1 H), 7.24 -

7.48 (m, 4 H), 12.12 (s, 1 H), 12.24 (s, 1 H); MS (ESI) m/z 1055.4 (M+H)⁺.

ABS

Example 4.54 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-[4-(4-cyclohexylpiperidin-l-yl)-3,5-difluorophenyl]-5-{6fluoro -2 -[(25) -1 - {(25)-2- [(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] - \Hbenzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 5 oxobutan-2-yl} carbamate 'H NMR (400 MHz, DMSO-7₆) δ ppm 0.65 - 0.97 (m, 12 H), 0.98 - 1.33 (m, 10 H), 1.50 - 2.25 (m,

H), 2.72 - 2.91 (m, 4 H), 3.53 (s, 6 H), 3.79 (s, 4 H), 4.04 (t, 7=8.1 Hz, 2 H), 5.11 (s, 2 H), 5.54 (dd, 7=14.7, 6.7 Hz, 2 H), 5.79 - 5.97 (m, 2 H), 7.03 (d, 7=6.7 Hz, 1 H), 7.13 (d, 7=6.9 Hz, 1 H), 7.24 7.46 (m, 4 H), 12.11 (s, 1 H), 12.23 (s, 1 H); MS (ESI+) m/z 1069.5 (M+H)⁺.

358

2016238925 07 Oct 2016

ABS

Example 4.55 methyl {(25)-l-[(25)-2-{5-[(2//,5//)-l-{3,5-difluoro-4-[(25)-2-phenylmorpholin-4-yl]phenyl}-5-{6fluoro -2 -[(25) -1 - {(25)-2- [(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] - \H5 benzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, DMSOY) δ ppm 0.60 - 0.95 (m, 12 H), 1.64 - 2.08 (m, 10 H), 2.09 - 2.25 (m, 4

H), 2.70 - 3.18 (m, 4 H), 3.53 (s, 6 H), 3.64 - 3.86 (m, 4 H), 3.91 (d, 7=11.4 Hz, 1 H), 4.03 (t, 7=8.2

Hz, 2 H), 4.48 (d, 7=7.5 Hz, 1 H), 5.10 (s, 2 H), 5.43 - 5.69 (m, 2 H), 5.80 - 6.03 (m, 2 H), 7.03 (d, 0 7=6.8 Hz, 1 H), 7.14 (d, 7=6.7 Hz, 1 H), 7.20 - 7.45 (m, 10 H), 12.10 (s, 1 H), 12.24 (s, 1 H); MS (ESI+) m/z 1065.4 (M+H)⁺.

Example 4.56 methyl [(25)-1-| (25)-2-[5-| (2//.5//)-1-{4-| 4-(2.4-difliiorophcnyl)pipcridin-1-yl|-3.5-difluorophcnyl[5-{6-fluoro-2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-l/7benzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 /7-benzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, DMSOY) δ ppm 0.68 - 0.92 (m, 14 H), 1.58 - 2.08 (m, 11 H), 2.09 - 2.27 (m, 4 20 H), 2.71 - 3.14 (m, 6 H), 3.52 (s, 6 H), 3.68 - 3.89 (m, 4 H), 3.98 - 4.10 (m, 2 H), 5.05 - 5.17 (m, 2 H),

5.48 - 5.68 (m, 2 H), 5.83 - 5.99 (m, 2 H), 6.95 - 7.08 (m, 2 H), 7.09 - 7.21 (m, 2 H), 7.25 - 7.46 (m, 5 H), 12.06 - 12.39 (m, 2 H); MS (ESI+) m/z 1099.3 (M+H)⁺.

359

2016238925 07 Oct 2016

Example 4.57 methyl {(25)-1 -|(25)-2-{5-|(2/?.5/?)-l-{3.5-difliioro-4-|4-(4-fliiorophcnyl)pipcridin-l-yl|phcnyl[-55 {6-fluoro-2-[(25)-1 -{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-\Hbenzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-benzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, DMSO-ty,) δ ppm 0.67 - 0.93 (m, 14 H), 1.53 - 2.09 (m, 11 H), 2.10 - 2.25 (m, 4

H), 2.83 - 3.15 (m, 6 H), 3.53 (s, 6 H), 3.69 - 3.88 (m, 4 H), 3.98 - 4.10 (m, 2 H), 5.05 - 5.17 (m, 2 H), 0 5.48 - 5.67 (m, 2 H), 5.83 - 5.99 (m, 2 H), 6.99 - 7.20 (m, 4 H), 7.22 - 7.47 (m, 6 H), 12.02 - 12.47 (m,

H); MS (ESI+) m/z 1081.4 (M+H)⁺.

ABS

Example 4.58 methyl {(25)-1-[(25)-2-{5-[(27?,57?)-l-[3,5-difluoro-4-(4-phenylpiperazin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-5yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'H NMR (400 MHz, DMSO-d₆) δ ppm 0.72 - 0.95 (m, 12 H) 1.69 (s, 1 H) 1.84 - 2.11 (m, 2 H) 2.20 (s, 4 H) 2.97 (s, 4 H) 3.09 (s, 4 H) 3.54 (s, 6 H) 3.82 (s, 4 H) 4.03 (q, J=7.05 Hz, 6 H) 5.15 (s, 2 H)

5.39 (s, 2 H) 5.95 (s, 2 H) 6.75 (s, 2 H) 6.90 (d, J=8.24 Hz, 2 H) 7.08 (t, 2 H) 7.17 (t, J=7.92 Hz, 2 H)

7.30 (s, 2 H) 7.48 (s, 2 H) 7.66 (s, 2 H) 7.92 (s, 2 H) 12.09 (s, 2 H); MS (ESI+) m/z 1028.4, (ESI-) m/z

1026.4 (M-H)’.

360

2016238925 07 Oct 2016

Example 4.59 methyl {(2S)-l-[(2S,47/)-2-{5-[(27/,57/)-l-[3,5-difluoro-4-(piperidm-l-yl)phenyl]-5-{2-[(2S,47/)-45 fluoro-l-{(2_lS)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-177-benzimidazol-5yl {pyrrolidin-2-yl] -177-benzi midazol-2-yl} -4-fluoropyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl{ carbamate 'H NMR (400 MHz, DMSO®) δ ppm 0.76 (m,16 H) 0.89 (m, 3 H) 1.45 (m, 5 H) 1.70 (m, 2 H) 1.85 (m, 1 H) 2.76 (d, 2 H) 3.17 (d, J=5.10 Hz, 2 H) 3.53 (s, 6 H) 3.87 - 4.13 (m, 4 H) 4.31 (m, 1 H) 5.17 0 (d, 2 H) 5.36 (m, 3 H) 5.57 (s, 1 H) 5.89 (d, 2 H) 7.09 (m, 2 H) 7.18 - 7.25 (m, 1 H) 7.29 (m, 3 H)

7.48 (m, 3 H) 12.22 (s, 2 H); MS (ESI+) m/z 987.4, (ESI-) m/z 985.2 (M-H)’.

ABS

F F

Example 4.60 methyl {(2.S')-l-|(2.S')-2-{5-|(2//.5//)-l-{3.5-difluoro-4-|4-(pyrimidin-2-yl)pipcrazin-l-yl|phcnyl{-5{6-fluoro-2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)ammo]-3-methylbutanoyl}pyrrolidm-2-yl]-177benzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-I H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, DMSO®) δ ppm 0.67 - 0.93 (m, 12 H) 1.99 (m, 16 H) 2.18 (m, 4 H) 2.87 (m, 4

H) 3.53 (s, 6H) 3.56 m, 2H) 3.74 (m, 10 H) 5.11 (m, 2 H) 5.53 (m, 2 H) 5.90 (m, 2 H) 6.60 (t, J=4.72

Hz, 1 H) 7.04 (m, 2 H) 7.32 (m, 4 H) 8.33 (d, J=4.77 Hz, 2 H) 12.14 (s, 1 H) 12.22 (s, 1H); MS (ESI+) m/z 1066.4, (ESI-) m/z 1064.1 (M-H)’.

361

2016238925 07 Oct 2016

ABS

Example 4.61 methyl {(25)-l-[(25)-2-{5-[(27?,57?)-l-{3,5-difluoro-4-[4-(5-methyl-2-thienyl)piperidin-l-yl]phenyl}5-{6-fluoro-2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lHbenzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 5 oxobutan-2-yl} carbamate

1H NMR (400 MHz, DMSO-D6) δ ppm 0.71 - 0.98 (m, 12 H), 1.49 - 2.31 (m, 18 H), 2.42 (s, 3 H), 2.87 - 3.11 (m, 7=14.1 Hz, 5 H), 3.59 (s, 6 H), 3.77 - 3.94 (m, 7=9.1 Hz, 4 H), 4.05 - 4.17 (m, 2 H), 5.08 - 5.26 (m, 2 H), 5.53 - 5.74 (m, 2 H), 5.89 - 6.05 (m, 2 H), 6.64 (d, 7=2.4 Hz, 1 H), 6.68 (d, 7=3.5 Hz, 1 H), 7.04 - 7.14 (m, 1 H), 7.16 - 7.25 (m, 1 H), 7.31 - 7.53 (m, 4 H), 12.09 - 12.23 (m, 1 H), 0 12.26 - 12.41 (m, 1 H); MS (ESI) m/z 1083.3 (M+H).

ABS

F F

Example 4.62 methyl {(25)-l-[(25)-2-{5-[(2R5R)-l-[3,5-difluoro-4-(4-fluoro-4-phenylpiperidin-l-yl)phenyl]-5-{6fluoro -2 -[(25) -1 - { (25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] - \H362 benzimidazol -5 -yl} pyrrolidin-2-yl] -6 -fluoro-1 H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate

Ή NMR (400 MHz, DMSO) δ 0.84 - 0.69 (m, 12H), 0.90 - 0.84 (m, 2H), 1.93 - 1.76 (m, 7H), 2.00 (dd, J = 6.8, 14.5, 8H), 2.23 - 2.12 (m, 5H), 3.52 (s, 6H), 3.87 - 3.73 (m, 4H), 4.08 - 3.97 (m, 2H),

5.16 - 5.06 (m, 2H), 5.65 - 5.48 (m, 2H), 5.99 - 5.86 (m, 2H), 7.06 (d, J= 6.7, 1H), 7.15 (d, J= 6.9,

1H), 7.31 (d, J= Ίβ, 3H), 7.36 (d, J= 7.7, 2H), 7.41 (t, J= 7.6, 4H), 12.19 (d, J= 44.3, 2H). MS (ESI) m/z 1081 (M+H)⁺

2016238925 07 Oct 2016

Example 5.1 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-|(mcthoxycarbonyl [amino |-3-mcthylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

In a 250 mL round-bottomed flask cooled in an ice bath was added (5)-6,6'-((2R,5R)-l-(3,5 difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-lHbenzo[</]imidazole) (2.57 mmol), (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.945 g, 5.40 mmol) and lH-benzo[</][ 1,2,3]triazol-l-ol hydrate (0.984 g, 6.43 mmol) in DMF (25 mL) to give an orange solution. 4-Methylmorpholine (2.83 mL, 25.7 mmol) and ^-((ethyliminojmethylene)Ν³0-dimethylpropane-1,3-diamine hydrochloride (1.232 g, 6.43 mmol) were added, and the mixture 20 was stirred at ambient temperature for 2 hours and then diluted into EtOAc. The EtOAc layer was washed with aqueous saturated NaHCO₃, H₂O, and saturated NaCl. The organic layer was treated with 3-mercaptopropyl silica for 1 hour, dried (Na₂SO₄), filtered and concentrated to a yellow foam (2.74 g). Purification by flash chromatography on a 120 g silica cartridge eluting with 2-5% methanol in dichloromethane afforded 1.7 g (61%) of the title compound as a yellow powder. The title 25 compound can additionally be purified by recrystallization from acetonitrile. 'H NMR (400 MHz,

DMSO-J₆) δ ppm 0.73 - 0.91 (m, 12 H) 1.60 - 1.74 (m, 6 H) 1.86 - 2.04 (m, 6 H) 2.17 - 2.30 (m, 4 H)

2.52 - 2.53 (m, 4 H) 2.84 - 3.02 (m, 4 H) 3.52 - 3.56 (m, 6 H) 3.78 - 3.87 (m, 3 H) 4.00 - 4.12 (m, 2 H)

363

5.10 - 5.18 (m, 2 H) 5.32 - 5.42 (m, 2 H) 5.88 - 5.95 (m, 2 H) 7.05 - 7.33 (m, 11 H) 7.41 (d, J=8.24

Hz, 1 H) 7.50 (d, J=8.35 Hz, 1 H) 11.97 - 12.30 (m, 2 H); MS (ESI+) m/z 1027 (M+H)⁺.

2016238925 07 Oct 2016

Example 5.2 methyl {(25)-l-[(25)-2-{5-[(2J?,5J?)-l-[4-(4,4-diphenylpiperidin-l-yl)-3,5-difluorophenyl]-5-{2-[(25)l-{(25)-2-|(mcthoxycarbonyl)amino|-3-mcthylbutanoyl [pyrrolidin-2-yl |-lf/-bcnzimidazol-5yl}pyrrolidin-2-yl] -I H-bc nzi m i dazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

In a 100 mL round bottom was added (5)-6,6'-((2/?.5/?)-l-(4-(4.4-diphcnylpipcridin-l-yl)0 3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)-lH-benzo[ri]imidazole) (0.385 g, 0.488 mmol), (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.180 g, 1.025 mmol), and \Hbenzo[<7][l,2,3]triazol-l-ol hydrate (0.187 g, 1.220 mmol) in DMF (25 mL) to give an orange solution. 4-Methylmorpholine (0.537 mL, 4.88 mmol) and A'^l-((cthylimino)mcthylcnc)-A'''.A'''dimethylpropane-1,3-diamine hydrochloride (0.234 g, 1.220 mmol) were added, and the mixture was stirred at ambient temperature for 2 hours and then diluted with EtOAc. The organic solution was washed sequentially with saturated NaHCO₃, H₂O, and saturated NaCl. The organic layer was treated with 3-mercaptopropyl silica for 1 hour, dried (Na2SO4), filtered and concentrated to a yellow foam. Purification by flash chromatography on a 24 g silica cartridge eluting with 2-7% methanol in CH₂C1₂provided material that was 90% pure by HPLC. A second chromatography of selected fractions on a 20 12 g silica cartridge eluting with 2-5% methanol in CH₂C1₂ gave the title compound as a cream colored solid (100 mg, 17%). Ή NMR (400 MHz, DMSO-4,) δ ppm 0.76 - 0.91 (m, 12 H) 1.68 (d, J=4.01 Hz, 2 H) 1.85 - 2.07 (m, 6 H) 2.19 (s, 4 H) 2.38 (s, 4 H) 2.86 (s, 4 H) 3.54 (s, 6 H) 3.82 (s, 4

H) 4.06 (t, J=8.35 Hz, 2 H) 5.10 - 5.17 (m, 2 H) 5.34 (d, J=7.16 Hz, 2 H) 5.85 (d, J=12.79 Hz, 2 H) 6.84 - 7.54 (m, 20 H) 12.06 (d, J=18.98 Hz, 2 H); MS (ESI+) m/z 1103 (M+H)⁺.

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2016238925 07 Oct 2016

Example 5.3 methyl {(2S,3R)-l-[(2S)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-(2-{(2S)l-|7V-(methoxycarbonyl)-O-methyl-L-threonyl ]pyrrolidin-2-yl }-lH-benzimidazol-5-yl)pyrrolidin-25 yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2 -yl} carbamate (S)-6,6'-((2R,5R)-l-(3,5-Difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(2-((.S')-pyrrolidin-2-yl)-17¥-benzo|c/|imidazolc) hydrochloride (0.12 g) was dissolved in dimethyl sulfoxide (2 mL) and treated with diisopropylethylamine (0.195 mL, 1.12 mmol) at ambient temperature followed by (2.S'.3/?)-3-mcthoxy-2-(mcthoxycarbonylamino)butanoic acid (0.059 g, 0.307 mmol) and HATU (0.112 g, 0.293 mmol). After 1 hour, the solution was diluted with water and extracted into dichloromethane, concentrated and purified by chromatography, eluting with 0-8% methanol in dichloromethane to give 0.071 g of a yellow solid (48%). 'H NMR (400 MHz, DMSOd₆) δ ppm 1.03 (dd, J=18.22, 6.18 Hz, 6 H) 1.63 - 1.72 (m, 6 H) 1.99 - 2.08 (m, 6 H) 2.15 - 2.26 (m, 6 H) 2.87 - 3.00 (m, 2 H) 3.10 (s, 3 H) 3.15 (s, 3 H) 3.17 - 3.20 (m, 1 H) 3.43 - 3.52 (m, 2 H) 3.54 (s, 6

H) 3.79 - 3.89 (m, 4 H) 4.25 - 4.30 (m, 2 H) 5.11 - 5.18 (m, 2 H) 5.35 - 5.42 (m, 2 H) 5.87 - 5.95 (m, 2

H) 7.09 (t, J=8.19 Hz, 2 H) 7.12 - 7.32 (m, 9 H) 7.41 (d, J=8.35 Hz, 1 H) 7.49 (d, J=8.78 Hz, 1 H) 12.03 (s, 1 H) 12.10 (s, 1 H); MS (ESI+) m/z 1059.4 (M+H)⁺.

Example 5.4

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2016238925 07 Oct 2016 methyl {(25)-l-[(25)-2-{5-[(27/,57/)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl }pyrrolidin-2-yl ]-17/-benzimidazol-5yl} pyrrolidin-2-yl] -1 H-be nzi m idazol -2 -yl} pyrrolidin-1 -yl] -3,3 -dimethyl-1 -oxobutan-2 -yl} carbamate (5)-6,6'-((27/, 57/)-1-(3,5-Difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,55 diyl)bis(2-((5)-pyrrolidin-2-yl)-17/-benzo[ri]imidazole) hydrochloride (0.12 g) was dissolved in dimethyl sulfoxide (2 mL) and treated with diisopropylethylamine (0.195 mL, 1.12 mmol) at ambient temperature followed by (5)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (0.058 g, 0.307 mmol) and HATU (0.112 g, 0.293 mmol). After 1 hour, the solution was diluted with water and extracted into dichloromethane. The organic phases were concentrated and purified by 0 chromatography, eluting with 0-6% methanol in dichloromethane to give the title compound (0.065 g, 44%) as a yellow solid . Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.89 (d, J=13.88 Hz, 18 H) 1.61 1.73 (m, 8 H) 1.95 - 2.08 (m, 4 H) 2.15 - 2.24 (m, 6 H) 2.86 - 3.02 (m, 4 H) 3.55 (s, 6 H) 3.78 - 3.85 (m, 4 H) 4.23 (dd, J=8.89, 4.66 Hz, 2 H) 5.13 - 5.22 (m, 2 H) 5.33 - 5.43 (m, 2 H) 5.92 (dd, J=12.85, 2.98 Hz, 2 H) 7.05 - 7.18 (m, 4 H) 7.20 - 7.29 (m, 5 H) 7.33 (s, 1 H) 7.42 (d, J=8.13 Hz, 1 H) 7.49 (d, .5 J=8.46 Hz, 1 H) 12.05 (d, J=1.63 Hz, 1 H) 12.09 (d, J=1.30 Hz, 1 H); MS (ESI+) m/z 1055.4 (M+H)⁺.

methyl {(25)-l-[(2S,47/)-2-{5-[(27/,57/)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2-[(2S,47/)-420 methoxy-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl }pyrrolidin-2-yl] - 177-benzimidazol5 -yl }pyrrolidin-2-yl] -17/-benzi midazol-2-yl} -4-methoxypyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate (S,7/)-6,6'-((27/,57/)-1-(3,5-Difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2((2S,47/)-4-methoxypyrrolidin-2-yl)-17/-benzo[ri]imidazole) (0.20g, 0.287 mmol) was dissolved in dimethyl sulfoxide (3 mL) and treated with diisopropylethylamine (0.400 mL, 2.29 mmol) at ambient temperature followed by (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.111 g, 0.631 mmol) and HATU (0.229 g, 0.603 mmol). After 2 hours, the solution was diluted with water and extracted into dichloromethane. The organic layer was concentrated and purified by chromatography, eluting with 0-6% methanol in dichloromethane to give the title compound (0.163 g, 56%) as a yellow solid. Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.71 - 0.84 (m, 12 H) 1.35 - 1.49 (m, 8 H) 1.69 (d,

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J=5.42 Hz, 2 H) 1.83 - 1.94 (m, 2 H) 2.22 - 2.32 (m, 4 H) 2.76 (s, 4 H) 3.29 (s, 6 H) 3.54 (s, 6 H) 3.87 (dd, J=11.11, 3.85 Hz, 2 H) 4.03 (q, J=7.05 Hz, 4 H) 4.21 (s, 2 H) 5.02 - 5.15 (m, 2 H) 5.36 (d, J=3.25

Hz, 2 H) 5.84 - 5.94 (m, 2 H) 7.04 - 7.11 (m, 2 H) 7.19 (s, 1 H) 7.27 - 7.34 (m, 3 H) 7.41 (d, J=8.24

Hz, 1 H) 7.48 (d, J=8.24 Hz, 1 H) 12.13 (s, 1 H) 12.19 (s, 1 H); MS (ESI+) m/z 1011.6 (M+H)⁺.

2016238925 07 Oct 2016

ABS

Example 5.6 dimethyl ({(2R,5R)-1 -[3,5-difluoro-4-(piperidin-1 -yl)phenyl]pyrrolidine-2,5-diyl}bis{1Hbcnzimidazolc-5.2-diyl(2.S')pyrrc)lidinc-2. l-diyl|(I.S')-l-cyclohcxyl-2-oxocthanc-2.10 diyl]} )biscarbamate (S)-6,6'-((2R,5R)-l-(3,5-Difluoro-4-(piperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((S)pyrrolidin-2-yl)-lH-benzo[<f] imidazole) (0.192 g, 0.302 mmol) was dissolved in dimethyl sulfoxide (4 mL) and treated with diisopropylethylamine (0.421 mL, 2.41 mmol) at ambient temperature followed by (.5)-2-cyclohcxyl-2-(mcthoxycarbonylamino)acctic acid (0.143 g, 0.663 mmol) and HATU (0.241 5 g, 0.633 mmol). After 1 hour, the solution was diluted with water and extracted into dichloromethane.

The organic phase was concentrated, and the residue was purified by chromatography, eluting with 08% methanol in dichloromethane to give the title compound (0.166 g, 53%) as a yellow solid. 'H NMR (400 MHz, DMSO-%) δ ppm 0.80 - 1.12 (m, 8 H) 1.36 - 1.70 (m, 24 H) 1.98 (d, J=4.45 Hz, 4 H) 2.15 - 2.25 (m, 4 H) 2.75 (s, 4 H) 3.52 (s, 6 H) 3.81 (d, J=2.39 Hz, 4 H) 4.08 (q, J=8.57 Hz, 2 H) 20 5.14 (d, J=4.23 Hz, 2 H) 5.36 (d, J=3.58 Hz, 2 H) 5.82 - 5.93 (m, 2 H) 7.10 (dd, J=13.93, 8.30 Hz, 2

H) 7.15 - 7.28 (m, 4 H) 7.42 (d, 1=7.37 Hz, 1 H) 7.48 (dd, J=8.35, 1.84 Hz, 1 H) 12.00 (s, 1 H) 12.16 (s, 1 H); MS (ESI+) m/z 1031.4 (M+H)⁺.

Example 5.7

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2016238925 07 Oct 2016 methyl {(25)-1 -| (25)-2-{6-| (2//.5//)-1-| 4-(3.5-dimcthylpipcridin-1-yl)-3.5-difluorophcnyl|-5-{2-| (25)l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl |-l//-bcnzimidazol-6yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Diisopropylethylamine (3 mL, 17.18 mmol) was added to a suspension of (5)-6,6'-((2R,57/)-15 (4-(3,5-dimethylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(2-((5)-pyrrolidin-2-yl)177-benzo [7] imidazole) (1.045 g, 1.572 mmol), (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.6852 g, 3.91 mmol), and HATU (1.4995 g, 3.94 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was diluted with dichloromethane, washed with water (2x), brine (lx), and concentrated. The residue was purified by 0 flash chromatography (2-5% methanol/dichloromethane) to afford the title compound (0.7107 g, 46%). ^XH NMR (400 MHz, DMSO-r/₆) δ ppm 0.50 (q, J = 11.9, 1H), 0.97 - 0.64 (m, 18H), 1.32 1.20 (m, 2H), 1.81-1.46 (m, 5H), 2.09 - 1.80 (m, 6H), 2.32 - 2.13 (m, 5H), 2.75 (dd, J = 10.0, 40.2, 2H), 3.18 - 3.05 (m, 1H), 3.54 (s, 6H), 3.82 (s, 4H), 4.14 - 3.95 (m, 2H), 5.14 (s, 2H), 5.36 (d, J = 7.2, 2H), 5.88 (d, J = 12.8, 2H), 7.14 - 7.02 (m, 2H), 7.19 (s, 1H), 7.33 - 7.23 (m, 3H), 7.41 (d, J = 8.2, 5 1H), 7.49 (d, J = 8.2, 1H), 12.37 - 11.98 (m, 2H); MS (ESI+) m/z 979 (M+H)⁺

Example 5.8 methyl {(25)-l-[(25)-2-{5-[(27/,57/)-l-{3,5-difluoro-4-[4-(trifluoromethyl)piperidin-l-yl]phenyl}-520 {2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-177-benzimidazol5-yl}pyrrolidin-2-yl] -1 H-bcnzimidazol-2-yl {pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl}carbamate (5)-6.6^(2//.5//)-1-(3.5-Difluoro-4-(4-(tri fl iioromcthyl)pipcridin-1-yl)phcnyl)pyrrolidinc-2.5diyl)bis(2-((5)-pyrrolidin-2-yl)-lH-benzo[i/]imidazole) tetrahydrochloride (250 mg, 0.294 mmol) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (113 mg, 0.647 mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (113 mg, 0.735 mmol) and EDAC (144 mg,

0.735 mmol) were added. The amber-colored solution was cooled to 0 °C. 4-Methylmorpholine (0.323 mL, 2.94 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 °C. After 2 hours, the reaction was diluted with EtOAc (50 mL) and washed with water (3x25 mL) and brine (25 mL). The organic phase was dried over anhydrous MgSO₄, filtered, and

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2016238925 07 Oct 2016 concentrated by rotary evaporation to a tan solid (300 mg). An aliquot (50 mg) of crude material was dissolved in 2 mL acetonitrile and 2 mL 0.1% TFA in H₂O, and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova-Pak HR C18 6pm 40x100 mm Prep Pak cartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, 5 then 10 minutes to 100% acetonitrile at 20 mL/minute (10 mL fractions). Pure fractions were treated with saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the neutralized solutions were combined in a 250-mL round bottom flask. The acetonitrile was removed by rotary evaporation, and extracted the remaining aqueous phase with EtOAc (2x50 mL). The combined organic extracts were dried over anhydrous MgSO₄, filtered, and concentrated by rotary 0 evaporation to afford the title compound as a white solid (18 mg). Repeated purification of an additional 100 mg as above by prep-HPLC in two 50-mg injections. Workup as above afforded additional title compound as a white solid (34 mg). 'H NMR (400 MHz, DMSO-0L) δ ppm 0.73 0.90 (m, 12 H), 1.23 (s, 1 H), 1.34 - 1.49 (m, 2 H), 1.63 - 1.76 (m, 4 H), 1.83 - 2.04 (m, 6 H), 2.11 2.25 (m, 4 H), 2.84 (m, 4 H), 3.52 (s, 6 H), 3.81 (br s, 4 H), 4.00 - 4.09 (m, 2 H), 5.08 - 5.18 (m, 2 H), 5 5.28 - 5.42 (m, 2 H), 5.89 (d, 7=12.79 Hz, 2 H), 7.06 (t, 7=7.26 Hz, 2 H), 7.16 - 7.32 (m, 4 H), 7.39 (d,

7=8.24 Hz, 1 H), 7.47 (d, 7=8.13 Hz, 1 H), 12.06 (two s, 2 H); MS (ESI+) m/z 1019 (M+H)⁺.

Example 5.9 methyl [(25)-1-| (25)-2-[5-| (2//.5//)-1-|4-(4-/i77-biitylpipcridin-1-yl)-3.5-difluorophcnyl|-5-{2-| (25)I-{(25')-2-|(mcthoxycarbonyl)amino|-3-mcthylbutanoyl (pyrrolidin-2-yl |-IH-bcnzimidazol-5yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate (5)-6.6'-( (2//, 5/?)-l-(4-(4-/i77-Biitylpipcridin-l -yl)-3,5-difluorophenyl)pyrrolidine-2,5diyl)bis(2-((5)-pyrrolidin-2-yl)-lH-benzo[7]imidazole) tetrahydrochloride (250 mg, 0.298 mmol) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (115 mg, 0.656 mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (114 mg, 0.745 mmol) and EDAC (146 mg, 0.745 mmol) were added, and then the amber-colored solution was cooled to 0 °C. 4Methylmorpholine (0.328 mL, 2.98 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 °C. After 18 hours, the reaction mixture was diluted with EtOAc (50 mL),

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2016238925 07 Oct 2016 washed with water (3x25 mL) and brine (25 mL). The organic phase was dried over anhydrous

MgSO₄, filtered, and concentrated by rotary evaporation to a yellow solid. Pre-purified by SiO₂ flash chromatography (Alltech Extract-Clean™ column, 10 g bed) eluting with 3% CH₃OH/CH₂C1₂ afforded a yellow solid (119 mg). An aliquot (50 mg) of the residue was dissolved in 2 mL acetonitrile and 2 mL 0.1% TFA in H₂O, and purified by RP-C18 HPLC (Waters Prep LC, 40 mm

Module with Nova-Pak HR C18 6 pm 40x100 mm Prep Pak cartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 mL/minute (10 mL fractions). Pure fractions were treated with saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the 0 solutions were combined in a 250-mL round bottom flask. The remaining 69 mg of material was purified by prep-HPLC as described above. The pure product-containing fractions were treated with saturated aq NaHCO₃ as above and combined in the same 250-mL round bottom flask. The acetonitrile was removed by rotary evaporation, the remaining aqueous phase was extracted with EtOAc (2x50 mL). The combined organic extracts were dried over anhydrous MgSO₄, filtered, and 5 concentrated by rotary evaporation to afford the title compound as a white solid (56 mg). 'H NMR (400 MHz, DMSO-4,) δ ppm 0.68 - 0.93 (m, 22 H), 1.09 - 1.25 (m, 2 H), 1.53 (d, 7=11.93 Hz, 2 H), 1.63 - 1.75 (m, 2 H), 1.80 - 2.08 (m, 7 H), 2.12 - 2.27 (m, 4 H), 2.71 - 2.91 (m, 5 H), 3.54 (s, 6 H), 3.82 (br s, 4 H), 4.06 (t, 7=8.35 Hz, 2 H), 5.09 - 5.19 (m, 2 H), 5.30 - 5.44 (m, 2 H), 5.89 (d, 7=12.69 Hz, 2 H), 7.02 - 7.11 (m, 2 H), 7.17 - 7.32 (m, 4 H), 7.40 (d, 7=8.24 Hz, 1 H), 7.49 (d, 7=8.13 Hz, 1 !0 H), 12.07 (two s, 2 H); MS (ESI+) m/z 1007 (M+H)⁺.

ABS

Example 5.10 methyl {(25)-1 -| (25)-2-] 5-| (2//.5//)-1-|4-(4.4-dimcthylpipcridin-1-yl)-3.5-difluorophcnyl|-5-{2-| (25)25 l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-127-benzimidazol-5yl} pyrrolidin-2-yl] -127-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate (5)-6.6'-((2//.5//)-l-(4-(4.4-Dimcthylpipcridin-l-yl)-3.5-difluorophcnyl)pyrrolidinc-2.5diyl)bis(2-((5)-pyrrolidin-2-yl)-127-benzo[<7]imidazole) pentahydrochloride (250 mg, 0.295 mmol) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (109 mg, 0.620 mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (104 mg, 0.679 mmol), and EDAC (133 mg,

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2016238925 07 Oct 2016

0.679 mmol) were added, and then the amber-colored solution was cooled to 0 °C. 4Methylmorpholine (0.325 mL, 2.95 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 °C. After 2 hours, the reaction mixture was diluted with EtOAc (50 mL), and washed with water (3x25 mL) and brine (25 mL). The organic phase was dried over anhydrous 5 MgSO₄, filtered, and concentrated by rotary evaporation to a tan solid. Purification by SiO₂ flash chromatography (3.8 cmxl5 cm) eluting with a step gradient of 3% to 4% CH₃OH/CH₂C1₂ afforded the title compound as a solid (115 mg). An aliquot (50 mg) was dissolved in 1.5 mL acetonitrile and

1.5 mL 0.1% TFA in H₂O, and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova-Pak HR C18 6 pm 40x100 mm Prep Pak cartridge) eluting with a 30 minutes gradient of 95:5 0 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 mL/minute (10 mL fractions). Pure fractions were treated with saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the solutions were combined in a 250-mL round bottom flask. Acetonitrile was removed by concentration in vacuo. The remaining aqueous phase was extracted with EtOAc (2x50 mL). The combined organic extracts were 5 dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the title compound as a white solid (33 mg). The remaining 65 mg of impure product (from silica gel column) were purified by RP-C18 prep HPLC as described above to obtain additional title compound as a white solid (33mg). ‘HNMR (400 MHz, DMSO-®,) δ ppm 0.75 - 0.91 (m, 12 H), 0.87 (s, 6 H), 1.21

- 1.35 (m, 4 Η), 1.63 - 1.77 (m, 2 Η), 1.81 - 2.09 (m, 6 H), 2.11 - 2.29 (m, 4 H), 2.49 - 2.59 (m, 2 H), !0 2.76 (s, 4 H), 3.54 (s, 6 H), 3.82 (br s, 4 H), 4.06 (t, 7=8.46 Hz, 2 H), 5.09 - 5.22 (m, 2 H), 5.30 - 5.44 (m, 2H), 5.89 (d, 7=12.79 Hz, 2 H), 7.03 - 7.11 (m, 2 H), 7.17-7.32 (m, 4 H), 7.41 (d, 7=8.13 Hz, 1

H), 7.49 (d, 7=8.02 Hz, 1 H), 12.07 (two s, 2 H); (ESI+) m/z 979 (M+H)⁺; MS (ESI-) m/z 977 (M-H)’.

ABS

Example 5.11 methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-[4-(6-azaspiro[2.5]oct-6-yl)-3,5-difluorophenyl]-5-{2-[(2S)-l{(2.S')-2-|(mcthoxycarbonyl)amino|-3-mcthylbutanoyl [pyrrolidin-2-yl |-lf/-bcnzimidazol-5yl} pyrrolidin-2-yl] -127-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

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2016238925 07 Oct 2016 (5)-6,6'-( (27/,57/)-1-(3,5-Difluoro-4-(6-azaspiro[2.5]octan-6-yl)phenyl)pyrrolidine-2,5diyl)bis(2-((5)-pyrrolidin-2-yl)-17/-benzo[<7]imidazole) tetrahydrochloride (250 mg, 0.309 mmol) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (119 mg, 0.680 mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (118 mg, 0.773 mmol) and EDAC (151 mg,

0.773 mmol), were added, and then the amber-colored solution was cooled to 0 °C. 4Methylmorpholine (0.340 mL, 3.09 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 °C. After 16.5 hours, the reaction mixture was diluted with EtOAc (50 mL), and washed with water (3x25 mL) and brine (25 mL). The organic phase was dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to a yellow solid. Pre-purification by SiO₂ flash chromatography (Alltech Extract-Clean™ column, 10 g bed) eluting with 3% CH₃OH/CH₂C1₂ to afforded a beige solid (172 mg). An aliquot (50 mg) was dissolved in 1.5 mL acetonitrile and 1.5 mL 0.1% TFA in H₂O, and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova-Pak HR C18 6 pm 40x 100mm Prep Pak cartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 .5 mL/minute (10 mL fractions). Pure fractions were treated with saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the solutions were combined in a 250-mL round bottom flask. Two additional 50 mg lots were purified by prep-HPLC as described above, and the pure product-containing fractions were treated with saturated aq NaHCO₃ as above and combined in the same 250-mL round bottom flask. The acetonitrile was removed by concentration in vacuo, !0 and the remaining aqueous phase was extracted with EtOAc (2x50 mL). The combined organic phases were dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the title compound as a white solid (42 mg). 'H NMR (400 MHz, DMSO-<7₆) δ ppm 0.22 (s, 4 H), 0.72 - 0.93 (m, 12 H), 1.21 - 1.36 (m, 5 H), 1.61 - 1.78 (m, 2 H), 1.83 - 2.08 (m, 7 H), 2.13 - 2.27 (m, 4 H), 2.81 (br s, 4 H), 3.53 (s, 6 H), 3.82 (br s, 4 H), 4.06 (t, 7=8.40 Hz, 2 H), 5.10-5.19 (m, 2 H), 5.29 25 - 5.45 (m, 2 H), 5.90 (d, 7=12.79 Hz, 2 H), 7.02 - 7.32 (m, 6 H), 7.41 (d, 7=8.24 Hz, 1 H), 7.49 (d,

7=8.24 Hz, 1 H), 12.07 (two s, 2 H); MS (ESI+) m/z 977 (M+H)⁺.

Example 5.12

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2016238925 07 Oct 2016 methyl {(25)-l-[(25)-2-{5-[(2R,5R)-l-[4-(3-azaspiro[5.5]undec-3-yl)-3,5-difluorophenyl]-5-{2-[(25)I-{(25)-2-|(mcthoxycarbonyl)amino|-3-mcthylbiitanoyl [pyrrolidin-2-yl |-lf/-bcnzimidazol-5yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate (5)-6,6'-((2R,5R)-l-(3,5-Difluoro-4-(3-azaspiro[5.5]undecan-3-yl)phenyl)pyrrolidine-2,55 diyl)bis(2-((5)-pyrrolidin-2-yl)-lH-benzo[7]imidazole) tetrahydrochloride (250 mg, 0.294 mmol) and (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (113 mg, 0.646 mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (113 mg, 0.735 mmol) and EDAC (144 mg, 0.735 mmol), were added, and then the mixture was cooled to 0 °C. 4-Methylmorpholine (0.323 mL, 2.94 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 °C 0 for 18 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3x25 mL) and brine (25 mL). The organic phase was dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to a beige foam. The crude material was purified by SiO₂ flash chromatography (3.8 cmxl5 cm) eluting with 4% CH₃OH/CH₂C1₂ to afford the title compound as a white solid (82 mg). Ή NMR (400 MHz, DMSO-4,) δ ppm 0.72 - 0.93 (m, 12 H), 1.22 - 1.41 (m, 15

H), 1.63 - 1.74 (m, 2 H), 1.80 - 2.07 (m, 7 H), 2.12 - 2.27 (m, 4 H), 2.75 (s, 4 H), 3.54 (s, 6 H), 3.82 (s, 4 H), 4.06 (t, 7=8.40 Hz, 2 H), 5.14 (d, 7=1.19 Hz, 2 H), 5.27 - 5.42 (m, 2 H), 5.88 (d, 7=12.69 Hz, 2 H), 7.03 - 7.11 (m, 2 H), 7.20 (s, 1 H), 7.29 (d, 7=5.96 Hz, 3 H), 7.40 (d, 7=8.24 Hz, 1 H), 7.49 (d, 7=8.24 Hz, 1 H), 12.07 (m, 2 H); MS (ESI+) m/z 1019 (M+H)⁺, (ESI-) m/z 1017 (M-H)’.

methyl {(25)-l-|(25)-2-{5-|(2/?.5/?)-l-|4-(l.3-dihydro-2H-isoindol-2-yl)-3.5-difluorophcnyl|-5-{2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-bcnzi midazol-5 yl} pyrrolidin-2-yl] -1 H-be nzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate (5)-6,6'-((2R,5R)-l-(3,5-Difluoro-4-(isoindolin-2-yl)phenyl)pyrrolidine-2,5-diyl)bis(2-((5)pyrrolidin-2-yl)-lH-benzo[7]imidazole) tetrahydrochloride (250 mg, 0.306 mmol) and (5)-2(methoxycarbonylamino)-3-methylbutanoic acid (118 mg, 0.673 mmol) were combined in anhydrous DMF (3 mL) under nitrogen. HOBT hydrate (117 mg, 0.765 mmol) and EDAC (150 mg, 0.765 mmol) were added, then the amber-colored solution was cooled to 0 °C. 4-Methylmorpholine (0.337

373

2016238925 07 Oct 2016 mL, 3.06 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was diluted with EtOAc (50 mL) and this mixture was washed with water (3x25 mL) and brine (25 mL). The organic phase over dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to a greenish-yellow solid. The solid was purified by

SiO₂ flash chromatography (3.8 cmxl5 cm) eluting with 4% CH₃OH/CH₂C1₂ to afford an off-white solid (104 mg). An aliquot (52 mg) was dissolved acetonitrile (2 mL) and 0.1% TFA in H₂O (2 mL) and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova-Pak HR C18 6 pm 40x100 mm Prep Pak cartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 0 mL/minute (10 mL fractions). Pure fractions were treated with saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the solutions were combined in a 500-mL round bottom flask. The remaining 52 mg of material were purified by prep-HPLC as described above and the pure product-containing fractions were treated with saturated aq NaHCO₃ as described above. The product containing fractions were combined in the same 500-mL round bottom flask.

The acetonitrile was removed by rotary evaporation. The remaining aqueous phase was extracted with EtOAc (2x50 mL). The combined organic phases were dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the title compound as a white solid (88 mg). 'H NMR (400 MHz, DMSO-fo) δ ppm 0.75 - 0.92 (m, 12 H), 1.61 - 2.08 (m, 8 H), 2.11 - 2.26 (m, 3 H), 2.57 (s, 2 H), 3.54 (s, 6 H), 3.83 (s, 4 H), 4.07 (t, 7=8.29 Hz, 2 H), 4.26 - 4.43 (m, 4 H), 5.10 - 5.23 !0 (m, 2 H), 5.33 - 5.50 (m, 2 H), 5.99 (d, 7=12.79 Hz, 2 H), 7.09 (t, 7=6.83 Hz, 2 H), 7.20 (s, 4 H), 7.22

- 7.37 (m, 4 H), 7.42 (d, 7=8.24 Hz, 1 H), 7.50 (d, 7=8.13 Hz, 1 H), 12.09 (m, 2 H); MS (ESI+) m/z 985 (M+H)⁺, (ESI-) m/z 983 (M-H)’.

ABS

Example 5.14 methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-[4-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3,5-difluorophenyl]-5{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-127-benzimidazol5-yl}pyrrolidin-2-yl] -1 H-bcnzimidazol-2-yl (pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl}carbamate Part A

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The compound 8-(4-((27/, 5//)-2.5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6difluorophenyl)-l,4-dioxa-8-azaspiro[4.5]decane can be transformed following the methods of

General Procedure 8.1 and General Procedure 9D (PtO2) to obtain dimethyl (2.S'.2'.S')-I.I'-((2.S'.2'.S')2,2'-(4,4'-((27/,57/)-l-(3,5-difluoro-4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)pyrrolidine-2,55 diyl)bis(2-amino-4,1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1 -diyl))bis(3 methyl -1 -oxobutane-2, l-diyl)dicarbamate.

Part B

In an oven-dried 10-mL round bottom flask, dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'((27/,57/)-1-(3,5-difluoro-4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)pyrrolidine-2,5-diyl)bis(20 amino-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-methyl-loxobutane-2,l-diyl)dicarbamate (200 mg, 0.191 mmol) was dissolved in anhydrous toluene (2 mL) under nitrogen. Glacial acetic acid (0.110 mL, 1.914 mmol) was added, and the solution was stirred in an oil bath at 60 °C. After 1.5 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed with saturated aq NaHCO₃ (25 mL). The organic phase was dried .5 over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the crude title compound as a tan solid (185 mg). An aliquot (93 mg) of the impure material was dissolved acetonitrile (2 mL) and 0.1% TFA in H₂O (2 mL) and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova Pak HR C18 6 pm 40x100 mm Prep Pak cartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 !0 minutes to 100% acetonitrile at 20 mL/minute. Pure fractions were immediately treated with saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the solutions were combined in a 500-mL round bottom flask. The remaining 92 mg were purified by preparative-HPLC as described above and the pure product-containing fractions were treated with saturated aq NaHCO₃ as described above. The additional fractions were combined in the same 50025 mL round bottom flask. The acetonitrile was removed by rotary evaporation, and the remaining aqueous phase was extracted with EtOAc (2x50 mL). The combined organic extracts were dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the title compound as a white solid (103 mg). 1H NMR (400 MHz, DMSOY) δ ppm 0.73 - 0.94 (m, 12 H), 1.51 - 1.61 (m, 4 H), 1.63 - 1.75 (m, 2 H), 1.83 - 2.10 (m, 8 H), 2.13 - 2.29 (m, 4 H), 2.86 (s, 4 H), 3.54 (s, 6 H), 3.83 30 (s, 8 H), 4.06 (t, 7=8.51 Hz, 2 H), 5.09 - 5.21 (m, 2 H), 5.30 - 5.42 (m, 2 H), 5.90 (d, 7=12.69 Hz, 2

H), 7.01 - 7.12 (m, 2 H), 7.17 - 7.32 (m, 4 H), 7.40 (s, 1 H), 7.49 (d, 7=8.24 Hz, 1 H), 11.71 - 12.53 (m, 2 H); MS (ESI+) m/z 1009 (M+H)⁺, (ESI-) m/z 1007 (M-H)’.

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2016238925 07 Oct 2016

Example 5.15 methyl {(2S)-l-[(2S)-2-{5-[(27/,57/)-l-[3,5-difluoro-4-(4-phenyl-3,6-dihydropyridin-l(2H)yl)phenyl]-5 - { 2-[(2® 1 - {(2® 2-[(methoxycarbonyl)amino]-3-methylbutanoyl} pyrrolidin-2-yl] - 1H5 benzimidazol-5-yl [ pyrrolidin-2-yl |-17/-bcnzimidazol-2-yl [ pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2yl} carbamate

Part A

The compound l-(4-((27/,57/)-2,5-bis(4-chloro-3-nitrophenyl)pyrrolidin-l-yl)-2,6difluorophenyl)-4-phenyl-l,2,3,6-tetrahydropyridine can be transformed following the methods of 0 General Procedure 8.1 and General Procedure 9E to obtain dimethyl (2.S'.2'.S')-l.l'-((2.S'.2'.S')-2.2'-(4.4'((27/,57/)-1-(3,5-difluoro-4-(4-phenyl-5,6-dihydropyridin-l(2H)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2amino-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-methyl-loxobutane-2,1 -diyl)dicarbamate.

PartB

In an oven-dried 5-mL round bottom flask, dimethyl (2S,2'S)-l,l'-((2S,2'S)-2,2'-(4,4'((27/,57/)-1-(3,5-difluoro-4-(4-phenyl-5,6-dihydropyridin-l(2H)-yl)phenyl)pyrrolidine-2,5-diyl)bis(2amino-4,l-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,l-diyl))bis(3-methyl-loxobutane-2,l-diyl)dicarbamate (75 mg, 0.071 mmol) was dissolved in anhydrous toluene (1 mL) under nitrogen. Glacial acetic acid (0.041 mL, 0.707 mmol) was added, and the solution was stirred 20 in an oil bath at 60 °C. After 1.5 hours, the yellow reaction mixture was cooled to room temperature, diluted in EtOAc (50 mL), and washed with saturated aq NaHCO₃ (25 mL). The organic phase was dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to a yellow solid (~80 mg). The residue was dissolved in 2 mL acetonitrile and 2 mL 0.1% TFA in H₂O, and purified by RP-C18 HPLC (Waters Prep LC, 40 mm Module with Nova-Pak HR C18 6 pm 40x100 mm Prep Pak 25 cartridge) eluting with a 30 minutes gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1%

TFA in H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 mL/minute (10 mL fractions).

Pure fractions were treated with saturated aq NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the solutions were combined in a 250-mL round bottom flask. The

376 acetonitrile was removed by rotary evaporation, and the remaining aqueous phase was extracted with

EtOAc (2x50 mL). The organic phase was dried over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the product as an off-white solid (34 mg). 'H NMR (400 MHz,

DMSO-ff) δ ppm 0.76 - 0.94 (m, 12 H), 1.70 (d, 7=4.55 Hz, 2 H), 1.83 - 2.10 (m, 6 H), 2.11 - 2.26 (m, 3 H), 2.44 (s, 1 H), 2.56 (s, 4 H), 3.09 (s, 2 H), 3.48 (s, 2 H), 3.54 (s, 6 H), 3.82 (s, 4 H), 4.07 (t,

7=8.35 Hz, 2 H), 5.09 - 5.22 (m, 2 H), 5.30 - 5.46 (m, 2 H), 5.95 (d, 7=12.90 Hz, 2 H), 6.09 (s, 1 H), 7.04 - 7.17 (m, 2 H), 7.19 - 7.25 (m, 2 H), 7.26 - 7.34 (m, 5 H), 7.36 - 7.45 (m, 3 H), 7.50 (d, 7=8.35 Hz, 1 H), 11.71 - 12.63 (m, 2 H); MS (ESI+) m/z 1025 (M+H)⁺, (ESI-) m/z 1023 (M-H)’.

2016238925 07 Oct 2016

ABS

O .0 ⁷

Example 6.1 methyl {(2.S')-I -|(2.S')-2-{5-|(2/?.5/?)-l -(4-/i’/7-butylphcnyl)-5-{5-fliioro-2-|(2.S')-l-{(2.S')-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-127-benzimidazol-6-yl }pyrrolidin-2yl] -6-fluoro-I //-bcnzi m i dazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

To 6,6'-[(2R,5R)-l-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis{5-fluoro-2-[(2S)-pyrrolidin-2yl|-1//-benzimidazole] was added DMF (1.0 mL) followed by Λ'-mcthylmorpholinc (0.045mL, 0.41 mmol), (.S')-2-(methoxycarbonylamino)-3-methylbutanoic acid (15mg, 0.09 mmol), EDC (20mg, 0.1 mmol) and HOBT (16mg, 0.1 mmol). The solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with H₂O and brine, dried (Na₂SO₄), filtered 20 and concentrated. The product was purified by reverse-phase HPLC chromatography (5-100% CH₃CN/0.1%TFA-H₂O); the desired fractions were neutralized with aqueous NaHCO₃ solution, extracted with EtOAc, dried, filtered and solvent evaporated to give the title compound (6.7mg, 7.2 pmol, 18%): Ή NMR (400 MHz, CDC1₃) δ ppm 10.48 (m, 1H) 10.25 (m, 1H) 7.39 (m, 1H) 7.14 (m, 1H) 6.98 (m, 3H) 6.29 (m, 1H) 5.54 (br s, 1H) 5.34 (br s, 4H) 4.31 (m, 1H) 3.82 (m, 2H) 3.70 (s, 6H) 25 3.51-3.65 (m, 2H) 3.03 (br s, 2H) 2.51 (br s, 2H) 2.23-2.40 (m, 2H) 2.14 (m, 4H) 1.95 (m, 4H) 1.27 (m, 2H) 1.09-1.23 (m, 9H) 1.07 (m, 3H) 0.87 (m, 9H) 0.67-0.79 (m, 2H); MS (ESI) m/z 924 (M+H)⁺.

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2016238925 07 Oct 2016

ABS

O

Example 6.2 methyl {(2.S)-1-|(2.S')-2-{5-| (2//.5.S')-1 -(4-/i77-butylphcnyl)-5-{5-fliioro-2-|(2.S')-l-{(25)-2[(mcthoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-1 H-benzimidazol-6-yl} pyrrolidin-25 yl] -6-fluoro -I H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl -1 -oxobutan-2 -yl} carbamate

From the HPLC purification of Example 6.1, the cis isomer (6.4mg, 6.9pmol, 17%) was also obtained: 'H NMR (400 MHz, CDC1₃) δ ppm 11.62 (s, IH) 11.37 (s, IH) 7.45-7.55 (m, 3H) 7.36 (d, IH) 7.04 (d, 2H) 6.92 (d, IH) 6.77 (d, IH) 6.41 (d, 2H) 5.36-5.40 (m, 2H) 5.33 (m, IH) 5.07 (t, IH) 3.98-4.07 (m, IH) 3.93 (m, IH) 3.74-3.86 (m, 2H) 3.72 (m, IH) 3.59 (m, 2H) 2.80 (m, IH) 2.50 (s,

6H) 2.32 (s, 4H) 1.86-2.27 (m, 7H) 1.78 (m, IH) 1.17 (s, 9H) 0.86-1.01 (m, 9H); MS (ESI) m/z 924 (M+H)⁺.

The following example compounds 6.3-6.11 can be made from the appropriate listed intermediate amine following generally the method of Example 6.1:

.5 Intermediate amines:

6,6'-[(2R,5R)-1 -(4-/i77-biitylphcnyl)pyrrolidinc-2.5-diyl|bis{7-fluoro-2-|(2.S')-pyrrolidin-2-yl|-1Hbenzimidazole} (ACD Name vl2);

6.6'-| (2//.55)-1-(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl|bis{7-fliioro-2-|(25')-pyrrolidin-2-yl|-1//benzimidazole} (ACD Name vl2);

6.6'-| (2//.5//)-1-(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl |bis{7-chloro-2-|(2.S')-pyrrolidin-2-yl ]-lHbenzimidazole} (ACD Name vl2);

6.6'-|(2//.5.S')-l-(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl |bis{7-chloro-2-|(2.S')-pyrrolidin-2-yl |-l//benzimidazole} (ACD Name vl2);

6.6'-|(2//.5//)-l-(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl |bis{7-mcthyl-2-|(2.S')-pyrrolidin-2-yl |-l//25 benzimidazole} (ACD Name vl2);

6.6'-|(2//.5.S')-l-(4-/i77-butylphcnyl)pyrrolidinc-2.5-diyl |bis{7-mcthyl-2-|(2.S')-pyrrolidin-2-yl |-l//benzimidazole} (ACD Name vl2);

6.6'-{(2//.5//)-l-|3-fliioro-4-(pipcridin-l-yl)phcnyl|pyrrolidinc-2.5-diyl}bis{5-fluoro-2-|(2.S')pyrrolidin-2-yl|-lf/-bcnzimidazolc} (ACD Name vl2);

378

6,6'-{(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)pyrrolidin-2-yl]- l/7-bcnzimidazolc } (ACD Name vl2); and

6,6'-{(2R,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2|(2.S')-pyrrolidin-2-yl|-l//-bcnzimidazolc[ (ACD Name vl2).

2016238925 07 Oct 2016

ABS

O /

Example 6.3 methyl {(2S)-l-[(2S)-2-{5-[(2R,5R)-l-(4-tert-butylphenyl)-5-{7-fluoro-2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-20 yl] -4-fluoro -1 H-bcnzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl -1 -oxobutan-2 -yl} carbamate ‘HNMR (400 MHz, CDC1₃) δ ppm 10.41-10.64 (m, 2H) 6.84-7.06 (m, 6H) 6.25-6.36 (m, 2H) 5.555.68 (m, 1H) 5.25-5.46 (m, 4H) 4.27-4.40 (m, 1H) 3.79-3.92 (m, 2H) 3.71 (s, 6H) 3.56-3.67 (m, 2H) 3.03-3.27 (m, 2H) 1.83-2.66 (m, 10H) 1.14 (s, 9H) 0.77-1.31 (m, 14H); MS (ESI) m/z 924 (M+H)⁺.

£BS

O

Example 6.4 methyl {(2S)-l-[(2S)-2-{5-[(2R,5S)-l-(4-tert-butylphenyl)-5-{7-fluoro-2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH-benzimidazol-6-yl}pyrrolidin-2yl] -4-fluoro-1 H-bcnzi midazol -2-yl}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate ‘HNMR (400 MHz, CDC1₃) δ ppm 10.54-10.71 (m, 2H) 7.54-7.68 (m, 2H) 7.00-7.21 (m, 4H) 6.4320 6.54 (m, 2H) 5.27-5.50 (m, 4H) 5.20 (br s, 2H) 4.29-4.42 (m, 1H) 3.80-3.94 (m, 2H) 3.71 (s, 6H)

3.59-3.69 (m, 2H) 3.04-3.29 (m, 2H) 1.86-2.66 (m, 10H) 1.18 (s, 9H) 0.79-1.33 (m, 14H); MS (ESI) m/z 924 (M+H)⁺.

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ABS

Example 6.5 methyl {(2S)-l-[(2S)-2-{5-[(27?,57?)-l-(4-tert-butylphenyl)-5-{4-chloro-2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-25 yl] -4-chloro-1 H-bcnzi midazol -2-yl {pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'HNMR (400 MHz, DMSO-ty,) δ 12.70 (s, OH), 12.39 (s, 1H), 8.07 (s, 1H), 7.32 (dd, J = 26.1, 8.1, 3H), 6.91 (d, J = 37.0, 4H), 6.08 (d, J = 7.9, 1H), 5.64 (s, 1H), 5.17 (s, 1H), 4.66 (s, 1H), 4.10 (d, J = 5.2, 1H), 3.86 (s, 3H), 3.52 (d, J = 14.1, 6H), 3.17 (d, J = 5.2, 1H), 2.30 - 2.10 (m, 2H), 2.00 (s, 4H), 1.77 (s, 1H), 1.23 (s, 1H), 1.18 - 1.01 (m, 9H), 1.01 - 0.72 (m, 11H); MS (APCI+) m/z 958.76 0 (M+H)⁺.

methyl {(25)-1-[(2S)-2-{5-[(27?,5S)-l-(4-tert-butylphenyl)-5-{4-chloro-2-[(2S)-l-{(2S)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-25 yl] -4-chloro-I H-bcnzi midazol -2-yl {pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate 'H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 8.06 (d, J = 3.3, 1H), 7.68 (d, J = 8.6, 2H), 7.48 (t, J = 12.5, 2H), 7.31 (d, J = 8.2, 2H), 7.00 (d, J = 8.1, 2H), 6.20 (d, J = 8.7, 2H), 5.16 (d, J = 32.0, 4H), 4.66 (s, 1H), 4.11 (s, 1H), 3.88 (s, 3H), 3.56 (d, J = 8.1, 6H), 2.30 - 2.09 (m, 5H), 2.02 (s, 7H), 1.80 (s, 2H), 1.23 (s, 2H), 1.09 (s, 9H), 1.00 - 0.78 (m, 12H); MS(APCI+) m/z 958.64 (M+H)⁺.

ABS

Example 6.7 methyl {(25)-l-[(25)-2-{5-[(27?,57?)-l-(4-tert-butylphenyl)-5-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-4-methyl-lH-benzimidazol-5380 yl}pyrrolidin-2-yl] -4-methyl-I H-bcnzi m i dazol -2-y I}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate 'H NMR (400 MHz, DMSO®) δ ppm 0.78 - 1.05 (m, 14 H), 1.06 (s, 9 H), 1.86 - 2.06 (m, 8 H), 2.09

- 2.31 (m, 4 H), 2.58 - 2.72 (m, 6 H), 3.54 (s, 6 H), 3.79 - 3.93 (m, 4 H), 4.02 - 4.17 (m, 2 H), 5.11 5 5.23 (m, 2 H), 5.42 - 5.51 (m, 2 H), 6.02 - 6.12 (m, 2 H), 6.71 - 6.83 (m, 2 H), 6.83 - 6.96 (m, 2 H),

7.04 - 7.19 (m, 2 H), 7.24 - 7.35 (m, 2 Η), 11.84 - 12.26 (m, 2 H).

2016238925 07 Oct 2016

ABS

Example 6.8 methyl {(25)-1-[(25)-2-{5-[(2R,55)-l-(4-tert-butylphenyl)-5-{2-[(25)-l-{(25)-20 [(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-4-methyl-lH-benzimidazol-5yl}pyrrolidin-2-yl] -4-methyl-I H-bcnzi m i dazol -2-y I}pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate

Ή NMR (400 MHz, DMSO®) δ ppm 0.79 - 1.06 (m, 12 H), 1.23 (s, 9 H), 1.87 - 2.31 (m, 7=30.69 Hz, 12 H), 2.58 - 2.65 (m, 7=3.25 Hz, 6 H), 3.55 (s, 6 H), 3.81 - 3.96 (m, 4 H), 4.01 - 4.19 (m, 2 H), 5 4.92 (s, 2 H), 5.12 - 5.26 (m, 2 H), 6.14 - 6.26 (m, 2 H), 6.86 - 7.02 (m, 2 H), 7.22 - 7.39 (m, 4 H),

7.57 - 7.79 (m, 2 Η), 11.90 - 12.32 (m, 2 H); MS (ESI) m/z = 916.4 (M+H)⁺.

methyl {(25)-l-[(25)-2-(6-fluoro-5-{(2R,5R)-5-{6-fluoro-2-[(25)-l-{(25)-220 [(methoxy carbonyl)amino] -3 -methylbutanoyl }pyrrolidin-2-yl] -1 H-bcnzi midazol-5 -yl} -1 -[3 -fluoro-4(piperidin-1 -yl)phenyl]pyrrolidin-2-yl}-I H-bcnzi midazol -2-yl [pyrrolidin-1 -yl]-3-methyl-1 -oxobutan2-yl} carbamate *HNMR (400 MHz, CDC1₃) δ ppm 10.21-10.67 (m, 2H) 6.55-7.99 (m, 6H) 5.95-6.14 (m, 1H) 5.195.56 (m, 6H) 4.25-4.39 (m, 1H) 3.77-3.92 (m, 2H) 3.70 (s, 6H) 3.42-3.76 (m, 3H) 2.95-3.17 (m, 2H)

381

2.64-2.95 (m, 2H) 2.43-2.64 (m, 1H) 1.78-2.42 (m, 11H) 0.62-1.78 (m, 18H); MS (ESI) m/z 969 (M+H)⁺.

2016238925 07 Oct 2016

methyl {(25)-1-[(25)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{6-fluoro-2-[(25)-l{(25)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5yl}pyrrolidin-2-yl] -6-fluoro-1 H-benzimidazol-2-yl [pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2 yl[ carbamate

To a solution of 6,6'-{(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]pyrrolidine-2,50 diyl[bis{5-fluoro-2-[(25)-pyrrolidin-2-yl]-lH-benzimidazole[ (64 mg, 0.095 mmol) in DMF (2378 pL) was added (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid (35.0 mg, 0.200 mmol), EDC (45.6 mg, 0.238 mmol), HOBT (36.4 mg, 0.238 mmol) and Λ'-mcthylmorpholinc (105 pL, 0.951 mmol), and the resultant solution was stirred at ambient temperature overnight. The reaction solution was diluted with EtOAc, washed with H₂O and brine, dried (MgSO4), fdtered and concentrated. The crude material was dissolved in 1:1 CH₃CN:0.1% TFA/H₂O and purified by HPLC (C18, 0-100% CH₃CN/0.1%TFA/H₂O). The product containing fractions were combined, made basic with saturated sodium bicarbonate solution, and extracted with EtOAc. The organic layer was dried (MgSO₄), filtered and concentrated to give the title compound (43.3 mg, 0.044 mmol, 46.1 % yield). The title compound can also be prepared according to General Procedure 12C described above. 'H NMR (400 20 MHz, CDC1₃) δ ppm 10.25-10.70 (m, 2H) 6.83-7.53 (m, 4H) 5.70-5.91 (m, 2H) 5.20-5.52 (m, 4H) 4.21-4.42 (m, 2H) 3.70 (s, 6H) 3.53-3.94 (m, 6H) 1.75-3.17 (m, 16H) 0.63-1.74 (m, 18H); MS (ESI) m/z 987 (M+H)⁺.

382

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Example 6.11 methyl {(25)-1-[(25)-2-{5-[(2Λ,5Λ)-1-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{6-fluoro-2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-benzi midazol-5 5 yl}pyrrolidin-2-yl] -6-fluoro-1 H-benzimidazol-2-yl [pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl[ carbamate 'H NMR (400 MHz, CDC1₃) δ ppm 10.54 (br s, 2H) 7.09-7.33 (m, 9H) 5.77-5.92 (m, 2H) 5.23-5.52 (m, 4H) 4.24-4.39 (m, 2H) 3.79-3.91 (m, 2H) 3.70 (s, 6H) 3.55-3.67 (m, 2H) 2.92-3.21 (m, 5H) 1.732.65 (m, 10H) 0.97-1.74 (m, 8H) 0.76-0.96 (m, 12H); MS (ESI) m/z 1063 (M+H)⁺.

Example 6.12 methyl {(25)-1-[(25)-2-{5-[(2Λ,5Λ)-1-[4-(6-azaspiro[2.5]oct-6-yl)-3,5-difluorophenyl]-5-{6-fluoro-2[(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-benzi midazol-5 15 yl[pyrrolidin-2-yl] -6-fluoro-1 H-benzimidazol-2-yl [pyrrolidin-1 -yl] -3 -methyl-1 -oxobutan-2yl[ carbamate

In an oven-dried 5-mL pear-shaped flask, dissolved (S)-2-(methoxycarbonylamino)-3methylbutanoic acid (56.6 mg, 0.323 mmol) in anhydrous CH₂C1₂ (1 mL) under nitrogen, added EDAC (63.2 mg, 0.323 mmol), and stirred at 20 °C for 20 min. The resulting solution was added via 20 gas-tight syringe to a solution of (S)-6,6'-((2R,5R)-l-(3,5-difluoro-4-(6-azaspiro[2.5]octan-6yl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole)

383

2016238925 07 Oct 2016 hydrochloride (91 mg) and diisopropylethylamine (0.188 mL, 1.077 mmol) in anhydrous CH₂C1₂ (2 mL) under nitrogen, added HOBt hydrate (49.5 mg, 0.323 mmol), and stirred at 20 °C for 1 hr. The reaction was diluted with CH₂C1₂ (50 mL), washed with water (25 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation to a dark yellow foam (-140 mg). Dissolved 70 mg of the impure material in 2 mL Acetonitrile and 2 mL 0.1% TFA in H₂O, and purified by RP-Ci₈

HPLC (Waters Prep LC, 40mm Module with Nova Pak HR C18 6pm 40x100mm Prep Pak cartridge) eluting with a 30 min gradient of 95:5 0.1% TFA in H₂O/Acetonitrile to 25:75 0.1% TFA in H₂O/Acetonitrile, then 10 min to 100% Acetonitrile at 20 mL/min. Pure fractions were treated with saturated aqueous NaHCO₃ (2 mL/tube), vortexed each tube to thoroughly neutralize TFA, and 0 combined the solutions in a 500-mL round bottom flask. Purified the remaining 70 mg by prep-HPLC as above and the pure product-containing fractions were treated with saturated aqueous NaHCO₃ as above and combined in the same 500-mL round bottom flask. Removed the Acetonitrile by rotary evaporation, extracted the remaining aqueous phase with EtOAc (2 x 50 mL), dried the combined organic extracts over anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the 5 product as a white solid (49 mg, 0.048 mmol). 'H NMR (400 MHz, DMSO-d₆) δ ppm 0.24 (s, 4 H),

0.68 - 0.91 (m, 12 H), 1.21 - 1.35 (m, 5 H), 1.67 - 2.07 (m, 9 H), 2.13 - 2.24 (m, 4 H), 2.84 (s, 4 H),

3.53 (s, 6 H), 3.73 - 3.87 (m, 4 H), 3.99 - 4.11 (m, 2 H), 5.02 - 5.23 (m, 2 H), 5.45 - 5.65 (m, 2 H),

5.81 - 5.99 (m, 2 H), 7.04 (d, 7=6.07 Hz, 1 H), 7.14 (d, 7=6.94 Hz, 1 H), 7.26 - 7.36 (m, 3 H), 7.41 (dd, 7=11.06, 6.18 Hz, 1 H), 11.73 - 12.63 (m, 2 H); MS (ESI+) m/z 1013 (M+H)⁺; MS (ESI-) m/z !0 1011 (M-Η)’.

Example 6.13 methyl {(2S,3R)-l-[(2S)-2-{5-[(2R,5R)-l-[4-(47ert-butylpiperidin-l-yl)-3,5-difluorophenyl]-5-(625 fluoro-2-{(2S)-l-[7V-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-127-benzimidazol-5yl)pyrrolidin-2-yl] -6-fluoro-1 H-bcnzi midazol-2-yl (pyrrolidin-1 -yl] -3 -methoxy-1 -oxobutan-2yl} carbamate

384

2016238925 07 Oct 2016 (2S,3R)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid (65.6 mg, 0.343 mmol) was dissolved in anhydrous CH₂C1₂ (1 mL) under nitrogen. EDAC (67.1 mg, 0.343 mmol) was added, and the mixture was stirred at 20 °C for 20 minutes. The resulting solution was added via to a solution of (S)-6,6'-((2R,5R)-l-(4-(4-/ert-butylpiperidin-l-yl)-3,5-difluorophenyl)pyrrolidine-2,5-diyl)bis(55 fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole) hydrochloride (100 mg) and diisopropylamine (0.200 mL, 1.143 mmol) in anhydrous CH₂C1₂ (2 mL) under nitrogen. HOBt hydrate (52.5 mg, 0.343 mmol) was added, and the mixture was stirred at 20 °C for 1 hour. The reaction was diluted with CH₂C1₂ (50 mL), washed with water (25 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation to a dark yellow foam (140 mg). The crude material (70 mg) was dissolved in acetonitrile (2 mL) and 0.1% TFA in H₂O (2 mL), and purified by RP-C_i8 HPLC (Waters Prep LC, 40 mm module with Nova-Pak® HR Cl8 6pm 40* 100mm Prep Pak cartridge) eluting with a 30 minute gradient of 95:5 0.1% TFA in H₂O/acetonitrile to 25:75 0.1% TFA in H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 mL/minute. Pure fractions were treated with saturated aqueous NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize TFA, and the fractions were combined in a 500-mL round bottom flask. The remaining 70 mg of material was purified by prep-HPLC as described above and the pure product-containing fractions were treated with saturated aqueous NaHCO₃ as above and combined in the same 500-mL round bottom flask. The acetonitrile was removed by rotary evaporation, the remaining aqueous phase was extracted with EtOAc (2x50 mL), the combined organic extracts were dried over anhydrous MgSO₄, filtered, and !0 concentrated by rotary evaporation to afford the product as a white solid (62 mg, 0.057 mmol). 'H

NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (s, 9 H), 0.92 (d, /=6.07 Hz, 2 H), 0.98 - 1.09 (m, 4 H), 1.12 - 1.22 (m, 2H), 1.44 - 1.63 (m, 3 H), 1.65 - 1.89 (m, 3 H), 1.91 -2.10 (m, 4 H), 2.11 -2.28 (m, 4 H),

2.73 - 2.92 (m, 4 H), 3.04 (d, /=1.73 Hz, 2 H), 3.13 (s, 3 H), 3.25 (d, /=3.47 Hz, 1 H), 3.41 - 3.50 (m,

H), 3.53 (s, 6 H), 3.72 - 3.92 (m, 4 H), 4.25 (q, /=7.99 Hz, 2 H), 5.02 - 5.17 (m, 2 H), 5.46 - 5.63 (m, 2 H), 5.79 - 6.00 (m, 2 H), 7.02 (d, /=6.72 Hz, 1 H), 7.08 - 7.18 (m, 2 H), 7.24 (d, /=8.02 Hz, 1

H), 7.33 (dd, /=10.36, 4.50 Hz, 1 H), 7.40 (dd, /=11.22, 6.23 Hz, 1 H), 11.84 - 12.63 (m, 2 H); MS (ESI+) m/z 1075 (M+H)⁺; MS (ESI-) m/z 1073 (M-H)’.

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Example 6.14 dimethyl ({(2R,5R)-l-[4-(4-tert-butylpiperidin-l-yl)-3,5-difluorophenyl]pyrrolidine-2,5-diyl}bis{(6fliioro-lf/-bcnzimidazolc-5.2-diyl)(2.S')pyrrolidinc-2. l-diyl|( I.S')-2-oxo-l-(tctrahydro-2f/-pyran-45 yl)ethane-2,1-diyl] })biscarbamate (S)-2-(Methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (74.5 mg, 0.343 mmol) was dissolved in anhydrous CH₂C1₂ (1 mL) under nitrogen. EDAC (67.1 mg, 0.343 mmol) was added, and the mixture was stirred at 20 °C for 20 minutes. The resulting solution was added to a solution of (S)-6.6'-((2R.5R)-l-(4-(4-/i77-biitylpipcridin-l-yl)-3.5-difliiorophcnyl)pyrrolidinc-2.50 diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole) hydrochloride (100 mg) and diisopropylethylamine (0.200 mL, 1.143 mmol) in anhydrous CH₂C1₂ (2 mL) under nitrogen. HOBt hydrate (52.5 mg, 0.343 mmol) was added, and the mixture was stirred at 20 °C for 1 hour. The reaction was diluted with CH₂C1₂ (50 mL), washed with water (25 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated by rotary evaporation to a dark yellow solid (210 mg). The impure material 5 (70 mg) was dissolved in 2 mL acetonitrile and 2 mL 0.1% TFA in H₂O, and purified by RP-C_i8

HPLC (Waters Prep LC, 40mm module with Nova-Pak® HR C18 6pm 40* 100mm Prep Pak cartridge) eluting with a 3 0 minute gradient of 95:5 0.1 % TFA in H₂O/acetonitrile to 25:750.1% TFA in H₂O/acetonitrile, then 10 minutes to 100% acetonitrile at 20 mL/minute. Pure fractions were treated with saturated aqueous NaHCO₃ (2 mL/tube), each tube was vortexed to thoroughly neutralize 20 TFA, and the fractions were combined in a 500-mL round bottom flask. The remaining material was purified in two 70 mg injections by prep-HPLC as described above, and the pure product-containing fractions were treated with saturated aqueous NaHCO₃ as above and combined in the same 500-mL round bottom flask. The acetonitrile was removed by rotary evaporation, the remaining aqueous phase was extracted with EtOAc (2x50 mL), the combined organic extracts were dried over 25 anhydrous MgSO₄, filtered, and concentrated by rotary evaporation to afford the product as a white solid (69 mg, 0.060 mmol). Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (s, 9 H), 0.89 - 1.01 (m, 1

H), 1.07 - 1.38 (m, 7 H), 1.39 - 1.63 (m, 6 H), 1.67 - 1.91 (m, 5 H), 1.92 - 2.05 (m, 4 H), 2.10 - 2.26 (m, 4 H), 2.71 - 2.95 (m, 5 H), 2.96 - 3.25 (m, 3 H), 3.52 (s, 6 H), 3.62 - 3.92 (m, 8 H), 4.06 - 4.23 (m,

386

Η), 5.10 (t, 7=6.23 Hz, 2 H), 5.39 - 5.65 (m, 2 H), 5.77 - 5.99 (m, 2 H), 7.01 (d, J=6.12 Hz, 1 H),

7.07 (d, 7=7.05 Hz, 1 H), 7.28 - 7.49 (m, 4 H), 11.78 - 12.42 (m, 2 H); MS (ESI+) m/z 1127 (M+H)⁺;

MS (ESI-) m/z 1125 (M-H)’.

2016238925 07 Oct 2016

ABS

Example 6.15 methyl {(2S,3R)-l-[(2S)-2-{5-[(2R,57/)-1-(3,5-difluoro-4-{4-[4-(trifluoromethyl)phenyl]piperazin-lyl }phcnyl)-5-(6-fliioro-2-{(2.S')-l-|A'-(mcthoxycarbonyl)-G-mcthyl-L-thrconyl |pyrrolidin-2-yl [-IHbenzimidazol -5 -yl)pyrrolidin-2-yl] -6 -fluoro-I H-bcn zi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methoxy-1 0 oxobutan-2-yl} carbamate (S)-6,6'-((2R,5R)-l-(3,5-Difluoro-4-(4-(4-(trifluoromethyl)phenyl)piperazin-lyl)phenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole) hydrochloride (88 mg), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (41 mg, 0.216 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (46 mg, 0.238 mmol), 15 hydroxybenzotriazole hydrate (36 mg, 0.238 mmol) and 4-methylmorpholine (0.095 mL, 0.864 mmol) were dissolved in DMF (3.0 mL), and the mixture stirred at room temperature for 3 hours. Afterwards, an isopropyl alcohol and chloroform mixture was added then extracted with 1 N aqueous hydrochloric acid. The organic extract was dried, filtered and concentrated, and then the residue was purified by chromatography (silica gel, methanol in dichloromethane) which afforded 71 mg of the title compound. Ή NMR (400 MHz, DMSO-7,) δ ppm 7.56 (m, 2H), 7.48 (d, J=8.8Hz, 2H), 7.34 (m,

2H), 7.18 (m, 2H), 7.04 (d, J=8.6Hz, 2H), 5.97 (m, 2H), 5.62 (m, 2H), 5.17 (m, 2H), 4.28 (m, 2H),

3.82 (m, 2H), 3.60 (m, 2H), 3.54 (s, 6H), 3.25 (m, 8H), 3.17 (s, 6H), 2.99 (m, 4H), 2.05 (m, 12H),

1.25 (m, 6H); MS (ESI) m/z 1164 (M+H)⁺.

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methyl {(2S)-l-[(2S)-2-{6-[(27?,57?)-l-{4-[4-(2,6-difluorophenyl)piperazin-l-yl]-3,5-difluorophenyl}5-{5-fluoro-2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-lH5 benzimidazol -6 -yl} pyrrolidin-2-yl] -5 -fluoro-1 H-benzi m i dazol -2 -yl} pyrrolidin-1 -yl] -3 -methyl-1 oxobutan-2 -yl} carbamate (S)-2-(Methoxycarbonylamino)-3-methylbutanoic acid (0.072 g, 0.410 mmole) and HOBt (0.063 g, 0.410 mmole) were combined in DMF (2 mL). To the clear solution was added EDAC (0.079 g, 0.410 mmole) with a 0.2 ml DMF rinse, and the resulting clear solution was stirred at room 0 temperature for 20 minutes. (S)-6,6'-((2R,5R)-l-(4-(4-(2,6-Difluorophenyl)piperazin-l-yl)-3,5difluorophenyl)pyrrolidine-2,5-diyl)bis(5-fluoro-2-((S)-pyrrolidin-2-yl)-lH-benzo[d]imidazole) hydrochloride (0.160 g) was dissolved in 2 ml DMF, treated with N-methylmorpholine (1.863 mmol, 0.205 ml), and then treated with the activated amino acid solution and the resulting clear brown solution was stirred at room temperature for 1 hour. The pH of the solution was measured to be 8 by .5 pH paper. Reaction progress was determined by LC-MS at 1 hour and analysis deemed reaction complete. The reaction mixture was concentrated in vacuo to a brown mobile oil. The oil was diluted with 50 ml EtOAc and washed with 30 mL 10% NaHCO₃. The layers were separated and the aqueous layer was extracted with another 50 mL EtOAc. The combined organic extracts were washed with 10% NaCl, dried over anhydrous Na₂SO₄(s), filtered and solvent removed in vacuo leaving a brown 20 oily residue. The residue was purified on a 12 g silica gel column eluted with a gradient of CH₂C1₂/CH₃OH, 99/1 to 95/5 over 13 minutes, then 95/5 to 90/10 over 8 minutes. The fractions containing product were combined and repurified on a 12 g gold column eluted with a gradient of CH₂C1₂/CH₃OH, 98/2 to 90/10 over 15 minutes. The fractions were concentrated in vacuo leaving a light brown solid as the title compound (50.3 mg). 'H NMR (400 MHz, DMSO-r/₆) δ ppm 0.82 (m, 25 12 H) 1.99 (m, 9 H) 2.18 (m, 2 H) 2.95 (m, 4 H) 3.05 - 3.17 (m, 5 H) 3.53 (s, 6 H) 3.79 (m, 4 H) 3.95

- 4.11 (m, 4 H) 5.11 (m, 2 H) 5.55 (m, 2 H) 5.91 (m, 2 H) 7.01 (m, 5 H) 7.29 (m, 4 H) 12.14 (m, 2 H); MS (ESI+) m/z 1100.3, (ESI-) m/z 1098.3(M-H)’.

388

2016238925 07 Oct 2016

Example 7.1 methyl {(25)-1-[(25)-2-(4-{4-[2-(4-/ert-butylphenyl)-l-(4-{2-[(25)-l-{(25)-2[ (methoxy carbonyl) amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-\ m i dazol -4 -yl} phenyl) - lH-pyrrol5 3 -yl]phenyl} -1 H-\ midazol-2-yl )pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

Example 7.1 A

2-(4-bromophcnylamino)-2-(4-/i77-butylphcnyl)acctonitrilc

To a solution of 4-bromoaniline (10.0 g, 58.1 mmol) in THF (100 mL) was added 4-tertbutylbenzaldehyde (9.72 mL, 58.1 mmol), acetic acid (13.3 mL, 233 mmol), potassium cyanide (3.79 g, 58.1 mmol) and water (50 mL). The resultant mixture was stirred at room temperature for 16 hours. The resultant solid that formed was collected by vacuum filtration, washed with hexane, and then dried to afford 15.3 g, (77%) of the title compound. 'H NMR (400 MHz, CDC1₃) δ ppm 7.49 (m,

4H), 7.37 (d, J=8.7 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 5.34 (d, J=8.1 Hz, 1H), 4.02 (d, J=8.0 Hz, 1H),

1.34 (s, 9H).

Example 7. IB (£)-3 -(4-bromophenyl)prop-2-en-1 -ol

To a solution of (£)-ethyl 3-(4-bromophenyl)acrylate (10.0 g, 39.2 mmol) in dichloromethane (151 mL) cooled to -78°C was added a solution of diisobutylaluminum hydride (1.0 M in dichloromethane, 82 mL, 82 mmol) dropwise over 15 minutes time. The solution was then stirred for an additional 2 hours followed by the addition of a solution of 10% aqueous sodium hydroxide (250 mL). The mixture was allowed to warm to room temperature, and then the mixture was extracted with dichloromethane. The organic layer was dried and concentrated to afford 8.35 g (100%) of the title compound used directly in the next reaction.

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Example 7.1C (/7)-3-(4-bromophcnyl)acryl aldehyde

To the product of Example 7. IB (8.35 g, 39.2 mmol) dissolved in dichloromethane (151 mL) was added pyridinium dichromate (22.11 g, 58.8 mmol), and the resultant mixture was stirred for 16 hours at room temperature. A solution of hexane was added, and the resultant mixture filtered through diatomaceous earth, and then concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried and then concentrated. The residue was purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 5.5 .0 g, (67%) of the title compound. Ή NMR (400 MHz, CDCfi) δ ppm 9.62 (d, J=7.6 Hz, 1H), 7.57 (d,

J=8.5 Hz, 2H), 7.42 (m, 3H), 6.70 (dd, J=15.9, 7.6 Hz, 1H).

Example 7. ID .5 l.3-bis(4-bromophcnyl)-2-(4-/i77-butylphcnyl)-l//-pyrrolc

To the product of Example 7.1C (0.676 g, 3.2 mmol) and the product from Example 7.1A (1.0 g, 2.91 mmol) was added ethanol (30 mL) followed by potassium hydroxide (0.163 g, 2.91 mmol), and the mixture was stirred at room temperature for 16 hours. Afterwards the mixture was concentrated. The residue was partitioned between water and ethyl acetate. The organic layers were 20 combined, dried and then concentrated. The residue was purified by chromatography (silica gel, hexanes in ethyl acetate) which afforded 150 mg, (10%) of the title compound. 'H NMR (400 MHz, CDCfi) δ ppm 7.37 (m, 3H), 7.32 (d, J=8.5, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 6.93 (m, 4H), 6.51 (dd, J=2.9 Hz, 1H), 1.29 (s, 9H).

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Example 7. IE

2-(4-terAbutylphenyl)-l,3-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-127-pyrrole

A solution of the product from Example 7.ID (150 mg, 0.295 mmol), 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(l,3,2-dioxaborolane) (165 mg, 0.648 mmol), potassium acetate (87 mg, 8.84 5 mmol) and [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (21.6 mg, 0.029 mmol) in dioxane (5.5 mL) was heated at 100°C for 18 hours. The mixture was then filtered through diatomaceous earth and concentrated to an oil which was dissolved in EtOAc and extracted with brine. The organic extract was concentrated to afford 230 mg of the title compound that was used directly in the next step.

Example 7. IF di-tert-butyl (2S,2'S)-2,2'-{[2-(4-tert-butylphenyl)-127-pyrrole-l,3-diyl]bis(benzene-4,l-diyl-127imidazole-4,2-diyl)}dipyrrolidine-l-carboxylate (ACD Name vl2)

The product from Example 7. IE (227 mg, 0.376 mmol), (S)-tert-butyl 2-(5-bromo-127imidazol-2-yl)pyrrolidine-1 -carboxylate or (.S')-/i77-butyl 2-(4-bromo-I f/-imidazol-2-yl (pyrrolidine-1 carboxylate (357 mg, 1.13 mmol), [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (27.5 mg, 0.038 mmol), and a solution of sodium carbonate (1.0 M in water, 1.13 mL, 1.13 mmol) were heated in a solution of ethanol (3 mL) and toluene (3 mL) at 85°C !0 for 18 hours. The mixture then had water (10 mL) added followed by extraction with EtOAc (2x10 mL). The organic extract was dried, filtered and concentrated, and then the residue was purified by chromatography (silica gel, methanol in dichloromethane) which afforded 29 mg, (9 %) of the title compound; MS (ESI) m/z 823 (M+H)⁺.

Example 7.1G

4,4'-{[2-(4-tert-butylphenyl)-127-pyrrole-l,3-diyl]dibenzene-4,l-diyl}bis{2-[(2S)-pyrrolidin-2-yl]-127imidazole} (ACD Name vl2)

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The product of Example 7. IF (29 mg, 0.035 mmol) was dissolved in dioxane (0.5 mL) and hydrochloric acid in dioxane (4.0 TV, 0.14 mL, 0.54 mmol) was added. The mixture was stirred at room temperature for 4 hours. Afterwards the mixture was concentrated to afford the title compound as a hydrochloride salt. MS (ESI) m/z 622 (M+H)⁺.

Example 7.1H methyl {(25)-1 -| (25)-2-(4- {4-| 2-(4-/<?r/-bntylphcnyl)-1 -(4-{ 2-| (25)-1 - {(25)-2[ (methoxy carbonyl) amino] -3 -methylbutanoyl} pyrrolidin-2-yl] -1 H-i m i dazol -4 -yl} phenyl) - lH-pyrrol3-yl]phenyl}-I H-i midazol-2-yl [pyrrol idi η-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

The product from Example 7.1G (22 mg, 0.036 mmol), (5)-2-(methoxycarbonylamino)-3methylbutanoic acid (12.7 mg, 0.072 mmol), N-(3-dimethylaminopropyl)-Ν’-ethylcarbodiimide hydrochloride (15.2 mg, 0.079 mmol), 1-hydroxybenzotriazole hydrate (12.2 mg, 0.079 mmol) and 4methylmorpholine (0.021 mL, 0.29 mmol) were dissolved in DMF (0.7 mL), and the mixture was stirred at room temperature for 3 hours. Afterwards, 1 N aqueous hydrochloric acid (5 mL) was added 5 followed by extraction with dichloromethane (2x5 mL). The organic extract was dried, filtered and concentrated. Then the residue was purified by chromatography (silica gel, methanol in dichloromethane) which afforded 3.3 mg, (10 %) of the title compound. 'H NMR (400 MHz, DMSOd₆) δ ppm 10.57 (s, 1H), 10.26 (s, 1H), 7.62 (m, 4H), 7.20 (m, 8H), 6.99 (m, 4H), 5.37 (m, 2H), 5.24 !0 (m, 2H), 4.30 (m, 2H), 3.80 (m, 2H), 3.08 (m, 1H), 2.96 (s, 3H), 2.88 (s, 3H), 2.30 (m, 2H), 2.19 (m, 2H), 2.08 (m, 2H), 1.92 (m, 2H), 1.23 (m, 9H), 0.85 (m, 12H); MS (ESI) m/z 936 (M+H)⁺.

ABS

-NO

Example 8 dimethyl ({(25)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]pyrrolidine-2,5-diyl}bis{4,lphenylenecarbamoyl(25)pyrrolidine-2,1 -diyl [(25)-3 -methyl-1 -oxobutane-1,2 -diyl]} )biscarbamate

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Example 8A l-(4-((2S,5S)-2,5-bis(4-nitrophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-phenylpiperidine

A mixture of Intermediate 6 (2.68 g, 5.49 mmol), 3,5-difluoro-4-(4-phenylpiperidin-lyl)aniline (1.90 g, 6.58 mmol) and diisopropylethylamine (9.58 mL, 54.9 mmol) in DMF (18.3 mL) was heated at 60 °C for 18 hours. Afterwards ethyl acetate was added to the solution followed by extraction with water. The organic extract was dried, filtered and concentrated then the residue purified by chromatography (silica gel, ethyl acetate in hexanes) which afforded 197 mg, (6 %) of the 0 title compound. MS (ESI) m/z 585 (M+H)⁺.

Example 8B

4,4'-((2S,5S)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5-diyl)dianiline

The product of Example 8A (197 mg, 0.337 mmol) was dissolved in a mixture of THF (3 mL), ethanol (3 mL) and water (0.5 mL), and then iron (95 mg, 1.69 mmol) and ammonium chloride (27 mg, 0.506 mmol) were added and the mixture heated at 80 °C for 3 hours. Afterwards ethyl acetate was added to the solution followed by extraction with sodium bicarbonate. The organic extract was dried, filtered and concentrated which afforded 177 mg (100%) of the title compound. 20 MS (ESI) m/z 525 (M+H)⁺.

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Example 8C (2S,2'S)-tert-butyl 2,2'-(4,4'-((2S,5S)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine2,5-diyl)bis(4,1 -phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-l -carboxylate

The product from Example 8B (177 mg, 0.337 mmol), (S)-l-(tertbutoxycarbonyl)pyrrolidine-2-carboxylic acid (160 mg, 0.742 mmol), N-(3-dimethylaminopropyl)N’-ethylcarbodiimide hydrochloride (162 mg, 0.843 mmol), 1-hydroxybenzotriazole hydrate (129 mg, 0.843 mmol) and 4-methylmorpholine (0.370 mL, 3.37 mmol) were dissolved in dichloromethane (3.5 mL), and the mixture stirred at room temperature for 19 hours. Afterwards, aqueous sodium 0 bicarbonate was added followed by extraction with dichloromethane. The organic extract was dried, filtered and concentrated, and then the residue was purified by chromatography (silica gel, methanol in dichloromethane) which afforded 130 mg, (42 %) of the title compound. MS (ESI) m/z 920 (M+H)⁺.

Example 8D (2S,2'S)-N,N'-(4,4'-((2S,5S)-l-(3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl)pyrrolidine-2,5diyl)bis(4,1 -phenylene))dipyrrolidine-2 -carboxamide

The product of Example 8C (130 mg, 0.141 mmol) was dissolved in dichloromethane (2.7 20 mL) and trifluoroacetic acid (0.27 mL, 3.5 mmol) and the mixture was stirred at room temperature for 1 hour. Afterwards the mixture was concentrated, the residue was dissolved in an isopropyl alcohol and chloroform mixture and then extracted with aqueous sodium bicarbonate. The organic phase was then dried and concentrated to afford 100 mg (99%) of the title compound. MS (ESI) m/z 719 (M+H)⁺.

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Example 8E dimethyl ({(25)-1 -[3,5 -difluoro-4-(4-phenylpiperidin-1 -yl)phenyl]pyrrolidine-2,5 diyl} bis {4,1 -phcnylcnccarbamoyl(2.S')pyrrolidinc-2.1 -di y 11 (2,S) -3 -methyl-1 -oxobutane-1,2diyl] })biscarbamate

The product from Example 8D (100 mg, 0.142 mmol), (S)-2-(methoxycarbonylamino)-3methylbutanoic acid (60 mg, 0.341 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (68 mg, 0.355 mmol), 1-hydroxybenzotriazole hydrate (54 mg, 0.355 mmol) and 4methylmorpholine (0.156 mL, 1.42 mmol) were dissolved in DMF (1.5 mL), and the mixture was stirred at room temperature for 19 hours. Afterwards, an isopropyl alcohol and chloroform mixture 0 was added and then extracted with aqueous sodium bicarbonate. The organic extract was dried, filtered and concentrated, and then the residue was purified by chromatography (silica gel, methanol in dichloromethane) which afforded 20 mg, (14 %) of the title compound. 'H NMR (400 MHz, DMSO-®,) δ ppm 10.03 (s, 2H), 7.53 (d, J = 8.5Hz, 4H), 7.30 (m, 9H), 5.83 (d, J= 12.6 Hz, 2H), 5.18 (m, 2H), 5.08 (m, 2H), 4.43 (m, 2H), 4.02 (m, 4H), 3.61 (m, 2H), 3.54 (s, 6H), 2.98 (m, 4H), 2.18 (m,

2H), 1.93 (m, 6H), 1.70 (m, 6H), 0.81 (m, 12H); MS (ESI) m/z 1033 (M+H)⁺.

Example 9 methyl {(25)-l-[(25)-2-(4-{4-[(2R,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-(4-{220 [(25)-1 - {(25)-2-[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2-yl] - 127-imidazol-4yl }phenyl)pyrrolidin-2-yl]phenyl} -1 H-i midazol-2-yl )pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-2yl} carbamate

395

Example 9A l-(4-((2R,5R)-2,5-bis(4-bromophenyl)pyrrolidin-l-yl)-2,6-difluorophenyl)-4-phenylpiperidine

A mixture of Intermediate 7 (2.35 g, 4.22 mmol), 3,5-difluoro-4-(4-phenylpiperidin-lyl)aniline (2.44 g, 8.45 mmol) and diisopropylethylamine (2.21 mL, 12.67 mmol) in acetonitrile (25 mL) was heated at 80°C for 9 hours. Afterwards the resultant solid was removed by fdtration and purified by chromatography (silica gel, hexanes in ethyl acetate then dichloromethane in hexanes) which afforded 130 mg, (4.7%) of the title compound. MS (ESI+) m/z 653 (M+H)⁺.

2016238925 07 Oct 2016

Example 9B l-(4-((2R,5R)-2,5-bis(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-l-yl)-2,6difluorophenyl) -4 -phenylpiperidine

A solution of the product from Example 9A (130 mg, 0.199 mmol), 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(l,3,2-dioxaborolane) (121 mg, 0.478 mmol), potassium acetate (59 mg, 0.598 mmol) and [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.04 mmol) in dioxane (4.5 mL) was heated at 100 °C for 3 hours. The mixture was then filtered through diatomaceous earth and concentrated to an oil which was dissolved in EtOAc and extracted with 1 3V aqueous hydrochloric acid. The organic extract was dried, filtered and concentrated, and then the residue was purified by chromatography (silica gel, ethyl acetate in hexanes) which afforded 50 mg, 20 (34 %) of the title compound. MS (ESI) m/z 747 (M+H)⁺.

Example 9C (2S,2'S)-tert-butyl 2,2'-(4,4'-(4,4'-((2R,5R)-l-(3,5-difluoro-4-(4-phenylpiperidin-lyl)phenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))bis(lH-imidazole-4,2-diyl))dipyrrolidine-lcarboxylate

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The product from Example 9B (50 mg, 0.067 mmol), Intermediate 1 (64 mg, 0.201 mmol), [l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.1 mg, 0.0084 mmol), and sodium carbonate (1.0 M in water, 0.27 mL, 0.27 mmol) were heated in ethanol (1.5 mL) and toluene (1.5 mL) at 85 °C for 17 hours. Water (10 mL) was added to the mixture followed by extraction with 5 dichloromethane. The organic extract was dried, filtered and concentrated, and then the residue was purified by chromatography (silica gel, methanol in dichloromethane) which afforded 51 mg, (79 %) of the title compound. MS (ESI) m/z 966 (M+H)⁺.

Example 9D l-(4-((2R,5R)-2,5-bis(4-(2-((S)-pyrrolidin-2-yl)-lH-imidazol-4-yl)phenyl)pyrrolidin-l-yl)-2,6difluorophenyl) -4 -phenylpiperidine

The product of Example 9C (50 mg, 0.052 mmol) was dissolved in dioxane (1.5 mL) and hydrochloric acid in dioxane (4.0 Λζ 0.65 mL, 2.6 mmol), and the mixture was stirred at room .5 temperature for 4 hours. Afterwards the mixture was concentrated to afford the title compound as a hydrochloride salt. MS (ESI) m/z 765 (M+H)⁺.

Example 9E methyl {(2S)-l-[(2S)-2-(4-{4-[(2R,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-(4-{220 [(25)-1 - {(2.S')-2-| (mcthoxycarbonyl )ami no | -3 -methylbutanoyl} pyrrolidin-2-yl] - I H-i midazol -4yl }phenyl)pyrrolidin-2-yl]phenyl} -1 H-\ midazol-2-yl )pyrrol idi η-1 -yl] -3 -methyl-1 -oxobutan-2 yl} carbamate

The product from Example 9D (40 mg, 0.052 mmol), (S)-2-(methoxycarbonylamino)-3methylbutanoic acid (18.3 mg, 0.105 mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide 25 hydrochloride (22.1 mg, 0.115 mmol), 1-hydroxybenzotriazole hydrate (17.6 mg, 0.115 mmol) and 4methylmorpholine (0.046 mL, 0.418 mmol) were dissolved in DMF (1.5 mL), and the mixture was stirred at room temperature for 19 hours. Afterwards, 1 N aqueous hydrochloric acid was added followed by extraction with dichloromethane. The organic extract was dried, filtered and concentrated, and then the residue was purified by chromatography (silica gel, methanol in 30 dichloromethane) which afforded 25 mg, (44 %) of the title compound. 'H NMR (400 MHz, DMSOd₆) δ ppm 7.64 (m, 5H), 7.23 (m, 11H), 5.89 (d, J= 12.8 Hz, 2H), 5.23 (m, 2H), 5.08 (m, 2H), 4.06 (m,

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2H), 3.80 (m, 4H), 3.53 (s, 6H), 2.96 (m, 4H), 2.18 (m, 2H), 1.99 (m, 6H), 1.70 (m, 6H), 0.83 (m,

12H); MS (ESI) m/z 1080 (M+H)⁺.

From the product of General Procedure 11C, the compounds of Examples 10.1 and 10.2 can be obtained by the steps of: (1) coupling with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid; (2) removal of the single Boe protecting group; and (3) coupling with a second selected carbamateprotected amino acid.

ABS

Example 10.1 methyl [(l_lS)-2-[(2S,3a5',6aS)-2-{5-[(27?,57?)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2[(2S,3a5',6aS)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[6]pyrrol-

2-yl ]-177-benzimidazol-5-yl }pyrrolidin-2-yl ]-177-benzimidazol-2-yl }hexahydrocyclopenta[6]pyrrol- (2/7) -yl] -2 -oxo -1 -(tetrahydro-277-pyran-4-yl)ethyl] carbamate

Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.70 - 0.91 (m, 6 H) 1.10 - 1.27 (m, 2 H) 1.34 - 1.49 (m, 8 H) .5 1.50 - 1.64 (m, 4 H) 1.65 - 1.81 (m, 4 H) 1.84 - 2.03 (m, 6 H) 2.05 - 2.18 (m, 4 H) 2.36 - 2.46 (m, 4 H)

2.72 - 2.86 (m, 6 H) 3.02 - 3.21 (m, 2 H) 3.54 (s, 6 H) 3.70 - 3.89 (m, 2 H) 3.97 - 4.17 (m, 2 H) 4.72 4.86 (m, 2 H) 5.07 - 5.20 (m, 2 H) 5.32 - 5.43 (m, 2 H) 5.84 - 5.94 (m, 2 H) 7.07 (t, J=10.08 Hz, 2 H)

7.17 - 7.27 (m, 2 H) 7.30 - 7.56 (m, 4 H) 11.92 - 11.99 (m, 1 H) 12.03 - 12.13 (m, 1 H); MS (ESI+) m/z 1073.4 (M+H)⁺.

ABS

Example 10.2

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2016238925 07 Oct 2016 methyl {(2S,3R)-l-[(2S,3aS,6aS)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(piperidin-l-yl)phenyl]-5-{2[(2S,3aS',6aS)-l-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[6]pyrrol2-yl ]-lH-benzimidazol-5-yl }pyrrolidin-2-yl ]-lH-benzimidazol-2-yl }hexahydrocyclopenta[6]pyrrol1 (2H) -y 1 ] -3 -methoxy-1 -oxobutan-2-yl} carbamate

Ή NMR (400 MHz, DMSO-4,) δ ppm 0.70 - 0.89 (m, 6 H) 0.99 (ddd, J=34.43, 6.29, 3.31 Hz, 3 H)

1.35 - 1.48 (m, 6 H) 1.50 - 1.63 (m, 4 H) 1.66 - 1.80 (m, 6 H) 1.83 - 2.00 (m, 6 H) 2.05 - 2.16 (m, 4 H)

2.72 - 2.83 (m, 4 H) 3.17 (s, 3 H) 3.21 - 3.28 (m, 4 H) 3.54 (s, 6 H) 4.02 (t, J=7.48 Hz, 1 H) 4.20 4.30 (m, 1 H) 4.80 (t, J=7.97 Hz, 2 H) 5.08 - 5.17 (m, 2 H) 5.32 - 5.43 (m, 2 H) 5.83 - 5.94 (m, 2 H)

7.05 (dd, J=8.24, 1.30 Hz, 2 H) 7.21 (s, 1 H) 7.30 (d, J=3.14 Hz, 1 H) 7.40 (d, J=7.92 Hz, 1 H) 7.45 0 7.56 (m, 3 H) 11.99 (dd, J=9.87, 1.63 Hz, 1 H) 12.04 - 12.13 (m, 1 H); MS (ESI+) m/z 1047.5 (M+H)⁺.

From the product of General Procedure 8B, Example IB (mono-displacement), the compounds of Examples 11.1 and 11.2 can be obtained by the steps of: (1) Buchwald reaction with an appropriate .5 second amide (see General Procedure 8); (2) nitro reduction (see General Procedure 9); and (3) cyclization (see General Procedure 10).

ABS

Example 11.1 methyl [(lS)-2-[(2S)-2-{5-[(2R,5R)-l-[3,5-difluoro-4-(4-phenylpiperidin-l-yl)phenyl]-5-{2-[(2S)-l20 {(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl }pyrrolidin-2-yl ]-lH-benzimidazol-5yl [ pyrrolidin-2-yl |-17/-bcnzimidazol-2-yl [ pyrrolidin-1 -yl]-2-oxo-1 -(tetrahydro-2H-pyran-4yl)ethyl]carbamate

Ή NMR (400 MHz, DMSO-d₆) δ ppm 0.74 - 0.91 (m, 6 H) 1.44 - 1.56 (m, 2 H) 1.62 - 1.75 (m, 6 H)

1.82 - 1.95 (m, 2 H) 1.97 - 2.07 (m, 4 H) 2.16 - 2.26 (m, 4 H) 2.87 - 3.16 (m, 7 H) 3.43 - 3.50 (m, 2 H)

3.53 (s, 6 H) 3.58 - 3.66 (m, 2 H) 3.70 - 3.78 (m, 2 H) 3.80 - 3.89 (m, 4 H) 4.06 (t, J=8.51 Hz, 2 H)

5.11-5.19 (m, 2 H) 5.33 - 5.43 (m, 2 H) 5.86 - 5.95 (m, 2 H) 7.06 - 7.11 (m, 2 H) 7.12 - 7.37 (m, 9 H)

7.42 (dd, J=7.92, 1.73 Hz, 1 H) 7.46 - 7.53 (m, 1 H) 12.04 - 12.20 (m, 2 H); MS (ESI+) m/z 1069.4 (M+H)⁺.

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Example 11.2 methyl {(25)-1 -| (25)-2-(5-{(2/?.5/?)-5-(2-cyclopcntyl-1 H-bcnzimidazol-5-yl)-1 -| 3.5-difluoro-4-(45 phenylpiperidin-1 -yl)phenyl]pyrrolidin-2-yl} -I H-bcnzi midazol-2-yl )pyrrolidi η-1 -yl]-3-methyl-1 oxobutan-2 -yl} carbamate 'HNMR (400 MHz, DMSO-4,) δ ppm 0.76 - 0.91 (m, 6 H) 1.59 - 1.73 (m, 10 H) 1.73 - 1.80 (m, 2 H)

1.83 - 1.94 (m, 4 H) 1.97 - 2.08 (m, 4 H) 2.16 - 2.24 (m, 1 H) 2.86 - 3.04 (m, 6 H) 3.19 - 3.29 (m, 1 H)

3.53 (s, 3 H) 3.79 -3.87 (m, 2 H) 5.11-5.19 (m, 1 H) 5.34 -5.42 (m, 2 H) 5.88 - 5.95 (m, 2 H) 7.03 0 7.11 (m, 2 H) 7.13 - 7.19 (m, 2 H) 7.20 - 7.27 (m, 4 H) 7.28 - 7.34 (m, 2 H) 7.40 (dd, J=13.88, 8.24

Hz, 1 H) 7.50 (d, J=8.02 Hz, 1 H) 12.05 (d, J=10.63 Hz, 1 H) 12.12 (d, J=3.90 Hz, 1 H); MS (ESI+) m/z 869.4 (M+H)⁺.

methyl {(25)-1-[(25)-2-(5-{3-[l-(4-tert-butylphenyl)-3-(3-{2-[(25)-l-{(25)-215 [(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] -1 H-i m i dazol-5 -yl} phenyl)azetidin-3 yl]phenyl} -I H-imidazol-2-yl )pyrrolidin-1 -yl] -3-methyl-1 -oxobutan-2-yl}carbamate

Example 12.1 A bi s (3 -bromophenyl)methanol

400

2016238925 07 Oct 2016 n-BuLi (26.5 mL, 42.4 mmol, 1.6M in hexane) was added to a solution of 1,3dibromobenzene (10 g, 42.4 mmol) in THF (50 mL) at -78 °C. After stirred for 2 h at -78 °C, the 3bromobenzaldehyde (7.84 g, 42.4 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm up to r.t. and stirred at 30 °C for 12 h. The reaction was quenched with aq.NH₄Cl (100 mL). The mixture was extracted with dichloromethane (80 mLx5). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether -Petroleum ether: EtOAc=20:l) to afford 8.4 g of the title compound (24.5 mmol, 58%). LC/MS: [M-18+1] = 325. ¹HNMR (DMSO-r/₆), 400MHz: δ 5.74 (d, 1H, 7=4.0 Hz), 6.19 (d, 1H, 7=4.4 Hz), 7.26-7.31 (m, 2H), 7.37-7.43 (m, 4H), 7.59 (s, 2 H).

Example 12. IB bi s (3 -bromophenyl)methanone

MnO₂ (21.61 g, 249 mmol) was added to a solution of bis(3-bromophenyl)methanol (8.4 g,

24.5 mmol) in dichloromethane (80 mL). The mixture was stirred at 25 °C for 12 h and then filtered. 5 The filter cake was washed with dichloromethane (60 mLx5). The filtrate was concentrated to afford

7.6 g of the title compound (22.3 mmol, 90%). LC/MS: [M+l] = 341. ¹HNMR (DMSO-r/₆), 400MHz: δ 7.52-7.56 (m, 2H), 7.71 (d, 2H, 7=7.2 Hz), 7.88-7.92 (m, 4H).

!0 Example 12. IC

2,2-bis(3-bromophenyl)oxirane

KOt-Bu (2.72 g, 24.26 mmol) was added to a stirred suspension of bis(3bromophenyl)methanone (7.5 g, 22.06 mmol) and trimethylsulfonium iodide (4.50 g, 22.06 mmol) in DMSO (20 mL) and the resulting mixture was stirred at 30 °C for 8 h. The mixture was diluted with 25 ethyl acetate (500mL), washed with water (500 mL x 3) and brine (500 mL). The organic layer was separated and evaporated in vacuo to afford the title compound which was used directly without further purification.

Example 12. ID

2,2-bis(3 -bromophenyl)propane-1,3 -diol

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A mixture of the crude 2,2-bis(3-bromophenyl)oxirane (7.4 g, 20.90 mmol) and ptoluenesulfonic acid monohydrate (360 mg, 2.1 mmol) in toluene (25 mL) was stirred at 95 °C for 1 h. The solution was washed with aq NaHCO₃ (10 mL) and water (20 mL). The organic layer was dried and concentrated. The residue was dissolved in EtOH (20 mL). To the solution was added 5 formaldehyde (15.56 mL, 209 mmol, 37% aqueous solution) and K₂CO₃ (1.44 g, 10.45 mmol). The mixture was stirred at 85°C for 12h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (60 mLx4). The combined organic layers were dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether-Petroleum ether: EtOAc=2:l) to afford 4.6 g of 2,2-bis(30 bromophenyl)propane-l,3-diol (11.9 mmol, 57% after two steps). LC/MS: [M-18+1] = 368. ¹HNMR (CDC1₃), 400MHz: δ 2.53 (brs, 2H), 2.41 (s, 4H), 7.09-7.20 (m, 4H), 7.36-7.40 (m, 4H).

OMs OMs

Example 12. IE

2,2-bis(3-bromophenyl)propane-l,3-diyl dimethane sulfonate

To a stirred solution of 2,2-bis(3-bromophenyl)propane-l,3-diol (6.0 g, 15.54 mmol) in dichloromethane (50 mL) at 0°C was added methanesulfonic chloride (27.1 g, 155 mmol) and Et₃N (17.3 mL, 124 mmol)to give an orange solution. The reaction mixture was stirred at 0 °C for lh, then at 40 °C for 8 h. The reaction was washed with aq. NH₄C1 (80 mL). The aqueous layer was extracted with dichloromethane (50 mLx3). The combined organic layers were dried and concentrated. The !0 residue was purified by chromatography (on silica gel column, Petroleum ether: EtOAc=2:1) to afford

3.2 g of the title compound (5.9 mmol, 38%). LC/MS: [M+18] = 560. ¹HNMR (CDC1₃), 400MHz: δ 2.93 (s, 6H), 4.49 (s, 4H), 7.15-7.48 (m, 8H).

Example 12. IF

3-azido-2,2-bis(3-bromophenyl)propyl methane sulfonate

To a solution of 2,2-bis(3-bromophenyl)propane-l,3-diyl dimethane sulfonate (3.6 g, 6.64 mmol) in DMPU (25 mL, 207 mmol) under N₂ was added NaN₃ (0.52 g, 7.97 mmol) with stirring. The mixture was heated to 110 °C for 5 h. After cooling to room temperature, the reaction mixture 30 was diluted with EtOAc (100 mL), and washed with water (30 mLx2) and brine (25 mL), dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with

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Petroleum ether: EtOAc=3:l) to afford 1.3 g of the title compound (2.66 mmol, 40%). LC/MS:

[M+18] = 507. ¹HNMR (CDC1₃), 400MHz: δ 2.83 (s, 3H), 4.07 (s, 2H), 4.77 (s, 2H), 7.07-7.09 (m,

2H), 7.21-7.31 (m, 4H), 7.44-7.46 (m, 2H).

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Example 12. IG diethyl 3,3 -bis(3 -bromophenyl)azetidin-1 -ylphosphonate

To a solution of 3-azido-2,2-bis(3-bromophenyl)propyl methanesulfonate (1.3 g, 2.66 mmol) in anhydrous toluene (10 mL) and anhydrous THF (5 mL) under N₂ was added triethyl phosphite (0.49 mL, 2.79 mmol) at 25 °C. The mixture was stirred for 18 h. The reaction was concentrated by 0 rotary evaporation in a dried apparatus. The residue was dried in vacuo, and used in the next reaction without further purification. The crude triethyl phosphorimidate was dissolved in anhydrous m-xylene (5 mL) under N₂ and heated in an oil bath at 150 °C for 12h. After cooled to room temperature, the solvent was removed by rotary evaporation (vacuum pump assisted) to give a thick light orange oil which was purified by prep-TLC (eluent with EtOAc: dichloromethane=l:5) to afford 960 mg of 5 diethyl 3,3-bis(3-bromophenyl)azetidin-l-ylphosphonate (1.9 mmol, 71% after two steps). LC/MS: [M+l] = 504. ¹HNMR (CDC1₃), 400MHz: δ 1.25-1.36 (m, 6H), 4.05-4.39 (m, 4H), 4.40 (d, 2H, J=5.2 Hz), 7.09-7.11 (m, 2H), 7.20-7.27 (m, 2H), 7.40-7.42 (m, 4H).

Example 12.1H

3,3 -bi s (3 -bromophenyl)azetidine

To a solution of diethyl 3,3-bis(3-bromophenyl)azetidin-l-ylphosphonate (960 mg, 1.9 mmol) in anhydrous dichloromethane (5 mL) under N₂ was added TFA (5 mL). The mixture was stirred at 20 °C for 3 h, then concentrated by rotary evaporation. The residue was dissolved in dichloromethane (20 mL) and washed with aq. NaHCO₃ (30 mL). The organic layer was dried and concentrated to afford 25 595 mg of the title compound (1.6 mmol, 85%) as a yellow oil which was used directly to next step without purification. LC/MS: [M+l] = 368.

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N

Example 12.11

3,3 -bi s (3 -bromophenyl)-1 -(4-tert-butylphenyl)azetidine

A mixture of 3,3-bis(3-bromophenyl)azetidine (60 mg, 0.163 mmol), 1-tert-butyl-45 iodobenzene (85 mg, 0.327 mmol), xantphos (9.46 mg, 0.016 mmol), Pd₂(dba)₃ (3.74 mg, 4.09 pmol) and tert-butoxide (18.85 mg, 0.196 mmol) in dioxane (5 mL) was stirred at 110 °C for 12 h. After the reaction was cooled to room temperature, water (15 mL) and dichloromethane (15 mL) was added. The aqueous phase was extracted with dichloromethane (15mLx3). The combined organic layers were dried and concentrated. The residue was purified by prep-HPLC (Instrument waters 2767 PHW004 0 Column YMC-Triart C18 150*20mm S-5um.l2nm Mobile Phase A: water (0.05% NH₄HCO₃) B: ACN Gradient 95-95% B in 8 min stop in 14 min Flow Rate(ml/min) 20.00 Detective Wavalength(nm) 214V254 Retention Time(min) 7.4 to afford 26 mg of the title compound (0.052 mmol, 31.8 % yield). LC/MS: [M+I] = 500.

Example 12.1 J l-(4-tert-butylphenyl)-3,3-bis(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidine

A mixture of 3,3-bis(3-bromophenyl)-l-(4-tert-butylphenyl)azetidine (50 mg, 0.100 mmol), bis(pinacolato)diboron (65.9 mg, 0.260 mmol), KOAc (58.8 mg, 0.599 mmol) and PdCl₂(dppf)20 CH₂C1₂ adduct (20.39 mg, 0.025 mmol) was stirred at 100 °C for 2 h under N₂. After cooling to room temperature, water (15 mL) and dichloromethane (15 mL) was added. The aqueous layer was extracted with dichloromethane (15mLx3). The combined organic layers were dried and concentrated. The residue was purified by prep-TLC (eluent with dichloromethane: hexane=l: 1) to afford 50 mg of the title compound (0.078 mmol, 78 % yield). LC/MS: [M-Ci₂H₂₀+l] = 430; [M-C₆H₁₀+l] = 512.

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Example 12. IK methyl {(25)-1-[(25)-2-(5-{3-[l-(4-tert-butylphenyl)-3-(3-{2-[(25)-l-{(25)-2[(methoxycarbonyl)amino] -3 -methylbutanoyl} pyrrolidin-2 -yl] -1 H-i m i dazol-5 -yl} phenyl)azetidin-3 5 yl]phenyl} -I H-i midazol-2-yl (pyrrol idin -1 -yl] -3 -methyl-1 -oxobutan-2-yl} carbamate

A mixture of l-(4-tert-butylphenyl)-3,3-bis(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl)azetidine (50 mg, 0.084 mmol), Intermediate 4 (66.0 mg, 0.177 mmol), PdCl₂(dppf)-CH₂C12 adduct (13.76 mg, 0.017 mmol) and K₂CO₃ (69.9 mg, 0.506 mmol) in dioxane (5 mL) was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with 0 dichloromethane (20 mL) and washed with aq. NH₄C1 (15 mLl). The aqueous layer was extracted with dichloromethane (15 mLx3), and the combined organic layers were washed with brine (25 mL), dried and concentrated. The residue was purified by prep-HPLC: Instrument waters 2767 PHW003 Column Boston C18 lOum 21*250mm Mobile Phase A:water(0.05%NH₄HC0₃); B:ACN Gradient 60-82% B in 8min, stop at 14min Flow Rate(ml/min) 30.00 Detective Wavelength(nm) 214V254 5 Retention Time(min) 8.32. The purity was 83% after first purification by prep-HPLC. The compound was further purified by prep-TLC (eluent with MeOH: dichloromethane=l: 15) to afford 22 mg of the title compound (0.024 mmol, 28.2 % yield). LC/MS: [M+l] = 926. 'HNMR (MeOD-ri₄), 400MHz: δ 0.77-0.85 (m, 12H), 1.18 (s, 9H), 1.88-2.23 (m, 10H), 3.07 (d, 2H, J= 6.4 Hz), 3.56 (s, 6H), 3.75-3.89 (m, 4H), 4.12-4.14 (m, 2H), 4.36-4.42 (m, 4H), 5.03-5.07 (m, 2H), 6.46-6.48 (m, 2H), 6.73-6.77 (m, !0 1H), 7.10-7.23 (m, 9H), 7.39-7.41 (m, 2H), 7.68-7.72 (m, 2H).

methyl {(25)-1-[(25)-2-(5-{3-[3-(3-{2-[(25)-l-{(25)-2-[(methoxycarbonyl)amino]-3methylbutanoyl {pyrrolidin-2-yl] -1 H-i midazol-5 -yl {phenyl)-1 -phenylazetidin-3 -yl] phenyl} - 1Himidazol -2 -yl)pyrrolidin-1 -yl] -3 -methyl -1 -oxobutan-2 -yl} carbamate

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N

Example 12.2 A

3,3 -bi s (3 -bromophenyl)-1 -phenylazetidine

A mixture of 3,3-bis(3-bromophenyl)azetidine (200 mg, 0.545 mmol), iodobenzene (222 mg, 5 1.090 mmol), xantphos (31.5 mg, 0.054 mmol), Pd₂(dba)₃ (12.47 mg, 0.014 mmol) and sodium tertbutoxide (62.8 mg, 0.654 mmol) in dioxane (3 ml) was stirred for 12 h at 100 °C. After cooling to room temperature, water (15 mL) and dichloromethane (15 mL) was added. The aqueous layer was extracted with dichloromethane (15mLx3). The combined organic layers were dried and concentrated. The residue was purified by prep-TLC (eluent with dichloromethane: EtOAc=5:1) to afford 140 mg of 0 the title compound (0.31 mmol, 58%). LC/MS: [M+l] = 444, Ret. Time: 2.69 min. ¹HNMR (CDC1₃), 400MHz: 4.42 (s, 4H), 6.54 (d, 2H, ./=7.6 Hz), 7.09-7.11 (m, 2H), 6.79 (t, 1H, ./=7.2 Hz), 7.17-7.26 (m, 6H), 7.37-7.45 (m, 4H).

Example 12.2B l-phenyl-3,3-bis(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidine

A mixture of 3,3-bis(3-bromophenyl)-l-phenylazetidine (140 mg, 0.284 mmol), KOAc (167 mg, 1.705 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (58.0 mg, 0.071 mmol) and bis(pinacolato)diboron (188 mg, 0.739 mmol) in dioxane (3 mL) was stirred at 110 °C for 2h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (20 mL) and washed with aq.

NH₄C1 (15 mL). The aqueous layer was extracted with dichloromethane (15 mLx3). The combined organic layers were washed with brine (25 mL). The organic layers was dried and concentrated. The crude product was purified by prep-TLC (eluent with dichloromethane: Hexane=l:2) to afford 142 mg of the title compound (0.209 mmol, 73.6 % yield). LC/MS: [M+l] = 538.

Example 12.2C

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2016238925 07 Oct 2016 methyl {(2S)-l-[(2S)-2-(5-{3-[3-(3-{2-[(2S)-l-{(2S)-2-[(methoxycarbonyl)amino]-3methylbutanoyl [pyrrolidin-2-yl] -1 H-\midazol-5 -yl [phenyl)-1 -phenylazetidin-3 -yl] phenyl} -\Himidazol -2 -yl)pyrrolidin-1 -yl] -3 -methyl -1 -oxobutan-2 -yl} carbamate

A mixture of l-phenyl-3,3-bis(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-25 yl)phenyl)azetidine (60 mg, 0.112 mmol), Intermediate 4 (88 mg, 0.235 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (18.24 mg, 0.022 mmol) and K₂CO₃ (93 mg, 0.670 mmol) in dioxane (5 mL) and water (1 mL) was stirred at 100 °C for 2 h under N₂. The reaction mixture was diluted with dichloromethane (20 mL) and washed with aq. NH₄C1 (15 mL). The aqueous phase was extracted with dichloromethane (15 mLx3). The combined organic layers was washed with brine (25 mL). The organic layers was dried and concentrated. The crude product was purified by prep-HPLC (Instrument waters 2767 PHW003 Column Boston C18 lOum 21*250mm Mobile Phase A:water (0.05%NH4HC03);B:ACN Gradient 45-70% B in 8min,stop at 14min Flow Rate(ml/min) 30.00 Detective Wavalength(nm) 214\254 Retention Time(min) 8.47. Then the compound was further purified by prep-TLC (eluent with MeOH : dichloromethane=l:15) to afford 20 mg of the title compound (0.022 mmol, 19.53 % yield). LC/MS: [M+l] = 870. 'HNMR (MeOD-J₄), 400MHz: δ 0.86-0.97 (m, 12H), 1.97-2.33 (m, 10H), 3.07 (d, 2H, J= 6.4 Hz), 3.66 (s, 6H), 3.83-3.99 (m, 5H), 4.21-4.23 (m, 2H), 4.49-4.55 (m, 5H), 5.13-5.16 (m, 2H), 6.61-6.63 (m, 2H), 6.73-6.77 (m, 1H), 7.19-7.58 (m, 12H), 7.78-7.80 (m, 2H).

The present invention also contemplates pharmaceutically acceptable salts of each title compound described in the above examples. All of the examples disclosed in U.S. Patent Application !0 Publication No. 2010/0317568 and U.S. Patent Application Serial Nos. 12/903,822 and 12/964,027 are also incorporated herein by reference.

When tested using HCV lb-Conl replicon assays in the presence of 5% FBS, each title compound in 1.1, 1.3, 1.5, 1.6, 1.7, 1.8, 2.1, 2.2, 2.4, 2.5, 2.6, 2.9, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 3.1, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.11, 3.12, 3.13, 3.15, 3.17, 3.18, 3.19, 3.20, 3.21, 3.22,

3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.30, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.40,

3.41, 3,42, 3.43, 3.44, 3.45, 3.46, 3.47, 3.48, 3.49, 3.50, 3.51, 3.52, 3.53, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6,

4.7, 4.8, 4.9, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.20, 4.21, 4.22, 4.23, 4.24, 4.26,

4.27, 4.28, 4.29, 4.30, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.40, 4.41, 4.42, 4.43, 4.44, 4.45, 4.46, 4.47, 4.49, 4.50, 4.51, 4.52, 4.53, 4.54, 4.55, 4.56, 4.57, 4.58, 4.59, 4.60, 4.61, 4.62, 5.1,

5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,

6.8, 6.9, 6.10, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16, 7.1, 8, 9, 10.1, 10.2, 11.1, and 11.2 showed an EC₅₀value of less than about 0.1 nM. When tested using HCV lb-Conl replicon assays in the presence of 5% FBS, each title compound in Examples 1.4, 2.8, 3.3, 3.9, 3.10, 3.16 and 4.25 showed an EC₅₀value of from about 0.1 to about 1 nM. When tested using HCV lb-Conl replicon assays in the presence of 5% FBS, each title compound in Examples 2.3, 2.7, 12.1 and 12.2 showed an EC₅₀ value

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2016238925 07 Oct 2016 of from about 1 to about 10 nM. The tile compounds of Example 1.2 and 3.14 showed an EC₅₀ value of over 10 μΜ when tested using HCV lb-Conl replicon assays in the presence of 5% FBS.

When tested using HCV 2a, 2b, 3a and 4a replicon assays in the absence of human plasma (HP), the EC₅₀ values of Example 5.1 were about at least 50-fold less than those of Example 4.25 (about 200-500 pM); and the EC₅₀ values of Example 3.20 were about at least 15 fold less than those of Example 4.25. The AUC value (as defined above) of Example 5.1 was about 30 fold greater than that of Example 2.9. When tested using HCV la replicon assays in the presence of 40% HP, the EC₅₀value of Example 6.1 against L31M, Y93H or Y93N mutant was at least 5-fold less than that of Example 109 (about 10-100 nM) of U.S. Patent Application Publication No. 2010/0317568 (U.S.

Patent Application Serial No. 12/813,301, hereinafter the ‘301 application); and the AUC value of Example 6.1 was about 9-fold greater than that of Example 109 of the ‘301 application. When tested using HCV 2a, 2b, 3a and 4a replicon assays in the absence of HP, the EC₅₀ values of Example 4.15, as well as Example 302 of the ‘301 application, were about 2-4 fold less than those of Example 163 (about 10-50 pM) of the ‘301 application. When tested using HCV 2b and 4a replicon assays in the absence of HP, the EC₅₀ values of Example 251 of the ‘301 application were about 2-fold less than those of Example 163 of the ‘301 application. When tested using HCV 2a, 2b, 3a and 4a replicon assays in the absence of HP, the EC₅₀ values of Example 120 of the ‘301 application were about at least 2-fold less than those of Example 164 (about 300-1200 pM) of the ‘301 application, and the EC₅₀values of Examples 245, 256 and 271 of the ‘301 application were at least about 10-fold less than !0 those of Example 164 of the ‘301 application; the AUC values of Example 245, 256 and 271 were at least about 10-fold greater than that of Example 164.

Each compound’s anti-HCV activity can be determined by measuring the activity of the luciferase reporter gene in the replicon in the presence of 5% FBS. The luciferase reporter gene is placed under the translational control of the poliovirus IRES instead of the HCV IRES, and HuH-7 25 cells are used to support the replication of the replicon.

The inhibitory activities of the compounds of the present invention can be evaluated using a variety of assays known in the art. For instance, two stable subgenomic replicon cell lines can be used for compound characterization in cell culture: one derived from genotype la-H77 and the other derived from genotype lb-Conl, obtained from University of Texas Medical Branch, Galveston, TX 30 or Apath, LLC, St. Louis, MO, respectively. The replicon constructs can be bicistronic subgenomic replicons. The genotype la replicon construct contains NS3-NS5B coding region derived from the H77 strain of HCV (la-H77). The replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. These two coding regions, separated by the FMDV 2a protease, comprise the first cistron of the bicistronic replicon construct, with the second cistron 35 containing the NS3-NS5B coding region with addition of adaptive mutations E1202G, K1691R, K2040R and S2204I. The lb-Conl replicon construct is identical to the la-H77 replicon, except that

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2016238925 07 Oct 2016 the HCV 5’ UTR, 3’ UTR, and NS3-NS5B coding region are derived from the lb-Conl strain, and the adaptive mutations are K1609E, K1846T and Y3005C. In addition, the lb-Conl replicon construct contains a poliovirus IRES between the HCV IRES and the luciferase gene. Replicon cell lines can be maintained in Dulbecco’s modified Eagles medium (DMEM) containing 10% (v/v) fetal 5 bovine serum (FBS), 100 IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen), and 200 mg/ml G418 (Invitrogen).

The inhibitory effects of the compounds of the invention on HCV replication can be determined by measuring activity of the luciferase reporter gene. For example, replicon-containing cells can be seeded into 96 well plates at a density of 5000 cells per well in 100 μΐ DMEM containing 0 5% FBS. The following day compounds can be diluted in dimethyl sulfoxide (DMSO) to generate a

200x stock in a series of eight half-log dilutions. The dilution series can then be further diluted 100-fold in the medium containing 5% FBS. Medium with the inhibitor is added to the overnight cell culture plates already containing 100 μΐ of DMEM with 5% FBS. In assays measuring inhibitory activity in the presence of human plasma, the medium from the overnight cell culture plates can be 5 replaced with DMEM containing 40% human plasma and 5% FBS. The cells can be incubated for three days in the tissue culture incubators after which time 30 μΐ of Passive Lysis buffer (Promega) can be added to each well, and then the plates are incubated for 15 minutes with rocking to lyse the cells. Luciferin solution (100 μΐ, Promega) can be added to each well, and luciferase activity can be measured with a Victor II luminometer (Perkin-Elmer). The percent inhibition of HCV RNA !0 replication can be calculated for each compound concentration and the EC₅₀ value can be calculated using nonlinear regression curve fitting to the 4-parameter logistic equation and GraphPad Prism 4 software. Using the above-described assays or similar cell-based replicon assays, representative compounds of the present invention showed significantly inhibitory activities against HCV replication.

The present invention also features pharmaceutical compositions comprising the compounds of the invention. A pharmaceutical composition of the present invention can comprise one or more compounds of the invention, each of which has Formula I (or I_A, I_B, I_c, I_D, I_E, I_E or I_G).

In addition, the present invention features pharmaceutical compositions comprising pharmaceutically acceptable salts, solvates, or prodrugs of the compounds of the invention. Without 30 limitation, pharmaceutically acceptable salts can be zwitterions or derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable salt retains the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation, or allergic response, has a reasonable benefit/risk ratio, is effective for the intended use, and is not biologically or otherwise undesirable.

The present invention further features pharmaceutical compositions comprising a compound of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. By way of

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2016238925 07 Oct 2016 illustration not limitation, these other therapeutic agents can be selected from antiviral agents (e.g., anti-HIV agents, anti-HBV agents, or other anti-HCV agents such as HCV protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, IRES inhibitors or NS5A inhibitors), anti-bacterial agents, anti-fungal agents, immunomodulators, anti-cancer or chemotherapeutic agents, anti5 inflammation agents, antisense RNA, siRNA, antibodies, or agents for treating cirrhosis or inflammation of the liver. Specific examples of these other therapeutic agents include, but are not limited to, ribavirin, α-interferon, β-interferon, pegylated interferon-α, pegylated interferon-lambda, ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Debio-025, NIM-811, R7128, R1626, R4048, T-1106, PSI-7977 (Pharmasset) (nucleoside polymerase inhibitor), PSI-7851 (Pharmasset) 0 (nucleoside polymerase inhibitor), PSI-938 (Pharmasset) (nucleoside polymerase inhibitor), PF00868554, ANA-598, IDX184 (nucleoside polymerase inhibitor), IDX102, IDX375 (non-nucleoside polymerase inhibitor), GS-9190 (non-nucleoside polymerase inhibitor), VCH-759, VCH-916, MK3281, BCX-4678, MK-3281, VBY708, ANA598, GL59728, GL60667, BMS-790052 (NS5A inhibitor), BMS-791325 (protease Inhibitor), BMS-650032, BMS-824393, GS-9132, ACH-1095 5 (protease inhibitor), AP-H005, A-831 (Arrow Therapeutics) (NS5A inhibitor), A-689 (Arrow

Therapeutics) (NS5A inhibitor), INX08189 (Inhibitex) (polymerase inhibitor), AZD2836, telaprevir (protease Inhibitor), boceprevir (protease Inhibitor), ITMN-191 (Intermune/Roche), BI-201335 (protease Inhibitor), VBY-376, VX-500 (Vertex) (protease Inhibitor), PHX-B, ACH-1625, IDX136, IDX316, VX-813 (Vertex) (protease Inhibitor), SCH 900518 (Schering-Plough), TMC-435 (Tibotec) !0 (protease Inhibitor), ITMN-191 (Intermune, Roche) (protease Inhibitor), MK-7009 (Merck) (protease

Inhibitor), IDX-PI (Novartis), BI-201335 (Boehringer Ingelheim), R7128 (Roche) (nucleoside polymerase inhibitor), MK-3281 (Merck), MK-0608 (Merck) (nucleoside polymerase inhibitor), PF868554 (Pfizer) (non-nucleoside polymerase inhibitor), PF-4878691 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset), PPI-461 (Presidio) (NS5A inhibitor), BILB-1941 (Boehringer Ingelheim), 25 GS-9190 (Gilead), BMS-790052 (BMS), Albuferon (Novartis), ABT-333 (Abbott) (non-nucleoside polymerase inhibitor), ABT-072 (Abbott) (non-nucleoside polymerase inhibitor), ritonavir, another cytochrome P450 monooxygenase inhibitor, or any combination thereof.

In one embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more 30 other antiviral agents.

In another embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other anti-HCV agents. For example, a pharmaceutical composition of the present invention can comprise a compound(s) of the present invention having Formula I, I_A, Ib, Ic, Id, Ie, If or I_G (or a salt, 35 solvate or prodrug thereof), and an agent selected from HCV polymerase inhibitors (including

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2016238925 07 Oct 2016 nucleoside or non-nucleoside type of polymerase inhibitors), HCV protease inhibitors, HCV helicase inhibitors, CD81 inhibitors, cyclophilin inhibitors, IRES inhibitors, orNS5A inhibitors.

In yet another embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other antiviral agents, such as anti-HBV, anti-HIV agents, or anti-hepatitis A, anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agents. Non-limiting examples of anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249, or other HIV protease, reverse transcriptase, integrase or fusion inhibitors. Any other desirable antiviral agents can also be included in a pharmaceutical composition of the present invention, as appreciated by those skilled in the art.

In a preferred embodiment, a pharmaceutical composition of the invention comprises a compound of the invention (e.g.., a compound of Formula I, I_A. Ib, Ic, Id, Ie, If or I_G, or preferably a compound described hereinabove, or a salt, solvate or prodrug thereof), and a HCV protease inhibitor. In another preferred embodiment, a pharmaceutical composition of the invention comprises a compound of the invention (e.g.., a compound of Formula I, I_A. I_B, Ic, Id, Ie, If or I_G, or preferably a compound described hereinabove, or a salt, solvate or prodrug thereof), and a HCV polymerase !0 inhibitor (e.g., a non-nucleoside polymerase inhibitor, or preferably a nucleoside polymerase inhibitor). In yet another preferred embodiment, a pharmaceutical composition of the present invention comprises (1) a compound of the invention (e.g.., a compound of Formula I, I_A. I_B, Ic, Id, Ie, If or I_G, or preferably a compound described hereinabove, or a salt, solvate or prodrug thereof), (2) a HCV protease inhibitor, and (3) a HCV polymerase inhibitor (e.g., a non-nucleoside polymerase 25 inhibitor, or preferably a nucleoside polymerase inhibitor). Non-limiting examples of protease and polymerase inhibitors are described above.

In still another embodiment, a pharmaceutical composition of the invention comprises (1) a compound of Formula I, I_A, Ib, Ic, Id, Ie, If or I_G, or preferably a compound selected from the title compounds of the above Examples or Table 5, or a salt, solvate or prodrug thereof, and (2) one or 30 more HCV inhibitors/modulators selected from ABT-072 (Abbott), ABT-333 (Abbott), ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), ACH-2928 (Achillion), alisporovir, ANA-598 (Anadys), ANA-773 (Anadys), AVL-181 (Avila), AVL-192 (Avila), AZD2836 (AstraZeneca), AZD7295 (Astra-Zeneca), BCX-4678 (BioCryst ), BI-201335 (Boehringer Ingelheim), BI207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-650032 (BMS), BMS35 790052 (BMS), BMS-791325 (BMS), BMS-824393 (BMS), boceprevir, CTS-1027 (Conatus), danoprevir, EDP-239 (Enanta), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-5885 (Gilead),

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GS-6620 (Gilead), GS-9132 (Gilead), GS-9256 (Gilead), GS-9451 (Gilead), GS-9620 (Gilead), GS9669 (Gilead), GSK625433 (GlaxoSmithKline), IDX-102 (Idenix), IDX-136 (Idenix), IDX-184 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix), IDX-375 (Idenix), INX-189 (Inhibitex), ITX-4520 (iTherx), ITX-5061 (iTherx), MK-0608 (Merck), MK-3281 (Merck), MK-5172 (Merck), narlaprevir,

NM-811 (Novartis), PF-4878691 (Pfizer), PHX-1766 (Phenomix), PPI-1301 (Presidio), PPI-461 (Presidio), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), RO5303253 (Roche), SCY-635 (Scynexis), tegobuvir, telaprevir, TMC-435 (Tibotec), TMC-647055 (Tibotec), TMC64912 (Medivir), vaniprevir, VBY708 (Virobay), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-500 (Vertex), VX-759 (Vertex), VX-813 (Vertex), 0 VX-985 (Vertex), or a combination thereof.

In another embodiment, a pharmaceutical composition of the invention comprises (1) a compound of Formula I, I_A, Ib, Ic, Id, Ie, If or I_G, or preferably a compound selected from the title compounds of the above Examples or Table 5, or a salt, solvate or prodrug thereof, and (2) one or more HCV protease inhibitors selected from ACH-1095 (Achillion), ACH-1625 (Achillion), ACH5 2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), BI-201335 (Boehringer Ingelheim), BMS650032 (BMS), boceprevir, danoprevir, GS-9132 (Gilead), GS-9256 (Gilead), GS-9451 (Gilead), IDX-136 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir, PHX-1766 (Phenomix), telaprevir, TMC-435 (Tibotec), vaniprevir, VBY708 (Virobay), VX-500 (Vertex), VX813 (Vertex), VX-985 (Vertex), or a combination thereof.

!0 In yet another preferred embodiment, a pharmaceutical composition of the invention comprises (1) a compound of Formula I, I_A, I_B, Ic, Id, Ie, If or I_G, or preferably a compound selected from the title compounds of the above Examples or Table 5, or a salt, solvate or prodrug thereof, and (2) one or more HCV polymerase inhibitors selected from ABT-072 (Abbott), ABT-333 (Abbott), ANA-598 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS25 791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix),

MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), 30 BCX-4678 (BioCryst), or a combination thereof. The polymerase inhibitor(s) can include (i) one or more nucleotide polymerase inhibitors selected from GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), INX-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), or a combination therefore; or (ii) one or more nonnucleoside polymerase inhibitors selected from ABT-072 (Abbott), ABT-333 (Abbott), ANA-598 35 (Anadys), BI-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir, GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK412

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3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or a combination thereof;

or (iii) both a nucleotide polymerase inhibitor(s) and a non-nucleoside polymerase inhibitor(s).

In a further embodiment, a pharmaceutical composition of the invention comprises (1) a compound of Formula I, I_A. Ib, Ic, Id, Ie, If or I_G, or preferably a compound selected from the title compounds of the above Examples or Table 5, or a salt, solvate or prodrug thereof, (2) one or more HCV protease inhibitors selected from ACH-1095 (Achillion), ACH-1625 (Achillion), ACH-2684 (Achillion), AVL-181 (Avila), AVL-192 (Avila), ΒΙ-201335 (Boehringer Ingelheim), BMS-650032 (BMS), boceprevir, danoprevir, GS-9132 (Gilead), GS-9256 (Gilead), GS-9451 (Gilead), IDX-136 (Idenix), IDX-316 (Idenix), IDX-320 (Idenix), MK-5172 (Merck), narlaprevir, PHX-1766 (Phenomix), telaprevir, TMC-435 (Tibotec), vaniprevir, VBY708 (Virobay), VX-500 (Vertex), VX813 (Vertex), VX-985 (Vertex), or a combination thereof, and (3) one or more HCV polymerase inhibitors selected from ABT-072 (Abbott), ABT-333 (Abbott), ANA-598 (Anadys), ΒΙ-207127 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir,

GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), ΙΝΧ-189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), GSK625433 (GlaxoSmithKline), BCX-4678 (BioCryst), ore !0 a combination thereof. The polymerase inhibitor(s) can include (i) one or more nucleotide polymerase inhibitors selected from GS-6620 (Gilead), IDX-102 (Idenix), IDX-184 (Idenix), ΙΝΧ189 (Inhibitex), MK-0608 (Merck), PSI-7977 (Pharmasset), PSI-938 (Pharmasset), RG7128 (Roche), TMC64912 (Medivir), or a combination therefore; or (ii) one or more non-nucleoside polymerase inhibitors selected from ABT-072 (Abbott), ABT-333 (Abbott), ANA-598 (Anadys), ΒΙ-207127 25 (Boehringer Ingelheim), BILB-1941 (Boehringer Ingelheim), BMS-791325 (BMS), filibuvir,

GL59728 (Glaxo), GL60667 (Glaxo), GS-9669 (Gilead), IDX-375 (Idenix), MK-3281 (Merck), tegobuvir, TMC-647055 (Tibotec), VCH-759 (Vertex & ViraChem), VCH-916 (ViraChem), VX-222 (VCH-222) (Vertex & ViraChem), VX-759 (Vertex), or a combination thereof; or (iii) both a nucleotide polymerase inhibitor(s) and a non-nucleoside polymerase inhibitor(s).

In still another embodiment, a pharmaceutical composition of the invention comprises (1) a compound of Formula I, I_A, I_B, Ic, Id, Ie, If or I_G, or preferably a compound selected from the title compounds of the above Examples or Table 5, or a salt, solvate or prodrug thereof, and (2) an cyclophilin inhibitor (e.g., alisporovir, NM-811 (Novartis), SCY-635 (Scynexis)), an entry inhibitor (e.g., ΙΤΧ-4520 (iTherx) or ΙΤΧ-5061 (iTherx)), another NS5A inhibitor (e.g., ), or a TLR-7 agonist 35 (e.g., GS-9620 (Gilead) or PF-4878691 (Pfizer)), and (3) optionally one or more HCV protease or polymerase inhibitors described above.

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A pharmaceutical composition containing multiple active ingredients can be either a coformulated product, a co-packaged product, or a combination thereof.

A pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable 5 carriers/excipients include sugars (e.g., lactose, glucose or sucrose), starches (e.g., com starch or potato starch), cellulose or its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose or cellulose acetate), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil or soybean oil), glycols (e.g., propylene glycol), buffering agents (e.g., magnesium hydroxide or aluminum hydroxide), agar, alginic acid, powdered tragacanth, malt, gelatin, talc, cocoa butter, 0 pyrogen-free water, isotonic saline, Ringer's solution, ethanol, or phosphate buffer solutions. Lubricants, coloring agents, releasing agents, coating agents, sweetening, flavoring or perfuming agents, preservatives, or antioxidants can also be included in a pharmaceutical composition of the present invention.

The pharmaceutical compositions of the present invention can be formulated based on their .5 routes of administration using methods well known in the art. For example, a sterile injectable preparation can be prepared as a sterile injectable aqueous or oleagenous suspension using suitable dispersing or wetting agents and suspending agents. Suppositories for rectal administration can be prepared by mixing dmgs with a suitable nonirritating excipient such as cocoa butter or polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore !0 melt in the rectum and release the dmgs. Solid dosage forms for oral administration can be capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose lactose or starch. Solid dosage forms may also comprise other substances in addition to inert diluents, such as lubricating agents. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can 25 additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, symps or elixirs containing inert diluents commonly used in the art. Liquid dosage forms may also comprise wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes, as described 30 in U.S. Patent No. 6,703,403. Formulation of drugs that are applicable to the present invention is generally discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975), and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker, New York, N.Y., 1980).

Any compound described herein, or a pharmaceutically acceptable salt thereof, can be used to 35 prepared pharmaceutical compositions of the present invention.

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In a preferred embodiment, a compound of the invention (e.g., a compound of Formula I, l_A.

lb, Ic, Id, Ie, If or I_G, or preferably a compound described hereinabove, or a salt, solvate or prodrug thereof) is formulated in a solid dispersion, where the compound of the invention can be molecularly dispersed in an amorphous matrix which comprises a pharmaceutically acceptable, hydrophilic polymer. The matrix may also contain a pharmaceutically acceptable surfactant. Suitable solid dispersion technology for formulating a compound of the invention includes, but is not limited to, melt-extrusion, spray-drying, co-precipitation, freeze drying, or other solvent evaporation techniques, with melt-extrusion and spray-drying being preferred. In one example, a compound of the invention is formulated in a solid dispersion comprising copovidone and vitamin E TPGS. In another example, 0 a compound of the invention is formulated in a solid dispersion comprising copovidone and Span 20.

A solid dispersion described herein may contain at least 30% by weight of a pharmaceutically acceptable hydrophilic polymer or a combination of such hydrophilic polymers. Preferably, the solid dispersion contains at least 40% by weight of a pharmaceutically acceptable hydrophilic polymer or a combination of such hydrophilic polymers. More preferably, the solid dispersion contains at least .5 50% (including, e.g., at least 60%, 70%, 80% or 90%) by weight of a pharmaceutically acceptable hydrophilic polymer or a combination of such polymers. A solid dispersion described herein may also contain at least 1% by weight of a pharmaceutically acceptable surfactant or a combination of such surfactants. Preferably, the solid dispersion contains at least 2% by weight of a pharmaceutically acceptable surfactant or a combination of such surfactants. More preferably, the solid dispersion !0 contains from 4% to 20% by weight of the surfactant(s), such as from 5% to 10% by weight of the surfactant(s). In addition, a solid dispersion described herein may contain at least 1% by weight of a compound of the invention, preferably at least 5%, including, e.g., at least 10%. In one example, the solid dispersion comprises 5% of a compound of the invention (e.g., a compound of Formula I, I_A, Ib, lc, Id, Ie, If or I_G, or preferably a compound described hereinabove, or a salt, solvate or prodrug 25 thereof), which is molecularly dispersed in a an amorphous matrix comprising 7% Vitamin E-TPGS and 88% copovidone; the solid dispersion can also be mixed with other excipients such as mannitol/aerosil (99:1), and the weight ratio of the solid dispersion over the other excipients can range from 5:1 to 1:5 with 1:1 being preferred. In another example, the solid dispersion comprises 5% of a compound of the invention (e.g., a compound of Formula I, I_A, I_B, Ic, Id, Ie, If or I_G, or preferably a 30 compound described hereinabove, or a salt, solvate or prodrug thereof), which is molecularly dispersed in a an amorphous matrix comprising 5% Span 20 and 90% copovidone; the solid dispersion can also be mixed with other excipients such as mannitol/aerosil (99:1), the solid dispersion can also be mixed with other excipients such as mannitol/aerosil (99:1), and the weight ratio of the solid dispersion over the other excipients can range from 5:1 to 1:5 with 1:1 being 35 preferred.

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Various additives can also be included in or mixed with the solid dispersion. For instance, at least one additive selected from flow regulators, binders, lubricants, fillers, disintegrants, plasticizers, colorants, or stabilizers may be used in compressing the solid dispersion to tablets. These additives can be mixed with ground or milled solid dispersion before compacting. Disintegrants promote a rapid disintegration of the compact in the stomach and keeps the liberated granules separate from one another. Non-limiting examples of suitable disintegrants are cross-linked polymers such as crosslinked polyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose or sodium croscarmellose. Non-limiting examples of suitable fillers (also referred to as bulking agents) are lactose monohydrate, calcium hydrogenphosphate, microcrystalline cellulose (e.g., Avicell), silicates, in particular silicium 0 dioxide, magnesium oxide, talc, potato or com starch, isomalt, or polyvinyl alcohol. Non-limiting examples of suitable flow regulators include highly dispersed silica (e.g., colloidal silica such as Aerosil), and animal or vegetable fats or waxes. Non-limiting examples of suitable lubricants include polyethylene glycol (e.g., having a molecular weight of from 1000 to 6000), magnesium and calcium stearates, sodium stearyl fumarate, and the like. Non-limiting examples of stabilizers include 5 antioxidants, light stabilizers, radical scavengers, or stabilizers against microbial attack.

The present invention further features methods of using the compounds of the present invention (or salts, solvates or prodrugs thereof) to inhibit HCV replication. The methods comprise contacting cells infected with HCV vims with an effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), thereby inhibiting the replication of HCV virus in the !0 cells. As used herein, “inhibiting” means significantly reducing, or abolishing, the activity being inhibited (e.g., viral replication). In many cases, representative compounds of the present invention can reduce the replication of HCV virus (e.g., in an HCV replicon assay as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

The compounds of the present invention may inhibit one or more HCV subtypes. Examples 25 of HCV subtypes that are amenable to the present invention include, but are not be limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including HCV genotypes la, lb, 2a, 2b, 2c, 3a or 4a. In one embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of HCV genotype la. In another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the 30 replication of HCV genotype lb. In still another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of both HCV genotypes la and lb.

The present invention also features methods of using the compounds of the present invention (or salts, solvates or prodrugs thereof) to treat HCV infection. The methods typically comprise 35 administering a therapeutic effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), or a pharmaceutical composition comprising the same, to an HCV patient,

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2016238925 07 Oct 2016 thereby reducing the HCV viral level in the blood or liver of the patient. As used herein, the term “treating” refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition, or one or more symptoms of such disorder or condition to which such term applies. The term “treatment” refers to the act of treating. In one embodiment, the methods comprise 5 administering a therapeutic effective amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof), or a pharmaceutical composition comprising the same, to an HCV patient, thereby reducing the HCV viral level in the blood or liver of the patient.

A compound of the present invention (or a salt, solvate or prodrug thereof) can be administered as the sole active pharmaceutical agent, or in combination with another desired drug, 0 such as other anti-HCV agents, anti-HIV agents, anti-HBV agents, anti-hepatitis A agents, antihepatitis D agents, anti-hepatitis E agents, anti-hepatitis G agents, or other antiviral drugs. Any compound described herein, or a pharmaceutically acceptable salt thereof, can be employed in the methods of the present invention. In one embodiment, the present invention features methods of treating HCV infection, wherein said methods comprise administering a compound of the invention (e.g., a compound of Formula I, I_A, Ib, Ic, Id, Ie, If or I_G, or preferably a compound described hereinabove, or a salt, solvate or prodrug thereof), interferon and ribavirin to an HCV patient. The interferon preferably is a-interferon, and more preferably, pegylated interferon-α such as PEGASYS (peginterferon alfa-2a).

In another embodiment, the present invention features methods of treating HCV infection, !0 wherein said methods comprise administering a compound of the invention (e.g., a compound of

Formula I, I_A, I_B, Ic, Id, Ie, If or I_G, or preferably a compound selected from the title compounds of the above Examples or Table 5, or a salt, solvate or prodrug thereof), and one or more HCV inhibitors/modulators described above, with or without interferon.

A compound of the present invention (or a salt, solvent or prodrug thereof) can be administered to a patient in a single dose or divided doses. A typical daily dosage can range, without limitation, from 0.1 to 200 mg/kg body weight, such as from 0.25 to 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose. Preferably, each dosage contains a sufficient amount of a compound of the present invention that is effective in reducing the HCV viral load in the blood or liver of the patient. The amount of the active ingredient, or the active ingredients that are combined, to produce a single dosage form may vary depending upon the host treated and the particular mode of administration. It will be understood that the specific dose level 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, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

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The present invention further features methods of using the pharmaceutical compositions of the present invention to treat HCV infection. The methods typically comprise administering a pharmaceutical composition of the present invention to an HCV patient, thereby reducing the HCV viral level in the blood or liver of the patient. Any pharmaceutical composition described herein can be used in the methods of the present invention.

In addition, the present invention features use of the compounds or salts of the present invention for the manufacture of medicaments for the treatment of HCV infection. Any compound described herein, or a pharmaceutically acceptable salt thereof, can be used to make medicaments of the present invention.

The compounds of the present invention can also be isotopically substituted. Preferred isotopic substitution include substitutions with stable or nonradioactive isotopes such as deuterium, ¹³C, ¹⁵N or ¹⁸O. Incorporation of a heavy atom, such as substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. In one example, at least 5 mol % (e.g., at least 10 mol %) of hydrogen in a compound of the present invention is .5 substituted with deuterium. In another example, at least 25 mole % of hydrogen in a compound of the present invention is substituted with deuterium. In a further example, at least 50, 60,70, 80 or 90 mole % of hydrogen in a compound of the present invention is substituted with deuterium. The natural abundance of deuterium is about 0.015%. Deuterium substitution or enrichment can be achieved, without limitation, by either exchanging protons with deuterium or by synthesizing the molecule with !0 enriched or substituted starting materials. Other methods known in the art can also be used for isotopic substitutions.

The foregoing description of the present invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the 25 invention. Thus, it is noted that the scope of the invention is defined by the claims and their equivalents.

Claims

1. A prodrug of methyl {(2X,37?)-l-[(2X)-2-{5-[(27?,57?)-l-{3,5-difluoro-4-[4-(4fluorophenyl)piperidin-l-yl]phenyl}-5-(6-fluoro-2-{(2X)-l-[7V-(methoxycarbonyl)-O-methyl-Lthreonyl]pyrrolidin-2-yl }-l//-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-IH-benzimidazol-2yl {pyrrolidin-1 -yl ]-3 -methoxy-1 -oxobutan-2-yl} carbamate.